Patent Application
20130309318
This application draws priority from GB Patent Application No. 1101193.9, filed Jan. 24, 2011, which application is incorporated by reference for all purposes as if fully set forth herein.
The present invention relates to anti-microbial silver oxide formulations, and, more particularly, to anti-microbial silver oxide formulations having improved whiteness and stability characteristics.
Silver oxides are known to have anti-microbial properties. Silver(II) oxide is known to be more effective than silver(I) oxide.
Skin creams containing silver(II) oxide have been reported to be efficacious in treating various medical conditions, including genital herpes, oral herpes, vaginitis, vaginal yeast infections, foot and nail fungus, burns, warts, and skin infections. These skin formulations are characterized by their creaminess and ease of application, which, inter alia, enables the polyvalent silver oxide to intimately contact the skin surface.
Disadvantageously, however, the various forms of silver oxide, and silver(II) oxide in particular, are dark gray or charcoal gray powders, and are thus extremely hard to hide within white creams used in various cosmetic or pharmaceutical topical applications. Moreover, the dark silver oxide particles may stain skin and clothing.
The inventor has perceived a need for further improvements in silver oxide formulations, and the subject matter of the present disclosure and claims is aimed at fulfilling this need.
According to the teachings of the present invention there is provided a topical formulation for application to exposed body tissue, the formulation comprising: (a) a silver oxide, and (b) at least one inorganic whitener; selected from the group of inorganic whiteners consisting of an inorganic magnesium compound and an inorganic calcium compound, said silver oxide and said inorganic whitener compound intimately dispersed within a carrier medium, and wherein a ratio of said inorganic whitener compound, to said silver oxide, is at least 0.2:1, by weight, within the formulation.
According to another aspect of the present invention there is provided a topical formulation for application to exposed body tissue, the formulation comprising: (a) a silver oxide; and (b) at least one inorganic whitener; wherein a ratio of said inorganic whitener compound, to said silver oxide, is at least 0.2:1, by weight, within the formulation.
According to further features in the described preferred embodiments, the initial whiteness value of the formulation is at least 4 reflective units.
According to still further features in the described preferred embodiments, the whiteness value of the formulation is, initially, at least 4 reflective units, at least 4.5 reflective units, at least 5 reflective units, at least 5.5 reflective units, or at least 6 reflective units, and wherein, after constant exposure to said ultraviolet light for 3 days, said value remains at least 3.5 reflective units, at least 3.75 reflective units, at least 4 reflective units, at least 4.5 reflective units, at least 5 reflective units, or at least 5.5 reflective units.
According to still further features in the described preferred embodiments, the initial whiteness value of the formulation is at least 4 reflective units, at least 4.5 reflective units, at least 5 reflective units, at least 5.5 reflective units, or at least 6 reflective units, and wherein, after constant exposure to said ultraviolet light for 3 days, a whiteness value of the formulation remains within 1.5 reflective units, within 1.25 reflective units, or within 1.0 reflective units of said initial whiteness value.
According to still further features in the described preferred embodiments, the formulation contains at least 0.05%, at least 0.10%, at least 0.2%, or at least 0.25%, by weight, of said silver oxide.
According to still further features in the described preferred embodiments, the formulation contains less than 3%, by weight, of said silver oxide.
According to still further features in the described preferred embodiments, the whitener is further selected to act as a stabilization agent that partially inhibits a darkening of the formulation when the formulation is exposed to ultraviolet light.
According to still further features in the described preferred embodiments, the formulation has a gray or light gray hue.
According to still further features in the described preferred embodiments, the carrier medium includes an oleaginous material.
According to still further features in the described preferred embodiments, the oleaginous material includes a wax.
According to still further features in the described preferred embodiments, the oleaginous material includes beeswax.
According to still further features in the described preferred embodiments, the carrier medium includes a liquid wax ester.
According to still further features in the described preferred embodiments, the liquid wax ester includes, predominantly includes, or consists essentially of jojoba oil.
According to still further features in the described preferred embodiments, the carrier medium includes a hydrogenated liquid wax ester.
According to still further features in the described preferred embodiments, the liquid wax ester includes, predominantly includes, or consists essentially of hydrogenated jojoba oil.
According to still further features in the described preferred embodiments, the whitener is an inorganic powder.
According to still further features in the described preferred embodiments, the topical formulation further comprises zinc oxide.
According to still further features in the described preferred embodiments, the whitener is further selected to act as a stabilization agent that partially inhibits a darkening of the formulation when the formulation is exposed to ultraviolet light.
According to still further features in the described preferred embodiments, the formulation contains at least 0.02%, at least 0.1%, at least 0.5%, at least 1%, at least 1.5%, at least 2%, at least 3%, at least 5%, or at least 7%, by weight, of said zinc oxide.
According to still further features in the described preferred embodiments, the formulation further includes a stabilization agent selected to partially inhibit a darkening of the formulation when exposed to ultraviolet light.
According to still further features in the described preferred embodiments, the whitener and said stabilization agent having a total concentration of at least about 0.01%, by weight, and said silver oxide having a concentration of at least about 0.01%, by weight.
According to still further features in the described preferred embodiments, the silver oxide includes, largely includes, mainly includes, predominantly includes, or consists essentially of a silver(II) oxide.
According to still further features in the described preferred embodiments, the silver oxide includes, largely includes, mainly includes, predominantly includes, or consists essentially of a silver(I) oxide.
According to still further features in the described preferred embodiments, the ratio of the stabilization agent to said zinc oxide, within the formulation, is at least 0.5:1, at least 1:1, at least 1.5:1, at least 2:1, at least 3:1, at least 5:1, or at least 7:1, by weight, said stabilization agent selected to partially inhibit a darkening of the formulation when the formulation is exposed to ultraviolet light.
According to still further features in the described preferred embodiments, the stabilization agent is selected from the group consisting of bentonite, magnesium hydroxide, calcium hydroxide, calcium carbonate, magnesium oxide, magnesium carbonate, and magnesium sulfate.
According to still further features in the described preferred embodiments, the formulation contains between 0.02% and 10% of said zinc oxide, and between 0.01% and 30% of said stabilization agent.
According to still further features in the described preferred embodiments, the inorganic whitener includes at least one inorganic whitener selected from the group consisting of magnesium oxide, magnesium hydroxide, and magnesium carbonate.
According to still further features in the described preferred embodiments, the stabilization agent includes magnesium oxide.
According to still further features in the described preferred embodiments, the formulation contains less than 0.5%, less than 0.3%, or less than 0.1% titanium dioxide, or is substantially free of said titanium dioxide.
According to still further features in the described preferred embodiments, the topical formulation further comprises zinc oxide, but contains less than 0.5%, less than 0.3%, or less than 0.1% thereof, and the ratio of said stabilization agent, said whitener, and said zinc oxide, to said silver oxide, is at least 0.5:1, at least 0.75:1, at least 1:1, at least 1.5:1, at least 2:1, at least 3:1, or at least 5:1, by weight, within the formulation.
According to still further features in the described preferred embodiments, the ratio of said stabilization agent, said whitener, and said zinc oxide, to said silver oxide, is at least 0.5:1, at least 0.75:1, at least 1:1, at least 1.5:1, at least 2:1, at least 3:1, or at least 5:1, by weight, within the formulation.
According to still further features in the described preferred embodiments, the total concentration of said whitener and said stabilization agent is at least 0.01%, at least 0.05%, at least 0.1%, at least 0.5%, at least 1%, at least 2%, at least 3%, at least 5%, at least 7%, or at least 10%.
According to still further features in the described preferred embodiments, the inorganic magnesium compound is selected from the group consisting of a magnesium oxide, a magnesium carbonate, and a magnesium sulfate.
According to still further features in the described preferred embodiments, the inorganic calcium compound is selected from the group consisting of a calcium oxide, a calcium carbonate, and a calcium sulfate.
According to still further features in the described preferred embodiments, the silver oxide has a dark hue.
According to still further features in the described preferred embodiments, the silver oxide has a hue within a range of shades between gray and black.
According to still further features in the described preferred embodiments, the formulation has a hue that is lighter than said hue of said silver oxide.
According to still further features in the described preferred embodiments, the formulation has a hue that is lighter than said hue of said silver oxide, after the formulation is subject to constant exposure to ultraviolet light for at least 3 days.
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, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention.
In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. Throughout the drawings, like-referenced characters are used to designate like elements.
In the drawings:
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 of construction and the arrangement of the components 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.
The medical device of the present invention contains both a silver oxide compound and a whitening agent, preferably in a carrier medium that may be a water-based cream or lotion, or an ointment that may include a wax and/or an oil. The formulation may include an emulsion, or be substantially emulsion-based.
The inventive silver oxide based medical device or formulation may have a generally white, off-white, light gray, or medium gray appearance. At lower ratios of whitening agent to silver oxide, the appearance of the medical device may be a deeper gray.
We have found that both silver(II) oxide, which is an extremely reactive material, and silver(I) oxide, which is somewhat less reactive, may deleteriously interact with various base materials within the formulation.
The formulations were then subjected to ultraviolet light for several days, and the whiteness of each of the formulations was monitored over time. We found that the measured reflectance or lightness of the AgO formulation decreased monotonically over time, as the formulation took on a progressively darker hue of gray. The reflectance decreased to 1.74 reflective units after 3 days, and further decreased to 1.02 reflective units after 6 days. Similarly, the measured reflectance or lightness of the Ag2O formulation decreased monotonically over time, as the gray formulation became progressively darker. The reflectance decreased to 3.35 reflective units after 1 day, 2.65 reflective units after 3 days, and further decreased to about 1.9 reflective units after 6 days.
Without wishing to be limited by theory, we believe that silver oxide (including both silver(II) oxide and silver(I) oxide), being a reactive material, interacts with at least one other material within the formulation, causing discoloration over time. This effect may be accelerated or augmented by exposure to sunlight. In sunlight, the discoloration may be apparent even within minutes.
We have found that this effect may actually be an acceleration of a process that occurs, albeit much more slowly, when the silver oxide based formulation is packaged in a container. Thus, the discoloration phenomenon may be significant because:
By adding various whiteners during the preparation of the formulations, we found that the appearance of the formulations became significantly lighter. In the case of zinc oxide, the measured whiteness value of the silver(II) oxide formulation (1% AgO, 7% ZnO) increased by almost 3 reflectance units, to about 5.43, and the measured whiteness value of the silver(I) oxide formulation (1% Ag2O, 7% ZnO) increased by slightly more than 3 reflectance units, to about 6.87. In the case of titanium dioxide, the measured whiteness value of the formulation (1% AgO, 7% TiO2) nearly doubled to about 5.33. Such light-colored formulations (cream, ointment, etc.) are much more aesthetically pleasing to users, and may pose less of a problem regarding staining of skin and clothing.
These formulations were then subjected to ultraviolet light for several days, in a procedure substantially identical to that used on the formulations described hereinabove, and the whiteness of each of the formulations was monitored over time.
Surprisingly, we found that with both ZnO and TiO2, the decrease in whiteness, as a function of UV exposure time, may actually be more pronounced than the corresponding decrease in whiteness of the identical formulation, without the additional whitener. In the case of the AgO/ZnO formulation, the whiteness value decreased by 2 reflective units within 3 days, and by 2.7 reflective units within 6 days.
Similar results were obtained with Ag2O: after 3 days, the whiteness value of an AgO/ZnO (1%, 7%) formulation decreased by about 1.9 reflective units; the whiteness value of an AgO/ZnO/TiO2 (1%, 3.5%, 3.5%) formulation decreased by about 3.8 reflective units.
Thus, while the use of such whiteners greatly improved the initial formulation color, the use of these whiteners raised additional issues. Both silver(I) and silver(II) oxides may interact with the zinc oxide and titanium dioxide, or with the carrier base in the presence of zinc oxide and/or titanium dioxide, causing significant discoloration within a day or days. This effect may be accelerated or augmented by exposure to direct sunlight, in which the discoloration may be effected within minutes.
Many of the tests on AgO-based formulations have been repeated for Ag2O-based formulations, which typically provide qualitatively similar results.
Immediately after preparation, all of the mixed formulations whiteners were significantly lighter than the AgO standard formulation. The AgO/bentonite formulation exhibited a reflectance just over 4 reflective units, a 48% increase with respect to the AgO standard formulation. The AgO/Ca(OH)2 and AgO/MgSO4 formulations both exhibited a reflectance of almost 5 reflective units (4.9 and 4.97, respectively), corresponding to more than an 80% increase with respect to the AgO standard formulation. In the case of calcium carbonate, the measured whiteness value of the formulation (1% AgO, 7% CaCO3) more than doubled to about 5.67.
The formulations were then subjected to ultraviolet light for several days, as described hereinabove, and the whiteness of each of the formulations was monitored over time. All of the formulations exhibited decreasing whiteness, as a function of UV exposure time. With the exception of the AgO/TiO2 formulation, all of the formulations maintain a substantially higher reflectance after 1 day, after 3 days, and after 6 days. Moreover, we observe that the decreasing whiteness is less pronounced in some of the formulations.
The other formulations, containing AgO along with bentonite, CaCO3, and Ca(OH)2, respectively, all exhibit a normalized formulation whiteness exceeding 0.7 after 3 days of UV exposure. The 1% AgO, 7% CaCO3 formulation exhibited a normalized formulation whiteness approaching 0.7, even after 6 days of UV exposure.
By sharp contrast, the absolute decrease in reflectance for the formulations containing AgO along with bentonite, CaCO3, MgSO4, and Ca(OH)2, was reduced with respect to the absolute decrease in reflectance for the AgO formulation after both 1 day and 3 days of UV exposure.
Immediately after preparation, all of the mixed formulations whiteners were significantly lighter than the AgO standard formulation. The AgO/Mg(OH)2 formulation exhibited 5.33 reflective units, a 96% increase with respect to the AgO standard formulation. The AgO/MgO and AgO/MgCO3 formulations exhibited almost 5.5 and 6.01 reflective units, respectively, corresponding to more than a 100% or 120% increase with respect to the AgO standard formulation.
The formulations were then subjected to ultraviolet light for several days, as described hereinabove, and the whiteness of each of the formulations was monitored over time. Although these formulations exhibited decreasing whiteness, as a function of UV exposure time, the decreasing whiteness was surprisingly moderate.
Over the course of clinical trials, we have found that treating wounds with an AgO/ZnO formulation may be considerably more efficacious than conventional treatments used in the controls. Moreover, the AgO/ZnO formulation exhibited a higher efficacy than a similar formulation containing a comparable concentration of AgO, but no ZnO. In addition, the AgO/ZnO formulation was found to improve the microcirculation and healing rate in both venous ulcerations and diabetic ulcerations.
The darkening of the AgO/ZnO formulation over time, and during exposure to UV light, may be a disadvantage in many applications. As best seen in
We have found that the appearance of formulations containing AgO and ZnO may be greatly enhanced by the addition of at least one stabilization agent adapted to at least partially inhibit a darkening of the formulation when exposed to ultraviolet light. The stabilization agent may advantageously act as a whitener as well.
By sharp contrast, when half of the zinc oxide is replaced with magnesium oxide, the initial whiteness is substantially maintained, but over the course of several days of UV exposure, the whiteness exhibited by the AgO/ZnO/MgO formulation (1% AgO/3.5% ZnO/3.5% MgO) is significantly higher than that of the base formulation. Surprisingly, the whiteness stays fairly constant over the first three days of UV exposure, and—perhaps even more surprisingly, the whiteness exhibited appears to be very similar to the whiteness (plotted in
Similarly, when half of the zinc oxide is replaced with calcium carbonate (CaCO3), the initial whiteness is substantially maintained. Over the course of several days of UV exposure, the whiteness exhibited by the AgO/ZnO/CaCO3 formulation (1% AgO/3.5% ZnO/3.5% CaCO3) is somewhat higher than that of the base formulation. Surprisingly, through the third day of UV exposure, the whiteness exhibited appears to be similar to the whiteness (plotted in the Figure, as a reference line) of an AgO/CaCO3 formulation containing 1% AgO, 7% CaCO3, and having no ZnO.
The formulations were subjected to ultraviolet light for several days, as described hereinabove, and the whiteness of each of the formulations was monitored over time. Although the mixed formulations exhibited decreasing whiteness as a function of UV exposure time, the decreasing whiteness was surprisingly moderate for both AgO-based and Ag2O-based mixed formulations.
Moreover, we have found with these exemplary mixed formulations, as well as with other mixed formulations, that the behavior of the Ag2O-based formulations and the Ag2O-based formulations, with respect to UV light exposure, is strikingly similar. By way of example, the measured whiteness for AgO/CaCO3, and Ag2O/CaCO3, is virtually identical for exposure times of 1 day, 3 days and 6 days.
Similarly, the measured whiteness values for the AgO/MgO and Ag2O/MgO formulations, respectively, are within 5% of each other initially, and remain within about 7% of each other for exposure times of 1 day, 3 days and 6 days.
Despite the significant differences in the chemical and physical properties of the carrier bases, we observe that the behavior of each type of formulation appears to be largely insensitive to the composition of the carrier base.
By sharp contrast, when half of the zinc oxide is replaced with magnesium oxide, the initial whiteness value is somewhat lower, but after three days of UV exposure, the whiteness value exhibited by the Ag2O/ZnO/MgO formulation (1% Ag2O/3.5% ZnO/3.5% MgO) is significantly higher than that of the Ag2O—ZnO formulation (1% Ag2O/7% ZnO). Surprisingly, the whiteness value stays fairly constant over the first three days of UV exposure. The whiteness value exhibited appears to be higher than the whiteness value (plotted in
The Ag2O/ZnO/CaCO3 formulation (1% AgO/3.5% ZnO/3.5% CaCO3) exhibits poor whiteness values when compared with both 1% Ag2O/7% ZnO and with 1% Ag2O/7% CaCO3.
Typically, the inventive formulations contain up to 5% silver oxide or up to 3% silver oxide, by weight. More typically, the formulations contain 0.01% to 3% silver oxide. The ratio of the whitener (without zinc oxide) and the stabilization agent to the silver oxide, within the formulation, is typically at least 0.2:1, at least 0.3:1, at least 0.5:1, at least 1:1, at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 7:1, or at least 10:1, by weight.
In preparing the various formulations of the present invention, we have discovered that within a specified range of weight ratios and/or compositions, the silver oxide based formulation is highly spreadable, despite the presence of the chalky whiteners and/or stabilization agents. We have found that formulations containing more than 20-25%, by weight, of the whiteners and/or stabilization agents, may display poor spreadability, and may generally be less efficacious from an anti-microbial standpoint.
Thus, the inventive formulations may contain up to 20% by weight, of at least one whitener and/or stabilization agent, more typically, up to 17% by weight, and more typically, up to 15% by weight. The formulations may typically contain at least 0.2%, at least 0.5%, at least 1%, at least 2%, at least 3%, or at least 5%, by weight, of the whitener and/or stabilization agent. Most formulations contain between 2% and 15%, between 2.5% and 12%, or between 3% and 10%, by weight, of the whitener and/or stabilization agent.
When both a whitener (e.g., zinc oxide) and a stabilization agent (e.g., Mg(OH)2 or MgO) are used, the formulations may typically contain at least 0.2%, at least 0.5%, at least 0.8%, at least 1%, at least 2%, at least 3%, or at least 5%, by weight, of the whitener, and more typically, between 0.8% to 10%, between 0.8% to 8%, or between 0.8% to 6%, by weight. The formulations may typically contain at least 0.2%, at least 0.5%, at least 0.8%, at least 1%, at least 2%, at least 3%, or at least 5%, by weight, of the stabilization agent, and more typically, between 0.8% to 8%, between 0.8% to 6%, or between 0.8% to 4%.
The ratio of stabilization agent to whitener may vary greatly, but is typically at least 0.1:1, at least 0.25:1, at least 0.5:1, at least 1:1, at least 2:1, at least 3:1, or at least 5:1, by weight. Typically, the ratio of stabilization agent to whitener may be up to 15:1, up to 12:1, up to 10:1, or up to 8:1, by weight.
Reference is now made to the following examples, which together with the above description, illustrate the invention in a non-limiting fashion.
The exemplary “standard base” silver oxide formulations provided hereinabove were prepared according to the following general procedure: jojoba oil was heated to 80° C. Beeswax was introduced, and the material was mixed thoroughly during cooling to about 55° C. Palmarosa oil was added, followed by at least one of a silver (II) oxide (AgO) and silver (I) oxide (Ag2O). Where appropriate, a solid (acting as a whitener and/or stabilization agent) such as an inorganic powder was introduced along with the silver oxide, although practical considerations may suggest that the addition be made prior to the introduction of the silver oxide, or sometime thereafter.
Mixing may be maintained throughout, and during cooling of the mixture to 35° C.-40° C.
Alternatively or additionally, various base components that are known to those skilled in the art may be used, including petrolatum, polyethylene polymers (such as: oxidized polyethylene homopolymer (Honeywell A-C® 629)), mineral oil, coconut oil, xanthum gum.
In the exemplary formulations described hereinabove, the weight ratio of the jojoba oil to beeswax was about 5.5 to 1. The palmarosa oil content was about 0.04% of the jojoba oil content. The total content of the beeswax, jojoba oil, silver oxide, and one or more whiteners and stabilization agents, within the formulations, typically exceeded 99%.
An exemplary general procedure for producing the inventive silver oxide based cream is as follows: a base material such as liquid wax ester (e.g., jojoba oil) is heated, preferably to around 80° C. Alternatively or additionally, various base components may be used, base components that will be known to those skilled in the art of topical formulation production, such as, but not limited to, petrolatum, polyethylene polymers (such as an oxidized polyethylene homopolymer (Honeywell A-C® 629)), mineral oils, coconut oil, and xanthum gum.
A thick base material (e.g., a wax such as beeswax, polyethylene polymers, or hydrogenated jojoba oil or the like) may be melted into the liquid wax ester or base material. The mixture may be mixed thoroughly as it is cooled, typically below about 60° C. An essential oil such as palmarosa oil may be added. Mixing may be continued as at least one of a whitener and a stabilization agent (both in the form of solid powders) is introduced. At least one silver oxide such as a silver (II) oxide or a silver (I) oxide is also introduced, before, after, or concurrently with the whitener and stabilization agent, and the mixing may be continued during cooling of the mixture to below about 40° C. The mixing may advantageously produce an intimately dispersed formulation in which the silver oxide and the whitener and/or stabilization agent may be distributed in a homogeneous or substantially homogeneous fashion within the carrier medium.
Water-based and emulsion-based formulations according to the present invention may be prepared according to the following exemplary procedure: to a container containing water or an aqueous solution may be added a viscosity-building agent (e.g., a smectite such as a bentonite or montmorillonite powder such as Gelwhite H, produced by Southern Clay Products, Inc., Gonzales, Tex.). Other viscosity-building clays, particularly clays in which the silicate layers are disposed in a sandwiched structure, may also be used. Other viscosity-building agents and thickeners may be used, e.g., carbomers. Preferably, such selected materials may exhibit good resistance to oxidation or chemical attack by the silver oxide or oxides.
The mixture is mixed or homogenized, typically for 0.5 to 2 hours. Silver(II) oxide and/or silver(I) oxide may be introduced at this stage of the processing. The whitener(s) and/or stabilization agent(s) may be introduced to the mixture, typically along with the silver oxide, or sometime therebefore or thereafter. 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).
Six formulations were prepared according to the general procedure provided above. The control formulation contained 1% AgO, 7% ZnO, and no additional whitener or stabilizing agent. The other five formulations contained various quantities of MgO, such that the total amount of zinc oxide and magnesium oxide equaled 7%. The composition of each formulation, along with the weight ratios of magnesium oxide to zinc oxide and magnesium oxide to silver oxide, are provided below in TABLE 1:
About 1 gram of each of Formulations B-F was smeared on a piece of 100% white cotton cloth, which was then exposed to white UV light for about one month. Periodically, the cloth was examined for change in color, and photographed.
These observations may be further supported by the photographs of the stains provided in
Perhaps more significantly, all of the formulations containing MgO appear to be lighter than corresponding Formulation A, which contains no MgO.
Formulation reflectance, lightness, or whiteness was evaluated as follows: approximately 1 gram of a particular sample (typically an ointment or cream) was spread on a 5 cm by 5 cm area of white cotton cloth and distributed evenly, typically using a metal spatula.
A LabScan XE spectrophotometer instrument (HunterLab, VA) was used to evaluate the reflectance of each sample. The working principle of the instrument pertains to the property of light reflection. The cloth sample is stored in a completely dark container. To measure the reflectance, the instrument exposes the sample to a controlled, repeatable pulse of light. The lightness of the sample is generally correlated with the reflectance: higher values correspond to lighter samples.
The spectrophotometer has a wavelength range of 375 nm to 750 nm and an optical resolution of 10 nm. The spectrophotometer measures reflected color using 0°/45° geometry.
Formulation reflectance was evaluated as a function of the exposure time to ultraviolet light, as follows: the LabScan XE spectrophotometer described in Example 9 was used. Each sample was continuously exposed to ultraviolet light produced by the illumination source. The continuous UV exposure is through a 254 nm, 6W UV bulb distributed by Cole-Parmer®. The distance between the UV source and the specimen or formulation was 18 inches (˜45.7 cm).
Sample preparation was substantially the same as that described in Example 9. After an initial measurement (“day 0”), additional measurements were made over the course of the exposure to ultraviolet light, typically on days 1, 3 and 6.
Five formulations were prepared according to the general procedure provided above. All the formulations contained 1% AgO, and were distinguished by their varying concentrations of MgO. Example 3 is provided for comparative purposes. The composition of each formulation, along with the weight ratios of magnesium oxide to silver oxide, are provided below in TABLE 2:
We observe that in all of the formulations containing MgO, the MgO behaved as a whitener and as a stabilizing agent. The initial whiteness values of the MgO-containing formulations were about 5 to 5.5 reflectance units. After one day of exposure to ultraviolet light, the whiteness values of the MgO-containing formulations dropped slightly, remaining close to or about 5 to 5.5 reflectance units. After three days of exposure to ultraviolet light, the whiteness values of the MgO-containing formulations dropped slightly, to about 4.6 to 5.3 reflectance units. After thirteen days of exposure to ultraviolet light, the whiteness values of the MgO-containing formulations dropped slightly, to about 4.0 to 4.6 reflectance units.
In
All of these results are exceptionally good when compared with Formulation G, containing a 7:1 ratio of ZnO to AgO, which retained only about 63% of its initial whiteness value, after three days of exposure to ultraviolet light.
Silver oxide formulations were prepared according to the general procedure provided in Example 2A. The active ingredients were:
Carrier ingredients were selected from beeswax, benzoic acid, bentonite, dimethicone, glycine, soybean oil, methylparaben, microcrystalline wax, mineral oil, panthenol, propylene glycol, propylparaben, sodium hydroxide, sorbitan sesquioleate, tocopheryl acetate, and water. A minute amount of fragrance was added to some of the formulations.
The silver(II) oxide based formulations generally exhibited an off-white or light gray appearance, suitable for topical formulations.
Silver oxide formulations were prepared according to the general procedure provided in Example 2A. The active ingredients were:
The carrier ingredients were substantially the same as those used in Example 16.
The silver(I) oxide based formulations generally exhibited an off-white, light gray, or medium gray appearance, suitable for topical formulations.
Silver oxide formulations were prepared according to the general procedure provided in Example 1. The active ingredients were:
The carrier was the standard base described in Example 1. The ratio of whitener and stabilization agent to silver oxide was 0.2:1 and 0.75:1. The ratio of whitener (and stabilization agent to zinc oxide was 0.27:1 and 1:1. The ratio of total whitener, zinc oxide and stabilization agent to silver oxide was 0.95:1 and 1.5:1. Under these conditions, both the silver(I) and the silver(II) oxide based formulations exhibited a generally off-white to slightly beige off-white appearance, suitable for topical formulations.
Silver oxide formulations were prepared according to the general procedure provided in Example 1. The active ingredients were:
The carrier was the standard base described in Example 1. The ratio of whitener, zinc oxide and stabilization agent to silver oxide was 2:1. The ratio of whitener and stabilization agent to zinc oxide was 1:1. As in Example 18, both the silver(I) and the silver(II) oxide based formulations exhibited a generally off-white to slightly beige off-white appearance, suitable for topical formulations.
Anti-microbial activity was evaluated indirectly using a Fisher educational spectrophotometer. This technique uses turbidity as an indicator of microbial growth. Bacterial samples were grown in a Muller-Hinton broth. Upon inoculation with the microbe, 4-5 mg samples of the exemplary formulations were loaded on to a 6 mm sterile disc, dropped into the broth, and allowed to incubate for 24 hours. After a pre-determined time, the samples were introduced to the spectrophotometer and the optical density (OD) measured. The OD reflects the turbidity of a sample, or the relative transparency of a sample to light passing therethrough, to the light detector on the distal side. Increasing OD may be generally correlated with an increased concentration of microbes.
Anti-microbial activity was evaluated using a Bel-Art Colony Counting System, Scienceware Colony Counting System Instrument. The colony counting system may be performed instead of, or complementary to, the above-described spectrophotometric method.
Bacterial samples were inoculated in Muller-Hinton broth and the anti-microbial formulations were loaded, as in the spectrophotometric test described in Example 11. After 24 hours, a drop of the media was taken and streaked on a Muller-Hinton agar plate. After the plates were inoculated for 24 hours, the number of colonies visible in the plates was counted. The number of colonies visible may be generally correlated with decreasing anti-microbial efficacy of the sample formulations.
All of the anti-microbial formulation containing cultures displayed pronounced anti-microbial activity. The least effective anti-microbial formulation was Sample 8, containing 1% Ag20 and 7% TiO2. The most effective anti-microbial formulations were Samples 3-5 and 8, all containing 1% Ag2O and containing 7% of Ca(OH)2, Mg(OH)2, MgCO3, or MgO, respectively.
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 Ag4O4 (often represented as Ag2O3.Ag2O), which may be generally referred to as AgO herein.
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 Ag2O.
As used herein in the specification and in the claims section that follows, the terms “homogeneous” and “substantially homogeneous”, with respect to a silver oxide formulation, are meant to be used according to their meaning in the art of topical formulation manufacturing.
As used herein in the specification and in the claims section that follows, the term “whiteness value” with respect to a substance or formulation, refers to a reflectance value, in reflectance units, as determined by a LabScan XE spectrophotometer instrument (HunterLab, VA), or the like. The spectrophotometer must be calibrated whereby the measured reflectance value of the following sample substances, is within 0.40 reflectance units, and preferably within 0.30 reflectance units or 0.20 reflectance units, of the respective measured reflectance values provided below:
Typically, a light gray formulation exhibits a reflectance of at least about 4.8 RU; a medium gray formulation exhibits a reflectance in a range of about 3.8 to about 4.8 RU; a dark gray formulation exhibits a reflectance of less than about 3.8 RU, and typically between about 1.0 and 3.8 RU or between 2.0 and 3.8 RU.
As used herein in the specification and in the claims section that follows, the term “initial whiteness value” with respect to a substance or formulation, refers to the whiteness value of the substance or formulation, prior to significant exposure to ultraviolet radiation. Typically, the initial whiteness value is measured within several minutes, or within an hour, from the time the substance or formulation is dispensed from its tube, vial, or the like.
As used herein in the specification and in the claims section that follows, the term “gray hue” and the like, with respect to a substance or formulation, is meant to include light gray, medium gray, dark gray, and off-white hues.
As used herein in the specification and in the claims section that follows, the term “stabilization agent” and the like, refers to a substance that retards or otherwise reduces the darkening of silver oxide formulations over time or over exposure to ultraviolet light. The term “stabilization agent” is meant to specifically exclude titania and zinc oxide.
As used herein in the specification and in the claims section that follows, the term “constant exposure to ultraviolet light” and the like relates to conditions identical or substantially identical to those delineated in Example 10, or to conditions determined and demonstrated by an expert in the art to yield identical or highly similar results with respect to the conditions delineated in Example 10.
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 “largely includes”, with respect to a component within a formulation, refers to a weight content of at least 30%.
As used herein in the specification and in the claims section that follows, the term “mainly includes”, with respect to a component within a formulation, refers to a weight content of at least 50%.
As used herein in the specification and in the claims section that follows, the term “predominantly includes”, with respect to a component within a formulation, refers to a weight content of at least at least 65%.
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.
| Number | Date | Country | Kind |
|---|---|---|---|
| GB1101193.9 | Jan 2011 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US12/22220 | 1/23/2012 | WO | 00 | 7/24/2013 |
