HK1083008B - Antiseptic solutions containing silver chelated with polypectate and edta - Google Patents

Description

Antimicrobial solution containing silver chelated with polypectate and EDTA

This application has a priority date based on provisional patent application No.60/413,379, filed on a date of 9/25/2002.

Technical Field

The present application relates to the formulation of antibacterial agents, and in particular to antibacterial agents containing at least one metal compound as a biocidal substance.

Background

Dental and medical professional journals have demonstrated the spread of infection that occurs in clinics, hospitals, wards, public facilities and other non-public facilities when physicians and staff fail to properly clean their hands. The dire consequences of lack of hygiene often occur, and physicians must clean their hands without boredom. Alcohol, hydrogen peroxide, and iodine and chlorine containing compounds have long been recognized as effective antimicrobial and antiviral substances, and thus their use in scrubbing and pre-surgical preparation is widely recognized. However, recent studies have shown that repeated application of many of these compounds is physiologically damaging to the skin. On the other hand, when a microbial population regularly encounters particular antimicrobial compounds, the microorganisms gradually evolve by developing chemical pumps that can expel those compounds, thus greatly reducing the effectiveness of the compounds as antimicrobial substances.

Certain metals have been shown to have antimicrobial properties. Mercuric solutions, such as the tinctures of merthiolate and mercurachrome, have been widely used as antimicrobial agents in the twentieth century. However, studies have shown that the use of these antibacterial agents results in the absorption of mercury through the skin, and comprehensive studies have shown that the ingestion of even small amounts of mercury results in mental retardation of children, promoting their cessation of development. Research has been extensively conducted to substitute antibacterial compounds that do not damage the central nervous system and do not harm the skin and mucous membranes.

Silver is a naturally occurring metal that, when used topically, has been shown to be lethal to a wide variety of pathogenic bacteria, fungi, molds, parasites, and viruses, yet relatively harmless to the human body. The tenuis's records from 700 to 100 years before the Gongyuan show that silver containers are used to preserve vinegar, water and pure wine during long-term trips and voyages. It is also known that early american immigrants and pioneers used copper, gold and silver coins for medical and water purification purposes. As early as the end of the 19 th century, the use of silver as a bactericide has been demonstrated. Silver has begun to be widely recognized as an effective bactericide and parasiticide for the past century, particularly the past two decades. For this application, silver is generally used in the form of a colloidal suspension of silver nitrate, silver oxide, or a silver compound. For example, silver nitrate drops are routinely placed on the eyes of neonates with the aim of protecting the eyes of the neonates, which may have become infected as they pass through the birth canal. Colloidal silver, which is elemental silver or silver oxide particles, is suspended in mineral oil or water matrices and is being popularized for various medical purposes through internal uptake and topical application. It is used for treating mastitis and mucosal infection.

There is no indication that the microorganism has or may develop a resistance to silver because it blocks respiration from the outside, rather than interfering with the organism's internal metabolism.

In the last decade extensive research has demonstrated that chelated silver is an effective antimicrobial agent. Antimicrobial action is reported to occur by blocking the respiration of microorganisms. Chelated silver is different from colloidal silver. Chelation means in solution, while colloidal means in suspension. In colloidal suspensions, the tiny silver particles are suspended or floating in an aqueous solution and are not uniformly dispersed throughout the liquid. When a metal ion forms a heterocyclic ring with a bidentate ligand, a chelating solution is formed. Examples of bidentate ligands are carbonate and oxalate ions and ethylenediamine. As a general rule, a five-or six-membered ring is advantageous. Because the chelated silver ions are chemically bound to the non-metallic ions, they are uniformly dispersed throughout the solution. The uniform dispersion of the chelated silver ions throughout the solution greatly enhances their antimicrobial action and efficacy throughout the process.

Three U.S. patents to James w. van Leuven include a liquid antimicrobial agent in which silver ions are chelated with sodium polypectate. U.S. patent No.4,184,974 to Van Leuven discloses a liquid cleanser, lubricant and topical biocidal material comprising lauryl diethanolamide, propylene glycol, glycerin, sodium polypectate, a water soluble detergent, silver ions, and sufficient base to maintain a pH in the range of 7.2 to 7.8, and distilled water. U.S. patent No.4,267,168, a continuation of the published' 974 patent, discloses a method of treating external tissue in humans using the liquid cleanser, lubricant and topical biocide disclosed in U.S. patent No.4,184,974. U.S. patent No.4,289,758, a continuation of the published' 168 patent, discloses a liquid biocidal material comprising about 100-400ppm sodium polypectate, about 13-250ppm silver ions, about 4-8% glycerol, sufficient base to maintain a ph in the range of 7.2-7.8, and distilled water.

One known disadvantage to the solution of the Van Leuven patent is the lack of long-term stability of the chelated silver ions. This stability is apparently due to the gradual decomposition of the polypectate molecules or the gradual formation of additional compounds that have a greater affinity for silver ions than the polypectate molecules. This decomposition is accelerated in the presence of extreme cold or heat and light. The hotter or more energetic the ingested light, the faster the decomposition.

Summary of The Invention

A liquid antimicrobial and cleaning agent having improved long term stability comprising at least the following major components: deionized water, silver ions, polypectate, and ethylenediaminetetraacetic acid (EDTA). The increased long-term stability and prolonged antimicrobial action of the solution is provided by strengthening the chelate bonds of the silver ions. Currently preferred embodiments of the cleanser also include glycerin, 1, 2-propanediol (i.e., propylene glycol), and at least one surfactant selected from any one of the families of alkyl sulfates, sulfonates, alkanolamides, betaines, amine oxides, sarcosinates, and sulfosuccinates. The preferred embodiment of the present technology has in fact been manufactured and sold as comprising the following ingredients in the following weight ratios: about 70-80% deionized water, 2.5-5.5% TEA dodecylbenzene sulfonate; 1.5-3.25% lauramide DEA; 5.5-11.5% glycerol; 3.0-5.5% propylene glycol; 0.005-0.015% sodium polypectate and 0.005-0.015% EDTA; 0.01-0.03% silver ions; and a buffer compound sufficient to achieve a pH in the range of 7.2-7.8.

Detailed Description

A liquid antimicrobial and cleaning agent having improved long term stability comprising at least the following major components: deionized water, silver ions, polypectate, and ethylenediaminetetraacetic acid (EDTA). The addition of EDTA to the formulation increases the strength of the chelate bond, thereby increasing its long-term stability.

Presently preferred embodiments of the present technology also include glycerin, 1, 2-propanediol (i.e., propylene glycol), and at least one surfactant selected from any one of the families of alkyl sulfates, sulfonates, alkanolamides, betaines, amine oxides, sarcosinates, and sulfosuccinates. The preferred embodiment of the present technology has in fact been manufactured and sold as comprising the following ingredients in the following weight ratios: about 70-80% deionized water, 2.5-5.5% TEA dodecylbenzene sulfonate; 1.5-3.25% lauramide DEA; 5.5-11.5% glycerol; 3.0-5.5% propylene glycol; 0.005-0.015% sodium polypectate and 0.005-0.015% EDTA; 0.01-0.03% silver ions; and a buffer compound sufficient to achieve a pH in the range of 7.2 to 7.8. When the pH is less than 7.0, the polypectinate will gel. A certain number of buffer compounds of the strong base-weak acid type may be used in the composition, provided they are compatible with the other raw materials present. Because ammonium hydroxide is well suited for use with the combination of sodium polypectate, EDTA, and silver nitrate, it can be used as a buffering compound and comprises about 0.03% of the total weight of the composition.

Sodium polypectate is commercially available or may be prepared by treating pectin with sodium carbonate in order to dissolve it. Polypectates rapidly chelate with alkaline earth metal ions such as calcium and magnesium.

To provide an aqueous environment which is conducive to the formation of chelate complexes of silver ions with EDTA or polypectate, a solution containing silver nitrate and ammonia (in the form of ammonium hydroxide) is first prepared and EDTA and/or polypectate is then added to the solution. Many complex ions and neutral molecules are known to coexist in equilibrium states with a mixture of silver nitrate and aqueous ammonia. Since EDTA and polypectate have a greater affinity for silver ions than ammonium and hydroxide ions, the formation of chelate complexes with the first two compounds can be promoted by the prior addition of ammonia to silver nitrate. The following stoichiometry is a typical application recipe for the chelation process. Parts a and B are prepared separately and then mixed together to form a chelated silver solution.

Part A

Silver nitrate 30-60 g

2 liters of deionized water

200 ml of ammonium hydroxide (what concentration

Part B

Ethylenediaminetetraacetic acid (EDTA)

Sodium polypectate 19.5 g

Glycerin 200 ml

5 liters of deionized water

Raw materials safety data sheets were prepared by the LaSal laboratory of Provo, utah indicating that the chelated silver formulations prepared according to the present invention meet OSHA hazard contact standards, 29 CFR1910.1200, and do not contain hazardous components. It was also determined that from a feeding standpoint, the formulation had little toxicity and that the rat acute oral LD50 level was approximately 5 grams per kilogram of body weight. It was also determined that the formulation had no primary skin irritation and had only mild to moderate irritation to the small animal eye.

Although the silver formulations of the present invention may not be generally harmful to vertebrates, they have significant antimicrobial properties. To investigate the antimicrobial effectiveness of the chelated silver formulations of the present invention, experiments have been conducted by the LaSal laboratory. A typical test was conducted at 20/8/2003 using the following method for a common infectious bacterium to determine the effectiveness of preparing a chelated silver solution according to the present invention.

1. The organisms were tested.

The test suspension was prepared by taking 5ml of culture of Staphylococcus aureus ATCC #6538 grown in ToddHewitt broth and shaking it in a 50ml conical polypropylene centrifuge tube at 37 deg.C and 250PRM for 20 hours. The culture was pelleted by centrifugation, washed with 5ml sterile 18M omega water, recentrifuged and then resuspended in a final container of 1ml sterile water.

2. And (4) neutralizing agent.

A neutralization solution was prepared with the following ingredients: tween 80- -10.0%, lecithin- -1.7%, tryptone- -1.0%, sodium thiosulfate- -0.6%, yeast extract- -0.5%, NaCl- -0.5%, cysteine- -0.04%, and Tamol- -6.0%. The solution is sterilized by autoclaving.

3. And (5) suspension testing.

3.1A 9.9ml aliquot of the chelated silver solution was placed in a sterile 20mm by 150mm tube. The tube was equilibrated in a water bath at 20 ℃.

2.2 the tube was inoculated with 100. mu.l of the test biological suspension and counted to zero. The tube was mixed vigorously to obtain a homogeneous suspension.

3.3 after exactly three minutes, 1ml of bio/chelated silver solution was transferred to 9ml of neutralizer. After two minutes, the neutralized suspension was serially diluted to 1: 10 in physiological saline (PPS).

3.4 the number of living organisms in each dilution tube was determined by membrane filtration. Aliquots of 1ml were removed from selected dilution tubes and plated in duplicate. The membrane was washed with sterile PPS at approximately 100mnl and then transferred to tryptase Soy Agar dishes. The dishes were incubated at 37 ℃ for 21 hours.

3.5 count the number of colonies on each filter and then calculate the log reduction value and the percentage of mortality value.

4. And (6) comparison.

4.1 titre of the test suspensions was determined by membrane filtration assay on 1: 10PSS dilutions of selected test organism suspensions.

4.2 neutralizer control determined by adding 1ml disinfectant to 9ml neutralizerThen at a ratio of 1: 1X 10 of 100. mu.l⁴The diluted test suspension was inoculated into the tube. The tube was allowed to stand for 20 minutes and then diluted to 1: 10 and 1: 100. 1ml aliquots from these three tubes were assayed twice by membrane filtration.

4.3 sterile control of each solution used in the test, done by filtering 1ml of sample in duplicate, 100ml aliquots were filtered for the PSS control.

5. Results

5.1 potency

Diluting: 10^-7 10^-8 10^-9

Number of Colony Forming Units (CFU): TNC 966

TNC 96 9

(TNC as the total number is not counted)

5.2 suspension testing

Staphylococcus/chelated silver diluted suspension: 10^-1 10^-2 10^-3

CFU of each dish after 3 minutes: 108150

117 9 0

5.3 neutralizer control

CFU of each dish after 3 minutes: undiluted 10^-1 10^-2

TNC TNC 128

TNC TNC 112

5.4 sterility control

Duplicate assays yielded the following CFU counts per solution:

PSS water neutralizer chelated silver solution

0 0 0 0

0 0 0 0

6. Results

Titration showed a viable staphylococcal concentration of 9.60X 10/ml of the original suspension⁹An organism. 9.9ml of chelated silver was inoculated with this suspension to give a 9.60X 10 solution per ml of assay tube⁷The initial concentration of the organism.

From the results of these procedures, it is allowed to calculate the Log Reduction (LR) value using the following formula:

LR ═ -Log (S/So), where S ═ concentration of living organisms after three minutes; and So zero initial concentration of living organisms.

PK＝(1-(S/So))×100。

Using these equations, LR values of 4.93 and PK values of 99.9988 were calculated. In summary, the chelated silver solution produced an almost 5-log reduction of Staphylococcus aureus in three minutes. This is equal to or greater than the antimicrobial activity of many other topical antimicrobial agents currently in use.

Although the invention has been disclosed as having particular formulations, each described with particular concentration ranges, it will be apparent to those skilled in the art that changes and modifications may be made without departing from the scope and spirit of the invention as claimed below.

Claims (5)

1. A liquid antimicrobial cleanser with enhanced long term stability comprising:

70-80% by weight of water;

at least one surfactant compound in an amount of 4.0 to 8.75% by weight;

5.5-11.5% by weight of glycerol;

3.0-5.5% by weight of 1, 2-propanediol;

0.005-0.015% by weight of sodium polypectate;

0.005-0.015% by weight of ethylenediaminetetraacetic acid;

0.01-0.03% by weight of silver ions; and

sufficient base to bring the pH to the range of 7.2 to 7.8;

wherein the sum of the contents of all the components in the liquid antibacterial detergent is 100 percent.

2. The antimicrobial cleanser of claim 1 wherein the at least one surfactant is selected from the group consisting of alkyl sulfates, sulfonates, alkanolamides, betaines, amine oxides, sarcosinates, and sulfosuccinates.

3. The antimicrobial cleanser of claim 1 wherein the at least one surfactant comprises: 2.5-5.5% by weight of TEA dodecylbenzene sulfonate and 1.5-3.25% by weight of lauramide DEA.

4. A liquid antimicrobial cleanser with enhanced long term stability comprises 70-80% by weight of water, 0.01-0.03% by weight of silver ions, 0.005-0.015% by weight of polypectate, 0.005-0.015% by weight of ethylenediaminetetraacetic acid, and 4.0-8.75% by weight of at least one surfactant compound; 5.5-11.5% by weight of glycerol; 3.0-5.5% by weight of 1, 2-propanediol; and sufficient base to bring the pH of the solution to the range of 7.2-7.8; wherein the sum of the contents of the components in the liquid antibacterial detergent is 100%, and the silver ions are chelated with both the polypectate and the ethylenediamine tetraacetic acid.

5. A method of preparing a liquid antimicrobial agent comprising the steps of:

mixing water, silver ions and ammonia water to form a silver-ammonium composite solution;

mixing ethylenediaminetetraacetic acid, sodium polypectate, glycerol, and water to form a chelating solution;

mixing the silver-ammonium composite solution with a chelating solution to form a chelated silver solution;

adding at least one surfactant compound to the chelated silver solution;

adding 1, 2-propanediol to the chelated silver solution; and

adding sufficient base to the chelated silver solution to bring the pH of the solution into the range of 7.2-7.8;

wherein the liquid antimicrobial agent comprises:

70-80% by weight of water;

0.01-0.03% by weight of silver ions;

0.005-0.015% by weight of sodium polypectate;

0.005-0.015% by weight of ethylenediaminetetraacetic acid;

4.0-8.75% by weight of at least one surfactant compound;

5.5-11.5% by weight of glycerol;

3.0-5.5% by weight of 1, 2-propanediol; and

0.03% by weight of aqueous ammonia;

wherein the sum of the contents of all the components in the liquid antibacterial agent is 100 percent.