WO2014037883A1

WO2014037883A1 - Topical antimicrobial formulations

Info

Publication number: WO2014037883A1
Application number: PCT/IB2013/058284
Authority: WO
Inventors: Bharat MADHAVAN; Perry Antelman
Original assignee: Aidance Skincare And Topical Solutions, Llc; Lampert, Shalom
Priority date: 2012-09-06
Filing date: 2013-09-04
Publication date: 2014-03-13

Abstract

An antibiotic formulation suitable for application to skin tissue, the formulation including: (a) a first agent containing silver(II) oxide; (b) at least a second agent selected from the group of anti-microbial agents consisting of benzalkonium chloride, benzethonium chloride, salicylic acid, clotrimazole, and miconazole; and (c) a base, the silver(II) oxide and the second agent being intimately dispersed within the base.

Description

Topical Antibiotic Formulations

This application draws priority from U.S. Provisional Patent Application Serial No. 61/697,750, entitled "TOPICAL ANTIBIOTIC FORMULATIONS", filed September 6, 2012. FIELD OF THE INVENTION

The present invention relates to topical antibiotic formulations.

SUMMARY OF THE INVENTION

According to an aspect of the present invention there is provided an antibiotic formulation suitable for application to skin tissue, the formulation including: (a) a first agent containing silver(II) oxide; (b) at least a second agent selected from the group of anti-microbial agents consisting of benzalkonium chloride, benzethonium chloride, salicylic acid, clotrimazole, and miconazole; and (c) a base, the silver(II) oxide and the second agent being intimately dispersed within the base.

According to another aspect of the present invention there is provided an antibiotic formulation suitable for application to skin tissue, the formulation including: (a) a first agent containing silver(II) oxide; (b) at least a second agent selected from the group of antimicrobial agents consisting of a quaternary ammonium salt, salicylic acid, and an azole; and (c) a base, the first and second agents being intimately dispersed within the base.

According to yet another aspect of the present invention there is provided an antibiotic formulation suitable for application to skin tissue, the formulation including: (a) a first agent containing silver(II) oxide; (b) at least a second antimicrobial agent selected from the group of antimicrobial agents consisting of a quaternary ammonium salt, salicylic acid, and an azole; and (c) a base, the first and second agents being intimately dispersed within the base, the first and second agents selected to provide a synergetic anti-microbial efficacy with respect to at least one strain of microbe.

According to yet another aspect of the present invention there is provided a topical antibiotic formulation having a drug-delivery system, the formulation including: (a) at least one anti-microbial agent selected from the group of anti-microbial agents consisting of benzalkonium chloride, benzethonium chloride, salicylic acid, clotrimazole, and miconazole; and (b) the drug-delivery system, including: (i) a silver(II) oxide; and (ii) a base, the silver(II) oxide and the anti-microbial agent being dispersed within the base.

According to further features in the described preferred embodiments, formulation contains, by weight, at least 0.0005%, at least 0.005%), at least 0.01%, at least 0.03%, at least 0.10%, at least 0.20%, at least 0.30%, or at least 0.50%, of the silver(II) oxide.

According to still further features in the described preferred embodiments, the formulation contains, by weight, at most 5%, at most 4%, at most 3%, or at most 2.5% of the silver(II) oxide.

According to still further features in the described preferred embodiments, the formulation contains silver(II) oxide within a range of 0.0005% to 4%, of 0.005% to 4%, of 0.002% to 4%, 0.0005% to 3%, 0.0005% to 2.5%, 0.0005% to 2.0%, or

0.0005% to 1.5%, by weight.

According to still further features in the described preferred embodiments, the formulation contains silver(II) oxide within a range of 0.005% to 3%, or 0.005% to

2.5%), by weight.

According to still further features in the described preferred embodiments, the formulation contains benzalkonium chloride.

According to still further features in the described preferred embodiments, the formulation contains benzethonium chloride.

According to still further features in the described preferred embodiments, the formulation contains salicylic acid.

According to still further features in the described preferred embodiments, the formulation contains clotrimazole.

According to still further features in the described preferred embodiments, the formulation contains miconazole.

According to still further features in the described preferred embodiments, the formulation contains silver(II) oxide and miconazole, in a weight ratio of at least 0.05:1, at least 0.10: 1, at least 0.25: 1, at least 0.5: 1, at least 0.75: 1, at least 1 : 1, at least 2: 1 , at least 4: 1 , or at least 7: 1. According to still further features in the described preferred embodiments, the formulation contains silver(II) oxide and clotrimazole, in a weight ratio of at least 0.05:1, at least 0.10: 1, at least 0.25: 1, at least 0.5: 1, at least 0.75: 1, at least 1 : 1, at least 2: 1 , at least 4: 1 , or at least 7: 1.

According to still further features in the described preferred embodiments, the formulation contains silver(II) oxide and salicylic acid, in a weight ratio of at least 0.005:1, at least 0.01 : 1, at least 0.05: 1, at least 0.10: 1, at least 0.15:1, at least 0.25: 1, at least 0.5: 1, at least 1 : 1 , or at least 2: 1.

According to still further features in the described preferred embodiments, the formulation contains silver(II) oxide and benzethonium chloride, in a weight ratio of at least 0.005: 1, at least 0.01 : 1, at least 0.05: 1, at least 0.10: 1, at least 0.15:1, at least 0.25 : 1 , at least 0.5: 1, at least 1 : 1 , at least 2: 1 , at least 4: 1 , or at least 7: 1.

According to still further features in the described preferred embodiments, the formulation contains silver(II) oxide and benzalkonium chloride, in a weight ratio of at least 0.005: 1, at least 0.01 : 1, at least 0.05: 1, at least 0.10: 1, at least 0.15: 1, at least 0.25 : 1 , at least 0.5: 1, at least 1 : 1 , at least 2: 1 , at least 4: 1 , or at least 7: 1.

According to still further features in the described preferred embodiments, the base includes a wax.

According to still further features in the described preferred embodiments, the base includes a liquid wax ester.

According to still further features in the described preferred embodiments, the base includes a humectant.

According to still further features in the described preferred embodiments, the liquid wax ester includes jojoba oil.

According to still further features in the described preferred embodiments, the base includes water.

According to still further features in the described preferred embodiments, the azole includes an imadazole.

According to still further features in the described preferred embodiments, the imadazole includes clotrimazole.

According to still further features in the described preferred embodiments, the imadazole includes miconazole.

According to still further features in the described preferred embodiments, the quaternary ammonium salt includes a quaternary ammonium chloride.

According to still further features in the described preferred embodiments, the quaternary ammonium salt includes a benzyl quaternary ammonium chloride.

According to still further features in the described preferred embodiments, the quaternary ammonium salt includes a benzyl dimethyl quaternary ammonium chloride.

According to still further features in the described preferred embodiments, the benzyl dimethyl quaternary ammonium chloride includes benzethonium chloride.

According to still further features in the described preferred embodiments, the benzyl dimethyl quaternary ammonium chloride includes benzalkonium chloride.

According to still further features in the described preferred embodiments, the formulation contains at least 3% or at least 5%, by weight, of the liquid wax ester.

According to still further features in the described preferred embodiments, the formulation contains at least 3% or at least 5%, by weight, of the humectant.

According to still further features in the described preferred embodiments, the formulation contains, by weight, between 3% and 85%, between 5% and 80%>, between 10% and 80%, between 12% and 55%, between 15% and 40%, or between 20% and 35%) of the liquid wax ester.

According to still further features in the described preferred embodiments, the silver(II) oxide consists largely of, predominantly of, or substantially of, tetrasilver tetroxide.

According to still further features in the described preferred embodiments, the base including a beeswax.

According to still further features in the described preferred embodiments, the formulation contains, by weight, at least 0.3%, at least 1%, at least 2.5%, or at least 4% zinc oxide.

According to still further features in the described preferred embodiments, a water concentration within the formulation is at least 7%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60%.

According to still further features in the described preferred embodiments, the first agent consists largely of, mainly of, predominantly of, or substantially of, silver(II) oxide.

According to still further features in the described preferred embodiments, the microbe is a fungus. According to still further features in the described preferred embodiments, the fungus is a topical fungus.

According to still further features in the described preferred embodiments, the microbial strain is bacterial.

According to still further features in the described preferred embodiments, the bacterial strain is a topical bacterial strain.

According to still further features in the described preferred embodiments, the formulation contains, by weight, at least 0.0005%, at least 0.005%), at least 0.01%, at least 0.03%, at least 0.10%, at least 0.20%, at least 0.30%, or at least 0.50%, of the silver(II) oxide containing first agent.

According to still further features in the described preferred embodiments, the formulation contains, by weight, at most 5%, at most 4%, at most 3%, or at most 2.5% of the silver(II) oxide-containing first agent.

According to still further features in the described preferred embodiments, the formulation contains the silver(II) oxide-containing first agent, within a concentration range of 0.0005% to 4%, of 0.005% to 4%, of 0.002% to 4%, 0.0005% to 3%, 0.0005% to 2.5%, 0.0005% to 2.0%, or 0.0005% to 1.5%, by weight.

According to still further features in the described preferred embodiments, the formulation contains, by weight, at least 0.0005%), at least 0.005%), at least 0.01%, at least 0.03%, at least 0.10%, at least 0.20%, at least 0.30%, or at least 0.50%, of the silver(II) oxide.

According to still further features in the described preferred embodiments, the formulation contains silver(II) oxide within a concentration range of 0.0005% to 4%, of 0.005% to 4%, of 0.002% to 4%, 0.0005% to 3%, 0.0005% to 2.5%, 0.0005% to 2.0%, or 0.0005% to 1.5%, by weight.

According to still further features in the described preferred embodiments, the drug-delivery system further includes at least one mineral selected from the group of minerals consisting of bentonite, magnesium oxide, and zinc oxide. BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only.

In the drawings:

Figure 1 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of E coli, using ointments in which the anti-microbial agent contains AgO, contains benzalkonium chloride, or contains both AgO and benzalkonium chloride;

Figure 2 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of E coli, using ointments in which the anti-microbial agent consists essentially solely of AgO, essentially solely of benzethonium chloride, or contains both AgO and benzethonium chloride;

Figure 3 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of S aureus, using ointments in which the anti-microbial agent consists essentially solely of AgO, essentially solely of benzethonium chloride, or contains both AgO and benzethonium chloride;

Figure 4 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of E fecalis, using ointments in which the anti-microbial agent consists essentially solely of AgO, essentially solely of benzethonium chloride, or contains both AgO and benzethonium chloride;

Figure 5 provides a plot of a microbial viability assay, normalized by a control assay, for a fungal culture of Candida albicans, using ointments in which the anti- microbial agent consists essentially solely of AgO, essentially solely of clotrimazole, or contains both AgO and clotrimazole;

Figure 6 provides a plot of a comparative microbial viability assay, normalized by a control assay, for a fungal culture of Candida albicans, using ointments in which the anti-microbial agent consists essentially solely of Ag₂0 (silver (I) oxide), essentially solely of clotrimazole, or contains both Ag₂0 and clotrimazole;

Figure 7 provides a plot of a microbial viability assay, normalized by a control assay, for a fungal culture of Candida albicans, using ointments in which the antimicrobial agent consists essentially solely of AgO, essentially solely of butenafme hydrochloride, or includes both AgO and butenafme hydrochloride;

Figure 8 provides a plot of a comparative bacterial viability assay, normalized by a control assay, for a bacterial culture of E coli, using ointments in which the antimicrobial agent consists essentially solely of benzethonium chloride, essentially solely of benzalkonium chloride, or includes both benzethonium chloride and benzalkonium chloride;

Figure 9 provides a plot of a microbial viability assay, normalized by a control assay, for a fungal culture of Candida albicans, using ointments in which the antimicrobial agent consists essentially solely of AgO, essentially solely of clotrimazole, or includes both AgO and clotrimazole;

Figure 10 provides a plot of a microbial viability assay, normalized by a control assay, for a fungal culture of Candida albicans, using ointments in which the antimicrobial agent consists essentially solely of AgO, essentially solely of miconazole, or includes both AgO and miconazole;

Figure 11 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of S aureus, using ointments in which the anti-microbial agent consists essentially solely of AgO, essentially solely of salicyclic acid, or includes both AgO and salicyclic acid;

Figure 12A provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of E coli, using ointments in which the anti-microbial agent contains AgO at high concentrations, or contains both AgO and benzalkonium chloride;

Figure 12B is a magnification of a portion of the plot provided in Figure 12 A;

Figure 13 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of E coli, using a water-based formulation containing both AgO and benzalkonium chloride;

Figure 14 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of E coli, using ointments in which the anti-microbial agent contains both AgO (~4%) and benzalkonium chloride (-0.1%);

Figure 15 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of E coli, using ointments containing AgO, benzalkonium chloride, or both AgO and benzalkonium chloride, and in which all of the ointments contain additional minerals; Figure 16 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of S using ointments containing AgO, benzethonium chloride, or both AgO and benzethonium chloride, and in which all of the ointments contain additional minerals; and

Figure 17 provides a plot of a bacterial viability assay, normalized by a control assay, for a bacterial culture of S using ointments containing AgO, benzalkonium chloride, or both AgO and benzalkonium chloride, and in which all of the ointments contain additional minerals.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description. The invention may be capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

We have found that tetrasilver tetroxide may be particularly reactive with respect to other components in topical formulations, thereby compromising the stability of the formulation. The formulation may then acquire, disadvantageously, a dark brown or black color. Moreover, the anti-microbial efficacy of the formulation may be appreciably compromised.

One aspect of the present invention relates to a formulation or medical device, based on tetrasilver tetroxide and at least one antimicrobial agent including a benzyl quaternary ammonium salt such as benzalkonium chloride and benzethonium chloride, salicylic acid, and an azole or imidazole such as clotrimazole and miconazole, that may be particularly efficacious in various bacteriostatic or bacteriocidal applications. Such formulations or medical devices may exhibit greatly improved stability, along with synergetic efficacy in the inhibition, treatment and cure of various medical conditions, including dermatological conditions.

Various formulations of the present invention exhibit no phase separations after three months, after six months, or after almost 1 year of shelf life.

We have discovered that tetrasilver tetroxide does not appear to react with these antimicrobial agents. More surprisingly, we have found that tetrasilver tetroxide does not render these antimicrobial agents inefficacious, nor does the presence of tetrasilver tetroxide appear to reduce their antimicrobial efficacy. In actuality, we have discovered that the co-presence of tetrasilver tetroxide and at least one of these antimicrobial agents results in an overall antimicrobial efficacy that surpasses the expected overall antimicrobial efficacy, based on a sum of the parts analysis (referred to herein as "synergy", "synergetic", or "synergetic effect").

Without wishing to be limited by theory, the surprisingly efficacious antimicrobial activity of the inventive formulations may be attributed to the silver(II) oxide within the base acting as a drug-delivery system that transports and/or directs the antimicrobial agents towards the microbes, thereby improving the efficacy of these antimicrobial agents.

These results have been demonstrated over a tetrasilver tetroxide concentration of 2-3ppm, up to a tetrasilver tetroxide concentration of about 5%. In one embodiment, the tetrasilver tetroxide concentration is at least 2ppm, at least 3ppm, at least 5ppm, at least 7 ppm, at least 10 ppm, at least 20 ppm, at least 50 ppm, or at least 100 ppm. In one embodiment, the tetrasilver tetroxide concentration is at most 5%, at most 4%, at most 3%, at most 2.5%, at most 2%, or at most 1.5%. In one embodiment, the tetrasilver tetroxide concentration is within a range of 3 ppm to 5%, 3 ppm to 4%, 5 ppm to 3%), 5 ppm to 2.5%, 5 ppm to 2%, 5 ppm to 1.5%, 20 ppm to 1.5%, or 50 ppm to 1.5%.

EXAMPLES

Reference is now made to the following examples, which together with the above description, illustrate the invention in a non-limiting fashion.

In these examples, the microbes used: Escherichia coli 10231 and

Staphylococcus aureus 0927, Enterococcus fecalis 29212, and Candida albicans 10231 were obtained from American type culture collection (ATCC).

With regard to materials and equipment, AgO was obtained from Ames

Goldsmith Inc. (New Jersey, USA). The AgO predominantly contains (silver (II) oxide). Ag₂0 (silver (I) oxide)(Catalog no. SI 090) was obtained from Spectrum

Chemicals (New Jersey, USA). Benzethonium chloride (BzCl) USP (Catalog no.

BE129), benzalkonium chloride (BkCl) USP (Catalog no. B1069), and salicylic acid (SA) USP (Catalog no. SA130), clotrimazole USP (Catalog no. CL127), miconazole nitrate USP (Catalog No. MI 150) and butenafme HC1 USP (Catalog no. TCI-B 3293) were obtained from Spectrum Chemicals (New Jersey, USA).

The SYTO® bacterial count kit and LIVE/DEAD® Funga Light™ Yeast Viability Kit were obtained from Invitrogen Inc. (Texas, USA). Bacterial culture broths and media were obtained from Remel Inc. (New York, USA).

The microbial shaking incubator (model 31 IDS, Labnet Inc.) and Attune Flow cytometer (Invitrogen Inc.) were used for bacterial culture and bacterial assay, respectively.

EXAMPLE 1

Bacterial Culture and Treatment Methodology 1. The bacterial cells were initially seeded in a culture flask containing tryptic soy agar, as per ATCC guidelines, in a 31 IDS incubator.

2. The cells take approximately 30 hours to reach 90% confluence. The cells were then individually seeded in test tubes containing 10 ml broth, and care was taken to maintain identical cell count in each tube. 3. For each experimental time point, a control tube was seeded as well.

4. Sterile paper discs were handled in a biological hood and 1% of the test formulation (ointment base with AgO, etc.) was carefully smeared therein.

5. The disc was then dropped into the test tube with the bacterial broth and placed into the shaking incubator. At the same time, an "empty" disk was dropped into the control bacterial broth.

6. The process was repeated several times, using various formulations and run lengths.

EXAMPLE 2 Bacterial Viability Assay

1. After the bacteria were allowed to be treated with a particular formulation for the designated time point (20-180 min), the tubes, along with a corresponding control, were removed from the incubator. Using sterile tweezers, the disc was removed and discarded and the bacteria were centrifuged at 5000 g for 30 seconds.

2. The bacterial pellet was re-suspended in 2 ml of fresh tryptic soy broth.

3. At this point, 2 μΐ of the SYTO® bacterial stain (component A) was added to the cells and incubated for 5 min.

4. After the incubation, 10 of component B were added, and incubation was continued for another 5 minutes. The samples were then analyzed using a flow cytometer. The flow cytometer provides the results as a percentage of the control, and using that as a scale, the number of cells may be mathematically determined. 5. The bacterial count is ascertained based on the stainability with the SYTO® stain. A new kit was used every 2 weeks, as the components start degrading after about 15 days.

Using the above-mentioned technique, samples were analyzed for cell viability, and the results were documented, as provided hereinbelow.

Fungal viability assay

1. After treating the fungus sample with a particular formulation for the designated time point (20-180 min), the tubes, along with a corresponding control, were removed from the incubator. Using sterile tweezers, the disc was removed and discarded and the fungus sample was centrifuged at 1000 g for 60 seconds.

2. The fungal pellet was re-suspended in 2 ml of fresh saboraud liquid media.

3. At this point, 10 μΐ of the LIVE/DEAD® Funga Light™ Yeast Viability Kit were added to the cells and incubated for 5 minutes.

4. The samples were then analyzed using a flow cytometer. The flow cytometer provides the results as a percentage of the control, and using that as a scale, the number of cells may be mathematically determined.

5. The fungal count is ascertained based on the stainability with the LIVE/DEAD® Funga Light™ Yeast Viability Kit. A new kit was used every 2 weeks, as the components start degrading after about 15 days. Using the above-mentioned technique, samples were analyzed for cell viability, and the results were documented, as provided hereinbelow. EXAMPLE 3

An exemplary general procedure for producing oil-based compositions and formulations (e.g., ointments) according to the present invention is as follows: an oil and/or liquid wax ester such as jojoba oil is heated, preferably to around 80C. A wax such as beeswax is preferably melted into the oil or liquid wax ester. The material may be mixed thoroughly as it is cooled, typically below about 60C. Optionally, an essential oil such as palmarosa oil may be added. Mixing may be continued as the tetrasilver tetroxide is introduced, and further mixing may ensue, typically for 0.5 to 2 hours, during cooling of the mixture to below about 40C. The formulation may then be poured into storage containers.

Typically, the formulations contain a total tetrasilver tetroxide content of 0.05% to 4%, by weight, and more typically, 0.1% to 3% tetrasilver tetroxide.

EXAMPLE 3 A

An exemplary general procedure for producing water-based tetrasilver tetroxide compositions and formulations according to the present invention is as follows: to a container containing water is added a viscosity-building agent, typically a smectite (e.g., a bentonite or montmorillonite powder such as Gelwhite H, produced by Southern Clay Products, Inc., Gonzales, Texas).

The mixture may be mixed or homogenized, typically for 0.5 to 2 hours. Tetrasilver tetroxide may be introduced at this stage of the processing. Optionally, a skin-protecting or skin-building agent such as zinc oxide may be introduced to the mixture, typically along with the tetrasilver tetroxide, or sometime therebefore or thereafter. Magnesium oxide may optionally be added at this time. The additional antimicrobial agents may be introduced after the addition of the above-mentioned ingredients. The oil and/or liquid wax ester (e.g., jojoba oil) may be introduced to the mixture during the mixing (e.g., blending or homogenizing).

Mixing may be continued as the tetrasilver tetroxide is introduced, and further mixing may ensue, typically for 5-60 minutes. The formulation may then be poured into storage containers.

More specifically, on a total formulation weight basis, bentonite (4%) may be added to deionized water (68%), and the mixture is blended for approximately 60 minutes. Jojoba oil (23%) is added and blending may ensue for an additional 45 minutes. ZnO, MgO, and AgO and/or various anti-microbial agents may be added; blending may then ensue, typically for at least an additional 30 minutes.

EXAMPLE 3B

An exemplary general procedure for producing emulsion-based tetrasilver tetroxide compositions and formulations according to the present invention is as follows: a liquid such as water may be mixed or blended, preferably at a high speed. A viscosity-building agent such as a smectite clay (e.g., bentonite) is preferably mixed into the water. Mixing may be continued, typically for 5 to 120 minutes, to assure a homogenous mixture. Mixing may be continued as an oil and/or liquid wax ester (e.g., jojoba oil) is mixed into the mixture. Mixing may be continued, typically for another 5 to 45 minutes, to assure a substantially homogenous suspension including an emulsion of oil and water, and suspended solids. Optionally, an essential oil such as palmarosa oil may be added. Mixing may be continued as the tetrasilver tetroxide is introduced. The optional introduction of a skin-protecting or skin-building agent such as zinc oxide may be effected along with the introduction tetrasilver tetroxide, or some time therebefore or thereafter. Similarly, other minerals such as MgO may be introduced. The OTC monographs are added right after adding the above-mentioned ingredients and further mixing may ensue, typically for 1 to 10 minutes. The temperature of the mixture is usually below 50C. The formulation may then be poured into storage containers.

EXAMPLE 4

A control formulation was prepared according to the method provided in Example 3. The base contained about 78% jojoba oil, 13% beeswax, 1% bentonite, 0.65%) zinc oxide, and 6.45%> magnesium oxide.

The control formulation was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2. EXAMPLE 5

An ointment containing 0.02% AgO was prepared according to the method provided in Example 3. The base contained approximately 78% jojoba oil, 13% beeswax, 1% bentonite, 0.65%> zinc oxide, and 6.45% magnesium oxide.

The ointment was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results, normalized by the control assay (Example 4), are plotted in Figure 1.

EXAMPLE 6

An ointment containing 0.1% benzalkonium chloride (BkCl) was prepared according to the method provided in Example 3. The base contained approximately 78%o jojoba oil, 13% beeswax, 1% bentonite, 0.65% zinc oxide, and 6.45% magnesium oxide.

EXAMPLE 7

An inventive formulation containing 0.01% AgO and 0.05% benzalkonium chloride (BkCl) was prepared according to the method provided in Example 3. The base contained approximately 78% jojoba oil, 13% beeswax, 1% bentonite, 0.65% zinc oxide, and 6.45% magnesium oxide.

The inventive formulation was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results, normalized by the control assay (Example 4), are plotted in

Figure 1.

EXAMPLE 8 An inventive formulation containing 0.016% AgO and 0.1% benzalkonium chloride (BkCl) was prepared according to the method provided in Example 3. The base contained approximately 78% jojoba oil, 13% beeswax, 1% bentonite, 0.65% zinc oxide, and 6.45% magnesium oxide.

EXAMPLE 9

An ointment containing 0.1% AgO was prepared according to the method provided in Example 3. The base contained approximately 78% jojoba oil, 13% beeswax, 1% bentonite, 0.65% zinc oxide, and 6.45% magnesium oxide.

The ointment was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2 Its correct.The assay results are plotted in Figure 2.

EXAMPLE 10

An ointment containing 0.1% benzethonium chloride (BzCl) was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 2.

EXAMPLE 11

An inventive formulation containing 0.05% AgO and 0.05% benzethonium chloride (BzCl) was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2. The assay results are plotted in Figure 2. EXAMPLE 12

An ointment containing 0.1% AgO was prepared according to the method provided in Example 3 using the base composition of Example 9. The ointment was introduced to a bacterial culture (S aureus) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 3.

EXAMPLE 13

An ointment containing 0.1% benzethonium chloride (BzCl) was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a bacterial culture (S aureus) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 3.

EXAMPLE 14

An inventive formulation containing 0.05% AgO and 0.05% benzethonium chloride (BzCl) was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a bacterial culture (S aureus) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 3. EXAMPLE 15

An ointment containing 0.1% AgO was prepared according to the method provided in Example 3 using the base composition of Example 9. The ointment was introduced to a bacterial culture (E fecalis) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 4.

EXAMPLE 16

An ointment containing 0.1% benzethonium chloride (BzCl) was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a bacterial culture (E fecalis) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 4.

EXAMPLE 17

An inventive formulation containing 0.05% AgO and 0.05% benzethonium chloride (BzCl) was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a bacterial culture (E fecalis) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 4.

EXAMPLE 18

An ointment containing 1% AgO was prepared according to the method provided in Example 3 using a base composition largely identical to that of Example 9. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2. The assay results are plotted in Figure 5.

EXAMPLE 19

An ointment containing 1% clotrimazole was prepared according to the method provided in Example 3, using the base composition of Example 18. The ointment was introduced to a microbial (fungal) culture — Candida albicans — according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 5.

EXAMPLE 20

An inventive formulation containing 0.5% AgO and 0.5% clotrimazole was prepared according to the method provided in Example 3, using the base composition of Example 18. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 5.

EXAMPLE 21

A comparative ointment containing 1% Ag₂0 (silver (I) oxide) was prepared according to the method provided in Example 3 using a base composition largely identical to that of Example 9. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 6.

EXAMPLE 22

A comparative ointment containing 0.5% Ag₂0 (silver (I) oxide) and 0.5% clotrimazole was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 6, along with the results from Examples

19 and 21.

EXAMPLE 23

A control formulation was prepared according to the method provided in

Example 3. The base contained about 78% jojoba oil, 13%> beeswax, 1%> bentonite, 0.65%) zinc oxide, and 6.45% magnesium oxide.

The control formulation was introduced to a microbial (fungal) culture — Candida albicans—according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

EXAMPLE 24

An ointment containing 1% AgO was prepared according to the method provided in Example 3 using a base composition largely identical to that of Example 23. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2. The assay results are plotted in Figure 7.

EXAMPLE 25

An ointment containing 1% butenafme hydrochloride was prepared according to the method provided in Example 3, using a base composition largely identical to that of Example 23. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 7. EXAMPLE 26

An ointment containing 0.13% AgO and 0.13% butenafme hydrochloride was prepared according to the method provided in Example 3, a base composition largely identical to that of Example 23. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 7.

EXAMPLE 27

An ointment containing 0.1% benzalkonium chloride (BkCl) was prepared according to the method provided in Example 3 using the base composition of Example 9. The ointment was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 8.

EXAMPLE 28

An ointment containing 0.1% benzethonium chloride (BzCl) was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2

The assay results are plotted in Figure 8.

EXAMPLE 29

An ointment formulation containing benzalkonium chloride 0.05% (BkCl) and 0.05%) benzethonium chloride (BzCl) was prepared according to the method provided in Example 3, using the base composition of Example 9. The ointment was introduced to a bacterial culture (E coli) according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 8.

EXAMPLE 30

An ointment containing 0.1% AgO was prepared according to the method provided in Example 3 using a base having the following composition: 78% Jojoba, 13% BW, 1 % Bentonite, Zinc Oxide 0.65%, Magnesium Oxide 6.45%.

The ointment was introduced to a microbial (fungal) culture— Candida albicans — according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 9.

EXAMPLE 31

An ointment containing 0.1% clotrimazole was prepared according to the method provided in Example 3, using the base composition of Example 30. The ointment was introduced to a microbial (fungal) culture — Candida albicans — according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 9.

EXAMPLE 32

An inventive formulation containing 0.05% AgO and 0.05% clotrimazole was prepared according to the method provided in Example 3, using the base composition of Example 30. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 9. EXAMPLE 33

An ointment containing 0.1% miconazole was prepared according to the method provided in Example 3, using the base composition of Example 30. The ointment was introduced to a microbial (fungal) culture— Candida albicans — according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 10.

EXAMPLE 34

An inventive formulation containing 0.05% AgO and 0.05% miconazole was prepared according to the method provided in Example 3, using the base composition of Example 30. The ointment was introduced to a microbial (fungal) culture— Candida albicans— according to the method described in Example 1. A fungal viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 10.

EXAMPLE 35

Water-based formulations containing 0.1 %> and 0.2%>, respectively, salicyclic acid, were prepared according to Example 3A. The formulations contained approximately 68%> deionized water, 23%> jojoba oil, 4%> ZnO, and 4%> MgO. Each formulation was introduced to a bacterial culture of S aureus according to the method described in Example 2. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 11.

EXAMPLE 36

A formulation containing 200ppm AgO was prepared according to the base composition and method provided in Example 35. The formulation was introduced to a bacterial culture of S aureus according to the method described in Example 2. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 11. EXAMPLE 37

The formulations of Example 35 were doped with lOOppm and 200ppm AgO, respectively. Each formulation was introduced to a bacterial culture of S aureus as in Examples 35 and 36. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 11.

EXAMPLE 38

Formulations containing AgO and AgO + additional antimicrobial agents in beeswax and jojoba oil were prepared according to the following procedure:

Beeswax is heated to about 170°F, and is added to jojoba oil (previously heated to a similar temperature). Silver(II) oxide is added and mixed well using a magnetic stir bar on a stir plate.

When the temperature reaches about 160°F, the at least one additional antimicrobial agent is added, and mixing is continued until the beeswax solidifies.

Any additional antimicrobial agents may be added, and mixing is continued till the beeswax solidifies.

The sample may then be subjected to assay. EXAMPLE 39

Formulations containing 7% AgO and 7% AgO + benzalkonium chloride were prepared according to the method described in Example 38.

The formulation was then introduced to a bacterial culture of E coli, and a bacterial viability assay was performed according to the procedure provided in Example 2.

The assay results are plotted in Figure 12 A. A magnification of a portion of the plot is provided in Figure 12B.

EXAMPLE 40

Formulations containing 20% AgO and 20% AgO + benzalkonium chloride were prepared according to the method described in Example 38.

The assay results are plotted in Figure 12A. A magnification of a portion of the plot is provided in Figure 12B. EXAMPLE 41

A formulation containing AgO (lOppm) and benzalkonium chloride (0.1%) was prepared according to the procedure for producing water-based tetrasilver tetroxide formulations provided in Example 3A. The formulation was then introduced to a bacterial culture of E coli, and a bacterial viability assay was performed according to the procedure provided in Example 2.

Assay results are plotted in Figure 13.

EXAMPLE 42

A formulation containing 4% AgO and 0.1% benzalkonium chloride was prepared according to the method described in Example 38.

Assay results are plotted in Figure 14.

EXAMPLES 43-45

An ointment containing 0.1% AgO, by weight of the total formulation, was prepared according to the method provided in Example 3. Approximately 0.02% of each of the minerals bentonite, zinc oxide, and magnesium oxide, by weight of the total formulation, were introduced and dispersed. The ointment was then introduced to a bacterial culture of E coli according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The basic procedure was repeated for a substantially identical ointment containing benzalkonium chloride (0.1%) in lieu of the AgO, and for a substantially identical ointment containing benzalkonium chloride (0.05%) in addition to the AgO (0.05%).

The assay results are plotted in Figure 15. EXAMPLES 46-48

An ointment containing 0.1% AgO, by weight of the total formulation, was prepared according to the method provided in Example 3. Approximately 0.02% of each of the minerals bentonite, zinc oxide, and magnesium oxide, by weight of the total formulation, were introduced and dispersed. The ointment was then introduced to a bacterial culture of S aureus according to the method described in Example 1. A bacterial viability assay was then performed according to the procedure provided in Example 2.

The basic procedure was repeated for a substantially identical ointment containing benzethonium chloride (0.1%) in lieu of the AgO, and for a substantially identical ointment containing benzethonium chloride (0.05%) in addition to the AgO (0.05%).

The assay results are plotted in Figure 16.

EXAMPLES 49-51

The assay results are plotted in Figure 17. As used herein in the specification and in the claims section that follows, the term "percent", or "%>", refers to percent by weight, unless specifically indicated otherwise.

Similarly, the term "ratio", as used herein in the specification and in the claims section that follows, refers to a weight ratio, unless specifically indicated otherwise.

As used herein in the specification and in the claims section that follows, the term "silver (II) oxide" refers to a silver oxide whose unit structure contains silver and oxygen in a substantially 1 : 1 molar ratio. The term "silver (II) oxide" is specifically meant to include Ag 0₄ (often represented as Ag₂03*Ag₂0) and AgO.

As used herein in the specification and in the claims section that follows, the term "silver (I) oxide" refers to a silver oxide whose unit structure contains silver and oxygen in a substantially 2: 1 molar ratio. The term "silver (I) oxide" is specifically meant to include Ag₂0.

As used herein in the specification and in the claims section that follows, the term "consists essentially solely of, with respect to AgO, means that the formulation containing the AgO is substantially devoid of non-silver containing anti-microbial agents such as benzalkonium chloride, miconazole, and salicyclic acid.

As used herein in the specification and in the claims section that follows, the term "largely includes", "consists largely of and the like, with respect to a component within a formulation, refers to a content of at least 30%, by weight.

As used herein in the specification and in the claims section that follows, the term "mainly includes", "consists mainly of," and the like, with respect to a component within a formulation, refers to a content of at least 50%, by weight.

As used herein in the specification and in the claims section that follows, the term "predominantly includes", "consists predominantly of, and the like, with respect to a component within a formulation, refers to a content of at least 65%, by weight.

It will be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. An antibiotic formulation suitable for application to skin tissue, the formulation comprising:

(a) a first agent containing silver(II) oxide;

(b) at least a second agent selected from the group of anti-microbial agents consisting of benzalkonium chloride, benzethonium chloride, salicylic acid, clotrimazole, and miconazole; and

(c) a base,

said silver(II) oxide and said second agent being intimately dispersed within said base.

2. The formulation of claim 1, the formulation containing, by weight, at least 0.0005%, at least 0.005%, at least 0.01%, at least 0.03%, at least 0.10%, at least 0.20%, at least 0.30%, or at least 0.50%, of said silver(II) oxide.

3. The formulation of claim 1 or claim 2, the formulation containing, by weight, at most 5%, at most 4%, at most 3%, or at most 2.5% of said silver(II) oxide.

4. The formulation of claim 1, the formulation containing said silver(II) oxide, within a range of 0.0005% to 4%, of 0.005% to 4%, of 0.002% to 4%, 0.0005% to 3%, 0.0005% to 2.5%, 0.0005% to 2.0%, or 0.0005% to 1.5%, by weight.

5. The formulation of claim 1, the formulation containing said silver(II) oxide, within a range of 0.005% to 3%, or 0.005% to 2.5%, by weight.

6. The formulation of any one of claims 1 to 5, the formulation containing said benzalkonium chloride.

7. The formulation of any one of claims 1 to 5, the formulation containing said benzethonium chloride.

8. The formulation of any one of claims 1 to 5, the formulation containing said salicylic acid.

9. The formulation of any one of claims 1 to 5, the formulation containing said clotrimazole.

10. The formulation of any one of claims 1 to 5, the formulation containing said miconazole.

11. The formulation of claim 10, containing said silver(II) oxide and said miconazole, in a weight ratio of at least 0.05:1, at least 0.10:1, at least 0.25:1, at least 0.5:1, at least 0.75:1, at least 1:1, at least 2:1, at least 4:1, or at least 7:1.

12. The formulation of claim 9, containing said silver(II) oxide and said clotrimazole, in a weight ratio of at least 0.05:1, at least 0.10:1, at least 0.25:1, at least 0.5:1, at least 0.75:1, at least 1:1, at least 2:1, at least 4:1, or at least 7:1.

13. The formulation of claim 8, containing said silver(II) oxide and said salicylic acid, in a weight ratio of at least 0.005:1, at least 0.01:1, at least 0.05:1, at least 0.10:1, at least 0.15:1, at least 0.25:1, at least 0.5:1, at least 1:1, or at least 2:1.

14. The formulation of claim 7, containing said silver(II) oxide and said benzethonium chloride, in a weight ratio of at least 0.005:1, at least 0.01:1, at least 0.05:1, at least 0.10:1, at least 0.15:1, at least 0.25:1, at least 0.5:1, at least 1:1, at least 2: 1 , at least 4: 1 , or at least 7:1.

15. The formulation of claim 6, containing said silver(II) oxide and said benzalkonium chloride, in a weight ratio of at least 0.005:1, at least 0.01:1, at least 0.05:1, at least 0.10:1, at least 0.15:1, at least 0.25:1, at least 0.5:1, at least 1:1, at least 2: 1 , at least 4: 1 , or at least 7:1.

16. The formulation of any one of claims 1 to 15, said base including a wax.

17. The formulation of any one of claims 1 to 16, said base including a liquid wax ester.

18. The formulation of any one of claims 1 to 16, said base including a humectant.

The formulation of claim 17, said liquid wax ester including jojoba oil. The formulation of any one of claims 1 to 16, said base including water.

21. An antibiotic formulation suitable for application to skin tissue, the formulation comprising:

(a) a first agent containing silver(II) oxide;

(b) at least a second agent selected from the group of antimicrobial agents consisting of a quaternary ammonium salt, salicylic acid, and an azole; and

(c) a base,

said first and second agents being intimately dispersed within said base.

22. The formulation of claim 21, wherein said azole includes an imadazole.

23. The formulation of claim 22, wherein said imadazole includes clotrimazole.

24. The formulation of claim 22, wherein said imadazole includes miconazole.

25. The formulation of claim 21, wherein said quaternary ammonium salt includes a quaternary ammonium chloride.

26. The formulation of claim 21, wherein said quaternary ammonium salt includes a benzyl quaternary ammonium chloride.

27. The formulation of claim 21, wherein said quaternary ammonium salt includes a benzyl dimethyl quaternary ammonium chloride.

28. The formulation of claim 27, wherein said benzyl dimethyl quaternary ammonium chloride includes benzethonium chloride.

29. The formulation of claim 27, wherein said benzyl dimethyl quaternary ammonium chloride includes benzalkonium chloride.

30. The formulation of claim 17, the formulation containing at least 3% or at least 5%, by weight, of said liquid wax ester.

31. The formulation of claim 18, the formulation containing at least 3% or at least 5%, by weight, of said humectant.

32. The formulation of claim 30, the formulation containing, by weight, between 3% and 85%, between 5% and 80%, between 10% and 80%, between 12% and 55%), between 15% and 40%>, or between 20%> and 35% of said liquid wax ester.

33. The formulation of any one of claims 21 to 32, wherein said silver(II) oxide consists largely of, predominantly of, or substantially of, tetrasilver tetroxide.

34. The formulation of any one of claims 21 to 33, said base including a beeswax.

35. The formulation of any one of claims 21 to 33, wherein said base includes water.

36. The formulation of any one of claims 21 to 35, the formulation containing, by weight, at least 0.3%, at least 1%, at least 2.5%, or at least 4% zinc oxide.

37. The formulation of any one of claims 21-36, wherein a water concentration within the formulation is at least 7%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60%.

38. The formulation of any one of claims 21 to 37, wherein said first agent consists largely of, mainly of, predominantly of, or substantially of, said silver(II) oxide.

39. An antibiotic formulation suitable for application to skin tissue, the formulation comprising:

(a) a first agent containing silver(II) oxide;

(b) at least a second antimicrobial agent selected from the group of antimicrobial agents consisting of a quaternary ammonium salt, salicylic acid, and an azole; and

(c) a base,

said first and second agents being intimately dispersed within said base, said first and second agents selected to provide a synergetic anti-microbial efficacy with respect to at least one strain of microbe.

40. The formulation of claim 39, wherein said microbe is a fungus.

41. The formulation of claim 40, wherein said fungus is a topical fungus.

42. The formulation of claim 39, wherein said strain of microbe is a bacterial strain.

43. The formulation of claim 42, wherein said bacterial strain is a topical bacterial strain.

44. The formulation of any of the above claims, the formulation containing, by weight, at least 0.0005%, at least 0.005%), at least 0.01%, at least 0.03%, at least 0.10%, at least 0.20%, at least 0.30%, or at least 0.50%, of said first agent.

45. The formulation of claim 44, the formulation containing, by weight, at most 5%), at most 4%, at most 3%, or at most 2.5% of said first agent.

46. The formulation of any of the above claims, the formulation containing said first agent, within a range of 0.0005% to 4%, of 0.005% to 4%, of 0.002% to 4%, 0.0005% to 3%, 0.0005% to 2.5%, 0.0005% to 2.0%, or 0.0005% to 1.5%, by weight.

47. The formulation of any of the above claims, the formulation containing, by weight, at least 0.0005%), at least 0.005%), at least 0.01%, at least 0.03%, at least 0.10%, at least 0.20%, at least 0.30%, or at least 0.50%, of said silver(II) oxide.

48. The formulation of claim 47, the formulation containing, by weight, at most 5%), at most 4%, at most 3%, or at most 2.5% of said silver(II) oxide.

49. The formulation of any of the above claims, the formulation containing said silver(II) oxide, within a range of 0.0005% to 4%, of 0.005% to 4%, of 0.002% to 4%, 0.0005% to 3%, 0.0005% to 2.5%, 0.0005% to 2.0%, or 0.0005% to 1.5%, by weight.

50. A topical antibiotic formulation having a drug-delivery system, the formulation comprising:

(a) at least one anti-microbial agent selected from the group of antimicrobial agents consisting of benzalkonium chloride, benzethonium chloride, salicylic acid, clotrimazole, and miconazole; and

(b) the drug-delivery system, including:

(i) a silver(II) oxide;

(ii) a base,

said silver(II) oxide and said anti-microbial agent being dispersed within said base.

51. The formulation of claim 50, the drug-delivery system further including at least one mineral selected from the group of minerals consisting of bentonite, magnesium oxide, and zinc oxide.