topical compositions, and their kits

专利摘要:
TOPICAL COMPOSITIONS AND METHODS OF USE OF THE SAME. The present invention relates generally to topical compositions and methods of using them.
公开号:BR112016002391B1
申请号:R112016002391-9
申请日:2015-01-27
公开日:2021-02-02
发明作者:Ryan Doxey；Jian Bao
申请人:Novan, Inc.；
IPC主号:

专利说明:

Related Requests
[001] This application claims the benefit of and priority to PCT / US2014 / 050345, filed on August 8, 2014, which claims the benefit of and priority to Provisional Patent Application Serial No. US 61 / 868,139, filed on August 21, 2013, and Provisional Patent Application Serial No. US 61 / 863,541, filed on August 8, 2013, whose descriptive reports of each are incorporated herein by reference in their entirety. Government Grant Statement
[002] The present invention was developed with government subsidy under Contract N °. W81XWH-11-C-0029 granted by the United States Department of Defense and under Grant No. 5R43AI096569 granted by the National Institutes of Health. The government has certain rights in the invention. Field of the Invention
[003] The present invention relates in general to topical compositions and methods of using them. Background
[004] Topical compositions that aid wound healing, such as the rate of healing, may be desirable. However, determining the topical compositions that can assist in wound healing can be challenging. Still, active pharmaceutical ingredients sensitive to moisture (APIs) (Active Pharmaceutical Ingredients) can present challenges when administered topically. Although the API can be incorporated into a topical hydrophobic composition so that it has adequate stability during the shelf life, this same stability can decrease the ability to administer the drug if moisture is the activating agent.
[005] The present invention can overcome prior disadvantages in the art by offering topical compositions and methods of using them. summary
[006] A first aspect of the present invention comprises a topical composition comprising a hydrophilic composition and a mixed hydrophobic composition. In some embodiments, the topical composition further comprises a nitric oxide-releasing active pharmaceutical ingredient.
[007] A second aspect of the present invention comprises a composition comprising: a hydrophobic base, at least one of an amphiphilic compound or an emulsifying agent; a polymer; a polyhydric alcohol; and water. In some embodiments, the composition further comprises a cosolvent. In some embodiments, the composition further comprises a nitric oxide releasing active pharmaceutical ingredient. In some embodiments, the composition further comprises a buffer and is optionally buffered to a pH of about 3 to about 9.
[008] Another aspect of the present invention comprises a composition for topical administration comprising a self-emulsifying mixture.
[009] Another aspect of the present invention comprises a kit comprising: a first composition comprising a hydrophilic composition; and a second composition comprising a hydrophobic composition. In some embodiments, the hydrophobic composition comprises an active pharmaceutical ingredient.
[0010] A further aspect of the present invention comprises a method for increasing the release of nitric oxide from a hydrophobic composition containing a modified diazeniodiolate macromolecule comprising: mixing a hydrophobic composition with a hydrophilic composition having a pH of about 4 to about 8 to form a mixture; and applying the mixture to an individual's skin.
[0011] Another aspect of the present invention comprises a method of stably storing a diazeniodiolate-modified macromolecule in a hydrophobic composition and releasing nitric oxide from the diazeniodiolate-modified macromolecule. Some embodiments include mixing the hydrophobic composition with a hydrophilic composition to form a mixture, where the hydrophobic composition comprises the diazeniodiolate modified macromolecule and the hydrophilic composition has a pH of about 4 to about 8.
[0012] A further aspect of the present invention comprises a method for providing a topical antimicrobial composition comprising: mixing a hydrophobic composition with a hydrophilic composition having a pH of about 4 to about 8 to form a mixture; and applying the mixture to an individual's skin.
[0013] Another aspect of the present invention comprises a method of increasing the rate of wound healing comprising: topically applying a mixture having a pH of about 4 to about 8.
[0014] The above aspects and other aspects of the present invention will now be described in more detail including other modalities described in this report. Brief Description of Drawings
[0015] Fig. 1 shows a graph of the release of NO from different formulations containing Nitricil® NVN4 ointment (1.8% w / w NO).
[0016] Fig. 2 shows a graph of the combined bacterial counts of MRSA Staphylococcus aureus ATCC BAA 1686 after application of treatment on days 4 and 7.
[0017] Fig. 3 shows a graph of the combined bacterial counts of MRSA Staphylococcus aureus ATCC BAA 1686 after applying the treatment on days 4 and 7.
[0018] Fig. 4 shows a graph of the bacterial counts of A. baumannii after the application of the treatment on days 4 and 7.
[0019] Fig. 5 shows a graph of the bacterial counts of S. aureus after the application of the treatment on days 4 and 7.
[0020] Fig. 6 shows a graph of bacterial counts of C. albicans after the application of the treatment on days 4 and 7.
[0021] Fig. 7 shows a graph of cumulative nitric oxide (NO) release over time for each of the three mixtures.
[0022] Fig. 8 shows a graph of NO release in real time over time for each of the three mixtures.
[0023] Fig. 9 shows a graph of cumulative nitric oxide (NO) release over time for each of the two ointments.
[0024] Fig. 10 shows a graph of NO release in real time over time for each of the two ointments.
[0025] Fig. 11 illustrates a schematic example of oil droplets covering an API with water surrounding the oil droplets. Detailed Description
[0026] The present invention will now be described more fully below. This invention can, however, be realized in different ways and should not be interpreted as limited to the modalities presented below. On the contrary, these modalities are offered to make this description thorough and complete, and to fully convey the scope of the invention to those skilled in the art.
[0027] The terminology used in describing the present invention is only intended to describe particular embodiments and is not intended to be limiting of the invention. As used in describing the invention and the appended claims, the singular forms "one", "one" and "o / a" are intended to also include plural forms, unless clearly indicated to the contrary by context.
[0028] Unless otherwise stated, all terms (including technical and scientific terms) used in this report have the same meaning as that commonly known to the person skilled in the art to which the invention belongs. It will also be understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the present application and the relevant technique and should not be interpreted in an idealized or excessively formal sense, unless expressly defined in this report. The terminology used in describing the invention is only intended to describe particular embodiments and is not intended to be limiting of the invention. All publications, patent applications, patents and other references mentioned in this report are incorporated in their entirety for reference. In the event of a conflict in terminology, this specification will prevail.
[0029] Also as used in this report, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the absence of combinations when interpreted in the alternative ("or").
[0030] Unless otherwise indicated by context, it is specifically intended that the various aspects of the invention described in this report can be used in any combination. In addition, the present invention also contemplates that in some embodiments of the invention, any aspect or combination of aspects presented in this report can be excluded or omitted. To illustrate, if the specification indicates that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disregarded.
[0031] As used in this report, the transitive phrase "consisting essentially of" (and grammatical variants) should be interpreted as covering the listed materials or steps "and those that do not materially affect the basic characteristic (s) and new (s) "of the claimed invention. See In re Herz, 537 F.2d 549, 551-52, 190 U.S.P.Q. 461, 463 (CCPA 1976) (emphasis on the original); see also MPEP § 2111.03. Accordingly, the term "consisting essentially of" as used in this report should not be construed as equivalent to "comprising."
[0032] The term "about", as used in this report when referring to a measurable value such as a quantity or concentration, among others, is intended to cover variations of ± 10%, ± 5%, ± 1%, ± 0, 5%, or even ± 0.1% of the specified value as well as the specified value. For example, "about X", where X is the measurable value, is intended to include X as well as variations of ± 10%, ± 5%, ± 1%, ± 0.5% or even ± 0, 1% of X. A range offered in this report for a measurable amount may include any other range and / or an individual amount.
[0033] In accordance with some embodiments of the present invention, the invention offers topical compositions. In some embodiments, a topical composition of the present invention comprises a mixture. "Mixture" as used in this report refers to a combination of at least two different compositions. In some embodiments, the at least two different compositions can be miscible. In particular embodiments, the term mixture refers to at least two different compositions being kept substantially isolated from one another until close to the time of use or application. In certain embodiments, the term mixture refers to at least two different compositions being kept substantially isolated from each other until their application, such as with products applied by the pharmacist. In some embodiments, one or more compositions present in a mixture can be kept substantially isolated from one or more other compositions present in a mixture. The term mixture is not intended to refer to a composition that is created at the time of producing the composition or product, such as by combining ingredients to create the composition. The combination of two or more different compositions, such as 2, 3, 4, 5, 6, 7 or more compositions, to form a mixture can be obtained by mixing, combining, contacting, application to the same area or region, emulsification, among others, of two or more different compositions. The combination of two or more different compositions can be done in order to induce a chemical reaction. A composition may be different from another composition in terms of the quantity or concentration of one or more components, in terms of the type (for example, chemical composition) of one or more components and / or in terms of the presence and / or absence of one or more components.
[0034] A mixture of the present invention can comprise at least one composition that modulates a property of another composition and / or a component present in the mixture. The modulated property can be compared with the composition and / or component property in the absence of the mixture. For example, the mixture can comprise at least one composition (that is, a first composition) that modulates the pH of another composition (that is, a second composition) and / or the release of an active pharmaceutical ingredient (API) in a another composition (that is, a second composition). As used in this report, API release refers to the release of the API itself and / or the release of one or more active agents from the API (for example, where a prodrug is the API and the active form of the drug can be released ). For example, in the modalities in which the API is a nitric oxide releasing API, references made to the release of the API may refer to the release of nitric oxide from the API. The pH of the mixture can be compared to the pH of the second composition when it is not mixed with the first composition. The release of the API from the mixture can be compared to the release of the API in the absence of the mixture (that is, the release of the individual API component and / or the release of the API from the second composition when the second composition is not in mixture. with the first composition).
[0035] "Modular", "modulating", "modulation" and grammatical variations thereof as used in this report refer to an increase or decrease in a property (for example, the pH and / or the release of an API) in a mixture of the present invention compared to the property in the absence of the mixture. As used in this report, the terms "increase", "increase", "increased", "increasing" and similar terms indicate an increase in a property (for example, the pH and / or the release of an API) of at least about 5%, 10%, 25%, 50%, 75%, 100%, 150%, 200%, 300%, 400%, 500% or more compared to the property in the absence of the mixture. As used in this report, the terms "reduce", "reduce", "reduced", "reduction" and similar terms refer to a reduction in a property (for example, the pH and / or the release of an API) of at least minus about 5%, 10%, 25%, 35%, 50%, 75%, 80%, 85%, 90%, 95%, 97% or more compared to the property in the absence of the mixture.
[0036] In some embodiments, a mixture can comprise at least two compositions (that is, a first composition and a second composition). The first composition can modulate the pH of the second composition and / or the release of an API present in the second composition or vice versa. Mixtures comprising two compositions are described in this report by way of illustration, but it is understood that the mixture may comprise more than two different compositions, such as, but without limitation, 2, 3, 4, 5, 6, 7 or more compositions. One or more of the compositions present in the mixture can modulate a property of another composition in the mixture. The modulated property can be the same property or a different property. In some embodiments, two or more different compositions in a mixture can together modulate a property of another composition in the mixture.
[0037] A mixture of the present invention can be formed by direct and / or indirect exposure of at least one component in a first composition to at least one component in a second composition. For example, a mixture can be formed by mixing and / or combining the first composition and the second composition before, during and / or after topical application to an individual. The mixture can comprise a single phase although it can be prepared from two different compositions. Another example of direct exposure of a first composition and a second composition to form a mixture can occur by applying one or more layers of the second composition to an individual and then applying one or more layers of the first composition to an individual or vice. -version. Indirect exposure can occur by applying a second composition to an individual and then applying a first composition to an individual through a substrate, such as, but not limited to, a cloth, bandage, gauze, among others, or vice versa to form a mixture.
[0038] In certain embodiments, the mixture can be self-emulsifying. In particular embodiments, the self-emulsifying mixture comprises a first composition comprising water and a second composition comprising an oil, amphiphilic agent and / or emulsifying agent. Examples of emulsifying agents include, but are not limited to, phosphatidyl choline; lecithin; surfactants such as polyethoxylated compounds including Tween 80, polysorbate 20, 21, 40, 60, 61, 65, 81, 85, 120 and other adducts with polyoxyethylene of sorbitan esters, fatty acids, fatty alcohols, lanolin, lanolin alcohols, castor oil (natural or hydrogenated) or alkylbenzenes; and any combination thereof.
[0039] A self-emulsifying mixture can form a spontaneous emulsion (for example, with the application of minimal mechanical energy or without mechanical energy) by combining at least two compositions of the mixture. In some embodiments, the self-emulsifying mixture may not require and / or need heat to form a spontaneous emulsion. In some embodiments, a self-emulsifying mixture can spontaneously emulsify via a chemical reaction under minimal mechanical and / or external force or no mechanical and / or external force to form a spontaneous emulsion. For example, the self-emulsifying mixture can be formed by an individual and / or another person by mixing the at least two compositions of the mixture with their own hands. In some embodiments, minimal mechanical strength can provide sufficient shear to emulsify the at least two compositions of the mixture. In some embodiments, the minimum mechanical strength to emulsify the at least two compositions of the mixture may have a shear rate in the range of about 1 s-1 to about 5,000 s-1, such as, for example, about 10 s-1 to about 200 s-1, about 100 s-1 to about 1000 s-1, about 500 s-1 to about 3000 s-1 or about 10 s-1 to about 2500 s -1.
[0040] The self-emulsifying mixture when forming an emulsion may contain and / or be a single phase. In some embodiments, the self-emulsifying mixture can be a coarse emulsion, a microemulsion or a nanoemulsion. In some embodiments, the self-emulsifying mixture may be an emulsion that is not separable or continuous and / or a homogeneous composition. In some embodiments, a self-emulsifying mixture can encapsulate a hydrophobic component in a hydrophilic component. As illustrated in Fig. 11, in some embodiments, a self-emulsifying mixture may contain droplets of an oil or hydrophobic phase with water or a hydrophilic phase surrounding the droplets, and the droplets may encapsulate an API.
[0041] In some embodiments, a self-emulsifying mixture can be formed by combining a hydrophobic composition and a hydrophilic composition. Some embodiments include that the hydrophobic composition comprises at least one hydrophobic base (for example, 1, 2, 3, 4 or more hydrophobic bases), an amphiphilic and / or cosolvent compound and that the hydrophilic composition comprises water, a humectant and / or a polymer. In some embodiments, the hydrophilic composition can be a hydrogel. In some embodiments, the hydrophobic composition may comprise an API, such as, for example, a NO-releasing API. In some embodiments, the hydrophobic composition can be a determinant of the fact that the composition is a self-emulsifying composition. In some embodiments, the hydrophobic composition may not comprise a component with a hydrophilic property, such as, for example, a strongly hydrophilic polyethylene glycol (for example, PEG 400). In some embodiments, the hydrophobic composition does not comprise a component with a hydrophilic-lipophilic equilibrium (HLB) value greater than 15.
[0042] In some embodiments, the mixture is a continuous emulsion (that is, an emulsion that does not separate). In some embodiments, the mixture may continue as a continuous emulsion and / or may remain joined as a single phase for at least 1, 2, 3, 4, 5, 6 or more days or 1, 2, 3, 4, 5, 6 or more weeks or 1, 2, 3, 4, 5, 6 or more months. In some embodiments, the mixture may be a continuous emulsion for a period of time sufficient to apply the composition to an individual. A composition that separates into two or more phases in 1 day of combining two or more parts of the composition is not considered a self-emulsifying mixture and / or a continuous emulsion.
[0043] In some embodiments, a self-emulsifying mixture may have a droplet size (for example, diameter) greater than 100 μm. In some embodiments, the self-emulsifying mixture may form or produce an emulsion that may have a droplet size of about 100 μm or less, such as, but without limitation, about 90 μm, 70 μm, 50 μm, 30 μm or less , or any individual range and / or value within those values. In some embodiments, the self-emulsifying mixture may form or produce an emulsion that may have a droplet size greater than 1 μm. In some embodiments, the self-emulsifying mixture may form or produce a nanoemulsion that may have a droplet size of about 400 nm or less, such as, but not limited to, about 300 nm, 200 nm, 100 nm, 50 nm or less , or any individual range and / or value within those values. In some embodiments, a self-emulsifying mixture may comprise droplets that are substantially uniform in size.
[0044] The first composition in the mixture can be configured to modulate the release of an API present in the second composition such as, but without limitation, an API that releases NO. In some embodiments, when a mixture comprising first and second compositions is formed, the water present in the first composition may contact the second composition to modulate the release of an API present in the second composition, such as, but without limitation, a NO-releasing API. . Alternatively or additionally, in some embodiments, the first composition in a mixture can modulate the pH of the second composition in the mixture, thereby modulating the release of an API present in the second composition, such as, but without limitation, a NO-releasing API. In some embodiments, the first composition in a mixture can be configured to provide water for the second composition in the mixture and / or configured to modulate the pH of the second composition in the mixture. In some embodiments, a blend of the present invention can increase the solubility of an API (for example, a NO-releasing API) and / or can increase the bioavailability of an API or an active component of an API (for example, NO) .
[0045] The inventors of the present invention surprisingly found that it was possible to prepare a mixture comprising an emulsion of water (i.e., a hydrophilic phase) and oil (i.e., a hydrophobic phase) that provided sufficient NO release. It was also surprisingly found by the inventors that it was possible to prepare a mixture having a single phase when combining a hydrophobic composition and a hydrophilic composition, and that such a composition could provide sufficient NO release. Self-emulsifying mixtures such as those described in this report were also surprisingly found by the inventors.
[0046] A mixture of the present invention can provide a particular release pattern for an API present in the mixture. The API release pattern can be determined by comparing the amount or concentration of API released over a period of time and / or the rate of API release from the mixture over a period of time. In some embodiments, the at least two different compositions present in the mix are selected to provide a particular API release pattern. The API release pattern may be desirable for a particular injury, illness, disorder or treatment indication. In some embodiments, the mixture can be configured to provide a particular release pattern of an API present in the mixture.
[0047] In some embodiments, the at least two different compositions present in the mixture can be selected to provide the mixture with a pH below about pH 11 such as, but without limitation, about 11, 10, 9, 8, 7, 6, 5, 4, 3 or less. In some embodiments, the at least two different compositions present in the mixture can be selected to provide the mixture with a pH greater than about pH 4 such as, but without limitation, about 4, 5, 6, 7, 8, 9, 10 , 11 or more. In certain embodiments, the pH of the mixture can vary between about pH 4 and about pH 11 such as, but not limited to, about pH 4 and about pH 9, about pH 7 and about pH 9, about pH 4 and about pH 8, pH 7 and about pH 10 or about pH 5 and about pH 7. In some embodiments, at least one of the compositions present in the mixture can maintain the pH of the mixture in a particular pH range. The pH of the mixture may vary over time and this may cause the rate of release of the API from the mixture to vary over time. For mixtures where the pH changes over time, the pH of the mixture can be measured within about 30 minutes after the combination, in some modalities, within about 10 minutes after the combination and, in some modalities, 2 minutes after the combination. combination. In some embodiments, the pH of the mixture can be measured about 5 minutes, 30 minutes, 1 hour and / or 24 hours after the combination.
[0048] A mixture of the present invention can provide immediate release of the API from the mixture and / or sustained release of the API from the mixture. As used in this report, immediate release refers to the release of 50% or more of the API within 4 hours of mixing and sustained release refers to the release of 50% of the API within 4 hours of mixing. In some embodiments, a mixture of the present invention can increase the amount of API released and / or the potency of an API present in at least one composition in the mixture while maintaining the pH of the mixture in a particular pH range compared to the release and / or the strength of the API in the composition in the absence of mixing. In certain embodiments, the pH of the mixture is kept below pH 9.
[0049] The API present in the mixture can be released from the mixture substantially continuously over a period of time. "Substantially continuous" and grammatical variants of it as used in this report refer to an API release from the mix all or part of the time so that on average the API release conveys a general beneficial effect to the individual. Therefore, there may be one or more intermittent and / or regular, short periods of time in which the API is not released, but the overall beneficial effect of the API on the individual continues. In some embodiments, the mixture may provide an API release pattern that is substantially continuous over a period of time and provide a therapeutically effective amount of the API over the period of time. In some embodiments, the amount of API released and / or the rate of API release may vary over a period of time. In certain embodiments, the blend may comprise two or more (for example, 2, 3, 4, 5 or more) release rates for the API.
[0050] The mixture can provide an API release pattern that is substantially constant over a period of time. "Substantially constant" as used in this report refers to a measurable value, such as the amount of API or API release rate, on average, ranging from less than about 20%, 15%, 10%, 5%, 1 % or less over a period of time. In some embodiments, the API release rate may be substantially constant for a period of time and vary over a period of time, consecutive or non-consecutive and vice versa.
[0051] In some embodiments, the mixture may provide an API release pattern having a quick release portion and a substantially constant release portion. The quick release portion may comprise an amount of API released from the administration (i.e., t = 0) up to 2 hours after the administration or any range within it, such as, but not limited to, 0 to 1 hour or 0 to 30 minutes after administration. The substantially constant release portion may comprise the amount of API released from immediately after the quick release portion until the final amount of API is released. An API can be released from a mixture of the present invention for any period of time. In some embodiments, an API can be released from the mixture for at least about 4 hours, 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more , or any individual range and / or value within these. The API released from the mixture can be released in an amount that altogether provides a beneficial effect to the individual and / or provides a therapeutically effective amount of the API over the period of time.
[0052] In some embodiments, a higher amount or concentration of the API may be released during the quick release portion compared to the substantially constant release portion or vice versa. In some embodiments, the amount of API released from the mixture during the quick release portion can be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100 %, 150%, 200%, 300%, 400%, 500% or more, or any range and / or individual value within these, of the amount of API released during the substantially constant release portion. In other embodiments, the amount of API released from the mixture during the substantially constant release portion can be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500%, or more, or any range and / or individual value within these, of the amount of API released during the quick release portion.
[0053] In particular embodiments, a first composition in a mixture can modulate the pH of a second composition in the mixture so that when the mixture is formed and / or applied to an individual's skin, the pH of the mixture is less than about 9 , in other modalities, less than about 8.5, in still other modalities, less than about 7, and in still other modalities, between about 5 and about 8. In some modalities, a first composition in a mixture can be configured to maintain and / or stabilize the pH of the mixture in a desired pH range such as, but not limited to, a pH range of about 3 to about 11, about 3 to about 9, about 4 to about 7, about 4 to about 6, or about 5 to about 8.
[0054] A mixture of the present invention may be suitable for topical administration. The mixture can comprise a single phase although it can be prepared or formed from two or more different compositions. The mixture can be buffered. In some embodiments, the mixture may comprise a hydrophobic composition and a hydrophilic composition. In certain embodiments, a hydrophobic composition and / or a hydrophilic composition can be a single agent or a compound (i.e., component). In other embodiments, a hydrophobic composition and / or a hydrophilic composition can comprise a composition having two or more agents or compounds. In some embodiments, a mixture may comprise a hydrogel and an ointment. The hydrogel and the ointment can form a mixture having a single phase that is optionally buffered. In some embodiments, the mixture comprises a hydrogel and an ointment, and the mixture may be in the form of a cream. In some embodiments, the mixture may be a self-emulsifying mixture and may comprise a hydrogel and an ointment.
[0055] In certain embodiments, a mixture of the present invention comprises a hydrophilic composition. The hydrophilic composition comprises at least one hydrophilic component. The hydrophilic composition can be a solution, suspension, lotion, gel, cream, hydrogel, among others. In some embodiments, the hydrophilic composition is in the form of a hydrogel. "Hydrogel", as used in this report, refers to a hydrophilic gel comprising a gelatinous matrix and water. Water can be present in a hydrophilic composition in an amount of about 50% to about 99% by weight of the hydrophilic composition, or any range and / or individual value among them, such as, but without limitation, about 55% at about 95%, about 65% to about 95%, about 70% to about 99%, about 75% to about 95%, about 80% to about 90%, or about 80% to about 85% by weight of the hydrophilic composition.
[0056] The hydrophilic composition can comprise means for maintaining and / or stabilizing the pH of a mixture of the present invention. The means for maintaining and / or stabilizing the pH of a mixture can be configured to control the pH of the mixture within a desired pH range. Examples of means for maintaining and / or stabilizing the pH of a mixture include, but are not limited to, buffers. Examples of buffers that can be used in a hydrophilic composition include, but are not limited to, acetic acid / acetate buffers; hydrochloric acid / citrate buffers; citrate-phosphate buffers; phosphate buffers; citric acid / citrate buffers; lactic acid buffers; tartaric acid buffers; malic acid buffers; glycine / HCl buffers; saline buffers such as phosphate-buffered saline (PBS), Tris-buffered saline (TBS), Tris-HCl, NaCl, Tween-buffered saline (TNT), phosphate-buffered saline, Triton X-100 ( PBT) and mixtures thereof; cacodylate buffers; barbital plugs; tris buffers; and any combination thereof.
[0057] A buffer can be present in the hydrophilic composition at a concentration of about 5 mmol to about 2 moles or any range and / or individual value among them, such as, but without limitation, about 10 mmoles to about 1 soft, about 100 mmoles to about 750 mmoles or about 200 mmoles to about 500 mmoles. In some embodiments, a buffer may be present in the hydrophilic composition in an amount of about 0.1% to about 20% by weight of the hydrophilic composition or any range and / or individual value among them, such as, but without limitation, about 0.1% to about 10%, about 1% to about 15%, about 10% to about 20%, about 5% to about 15% or about 1% to about 5 % by weight of the hydrophilic composition.
[0058] In some embodiments, the hydrophilic composition may comprise a phosphate buffer. Examples of phosphate buffers may include at least one phosphate salt such as, but not limited to, sodium phosphate (eg, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate and mixed sodium and aluminum phosphate), potassium phosphate (eg monobasic potassium phosphate and dibasic potassium phosphate), rubidium phosphate, cesium phosphate and ammonium phosphate, and / or at least one phosphoric acid such as, but not limited to, pyrophosphoric acid, triphosphoric acid and orthophosphoric acid . The hydrophilic composition may have a total phosphate concentration of about 5 mmoles to about 1 mole of phosphate or any range and / or individual value among them such as, but without limitation, about 10 mmoles to about 750 mmoles, about from 150 mmoles to about 500 mmoles or about 200 mmoles to about 400 mmoles. In certain embodiments, the hydrophilic composition may have a phosphate buffer present in an amount of about 1% to about 20% by weight of the hydrophilic composition, such as, but without limitation, about 1% to about 15% by weight. weight, about 5% to about 15% by weight, about 10% to about 20%, about 5% to about 10% by weight, about 1% to about 5% or about 4% about 8% by weight of the hydrophilic composition.
[0059] In certain embodiments, a hydrophilic composition can comprise a buffering agent. Examples of buffering agents include, but are not limited to, citric acid, acetic acid, lactic acid, boric acid, succinic acid, malic acid, sodium hydroxide, potassium hydroxide and any combination thereof. A buffering agent can be present in a hydrophilic composition of the present invention in an amount of about 0.01% to about 5% by weight of the hydrophilic composition or any range and / or individual value among them such as, but without limitation , about 0.05% to about 3%, about 1% to about 4%, or about 1.5% to about 3.5% by weight of the hydrophilic composition.
[0060] In some embodiments, the hydrophilic composition does not comprise or substantially lack a buffer and / or a buffering agent. In some embodiments, the hydrophilic composition is non-buffered (i.e., the pH of the hydrophilic composition is not stabilized with a buffer and / or a buffering agent).
Therefore, in certain embodiments, a mixture of the present invention may comprise a hydrophilic composition such as, but not limited to, a hydrogel, which is optionally buffered. The hydrophilic composition can be pH dependent. The hydrophilic composition can be configured to have a buffering capacity of at least about 4 to about 8, or any range and / or individual value among them, such as, but without limitation, about 4 to about 7 , about 5 to about 6, about 5 to about 8 or about 6 to about 8. The hydrophilic composition can be configured to maintain and / or stabilize the pH of a mixture within about 0.5 or more pH units such as, for example, about 1, 2 or 3 pH units, from the pH of the hydrophilic composition. The pH of the mixture can be maintained and / or stabilized when the mixture is formed and / or at the application site (for example, an individual's skin and / or a wound bed) of the mixture. For example, when a mixture comprising a hydrophilic composition having a pH of about 5 is formed with an additional composition and applied to an individual's skin, the hydrophilic composition can be configured to maintain and / or stabilize the pH of the mixture within about 0.5 pH unit of the pH of the hydrophilic composition (i.e., the hydrophilic composition can maintain the pH of the mixture in a pH range of about 4.5 to 5.5). In some embodiments, a hydrophilic composition can be configured to maintain and / or stabilize the pH of a mixture in a pH range from about pH 3 to about pH 6, about pH 3 to about pH 5, about pH 3 to about pH 4, about pH 4 to about pH 8, about pH 4 to about pH 7, about pH 4 to about pH 6, about pH 5 to about pH 7, about pH 5 to about pH 6, about pH 6 to about pH 7 or any range within them. The mixture can therefore provide a particular pH to the application site (e.g., wound bed), which can increase or decrease the pH of the application site in the absence of the mixture.
[0062] A hydrophilic composition of the present invention can have any suitable pH, such as a pH of about 1 or more (for example, about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14). In some embodiments, the hydrophilic composition can be configured to have a pH in the range of about 3 to about 8 or any range and / or individual value among them, such as about 3 to about 4 or about 4 to about 6. In certain embodiments, the hydrophilic composition can be configured to have a pH of about 5. In some embodiments, the hydrophilic composition can be buffered.
[0063] A hydrophilic composition can comprise a natural and / or synthetic polymer. Examples of polymers include, but are not limited to, polysaccharides such as chitosan and chitin; charged celluloses and pharmaceutically acceptable salts thereof; acrylic acids such as polyacrylic polymers such as polyacrylic acid, polyacrylate polymers, cross-linked polyacrylate polymers, cross-linked polyacrylic acids, polyacrylic acid polymers commercially available from Lubrizol of Wickliffe, Ohio under the trademark CARBOPOL®, and mixtures thereof; and any combination thereof. In some embodiments, a hydrophilic composition comprises a charged cellulose or a pharmaceutically acceptable salt thereof. Examples of charged celluloses or pharmaceutically acceptable salts thereof include, but are not limited to, ionic celluloses, carboxymethyl cellulose and its salts, hydroxyethyl carboxymethyl cellulose, hydroxypropyl carboxymethyl cellulose, sulfoethyl cellulose, hydroxyethyl sulfoethyl cellulose, hydroxypropyl cellulose hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose. , methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, carrageenan, chitosan, xanthan gum, sodium alginate, propylene glycol alginate, alginic acid and its salts and any combination thereof. In some embodiments, a hydrophilic composition may comprise carboxymethyl cellulose and / or a salt thereof. In some embodiments, a hydrophilic composition can comprise ethoxylated, quaternized hydroxyethyl cellulose. In some embodiments, a hydrophilic composition may comprise chitosan.
[0064] A polymer such as, but not limited to, charged cellulose or a pharmaceutically acceptable salt thereof, may be present in a hydrophilic composition in an amount of about 0.1% to about 15% by weight of the hydrophilic composition or any range and / or individual value among them, such as, but without limitation, about 0.3% to about 10%, about 0.5% to about 10%, about 1% to about 10% or about 1% to about 5% by weight of the hydrophilic composition. In certain embodiments, a polymer such as, but not limited to, charged cellulose and / or a pharmaceutically acceptable salt thereof (for example, carboxymethyl cellulose and salts thereof) may be present in a hydrophilic composition in an amount of about 0.1 %, 0.3%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14 % or 15% by weight of the hydrophilic composition or any range and / or individual value among them.
[0065] A hydrophilic composition can comprise a polyhydric alcohol. Examples of polyhydric alcohols include, but are not limited to, glycerol, glycols, propylene glycol, hexylene glycol, polyethylene glycol, polypropylene glycol, triethylene glycol, neopental glycols, triethanolamine, diethanolamine, ethanolamione, butylene glycol, polyethylene glycol, n-methyl diethanolamine , isopropanolamine, sorbitol, arabitol, erythritol, MSM, isomalt, lactitol maltitol, mannitol, xylitol, treitol, ribitol, galactitol, fucitol, iditol, inositol, volemitol and any combination thereof. In some embodiments, a hydrophilic composition can comprise glycerol. In some embodiments, a hydrophilic composition can comprise a glycol, such as hexylene glycol.
[0066] A polyhydric alcohol can be present in a hydrophilic composition in an amount of about 1% to about 30% by weight of the hydrophilic composition or any range and / or individual value among them, such as, but without limitation , about 1% to about 25%, about 5% to about 15%, about 5% to about 20%, about 10% to about 30% or about 15% to about 25% by weight of the hydrophilic composition. In certain embodiments, a polyhydric alcohol may be present in a hydrophilic composition in an amount of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10 %, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% by weight of the hydrophilic composition or any range and / or individual value among them.
[0067] A hydrophilic composition can comprise a preservative. A preservative can be present in a hydrophilic composition in an amount of about 0.01% to about 2% by weight of the composition or any range and / or individual value among them such as, but without limitation, about 0.05 % to about 1%, about 0.05% to about 0.5% or about 0.1% to about 1% by weight of the hydrophilic composition. In certain embodiments, a preservative is present in a hydrophilic composition in an amount of about 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0, 07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0, 8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8% , 1.9% or 2% by weight of the hydrophilic composition or any range and / or individual value among them.
[0068] Examples of preservatives that may be present in a hydrophilic composition of the present invention include, but are not limited to, sorbic acid, benzoic acid, methyl paraben, propyl paraben, methyl chloro isothiazolinone, methyl isothiazolinone, diazolidinyl urea, chlorobutanol, trichloride, chloride benzethonium, p-hydroxybenzoate, chlorhexidine, digluconate, hexadecyltrimethyl ammonium bromide, alcohols, benzalkonium chloride, boric acid, bronopol, butylparaben, butylene calcium acetate, calcium chloride, calcium lactate, carbon dioxide, cationic, and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, dimethyl ether, ethylparaben, glycerin, hexetidine, imidureia, isopropyl alcohol, lactic acid, phenothioglycerol, phenoxylic alcohol phenylethyl, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, metabisulfite potassium, potassium sorbate, propionic acid, propyl gallate, propylene glycol, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium sulfite, sodium propionate, sodium metabisulfite, xylitol, sulfur dioxide, carbon dioxide and any combination thereof.
[0069] A hydrophilic composition can comprise a neutralizing agent. A neutralizing agent may be present in a hydrophilic composition in an amount sufficient to provide the hydrophilic composition with a pH of about 3 to about 8, or any individual range and / or value among them such as, but without limitation, about 4 to about 7 or about 6 to about 7. In some embodiments, a neutralizing agent adjusts the pH of the hydrophilic composition. In certain embodiments of the present invention, a neutralizing agent may be present in a hydrophilic composition of the present invention in an amount sufficient for the hydrophilic composition to have a pH of about 3, 3.5, 4, 4.5, 5, 5 , 5, 6, 6.5, 7, 7.5 or 8 or any range and / or individual value among them. Examples of neutralizing agents that may be present in a hydrophilic composition include, but are not limited to, bases such as sodium hydroxide, potassium hydroxide and mixtures thereof; acids such as hydrochloric acid, citric acid, acetic acid and mixtures thereof; sodium carbonate; trolamine; tromethamine; aminomethyl propanol; triisopropanolamine; aminomethyl propanol; tetrahydroxypropyl ethylenediamine; Tetrasodium EDTA; suttocide A; and any combination thereof.
[0070] According to some modalities, a hydrophilic composition can be antimicrobial. A hydrophilic composition can be cosmetically elegant. "Cosmetically elegant", as used in this report, refers to a composition that is attractive for application to the skin, which can include mucosa. In some embodiments, a composition may be cosmetically elegant for the skin and / or mucosa. A cosmetically elegant composition of the present invention can have one or more of the following properties: consistency or viscosity suitable for topical application (for example, easy to spread on the skin and does not run), texture suitable for topical application (a smooth or soft composition that it is not sandy), absorption capacity and / or permeation through the skin, not sticky or sticky, leaves no residue, leaves the skin with a good feeling and after application does not leave the skin oily or dry. In some embodiments, a hydrophilic composition may have a viscosity of about 5,000 cP (centipoise) to about 100,000 cP, or any range and / or individual value among them, such as, but without limitation, about 10,000 cP at about 50,000 cP, about 20,000 cP to about 40,000 cP, about 30,000 cP to about 50,000 cP, about 50,000 cP to about 100,000 cP or about 30,000 cP to about 75,000 cP.
[0071] A hydrophilic composition such as, but not limited to, a hydrogel, of the present invention may be suitable in a mixture of the present invention with one or more, such as, but without limitation, 2, 3, 4 or more, different compositions . A hydrophilic composition, such as, but not limited to, a hydrogel, of the present invention can be used as a drug delivery system and / or a drug delivery system when in a mixture of the present invention. For example, a hydrophilic composition can be configured to modulate the release of an active pharmaceutical ingredient (API) in a second composition when a mixture comprising the hydrophilic composition and the second composition is formed and / or administered. Alternatively or additionally, a hydrophilic composition can be configured to modulate the pH of a second composition when a mixture comprising the hydrophilic composition and the second composition is formed and / or administered. In some embodiments, a hydrophilic composition can be configured to modulate the pH of a second composition comprising a nitric oxide releasing API (NO) and / or the rate of NO release from an NO releasing API when a mixture comprising the hydrophilic composition and the second composition is formed and / or administered. In certain embodiments, the second composition may be a hydrophobic composition, such as, but not limited to, an ointment. In some embodiments, a hydrophilic composition can be configured to modulate the pH of a mixture in which it is present within a desired pH range.
[0072] A mixture of the present invention can have any suitable pH. In some embodiments, the mixture can have a pH of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14. In some embodiments, the mixture can be configured in order to have a pH in the range of about pH 2 to about pH 9, such as about pH 4 to about pH 9, about pH 3 to about pH 6, about pH 3 to about pH 5, about pH 3 to about pH 4, about pH 4 to about pH 8, about pH 4 to about pH 7, about pH 4 to about pH 6, about pH 5 to about pH 7, about pH 5 to about pH 6, about pH 6 to about pH 7, about pH 4 to about pH 8 or about pH 5 to about pH 8, or any other range within these. In certain embodiments, a mixture of the present invention is buffered to have a suitable pH. In some embodiments, a mixture of the present invention is un Buffered and / or the mixture does not comprise or is substantially devoid of a buffer and / or a buffering agent.
[0073] In some embodiments, a mixture of the present invention may comprise an active pharmaceutical ingredient (API). Any suitable API or combination of APIs can be included in a mixture of the present invention. Examples of APIs include, but are not limited to, antimicrobial agents, anti-acne agents, anti-inflammatory agents, analgesic agents, anesthetic agents, antihistamines, antiseptic agents, immunosuppressants, anti-hemorrhagic agents, vasodilators, wound healing agents, anti-film agents and any combination thereof. Examples of APIs include, but are not limited to, those described in International Application No. PCT / US2013 / 028223, which is hereby incorporated by reference in its entirety. In some embodiments, the mixture and / or the API does not comprise acidified nitrite. "Acidified nitrite", as used in this report, refers to a nitric oxide releasing composition where the main nitric oxide releasing mechanism is when a nitrite is reduced, in the presence of an acid, to dinitrogen trioxide, which can decompose in nitric oxide and nitrous oxide.
[0074] Examples of antimicrobial agents include, but are not limited to, penicillins and related drugs, carbapenems, cephalosporins and related drugs, erythromycin, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, sodium fusidate, lincomycin, clincomycin, macrogin, clindamycin, polymyxins, rifamycins, spectinomycosine, tetracyclines, vanomycin, teicoplanin, streptogramins, antifolate agents including sulfonamides, trimethoprim and their combinations and pyrimethamine, synthetic antibacterials including nitrofurans, methenamine mandelate and methenamine hipurate, fluoroquinolone, nitroimidazones, fluoroquinolides , para-aminosalicylic acid (PAS), cycloserine, capreomycin, ethionamide, protionamide, thiacetazone, viomycin, eveminomycin, glycopeptide, glyclyclicline, ketolides, oxazolidinone; imipenem, amikacin, netylmycin, fosfomycin, gentamicin, ceftriaxone, Ziracim, Linezolid, Sinercida, Aztreonam and Metronidazole, Epiroprim, Sanfetrinem sodium, Biapenem, Dinemicina, Cefluprenam, Cefoselem, Cefluprenam, Cefoselem, Cefoselem, Cefulelil, Sanfetrin, Sulopenem, ritipenam acoxil, Ciclothialidina, micacocidina A, carumonam, Cefozopram and Cefetamete pivoxil.
[0075] Examples of topical anti-acne agents include, but are not limited to, adapalene, azelaic acid, benzoyl peroxide, clindamycin and clindamycin phosphate, doxycycline, erythromycin, queeratolytics such as salicylic acid and retinoic acid (Retin-A '), norgestimate, organic peroxides, retinoids such as isotretinoin and tretinoin, sodium sulfacetamide and tazarotene. Particular anti-acne agents include adapalene, azelaic acid, benzoyl peroxide, clindamycin (e.g., clindamycin phosphate), doxycycline (e.g., doxycycline hydrate), erythromycin, isotretinoin, norgestimate, sodium sulfacetamide, tazaretene, tetretinate and acetetinate.
[0076] Examples of antihistamine agents include, but are not limited to, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate, isotypendyl hydrochloride, triphenamine hydrochloride, promethazine hydrochloride, hydrochloride between promazine others. Examples of local anesthetic agents include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, 2- (dieethylamino) hydrochloride ethyl p-butylaminobenzoic acid ester, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, oxyprocaine, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, diclonin and diclonine hydrochloride.
[0077] Examples of antiseptic agents include, but are not limited to, alcohols, quaternary ammonium compounds, boric acid, chlorhexidine and chlorhexidine derivatives, iodine, phenols, terpenes, bactericides, disinfectants including thimerosal, phenol, thymol, benzalkonium chloride, chloride benzethonium, chlorhexidine, povidone iodine, cetylpyridinium chloride, eugenol and trimethylammonium bromide.
[0078] Examples of anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory agents (NSAIDs); propionic acid derivatives such as ibuprofen and naproxen; acetic acid derivatives such as indomethacin; enolic acid derivatives such as meloxicam, acetaminophen; methyl salicylate; monoglycol salicylate; aspirin; mefenamic acid; flufenamic acid; indomethacin; diclofenac; alclofenac; sodium diclofenac; ibuprofen; ketoprofen; naproxen; pranoprofen; fenenoprofen; sulindac; fenclofenac; clidanac; flurbiprofen; fentiazaque; bufexamaco; piroxicam; phenylbutazone; oxfenbutazone; clofezone; pentazocine; mepirizole; thiaramide hydrochloride; steroids such as clobetasol propionate, betamethasone dipropionate, halbetasol propionate, diflorasone diacetate, fluocinonide, halcinonide, amcinonide, deoxymethasone, acetonide triamcinolone, mometasone furoate, fluticasone propionate, flutonone acetone, propionate, flutamine, proponate , fluocinolone acetonide, hydrocortisone valerate, prednicarbate, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone and others known in the literature, predonisolone, dexamethasone, fluocinolone acetonide, hydrocortisone acetate, betonisone, acetone, acetone, acetone, acetone, acetone, acetone, hydrochloride flumetasone, fluorometholone, beclomethasone diproprionate, fluocinonide, topical corticosteroids and may be one of the lowest potency corticosteroids such as hydrocortisone, hydrocortisone-21-monoesters (eg hydrocortisone-21-acetate, hydrocortisone-21-butyrate, hydro cortisone-21-propionate, hydrocortisone-21-valerate, etc.), hydrocortisone-17,21-diesters (e.g. hydrocortisone-17,21-diacetate, hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17,21 -dibutyrate, etc.), alclomethasone, dexamethasone, flumetasone, prednisolone or methylprednisolone or it may be a higher potency corticosteroid such as clobetasol propionate, betamethasone benzoate, betamethasone dipropionate, diflorasone diacetate, fluocyanone, fluocinone, momocinone -acetonide.
[0079] Examples of analgesic agents include, but are not limited to, alfentanil, benzocaine, buprenorphine, butorfanol, butambem, capsaicin, clonidine, codeine, dibucaine, encephalin, fentanyl, hydrocodone, hydromorphone, indomethacin, lidocaine, levorpholine, meperidine, meperidine, meperidine, meperidine, meperidine, , nicomorphine, opium, oxybutocaine, oxycodone, oxymorphone, pentazocine, pramoxin, proparacaine, propoxyphene, proximetacaine, sufentanil, tetracaine and tramadol.
Examples of anesthetic agents include, but are not limited to, alcohols such as phenol; benzyl benzoate; calamine; chloroxylenol; diclonin; ketamine; menthol; pramoxin; resorcinol; loosen; procaine-type drugs such as benzocaine, bupivacaine, chloroprocaine; cinchocaine; cocaine; dexivacaine; diamocaine; dibucaine; ethidocaine; hexylcaine; levobupivacaine; lidocaine; mepivacaine; oxetazaine; prilocaine; procaine; proparacaine; propoxycaine; pyrrocaine; risocaine; rhodocaine; ropivacaine; tetracaine; and derivatives, such as pharmaceutically acceptable salts and esters including bupivacaine HCl, chloroprocaine HCl, diamocaine cyclamate, dibucaine HCl, diclonin HCl, ethidocaine HCl, levobupivacaine HCl, lidocaine HCl, mepivacaine HCl, mepivacaine HCl , HCl of prilocaine, HCl of procaine, HCl of proparacaine, HCl of propoxicaine, HCl of ropivacaine and HCl of tetracaine.
[0081] Examples of anti-hemorrhagic agents include, but are not limited to, thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, sodium carbaxochrome sulfanate, rutin and hesperidin.
[0082] An API can be present in any of the compositions used to form a mixture of the present invention. In certain embodiments, at least one composition used to form a mixture comprises a nitric oxide (NO) releasing API. In some embodiments, at least one composition used to form a mixture does not contain an API, such as, but without limitation, a NO-releasing API. In some embodiments, a composition used to form a mixture may comprise at least one API, but the composition does not comprise a NO-releasing API. In certain embodiments, a mixture comprises a hydrophilic composition and the hydrophilic composition does not comprise an NO-releasing API. In some embodiments, a mixture of the present invention does not comprise an active pharmaceutical ingredient (API).
[0083] In certain embodiments, a mixture of the present invention may comprise at least one API, such as, but without limitation, an active nitric oxide releasing pharmaceutical ingredient. In some embodiments, a mixture of the present invention comprises a nitric oxide releasing active pharmaceutical ingredient in an amount of about 0.01% to about 5% w / w nitric oxide or any individual range and / or value among them , such as about 0.1% to about 3%, about 0.1% to about 1.5% or about 1% to about 5% w / w nitric oxide.
[0084] "Nitric oxide releasing active pharmaceutical ingredient" and "NO releasing API", as used in this report, refer to a compound or other composition that provides nitric oxide to an individual's skin, but is not gaseous nitric oxide. In some embodiments, the NO-releasing API includes a nitric oxide-releasing compound, hereinafter referred to as "NO-releasing compound." An NO-releasing compound includes at least one NO-donor, which is a functional group that can release nitric oxide under certain conditions. In some embodiments, the at least one NO donor of a NO releasing compound releases NO when in contact with a composition of the present invention. In certain embodiments, a composition of the present invention modulates the amount of NO released from an NO releasing compound and / or the rate of NO released from an NO releasing compound. In some embodiments, a composition of the present invention increases the amount of NO released from an NO-releasing compound and / or the rate of NO released from an NO-releasing compound.
[0085] Any suitable NO-releasing compound can be used. In some embodiments, the NO-releasing compound includes a small molecule compound that includes an NO-donating group. "Small molecule compound" as used in this report is defined as a compound having a molecular weight of less than 500 daltons and includes organic and / or inorganic small molecule compounds. In some embodiments, the NO-releasing compound includes a macromolecule that includes a NO-donor group. A "macromolecule" is defined in this report as any compound that has a molecular weight of 500 daltons or more. Any suitable macromolecule can be used, including cross-linked or non-cross-linked polymers, dendrimers, metal compounds, organometallic compounds, inorganic based compounds and other macromolecular bases. In some embodiments, the macromolecule has a nominal diameter ranging from about 0.1 nm to about 100 μm and can comprise the aggregation of two or more macromolecules, with which the macromolecular structure is further modified with a NO donor group. .
[0086] In some embodiments, the NO-releasing compound includes a diazenodiolate functional group as a NO-donor group. The diazenodiolate functional group can produce nitric oxide under certain conditions, such as when exposed to water. As another example, in some embodiments, the NO-releasing compound includes a nitrosothiol functional group as the NO donor. The NO donor can produce nitric oxide under certain conditions, such as when exposed to light. Examples of other NO donor groups include nitrosamine, hydroxyl nitrosamine, hydroxyl amine and hydroxyurea. Any suitable combination of NO donors and / or NO releasing compounds can also be used in a second composition as already described in this report. Additionally, the NO donor can be incorporated into or on the small molecule or macromolecule through covalent and / or non-covalent interactions.
[0087] An NO-releasing macromolecule may be in the form of an NO-releasing particle, such as those described in US Patent Application Publication No. 2009/0214618 and in US Patent No. 8,282,967, the descriptions of which are incorporated herein. integrity as a reference. Other non-limiting examples of NO-releasing compounds include NO-releasing zeolites such as those described in US Patent Publication No. 2006/0269620 or 2010/0331968; NO-releasing metal organic structures (MOFs) such as those described in US Patent Application Publications No. 2010/0239512 or 2011/0052650; NO-releasing multi-donor compounds such as those described in International Publication No. WO / 2013/029009; dendrimers or NO-releasing metal structures such as those described in US Publication No. 2009/0214618; nitric oxide releasing coatings such as those described in US Publication No. 2011/0086234; and compounds such as those described in US Publication No. 2010/0098733. The descriptions of each of the references in this paragraph are hereby incorporated in their entirety by way of reference. In addition, NO-releasing macromolecules can be manufactured in the manner described in International Publication No. WO / 2012/100174, the description of which is incorporated herein in its entirety as a reference.
[0088] In some embodiments, a mixture of the present invention can increase the amount of NO released from the mixture compared to the amount of NO released from at least one composition used to form the mixture over the same period of time. For example, when a mixture comprising a hydrophilic composition and a hydrophobic composition such as, but not limited to, an ointment already described in this report, is formed, the amount of NO released from the mixture can be increased compared to the amount of NO released from the hydrophobic composition alone (i.e., in the absence of the hydrophilic composition or mixture). In certain embodiments, a mixture of the present invention can increase the amount of NO released by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90, 100%, 150%, 200%, 300%, 400%, or more, or any range and / or individual value among them, compared to the amount of NO released from at least one composition used to form the mixture during the same period of time. A mixture of the present invention can release about 1.5 to about 100 times more NO than the amount of NO from at least one composition used to form the mixture over the same period of time, or any range and / or individual value among them such as, but without limitation, about 2 to about 10 times more NO or about 5 to about 50 times more NO.
[0089] According to some modalities, a mixture comprises means for stabilizing and / or maintaining the pH of the mixture. Example means for stabilizing and / or maintaining the pH of the mixture include, but are not limited to, buffers such as those described in this report. In some embodiments, the mixture may comprise a nitric oxide releasing active pharmaceutical ingredient in an amount of about 0.01% to about 5% w / w nitric oxide and have a pH of about 4 to about 9 A blend of the present invention can be cosmetically elegant and / or antimicrobial. In some embodiments, a mixture of the present invention is self-emulsifying.
[0090] In some embodiments, a mixture of the present invention may comprise a hydrophilic composition as already described in this report and a hydrophobic composition. The hydrophobic composition can be a liquid, solution, ointment, among others. The hydrophobic composition comprises at least one hydrophobic component, such as, but not limited to, a hydrophobic base. Examples of hydrophobic compositions include those described in International Orders Nos PCT / US2010 / 046173 and PCT / US2013 / 028223, which are hereby incorporated by reference in their entirety. In some embodiments, the hydrophobic composition is an ointment.
In some embodiments, a blend of the present invention may comprise a polymer such as, but not limited to, a charged cellulose or a pharmaceutically acceptable salt thereof; a humectant such as, but not limited to, polyhydric alcohol; Water; a hydrophobic base; an amphiphilic compound and / or a cosolvent. The mixture may be non-buffered and / or the mixture does not comprise or is substantially devoid of a buffer and / or a buffering agent. In some embodiments, the mixture can have a pH in the range of about pH 4 to about pH 8.
[0092] In certain embodiments, a blend of the present invention may comprise a polymer, such as, but not limited to, a charged cellulose or a pharmaceutically acceptable salt thereof; a polyhydric alcohol; a hydrophobic base; an API; and optionally an amphiphilic compound or an emulsifying agent. In some embodiments, the API may comprise a NO-releasing compound. The mixture can further comprise a buffer such as, but without limitation, a phosphate buffer, and can be buffered to reach a pH of about 4 to about 9 or any individual range and / or value among them.
[0093] At least one hydrophobic base may be present in a mixture of the present invention. In some embodiments, a hydrophobic base may be present in a hydrophobic composition that can be used to form a mixture of the present invention. "Hydrophobic base" as used in this report refers to a fat, wax, natural and / or synthetic oil and / or the like. Any hydrophobic base can be used in a mixture of the present invention. In certain embodiments, a mixture comprises two or more hydrophobic bases, such as, but without limitation, 2, 3, 4, 5 or more hydrophobic bases. In certain embodiments, a hydrophobic base, in addition to having hydrophobic properties, can also have hydrophilic properties and can therefore be an amphiphilic base. Examples of hydrophobic bases include, but are not limited to, branched and unbranched hydrocarbons, branched and unbranched hydrocarbon waxes, petroleum jelly, hydrocarbon gel, liquid paraffin, white petrolatum, petrolatum, microcrystalline wax, andelila wax, carnauba wax, lanolin (wool wax), wool wax alcohol, esparto wax, cork wax, guaruma wax, rice bran wax, sugar cane wax, berry wax, ouricuri wax ", soy wax , jojoba oil, uropigian grease, ceresin, paraffin waxes, microceras, vegetable oils, animal oils, carnauba wax, beeswax, cocoa butter, solidified fat, mineral oil, vegetable oil, avocado oil, borage oil , canola oil, castor oil, chamomile oil, coconut oil, corn oil, cottonseed oil, rapeseed oil, morning primrose oil, saffron oil, sunflower oil, soybean oil , sweet almond, palm oil, palm kernel oil, oil and arctium lappa seed, sesame oil, official borgo seed oil, brassica campestris oleifera oil, brevoortia oil, bubulum oil, cistus ladaniferus oil, elaeis guineensis oil, almond oil, pine oil, oil olive oil, peanut oil, wheat germ oil, grape seed oil, thistle oil, lard, tallow, palm oil, illipê butter, shea butter, cocoa butter, kokum butter, salted butter , lecithin, Japanese lanolin wax, partially hydrogenated vegetable oils, hydrophobic polymers and any combination thereof.
[0094] In some embodiments, a hydrophobic base may comprise a hydrophobic polymer. Any hydrophobic polymer can be used in a mixture of the present invention. Examples of hydrophobic polymers include, but are not limited to, hydrocarbon polymers and / or copolymers, aromatic polyurethanes, silicone rubber, polysiloxanes, polycaprolactone, polycarbonate, polyvinyl chloride, polyethylene, polyethylene glycols (6-4000), poly-L-lactide , poly- DL-glycolide, polyetheretherketone (PEEK), polyamide, polyimide and polyvinyl acetate. In certain embodiments, a hydrophobic base may be an amphiphilic base, such as, but not limited to, a polyethylene glycol (6-4000). In particular embodiments of the present invention, a mixture of the present invention comprises one or more hydrocarbon polymers and / or copolymers. In certain embodiments, a blend of the present invention may comprise one or more hydrocarbon polymers and / or copolymers, such as, but not limited to, those commercially available from Calumet Specialty Products Partners of Indianapolis, IN under the trademark Versagel® and / or those commercially available from Croda International Plc of East Yorkshire, United Kingdom under the trade name Crodabase SQ.
[0095] In some embodiments, a mixture may comprise at least one hydrophobic base comprising one or more vegetable and / or mineral oils. Any suitable oil can be used in the mixtures of the present invention. Examples of mineral oils include, but are not limited to, light mineral oil, white mineral oil, paraffinic oils, naphthenic oils, aromatic oils and any combination thereof.
[0096] One or more hydrophobic bases may be present in a hydrophobic composition used to form a mixture of the present invention. One or more hydrophobic bases (for example, 1, 2, 3, 4, 5 or more hydrophobic bases), alone or together, can be present in a hydrophobic composition at a concentration of about 1% to about 99% by weight of the hydrophobic composition or any range and / or individual value among them, such as, but without limitation, from about 2% to about 20% by weight, about 1% to about 10% by weight, about 1% about 15% by weight, about 15% to about 65% by weight, about 25% to about 98% by weight, about 30% to about 98% by weight, about 35% to about from 99% by weight, about 35% to about 90% by weight, about 25% to about 50% by weight, about 25% to about 55% by weight, about 30% to about 50 % by weight, about 35% to about 55% by weight, about 40% to about 80% by weight, about 50% to about 90% by weight, about 65% to about 95% in about 70% to about 80% by weight, about 75% to about 95% by weight, about 80% to about 99% by weight, about from 90% to about 99% by weight, or about 50% to about 70% by weight of the hydrophobic composition. In certain embodiments, one or more hydrophobic bases, alone or together, may be present in a hydrophobic composition used to form a mixture in a concentration of about 50% to about 90% by weight of the hydrophobic composition. In some embodiments, one or more hydrophobic bases, alone or together, may be present in a hydrophobic composition used to form a mixture in a concentration of from about 70% to about 99% by weight of the hydrophobic composition.
[0097] "Amphiphilic compound" as used in this report refers to a compound comprising hydrophilic and hydrophobic properties. An amphiphilic compound can comprise two or more compounds, each of which can provide hydrophilic and / or hydrophobic property. In some embodiments, the amphiphilic compound may comprise a compound having hydrophilic and hydrophobic properties. In particular embodiments of the present invention, an amphiphilic compound can absorb moisture without substantially absorbing vaporous moisture. An amphiphilic compound can have a hydrophilic-lipophilic balance (HLB) value of 12 to 20 or any range and / or individual value among them, such as, but not limited to, 15 to 20 or 18 to 20. In certain embodiments of this invention, an amphiphilic compound can have an HLB value of 19.
[0098] Examples of amphiphilic compounds include, but are not limited to, fatty acid esters. One or more fatty acid esters can be present in a mixture of the present invention, such as 2, 3, 4 or more fatty acid esters. Examples of fatty acid esters include, but are not limited to, C6-C22 alkyl and / or alkenyl fatty acid esters such as methyl laurate, ethyl laurate, ethyl myristate, ethyl palmitate, ethyl linoleate, propyl isobutylate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, oleyl myristate, oleyl stearate and oleyl oleate; ether-esters such as fatty acid esters of ethoxylated fatty alcohols; esters of polyhydric alcohols such as esters of monoacids and fatty diacids of ethylene glycol, monoacid esters and fatty diacids of diethylene glycol; polyethylene glycol (6-2000) fatty acid monoesters and / or diesters such as PEG-6-laurate, PEG-6-stearate, PEG-8-dilaurate, PEG-8-distearate, etc .; esters of polyethylene glycol glycerol fatty acids such as PEG-20-glyceryl laurate, PEG-20-glyceryl stearate and PEG-20-glyceryl oleate; esters of propylene glycol monoacids and fatty diacids; 2000 polypropylene glycol monooleate; 2000 polypropylene glycol monostearate; ethoxylated propylene glycol monostearate; esters of glycerol monoacids and fatty diacids; polyglycerol fatty acid esters such as polyglyceryl-10 laurate, etc .; ethoxylated glyceryl monostearate; 1,3-butylene glycol monostearate; 1,3-butylene glycol distearate; polyoxyethylene polyol fatty acid ester; esters of sorbitan fatty acids including sorbitan trioleate and sorbitan monolaurate; polyethylene glycol sorbitan fatty acid esters such as PEG-6 sorbitan monooleate; polyoxyethylene sorbitan fatty acid esters including polyoxyethylene (20) sorbitan monolaurate; esters of sucrose fatty acids such as sucrose monopalmitate and sucrose monostearate; wax esters such as beeswax, epermacete, myristyl myristate, stearyl stearate and arachidyl beenate; polyethylene glycol alkyl ethers such as PEG-10 oleyl ether or PEG-9 cetyl ether; polyethylene glycol alkyl phenols such as PEG-10-100 nonyl phenol; polyoxyethylene-polyoxypropylene block copolymers such as poloxamer 188; sterol esters such as cholesterol fatty acid esters and any combination thereof.
[0099] In certain embodiments, a fatty acid ester may comprise a polyethylene glycol glyceride (PEG). The polyethylene glycol portion of a PEG glyceride may provide the hydrophilic property of an amphiphilic compound and may include, but is not limited to, PEG 5-1000 or any individual range and / or value among them, and any combination thereof. The glyceride portion of a PEG glyceride may provide the hydrophobic property of an amphiphilic compound and may include, but is not limited to, a natural and / or hydrogenated oil, such as, but not limited to, castor oil, hydrogenated castor oil, vitamin A, vitamin D, vitamin E, vitamin K, a vegetable oil (for example, corn oil, olive oil, peanut oil, palm kernel oil, apricot kernel oil, almond oil, etc.) and any combination of themselves. Examples of polyethylene glycol (PEG) glycerides include, but are not limited to, PEG-20 castor oil, PEG-20 hydrogenated castor oil, PEG-20 corn glycerides, PEG-20 almond glycerides; PEG-23 trioleate, PEG-40 palm kernel oil, caprylic / capric glycerides PEG-8, caprylic / capric glycerides PEG-6, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, tocopheryl succinate PEG-1000 and any combination thereof . In some embodiments, a fatty acid ester may comprise a PEG 5-30 (i.e., PEG 5, 6, 7, 8, 9, 10, etc.) and a caprylic / capric glyceride. In particular embodiments, a mixture may comprise a caprylic / capric PEG-5-glyceride, a caprylic / capric PEG-6-glyceride, a caprylic / capric PEG-7-glyceride and / or a caprylic / capric PEG-8-glyceride. In certain embodiments, a mixture may comprise one or more fatty acid esters such as, but not limited to, those commercially available from Sasol of Hamburg, Germany, under the trademark SOFTIGEN®.
[00100] An amphiphilic compound can be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 0.5% to about 30% by weight of the hydrophobic composition or any range and / or individual value within these, such as, but without limitation, from about 0.5% to about 10% by weight, from about 2% to about 20% by weight, about 1% to about 10% in weight, about 1% to about 5% by weight, or about 5% to about 15% by weight of the hydrophobic composition. In certain embodiments, an amphiphilic compound can be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 10% by weight of the hydrophobic composition. In some embodiments, an amphiphilic compound may be present in a hydrophobic composition used to form a mixture of the present invention in a concentration of from about 0.5% to about 10% by weight of the hydrophobic composition.
[00101] A mixture of the present invention can further comprise one or more excipients. In some embodiments, one or more excipients may be present in a hydrophobic composition that can be used to form a mixture of the present invention. Excipients for use in pharmaceutical compositions are well known in the literature and examples can be found in Handbook of Pharmaceutical Excipients (Rowe, R.C. et al., APhA Publications; 5th ed., 2005). Excipient classes may include, but are not limited to, an emollient, a humectant, a co-solvent, a pH modifier, a water-repellent agent, an anti-foaming agent, a surfactant, a solubilizer, an emulsifying agent, a wetting agent, an enhancer penetration, an antioxidant and / or a solvent. Excipients can be present in a mixture of the present invention in any suitable concentration. In some embodiments, an excipient may be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 1% to about 20% by weight of the hydrophobic composition or any range and / or individual value between them. , such as, but without limitation, from about 1% to about 15% by weight, about 1% to about 10% by weight, or about 5% to about 10% by weight of the hydrophobic composition.
[00102] In some embodiments, a mixture may also comprise a cosolvent. A cosolvent can be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 1% to about 30% by weight of the hydrophobic composition or any range and / or individual value between them, such as, however without limitation, about 1% to about 15% by weight, about 1% to about 20%, from about 2% to about 20% by weight, about 5% to about 25% by weight or about 5% to about 15% by weight of the hydrophobic composition. In certain embodiments of the present invention, a cosolvent can be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 10% to about 15% by weight of the hydrophobic composition. In some embodiments, a cosolvent may be present in a hydrophobic composition used to form a mixture of the present invention in a concentration of from about 1% to about 15% by weight of the hydrophobic composition.
[00103] Examples of cosolvents include, but are not limited to, a fatty acid ester, propylene glycol, glycerol, polyethylene glycol, a silicone such as cyclomethicone and any combination thereof. In some embodiments, a cosolvent may comprise a neutral oil. In certain embodiments, a cosolvent comprises an ester of caprylic and / or capric fatty acid, such as a caprylic and / or capric triglyceride. Examples of cosolvents include, but are not limited to, those commercially available from Sasol of Hamburg, Germany, under the trade name MIGLYOL®.
[00104] A mixture can comprise a humectant. Any suitable humectant or combination of humectants can be used. A humectant can be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 1% to about 25% by weight of the hydrophobic composition or any individual range and / or value therebetween, such as, however without limitation, from about 1% to about 15% by weight, from about 2% to about 20% by weight, about 5% to about 10% by weight or about 5% to about 15% by weight of the hydrophobic composition. In certain embodiments, the humectant can be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 10% to about 15% by weight of the hydrophobic composition.
[00105] Examples of humectants include, but are not limited to, polyhydric alcohols, such as diethylene glycol monoethyl ether and methoxypolyethylene glycol; glycerols such as propylene glycol, glycerol, isopropanol, ethanol, ethylene glycol, polyethylene glycol, ethoxydiglycol or mixtures thereof; sugar polyols, such as sorbitol, xylitol and maltitol; polyols such as polydextroses; dimethyl isosorbide; quillaia; urea; and any combination thereof. In particular embodiments of the present invention, a humectant comprises an alkylene glycol, such as hexylene glycol, butylene glycol, pentylene glycol and any combination thereof.
[00106] A mixture can comprise an emulsifying agent. Any suitable emulsifying agent or combination of emulsifying agents can be used. An emulsifying agent can be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 2% to about 97% by weight of the hydrophobic composition or any range and / or individual value between them, such as , but without limitation, about 2% to about 20% by weight, about 5% to about 15% by weight, about 10% to about 30% by weight, about 25% to about 99 % by weight or about 25% to about 70% by weight of the hydrophobic composition. In certain embodiments, an emulsifying agent can be present in a hydrophobic composition used to form a mixture of the present invention at a concentration of about 10% to about 50% by weight of the hydrophobic composition.
[00107] Examples of emulsifying agents include, but are not limited to, phosphatidyl choline; lecithin; surfactants such as polyethoxylated compounds including Tween 80 polysorbate 20, 21, 40, 60, 61, 65, 81, 85, 120 and other polyoxyethylene adducts of sorbitan esters, fatty acids, fatty alcohols, lanolin, lanolin alcohols castor (natural or hydrogenated) or alkylbenzenes; fatty alcohols such as cetyl alcohol, stearyl alcohol, beenyl alcohol, myristyl alcohol and cetostearyl alcohol; fatty acid esters such as those commercially available from Sasol of Hamburg, Germany, under the MIGLYOL® trademark and any combination thereof.
[00108] According to some embodiments, a hydrophobic composition used to form a mixture of the present invention can comprise at least one hydrophobic base in an amount of about 55% to about 99% by weight of the hydrophobic composition and an API such as , but without limitation, a nitric oxide releasing API. In certain embodiments, the at least one hydrophobic base may be present in the hydrophobic composition in an amount of about 70% to about 80% by weight of the hydrophobic composition. In some embodiments, an amphiphilic base may be present in the hydrophobic composition in an amount of about 15% to about 45% by weight of the hydrophobic composition. The hydrophobic composition can optionally comprise a cosolvent in an amount of about 2% to about 30% by weight of the hydrophobic composition, a humectant in an amount of about 5% to about 10% by weight of the hydrophobic composition, an agent emulsifier in an amount of about 5% to about 25% by weight of the hydrophobic composition and / or an amphiphilic compound in an amount of about 1% to about 10% by weight of the hydrophobic composition. The hydrophobic composition can be in the form of an ointment.
[00109] In some embodiments, a hydrophobic composition used to form a mixture of the present invention can comprise one or more hydrophobic bases in an amount of about 25% to about 99% by weight of the hydrophobic composition. In certain embodiments, the at least one hydrophobic base may be present in the hydrophobic composition in an amount of about 15% to about 65%, about 25% to about 55%, or about 35% to about 55% in weight of the hydrophobic composition and / or about 1% to about 15%, about 1% to about 10% or about 1% to about 5% by weight of the hydrophobic composition. In some embodiments, the total amount of one or more hydrophobic bases present in the hydrophobic composition can be about 65% to about 98% by weight of the hydrophobic composition. In some embodiments, an amphiphilic compound may be present in the hydrophobic composition in an amount of about 0.5% to about 10% by weight of the hydrophobic composition. The hydrophobic composition can comprise a cosolvent in an amount of about 1% to about 20% by weight of the hydrophobic composition. In some embodiments, an API such as, but not limited to, a nitric oxide releasing API may be present in the hydrophobic composition. The hydrophobic composition can be in the form of an ointment.
[00110] In some embodiments, a hydrophobic composition used to form a mixture of the present invention may comprise one or more hydrophobic bases in an amount of about 25% to about 99% by weight of the hydrophobic composition, an amphiphilic compound in an amount from about 0.5% to about 15% by weight of the hydrophobic composition and a cosolvent in an amount of about 1% to about 20% by weight of the hydrophobic composition. In certain embodiments, two or three or more hydrophobic bases may be present in the hydrophobic composition. Some embodiments include that at least one hydrophobic base may be present in the hydrophobic composition in an amount of about 15% to about 65%, about 25% to about 55%, or about 35% to about 55% by weight of the hydrophobic composition and / or about 1% to about 15%, about 1% to about 10% or about 1% to about 5% by weight of the hydrophobic composition. The hydrophobic composition can be in the form of an ointment.
[00111] In some embodiments, a mixture of the present invention may comprise a hydrophilic composition, which may comprise water, a polymer such as, but not limited to, a charged cellulose or a pharmaceutically acceptable salt thereof, and a humectant, such as, but not limited to, a polyhydric alcohol, in a mixture with a hydrophobic composition, which may comprise at least one hydrophobic base. The hydrophilic composition can be buffered and / or it can be in the form of a hydrogel. In some embodiments, the hydrophilic composition may be non-buffered and / or the hydrophilic composition does not comprise or substantially lack a buffer and / or a buffering agent. In some embodiments, the hydrophilic composition may comprise a polymer in an amount from about 0.5% to about 10% by weight of the hydrophilic composition, a humectant in an amount from about 1% to about 20% and water in an amount of about 70% to about 99%.
[00112] In some embodiments, a blend of the present invention may comprise a buffered hydrogel in admixture with a hydrophobic composition comprising at least one hydrophobic base and an API. The API can comprise a NO-releasing API. The hydrophobic composition can further comprise one or more of an amphiphilic compound, a cosolvent, a humectant and any combination thereof. In certain embodiments, the mixture can be formed by mixing. In some embodiments, the mixture is self-emulsifying. The mixture can comprise a single phase.
[00113] In some embodiments, the hydrophilic composition, the hydrophobic composition and / or the mixture can be sterilized. Some embodiments include that the hydrophilic composition is sterilized and does not comprise a preservative.
[00114] In accordance with the modalities of the present invention, a kit can be provided. In some embodiments, the kit may comprise a first composition and a second composition. The first composition can comprise a hydrophilic composition. The second composition can comprise an API, such as, but not limited to, a NO-releasing API. In some embodiments, the second composition may comprise at least one hydrophobic base. In particular modalities, the second composition comprises an ointment such as that already described in this report and / or as those described in International Orders Nos PCT / US2010 / 046173 and PCT / US2013 / 028223, which are incorporated herein in their entirety for reference.
[00115] In some embodiments, a kit may comprise a first composition and a second composition that are stored separately. In some embodiments, a kit of the present invention may comprise means for forming a mixture with the first composition and the second composition such as, but without limitation, by mixing, combining, contacting, among others, the compositions before application to an individual . A kit can be configured to mix the two compositions when administered and / or for application to an individual. In some embodiments, a kit can be configured to offer a blend with increased API performance and / or activity compared to increased API performance and / or activity in the absence of one or more compositions in the mixture.
[00116] In use, a mixture can be formed with a first composition and a second composition and then applied to an individual's skin and, in some modalities, including the mucosa. For example, the mixture can be administered topically to one or more of the hand, finger, foot, toe, arm, leg, trunk, anus, genitals, face, a mucous membrane (including a body cavity), nail , etc., of an individual. In other embodiments, at least one composition in the kit can be applied to the skin of an individual and then at least one different composition in the kit can be applied to the same skin of the individual.
[00117] In some embodiments, the mixture comprises a first composition comprising a hydrophilic composition and a second composition comprising a hydrophobic composition. The ratio of the hydrophilic composition to the hydrophobic composition can be about 5: 1 or less, in other embodiments, about 4: 1 or less, about 3: 1 or less, about 2: 1 or less or about 1: 1. In certain embodiments, the ratio is about 3: 1. In other modalities, the ratio is about 1: 1. The mixture can be applied to an individual in such a proportion. In certain embodiments, a kit of the present invention comprises means for administering and / or distributing the first and second compositions in the appropriate amounts to achieve the desired ratio. In some embodiments, the proportion of the first composition and the second composition in the mixture can be adjusted and / or modified to achieve a desired API release pattern.
[00118] With the provision of a hydrophilic composition and a hydrophobic composition that are mixed when applied to an individual's skin it is possible to obtain a longer shelf life of a kit of the present invention than that obtained if the compositions were stored and / or mixed with each other in the kit. For example, the formulation and loading of an API in a hydrophobic composition can provide a stable product with a long shelf life. Thus, for example, the pH and / or water content of the hydrophobic composition can be adjusted to reduce or minimize the release of the API, such as an API activated with water, to provide a composition that is stable at room temperature. The hydrophilic composition can then be combined with the hydrophobic composition to adjust the combined pH and / or provide water to activate the API. The hydrophobic composition can be combined with the hydrophilic composition in different proportions to provide the desired release, pH and / or dose in the mixture. Such an approach may allow a simple production process to be used to produce a more complex and expensive hydrophobic composition and then particular products defined by the composition and / or the amount of the hydrophilic composition with which the hydrophobic composition is mixed.
[00119] As used in this report, the term "shelf life" refers to the length of time that a product (for example, a composition and / or kit of the present invention) maintains the ability to release a therapeutically effective amount of an API , such as, but not limited to, nitric oxide, in an unopened packaging stored under recommended storage conditions. The shelf life can, for example, be evidenced by the "use until" or "best if used until" date for the product, the product's expiration date stipulated by the manufacturer and / or the actual characteristics of the product after the specified time. Therefore, the term "shelf life" as used in this report should be interpreted to include both the "effective" shelf life of the product and the "expected" shelf life of the product, unless otherwise specified. As will be recognized by the person skilled in the art, the rate of nitric oxide release in a composition under packaged and / or stored conditions may be different (that is, faster or slower) than the rate of nitric oxide release when the composition is in use (for example, when the composition comprising the NO-releasing API is in admixture with another composition). In certain embodiments, the rate of release of nitric oxide from a composition of the present invention may be faster when the composition is in use compared to the rate of release of nitric oxide when a composition comprising the API has been packaged and / or stored.
[00120] In some embodiments, the product's shelf life is the time that the product maintains the capacity to release at least 50% of the initial amount of nitric oxide that the product can release when packaged. In other embodiments, the product's shelf life is the time that the product maintains the ability to release at least 70%, at least 80%, at least 90%, at least 95%, or at least 98% of the initial amount of nitric oxide that the product can release when packaged. In some embodiments, the product's shelf life is the time that the product maintains the ability to release a therapeutically effective amount of nitric oxide over a desired period of time. In some embodiments, the recommended storage conditions are room temperature. In some embodiments, the recommended storage conditions are refrigerated storage conditions. In particular modalities, the conditions of storage under refrigeration vary between 1 ° C-12 ° C or any range and / or individual value between them.
[00121] Other embodiments may offer packaged compositions of the present invention that have a shelf life of at least about 7 days after opening the package. In other embodiments, the service life is at least about 30 days, at least about 60 days or at least about 90 days. In still other embodiments, the packaged compositions have a shelf life of at least about 60 days to at least about 730 days. As used in this report, the term "shelf life" refers to the length of time that the product maintains the ability to release a therapeutically effective amount of nitric oxide from an open container when applied as recommended and when stored under recommended storage conditions . The useful life can, for example, be evidenced by the time recommended by the manufacturer to dispose of the product after opening or measurements of the characteristics of the product after opening.
[00122] Therefore, the term "useful life" as used in this report should be interpreted to include both an "effective" product life and the "expected" product life, unless otherwise specified. In some embodiments, the product's useful life is the time that the product maintains the capacity to release at least 50% of the initial amount of nitric oxide that the product can release when the package is opened. In other embodiments, the product's useful life is the time that the product maintains the capacity to release at least 70%, at least 80%, at least 90%, at least 95% or at least 98% of the initial amount of nitric oxide that the product can release when the packaging is opened. In some embodiments, the recommended storage conditions after opening are room temperature. In particular embodiments, the recommended storage conditions after opening are refrigerated conditions.
[00123] As will be understood by those skilled in the art in light of the present description, a hydrophilic composition, such as those described in this invention, can provide means to adjust the pH of a pharmaceutical composition as well as means to activate an API of a pharmaceutical composition. In some embodiments, a hydrogel, such as those described in this invention, can provide a means for maintaining and / or stabilizing the pH of a hydrophobic composition when used to form a mixture with the hydrogel. The means to maintain and / or stabilize the pH of a mixture can be configured to activate and / or initiate the release of an API. In particular embodiments, a hydrogel of the present invention can provide a means for maintaining and / or stabilizing the pH of a mixture comprising a modified cocondensed polysiloxane macromolecule diazenodiolate. In some embodiments, the pH can be maintained and / or stabilized within a pH range of about 5 to about 8. In other embodiments, a hydrogel of the present invention can provide a means for releasing nitric oxide from a pharmaceutical composition. comprising a modified co-condensed polysiloxane diazenodiolate macromolecule.
[00124] According to some embodiments, a method of the present invention comprises administering a composition of the present invention to an individual's skin, including mucosa. For example, the composition can be administered to one or more regions chosen from hand, finger, foot, toe, arm, leg, trunk, anus, genitals, face, a mucous membrane (including a body cavity), nail etc. of an individual. In certain embodiments, the composition can be topically administered. In some embodiments, a hydrophilic composition of the present invention can be topically administered to an individual's skin. In certain embodiments, a mixture comprising a hydrophobic composition and a hydrophilic composition can be topically administered to an individual's skin. The mixture can comprise at least one API, such as, but without limitation, a NO releasing API.
[00125] A method of the present invention may comprise forming a mixture before and / or during the administration step. A mixture can be prepared by mixing, combining, contacting, applying to the same area or region, emulsifying, among others, a hydrophilic composition such as, but not limited to, a hydrogel, and a hydrophobic component such as, but not limited to, a ointment.
[00126] In some embodiments, a method of the present invention comprises delivering a therapeutically effective amount of nitric oxide to an individual's skin. As used in this report, the term "therapeutically effective amount" refers to an amount of an API, such as, but not limited to, nitric oxide, which produces a therapeutically useful response in an individual. Those skilled in the art will understand that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the individual.
[00127] The present invention is useful in both veterinary and human applications. Suitable individuals to be treated with an embodiment of the method of the invention include, but are not limited to, birds and mammals. The mammals of the present invention include, but are not limited to, canines, felines, cattle, goats, horses, sheep, porcines, rodents (for example, rats and mice), lagomorphs, primates (for example, apes and humans), non-human primates (for example, monkeys, baboons, chimpanzees, gorillas), among others, and mammals in utero. Any mammalian individual in need according to the present invention is suitable. Human subjects of both sexes and at any stage of development (i.e., newborn, baby, child, adolescent, adult) can be treated in accordance with the present invention. In some embodiments of the present invention, the individual is a mammal and in certain embodiments the individual is a human being. Human individuals include men and women of all ages including individuals in the fetal, neonatal, infant, juvenile, adolescent, adult and geriatric stages as well as pregnant women. In particular embodiments of the present invention, the individual is an adolescent and / or adult human being.
Illustrative birds according to the present invention include chickens, ducks, turkeys, geese, quails, peacocks, ratites (for example, ostrich) and domestic birds (for example, parrots and canaries) and birds in ovo.
[00129] The methods of the present invention can also be performed on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, cattle and horses for veterinary purposes and / or for drug evaluation and drug development purposes.
[00130] In particular embodiments of the present invention, the individual has a "need for" a method of the present invention, for example, the individual has been diagnosed, is at risk of having and / or is believed to have a disease or disorder that can be treated using a method of the present invention. In some modalities, the individual has a skin disease, such as, but without limitation, acne, atopic dermatitis and / or psoriasis. In other modalities, the individual has a wound, such as, but without limitation, a decubitus bed, a burn, a chronic leg ulcer of venous origin and / or a diabetic foot ulcer. In some embodiments of the present invention, the individual has an inflammatory skin condition or disease. In some embodiments of the present invention, the individual has an infection, such as a viral, bacterial or fungal infection, and, in particular embodiments, an infection with a cutaneous symptom. In some modalities, the individual has a cosmetic condition, such as a scar, chicken foot, etc. In still other modalities, the individual has skin cancer.
[00131] "Treating", "treating" or "treating" (and grammatical variations thereof) as used in this report refer to any type of treatment that conveys a benefit to an individual and may mean that the severity of the individual's condition it is reduced, benefited and / or improved at least partially and / or that some relief, slowdown or decrease in at least one clinical symptom is obtained and / or that a delay in the evolution of the disease or disorder occurs. In particular embodiments, the severity of a skin disease can be reduced in an individual compared to the severity of the skin disease in the absence of a method of the present invention. In other embodiments, a method of the present invention can improve wound healing and / or prevent infection.
[00132] A composition of the present invention can be applied topically to any part of an individual's skin. However, in some embodiments, the individual's face is treated by a method described in this invention. In addition, in some embodiments, the individual's torso is treated by a method described in this invention. In certain embodiments, a composition of the present invention is applied to a wound present in an individual.
[00133] According to some modalities, a method for increasing the release of nitric oxide from a hydrophobic composition containing a diazenediolate modified macromolecule can be provided. The method may comprise forming a mixture; and applying the mixture to an individual's skin. The mixture can comprise at least one hydrophilic composition and at least one hydrophobic composition comprising a diazenediolate modified macromolecule. In some embodiments, the hydrophilic composition can have a pH of about 4 to about 6. The formation step or the mixing step can be carried out on the individual's skin or can be carried out before applying the mixture to the individual's skin. .
[00134] A method of the present invention can increase the amount of nitric oxide released by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90, 100%, 150%, 200%, 300%, 400%, or more, or any range and / or individual value between them compared to the amount of NO released in the absence of a method of the present invention during the same period of time. A method of the present invention can provide a release of NO which is increased by about 1.5 to about 100 times over the amount of NO released in the absence of a method of the present invention over the same period of time or any range and / or individual value between them, such as, but without limitation about 2 to about 10 times or about 5 to about 50 times.
[00135] In other embodiments, a method for providing a topical antimicrobial composition can be provided. The method may comprise forming a mixture; and applying the mixture to an individual's skin. The mixture can comprise at least one hydrophilic composition and at least one hydrophobic composition. In some embodiments, the hydrophobic composition may comprise a macromolecule modified with diazenodiolate. In some embodiments, the hydrophilic composition can have a pH of about 4 to about 6. The formation step or the mixing step can be carried out on the individual's skin or can be carried out before applying the mixture to the individual's skin. . A method of the present invention can inhibit the growth of a pathogen, such as by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90, 100%, 150%, 200% or more compared to the growth of a pathogen in the absence of a method of the present invention.
[00136] A method to increase the rate of wound healing can also be offered. The method may comprise topically applying a mixture of the present invention to a wound. The mixture can comprise at least one hydrophilic composition and at least one hydrophobic composition. In some embodiments, the hydrophobic composition may comprise a macromolecule modified with diazenodiolate. In some embodiments, the hydrophilic composition may have a pH of about 4 to about 6. The mixture may be antimicrobial and / or may be configured to buffer the wound to a pH below 7. In some embodiments, a method of the present invention can increase the rate of wound healing by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90, 100%, 150%, 200% or more compared to the healing rate of a similar wound in the absence of a method of the present invention and / or compared to the healing rate of a similar wound to which a conventional topical treatment is applied (eg, antibiotic ointment triple). In some embodiments, a method of the present invention can increase the availability of oxygen in the tissue and / or reduce the histotoxicity of a bacterial end product.
[00137] A composition, kit and / or method of the present invention can minimize and / or prevent the degradation of at least one API such as, but without limitation, a NO-releasing API. In some embodiments, a composition of the present invention can be configured to provide a repetitive rate and / or pattern of NO release for a variety of therapeutic sites with different moisture contents. In certain embodiments, a composition of the present invention can be configured to provide a rate of NO release that is independent of the moisture content present in a therapeutic site.
[00138] The present invention is explained in more detail in the following non-limiting examples. Examples Example 1
[00139] An in vitro test comparing the release of nitric oxide from an ointment in combination with different hydrophilic phases was carried out. The ointment was combined either with liquid nitrogen (ie in the liquid phase), water in a 1: 2 ratio (ointment: water) or a hydrogel in a 1: 1 ratio. The formulation for the ointment and the hydrogel are shown in Table 1. Table 1: Ointment and hydrogel formulation.


[00140] The in vitro nitric oxide release test showed a significant difference before and after the addition of the hydrophilic phase even in carrier gas with maximum moisture content. The ability of the hydrophilic phase to promote the release of nitric oxide from the hydrophobic phase, especially at a lower load of Nitricil® NVN1, is significantly greater than water alone. Although not wishing to be limited to any particular theory, the results suggest that the efficiency to provide proton access to the drug substance in the hydrophobic phase increases markedly with excipients with emollient and solubilizing capacity (Table 2). Table 2: Release of nitric oxide from a 1% Nitricil® NVN1 ointment in combination with different hydrophilic phases.

[00141] The results demonstrate that the hydrogel works well to promote the release of nitric oxide from the hydrophobic ointment with a lower charge of Nitricil® NVN1. However, when the potency for the medicated product increases, the release kinetics does not follow the load capacity (that is, the release of nitric oxide does not increase proportionally with the percentage of the medicated substance). The slow release becomes more significant with the drug substance load exceeding 10% by weight. While wishing to be limited to any particular theory, it is believed that the pH of the final formulation is too high for the higher drug product to be released effectively. Example 2
[00142] It was found by the present inventors that in order to maintain a controlled release of nitric oxide from the medicated product with different charges, the concentration of the key reagent, proton, needs to be maintained. This means that the final pH of a composition comprising a hydrophilic phase (for example, a hydrogel) and a hydrophobic phase (for example, an ointment) needs to fall within a specific range at different potencies. To achieve this, the hydrophilic phase of the composition can be designed to have a buffer capacity greater than that of the hydrophobic phase at the highest potency of the target drug product.
[00143] In order to have both a large buffer capacity and a desired range of the final formulation at pH 5-8, monobasic phosphoric acid was selected as a buffer for the hydrogel. For the [H2PO4] - ion, the pKa is 7.2. According to the Henderson-Hasselbalch equation (Equation 1), the pH of the solution at an equal concentration of acid and base will be in the same ideal neutral condition as the medicated product, (pH = 7.2), giving it a buffering capacity great. Equation 1 Henderson-Hasselbalch equation.

[00134] A hydrogel was prepared with 400 mmol of monobasic phosphoric acid (ie, phosphate buffered hydrogel) and having a pH value of 4.8 (+/- 0.1) (Table 3). The hydrogel was then mixed with a Nitricil® NVN4 ointment having a nitric oxide load of 0.9% by weight to determine the results of the nitric oxide release. Table 3 presents the formulations for the ointment and the hydrogel. Table 3: Ointment and hydrogel formulations.

[00135] When the phosphate-buffered hydrogel was mixed with the ointment, the pH increased, but to a much lower degree compared to the phosphate-free hydrogel formulation described in Example 1. Table 4 shows the results of the oxide release nitric acid in vitro of a phosphate-buffered ointment / hydrogel combination with three different NO charges. The phosphate-buffered ointment / hydrogel combination is compared with two distinct combinations of the ointment with one of two non-buffered hydrogel formulations at different pH values. The non-buffered hydrogel formulations have the composition shown in Table 1 and a pH of 4 and 6, respectively. The results clearly show that the phosphate-buffered hydrogel can stabilize the pH of the final formulation in the desired range and promote high levels of nitric oxide release in all three charges. Table 4: Nitric oxide release and pH data in vitro for mixtures of Nitricil® NVN4 ointment.

Example 3
[00136] A comparison of the release of nitric oxide from a Nitricil® NVN4 ointment with a charge of 1.8% NO in the absence of moisture and with different moisture sources (ie hydrophilic phases). The formulation of the ointment is shown in Table 3. Two different moisture sources were combined with the ointment. The first source of moisture was a neutral hydrogel with a pH of 6 and having a formulation described in Example 1, Table 1, and the second was a phosphate buffered hydrogel having a formulation described in Example 2, Table 3. Fig. 1 shows the release of NO from the ointment alone and the release of NO from ointment / hydrophilic phase mixtures, and the results are shown in Table 5. Table 5: NO release parameters for different formulations containing Nitricil ointment ® NVN4 (1.8% w / w NO).
Example 4
[00137] Three Nitricil® NVN4 ointment formulations having different NO loads were each combined with a phosphate buffered hydrogel in a 1: 1 ratio to form a mixture. The formulations for the ointment and for the hydrogel are shown in Table 6. Table 6: Ointment and hydrogel formulations.


[00138] The vehicle ointment did not contain the medicated product, Nitricil® NVN4, but contained all the other components of the Nitricil® NVN4 ointment formulations. Mupirocin was used as a positive control. These formulations (i.e., the test articles) were then tested for efficacy against Staphylococcus aureus MRSA in a porcine animal model. The bacterial counts of ATCC BAA 1686 were made on days 4 and 7 after the application of the treatment.
[00139] Three pigs free of specific pathogens (Looper Farms, NC) were anesthetized and 51 rectangular wounds (10 mm * 7 mm x 0.5 mm deep) were made in the paravertebral and thoracic areas with an electrodermatome ("electrokeratome") . The wounds were separated by 15 mm of intact skin and individually covered with a dressing. Eight wounds were randomly assigned to each treatment group (6) and baseline level. A fresh culture of S. aureus cepa BAA-1686 was prepared from a TSA plate grown overnight at 37 ° C. S. aureus from the night culture was resuspended in 4.5 mL of saline until a solution corresponding to 1010 CFU / mL was obtained. Serial dilution was done to create an initial inoculum concentration of 106 CFU / mL. 25 μl of the inoculum suspension was inoculated into each wound by rubbing it with a sterile spatula for 10 seconds. All wounds were covered individually with a polyurethane film dressing (TEGADERM®). Bacterial biopellets were allowed to form for 48 hours before treatment. The treatment groups were treated with approximately 200 mg of the test article which were spread to cover the wound and the surrounding intact area with a sterile spatula and were covered with a film dressing. At the time of the evaluation, 4 wounds per treatment group were recovered in 1 mL of neutralization solution and diluted seriously. Serial dilutions were subsequently plated on "Oxacillin Resistance Screening Agar" (ORSA) and incubated for 24 hours at 37 ° C before the census of viable colonies. The bacterial counts of MRSA BAA-1686 following treatment are shown in Figs. 2 and 3.
[00140] Although not wishing to be limited to any particular theory, the data suggest that Nitricil® macromolecules exhibit robust antimicrobial activity against biopelleted inlaid S. aureus. Unlike traditional antibiotics, Nitricil® NVN4 was effective in reducing populations in the bio-film. Nitricil® macromolecules can be an effective therapy for the treatment of chronic S. aureus infections and can be an effective antimicrobial agent in vivo using a partial-thickness wound model. Example 5
[00141] Ointment formulations were prepared as shown in Tables 7 and 8, which list the percentage by weight of each component of the respective ointment formulation. Buffered hydrogel formulations were prepared as shown in Table 9, which lists the weight percentage of each component of the respective buffered hydrogel formulation and the pH of each buffered hydrogel formulation. Table 7: Composition of exemplary ointment formulations.
Table 8: Composition of other exemplary ointment formulations.

Table 9: Composition of exemplary buffered hydrogel formulations.

Example 6
[00142] Three pigs free of specific pathogens (Looper Farms, NC) by microorganism were anesthetized and 51 rectangular wounds (10 mm x 7 mm x 0.5 mm deep) were made in the paravertebral and thoracic areas with an electrodermatome. The wounds were separated by 15 mm of intact skin and individually covered with a dressing. Eight wounds were randomly assigned to each treatment group and baseline level. After creating burns / wounds, 25 μl of Acinetobacter baumannii (AB 09-001 *), methicillin-resistant S. aureus (MRSA USA300) and Candida albicans (CA 09-024 *) were used to inoculate each wound by rubbing (106 CFU / mL) inocula in each wound with a teflon spatula for approximately 30 seconds. All wounds were covered individually with a polyurethane film dressing (TEGADERM ™). Bacterial biopellets were allowed to form for 48 hours before treatment.
[00143] The treatment groups were treated with approximately 200 mg of the test article which were spread to cover the wound and the surrounding intact area with a sterile spatula and were covered with a dressing. The test articles included the three Nitricil® NVN4 ointment formulations having different NO loads described in Table 6 of Example 4, which were each combined with the phosphate buffered hydrogel described in Table 6 of Example 4. The ointment vehicle did not contain the medicated product, Nitricil® NVN4, but contained all other components in the formulations of the Nitricil® NVN4 ointment. Silver sulfadiazine was used as a positive control.
[00144] At the time of the evaluation, 4 wounds per treatment group were recovered in 1 ml of neutralization solution and diluted seriously. Serial dilutions were subsequently plated in selective media and incubated for 24 hours at 37 ° C before enumeration of viable colonies. Colonies were counted and colony-forming units per mL (CFU / mL), Log CFU / mL, Log CFU / mL mean and standard deviation were calculated. A unilateral analysis of variance (ANOVA) was used for statistical analysis. A p-value less than 0.05 was considered significant. Fig. 4 shows the results for A. baumannii, Fig. 5 shows the results for S. aureus and Fig. 6 shows the results for C. albicans.
[00145] Although not wishing to be limited to any particular theory, the data suggest that Nitricil® macromolecules are an effective antibacterial against A. baumannii, S. aureus and C. albicans embedded in biopellicle. Therefore, Nitricil ™ macromolecules can be an effective therapy for the treatment of chronic infections by A. baumannii, S. aureus and C. albicans and can be an effective antimicrobial agent in vivo using a partial-thickness wound model. Example 7
[00146] The release of nitric oxide from three different mixtures was compared. The mixtures were formed with an ointment formulation, TO-007b shown in Table 10, having varying concentrations of Nitricil® NVN4 and a hydrogel formulation, Phogel48 as provided in Table 6 of Example 4. The ointment formulations had 3.2% Nitricil ® NVN4 (0.3% NO content), 6.4% Nitricil® NVN4 (0.9% NO content) or 12.8% Nitricil® NVN4 (1.8% NO content) and were combined with the hydrogel in a 1: 1 ratio. Table 10: Ointment formulation.

[00147] The release of NO in real time and cumulative NO for the different mixtures is shown in Table 11. The release of cumulative NO over time for the mixtures is shown in Fig. 7 and the concentration in real time of release of NO over time for mixtures and shown in Fig. 8. Table 11: NO release properties from mixtures.
Example 8
[00148] The release of nitric oxide from two different ointments has been compared. The ointment formulation was TO-007b, shown in Table 12, containing either 12.8% Nitricil® NVN4 (1.8% NO content) or 2% Nitricil® NVN1 (0.3% NO content). The release of NO in real time and the cumulative NO for the different ointments is shown in Table 13. The release of cumulative NO over time for the mixtures is shown in Fig. 9 and the real time concentration of NO release to the over time for the mixtures is shown in Fig. 10. Table 12: Ointment formulations.

Table 13: NO release properties of ointments.
Example 9
[00149] Topical compositions were prepared having a hydrophobic composition and a hydrophilic composition. The hydrophobic and hydrophilic compositions were separately stored in a double pump chamber without ventilation and subsequently mixed to form the topical composition. Topical compositions are provided in Tables 14-16. Table 14: Formulation for a topical composition having a hydrophobic composition and a hydrophilic composition
Table 15: Topical compositions having a hydrophobic composition and a hydrophilic composition

Table 16: Topical compositions having a hydrophobic composition and a hydrophilic composition


[00150] The above is illustrative of the present invention and should not be considered as limiting it. The invention is defined by the claims that follow, with equivalents of the claims to be included here. All publications, patent applications, patents, patent publications and other references mentioned here are incorporated by reference in their entirety for the teachings relevant to the sentence and / or paragraph where the reference is presented.

权利要求:
Claims (32)
[0001]
1. Topical composition, characterized by the fact that it comprises: a hydrophilic composition, and a hydrophobic composition in mixture; the hydrophilic composition being a hydrogel and comprising a buffer, a polymer, a polyhydric alcohol and water, the water being present in an amount of 50% to 99% by weight of the hydrophilic composition; the hydrophobic composition comprising an active pharmaceutical ingredient, at least one hydrophobic base and at least one amphiphilic compound and / or emulsifying agent, the active pharmaceutical ingredient comprising a macromolecule functionalized with diazeniumdiolate; and the topical composition is self-emulsifying and is an emulsion.
[0002]
2. Topical composition according to claim 1, characterized by the fact that the hydrophilic composition has a pH of 3 to 8.
[0003]
Topical composition according to claim 1, characterized in that the polymer is a cellulose or a pharmaceutically acceptable salt thereof, chitosan, an acrylic acid polymer, or any combination thereof.
[0004]
Topical composition according to any one of claims 1 to 3, characterized in that the hydrophilic composition has a viscosity of 5000 cP to 100,000 cP.
[0005]
Topical composition according to any one of claims 1 to 4, characterized by the fact that it is continuous.
[0006]
Topical composition according to any one of claims 1 to 5, characterized by the fact that it has a pH of 3 to 9.
[0007]
Topical composition according to any one of claims 1 to 6, characterized in that the macromolecule functionalized by diazeniumdiolate comprises a co-condensed NO-releasing silica particle.
[0008]
Topical composition according to any one of claims 1 to 7, characterized in that the buffer is a phosphate buffer, or the buffer comprises acetic acid and an acetate.
[0009]
Topical composition according to any one of claims 1 to 8, characterized in that it further comprises a co-solvent.
[0010]
Topical composition according to claim 10, characterized in that the hydrophobic composition comprises at least two hydrophobic bases.
[0011]
Topical composition according to claim 9 or 10, characterized in that the hydrophobic composition comprises: at least one hydrophobic base at a concentration of 25% to 98% by weight of the hydrophobic composition; o at least one amphiphilic compound and / or emulsifying agent at a concentration of 0.5% to 10% by weight of the hydrophobic composition; and a co-solvent at a concentration of 1% to 20% by weight of the hydrophobic composition; and the hydrophilic composition comprising: the polymer at a concentration of 0.5% to 10% by weight of the hydrophilic composition; and polyhydric alcohol at a concentration of 5% to 20% by weight of the hydrophilic composition.
[0012]
Topical composition according to any one of claims 1 to 11, characterized in that it is a continuous emulsion that remains as a single phase for at least 2 days.
[0013]
13. Topical composition according to any one of claims 1 to 12, characterized in that the hydrophilic composition and the hydrophobic composition are present in a ratio of 1: 1, 2: 1 or 3: 1 (hydrophilic composition: composition hydrophobic).
[0014]
14. Kit, characterized by the fact that it comprises: a first composition comprising a hydrophilic composition; and a second composition comprising a hydrophobic composition, the hydrophilic composition being a hydrogel and comprising a buffer, cellulose or a pharmaceutically acceptable salt thereof, a polyhydric alcohol and water, in an amount of 50% to 99% in weight of the hydrophilic composition, the hydrophobic composition comprising an active pharmaceutical ingredient, an amphiphilic compound and at least one hydrophobic base, and the active pharmaceutical ingredient comprising a macromolecule functionalized by diazeniumdiolate.
[0015]
15. Kit according to claim 14, characterized by the fact that the hydrophilic composition has a pH of 4 to 8.
[0016]
16. Composition according to claim 1, characterized by the fact that it comprises a hydrogel, having a pH of 4 to 5, with the hydrogel having a buffering capacity to maintain the pH of the mixture within 2 pH units of the hydrogel , and the functionalized macromolecule diazeniumdiolate is present in the second composition with a concentration of 0.01% to 30% by weight of the second composition.
[0017]
17. Composition according to claim 16, characterized by the fact that the hydrogel has a buffering capacity to maintain the pH of the mixture within 1 pH unit of the hydrogel.
[0018]
18. Composition according to claim 16 or 17, characterized in that the hydrogel has a buffering capacity to maintain the pH of the mixture within 0.5 pH unit of the hydrogel.
[0019]
19. Composition according to any one of claims 16 to 18, characterized in that the second composition comprises at least two hydrophobic bases.
[0020]
20. Composition according to any one of claims 16 to 19, characterized in that the functionalized macromolecule diazeniumdiolate is present in the second composition in a concentration of about 0.01% to about 20% by weight of the second composition.
[0021]
21. Composition according to any one of claims 16 to 20, characterized in that the diazeniumdiolate functionalized macromolecule comprises a particle of silica co-condensed with NO.
[0022]
22. Composition according to any one of claims 16 to 21, characterized in that the diazeniumdiolate functionalized macromolecule comprises a co-condensed silica network composed of methylaminopropyl trimethoxysilane (MAP3) and tetra methyl orthoxy silicate (TMOS) and / or methylaminopropyl trimethoxysilane (MAP3) and tetraethyl orthoxy silicate (TEOS).
[0023]
23. Composition according to any one of claims 16 to 22, characterized in that the diazeniodiolate functionalized macromolecule is present in the second composition at a concentration of 4% by weight of the second composition.
[0024]
24. Composition according to any one of claims 16 to 23, characterized in that the functionalized macromolecule diazeniumdiolate is present in the second composition at a concentration of 8% by weight of the second composition.
[0025]
25. Composition according to any one of claims 16 to 24, characterized in that the functionalized macromolecule diazeniumdiolate is present in the second composition at a concentration of 12% by weight of the second composition.
[0026]
26. Composition according to any one of claims 16 to 25, characterized in that the first composition comprises a phosphate buffer.
[0027]
27. Composition according to any one of claims 16 to 26, characterized in that the first composition comprises acetic acid and an acetate.
[0028]
28. Composition according to claim 1, characterized by the fact that it comprises a hydrogel with a buffering capacity to maintain the pH of the additive within 2 pH units of the hydrogel, and the functionalized macromolecule diazeniumdiolate is present in the second composition with a concentration of 0.01% to 30% by weight of the second composition.
[0029]
29. Composition according to claim 28, characterized by the fact that the first composition is a hydrogel with a pH of 4 to 6.
[0030]
30. Composition according to claim 28 or 29, characterized in that the hydrogel has a buffering capacity to maintain the pH of the additive within 1 pH unit of the hydrogel.
[0031]
31. Composition according to any one of claims 28 to 30, characterized in that the hydrogel has a buffering capacity to maintain the pH of the additive within 0.5 pH unit of the hydrogel.
[0032]
32. Composition according to any one of claims 28 to 31, characterized in that the diazeniodiolate functionalized macromolecule comprises a co-condensed silica network composed of methylaminopropyl trimethoxysilane (MAP3) and tetra methyl orthoxy silicate (TMOS) and / or methylaminopropyl trimethoxysilane (MAP3) and tetraethyl orthoxy silicate (TEOS).

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法律状态:
2018-04-17| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-05-15| B07B| Technical examination (opinion): publication cancelled [chapter 7.2 patent gazette]|

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2019-08-27| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-07-14| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-12-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-02-02| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/01/2015, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201361863541P| true| 2013-08-08|2013-08-08|

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US201361868139P| true| 2013-08-21|2013-08-21|

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USPCT/US2014/050345|2014-08-08|

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