Topical suspension formulations for delivering nitric oxide to the skin

Abstract

Disclosed is a multiphasic mixture that generates nitric acid in situ for the treatment of topical dermatological conditions.

Description

Topical Suspension Formulations for Delivering Nitric Oxide to the SkinBackground

[0001] A number of benefits have been identified regarding the use of nitric oxide to help or treat humans and animals having a variety of medical conditions, particularly those associated with the skin. Since nitric oxide is a gas and is considered an unstable molecule, it remains a challenge to develop dermatological topical agents that can consistently promote the formation of, and provide nitric oxide to, the skin of a human or animal. What continues to be needed, therefore, is nitric oxide delivery monotherapy and combination products that can generate nitric oxide in situ, and that have a range of therapeutic properties.Summary

[0002] These and other needs are met by the present invention. In one aspect, what is provided is a multiphasic topical dermatologic composition comprising:a first composition comprising water and a pharmaceutically acceptable acid;a second composition comprising water and a nitric oxide precursor;wherein at least one of the first and second compositions comprises a pharmaceutically acceptable thickening agent and at least one pharmaceutically acceptable therapeutic agent that is not soluble in water; andwherein the first and second compositions, upon mixing, produce a pharmaceutically acceptable resultant multiphasic mixture containing nitric oxide and the at least one pharmaceutically acceptable agent that is not soluble in water.

[0003] In another aspect, what is provided is a multiphasic topical dermatologic composition comprising:a first composition comprising water and a pharmaceutically acceptable acid;a second composition comprising water and a nitric oxide precursor;wherein the first composition comprises a pharmaceutically acceptable thickening agent and at least one pharmaceutically acceptable therapeutic agent that is not soluble in water; and wherein the first and second compositions, upon mixing, produce a pharmaceutically acceptable resultant multiphasic mixture containing nitric oxide and the at least one pharmaceutically acceptable agent that is not soluble in water.

[0004] In a further aspect, what is provided is a multiphasic topical dermatologic compositioncomprising:a first composition comprising water and a pharmaceutically acceptable acid;a second composition comprising water and a nitric oxide precursor;wherein the second composition comprises a pharmaceutically acceptable thickening agent and at least one pharmaceutically acceptable therapeutic agent that is soluble in water; and wherein the first and second compositions, upon mixing, produce a pharmaceutically acceptable resultant multiphasic mixture containing nitric oxide and the at least one pharmaceutically acceptable agent that is not soluble in water.

[0005] In a further aspect, what is provided is a multiphasic topical dermatologic composition comprising:a first composition comprising water and a pharmaceutically acceptable acid;a second composition comprising water and a nitric oxide precursor;wherein the first and second compositions independently comprise a pharmaceutically acceptable thickening agent and at least one of the first and second compositions comprises at least one pharmaceutically acceptable therapeutic agent that is soluble in water; and wherein the first and second compositions, upon mixing, produce a pharmaceutically acceptable resultant multiphasic mixture containing nitric oxide and the at least one pharmaceutically acceptable agent that is not soluble in water.Brief Description of the Drawings

[0006] FIG. 1 is a morphology depiction of two aqueous solutions containing both nitric oxide and an additional agent.

[0007] FIG. 2 is a morphology depiction of two immiscible solutions containing both nitric oxide and an additional agent.

[0008] FIG. 3 is a baseline chart of NOx production for an acidic gel / nitrite gel.

[0009] FIG. 4 is a baseline chart of NOx production for an acidic lotion / nitrite lotion.

[0010] FIG. 5-1 is a chart of NOx production for an acidic gel / nitrite gel with 5 percent lanolin added.

[0011] FIG. 5-2 is a chart of NOx production for an acidic lotion / nitrite lotion with 5 percent lanolin added.

[0012] FIG. 6-1 is a chart of NOx production for an acidic gel / nitrite gel with 5 percent shea added.

[0013] FIG. 6-2 is a chart of NOx production for an acidic lotion / nitrite lotion with 5 percent shea added.

[0014] FIG. 7-1 is a chart of NOx production for an acidic gel / nitrite gel with 5 percent collagen added.

[0015] FIG. 7-2 is a chart of NOx production for an acidic lotion / nitrite lotion with 5 percent collagen added.

[0016] FIG. 8 is a chart of NOx production for an acidic gel / nitrite oil with 5 percent benzalkonium chloride added.

[0017] FIG. 9 is a chart of NOx production for an acidic gel / nitrite oil with 5 percent collagen added.

[0018] FIG. 10 is a chart of NOx production for a stearic acid oil with 5 percent collagen added / nitrite gel.

[0019] FIG. 11 is a chart of NOx production for a stearic acid oil with 5 percent benzalkonium chloride added / nitrite oil.

[0020] FIG. 12 is a chart of NOx production for a stearic acid oil / nitrite oil with 5 percent collagen added.

[0021] FIG. 13 is a chart of NOx production for Gel Al mixed with Gel B containing suspended collagen (1% w / w).

[0022] FIG. 14 is a chart of NOx production for Gel B mixed with Gel Al containing suspended lidocaine (1% w / w).

[0023] FIG. 15 is a chart of NOx production for Gel B containing dispersed tea tree oil (1% w / w) mixed with Gel Al containing dispersed tea tree oil (1% w / w).

[0024] FIG. 16 is a chart of NOx production for Gel A2 mixed with Gel B containing suspended collagen (1% w / w).

[0025] FIG. 17 is a chart of NOx production for Gel B mixed with Gel A2 containing suspended lidocaine (1% w / w).

[0026] FIG. 18 is a chart of NOx production for Gel B containing dispersed tea tree oil (1% w / w) mixed with Gel A2 containing dispersed tea tree oil (1% w / w).

[0027] FIG. 19 is a chart of NOx production for lidocaine (1% w / w) suspended in Shea Lotion mixed with Standard Lotion / sodium nitrite.Detailed DescriptionEmbodiments

[0028] As provided above, in one aspect, what is provided is a topical dermatologic composition comprising:a first composition comprising water and a pharmaceutically acceptable acid;a second composition comprising water and a nitric oxide precursor;wherein at least one of the first and second compositions comprises a pharmaceutically acceptable thickening agent and at least one pharmaceutically acceptable therapeutic agent that is not soluble in water; andwherein the first and second compositions, upon mixing, produce a pharmaceutically acceptable resultant multiphasic mixture containing nitric oxide and the at least one pharmaceutically acceptable agent that is not soluble in water.First Composition

[0029] The first composition of the topical dermatologic composition comprises water and a pharmaceutically acceptable acid.

[0030] In one embodiment, the pharmaceutically acceptable acid is soluble in water at standard temperature and pressure (298 K and 1 atmosphere of pressure) and neutral or acidic pH. In another embodiment, the pharmaceutically acceptable acid is insoluble in water at standard temperature and pressure (298 K and 1 atmosphere of pressure) and neutral or basic pH.

[0031] In another embodiment, the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophobic acid. By "lipophobic acid" is meant an acid that is insoluble soluble in substances such as oils and other nonpolar liquids, as well as nonpolar substances such as fats, typically at standard temperature and pressure (298 K and 1 atmosphere of pressure).

[0032] As used herein “insoluble” encompasses to “practically insoluble or insoluble” compounds as defined under the U. S. Pharmacopoeia 32, General Notices, which is greater or equal to 10,000 mass of the solvent required to dissolve one gram of the solute taken by a technique known to a person of ordinary skill such as the shake-flask method.

[0033] In a further embodiment, the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophobic acid selected from the group consisting of citric acid, lactic acid, salicylic acid, phosphoric acid, ascorbic acid, hydrochloric acid, acetic acid, hyaluronic acid, hypochlorous acid, and medicinal honey.

[0034] In a further embodiment, the pharmaceutically acceptable acid is a pharmaceuticallyacceptable lipophobic acid selected from the group consisting of citric acid, lactic acid, ascorbic acid, acetic acid, hyaluronic acid, hypochlorous acid, and medicinal honey, or combinations thereof.

[0035] In another embodiment, the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophilic acid. By "lipophilic acid" is meant an acid with a significant amount of aliphatic character.

[0036] In another embodiment, the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophilic acid. A "lipophilic acid" is typically a carboxylic acid including short chain fatty acids that may be selected from the group consisting of acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, crotonic acid, sorbic acid, adipic acid, pimelic acid, benzoic acid, p-hydroxybenzoic acid, cinnamic acid, salicylic acid, acetylsalicylic acid an omega 3-fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, an omega-9 fatty acid, linolenic acid, caproic acid (C6), caprylic acid (C8), capric acid (CIO), undecyl acid (Cl 1), lauric acid (C12), myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16), heptadecanoic acid (C17), stearic acid (Cl 8), and a caprylic triglyceride, or combinations thereof.

[0037] In one embodiment the first composition comprises 0.5-25 percent (w / w) of a pharmaceutically acceptable acid in water. In another embodiment, the first composition comprises 2.5-25 percent (w / w) of a pharmaceutically acceptable acid in water. In a further embodiment, the first composition comprises 5-10 percent (w / w) of a pharmaceutically acceptable acid in water.Second Composition

[0038] The second composition of the topical dermatologic composition comprises water and a nitric oxide precursor.

[0039] In an embodiment, the nitric oxide precursor of the second composition is selected from the group consisting of nitrites (sodium nitrite, potassium nitrite, ), nitrates (sodium nitrate, potassium nitrate), diazeniumdiolates (NONOates), NO-impregnated polymers (PEG-NO, PANNO, PVP-NO, NO dendrimers, NO donating zeolites, ), nano-crystalline NO particles, NO-metal complexes, nitroprusside, nitrosamine, nitrate esters (nitroglycerin, isosorbide dinitrite,), nitrosothiols (S-nitroso-albumin, S-nitroso-N-acetyl-DL-penicillamine, S -nitroso-glutathione, S-nitroso-cystine,), L-arginine, NO upregulators (L-arginine, L-citrulline, ), and NO donors (molsidomine), or combinations thereof.

[0040] In a further embodiment, the NO precursor is lipophobic.

[0041] In a further embodiment, the NO precursor is lipophobic and is selected from the group consisting of sodium nitrite, potassium nitrite, or combinations thereof.

[0042] In a further embodiment, the NO precursor is lipophilic.

[0043] In a further embodiment, the NO precursor is lipophilic and is selected from the group consisting of diazeniumdiolate and nitrosothiols, or a combination thereof.Pharmaceutically Acceptable Suspending or Thickening Agent

[0044] At least one of the first and second compositions comprises a pharmaceutically acceptable suspending agent or thickening agent and at least one pharmaceutically acceptable therapeutic agent. In the present application the terms "suspending agent" and "thickening agent" may be used interchangeably.

[0045] The pharmaceutically acceptable suspending or thickening agent is selected from the group consisting of agents provided in the United States Pharmacopeial Convention, Inc., 2007Table of Pharmaceutically Acceptable Suspending or Thickening Agents Aaa a CtoatoAga ttola? GuruAfersMK Acs? Gus? £5? >Aigm® Aei Hydmxyothyi CGluicwAlum, sum Atoms? warn Hydfoxygfupyl CaltoGsaAtkgtogito Activate Hyprxwtae itowriy dmxyp pyl Arngtogs®. Colloidal Act? ad am ictostosalAlagm<toum Aluminum SJlltoto*(tetsmito todfito WlS^rs;tdagrao M®th lWlul<msCasbomur sic Miij csysiailina tototoaCar&siw 934 PoctlnItofeoms? 3-34C Puiyethytene G ida( w 940 Polyvinyl xdmsCarbmmm 941 Pwdow1343 N<3i5> l<m<a Gly<to Alginate CA? fed ft W C»1 xsl y$ diltorn tJksto sCaabow? Ho s aly r SiOw CkttoM CtdlttoaiC a? b<3 f I torn ly ma f Sodium Algismtato?lmxy?totoli®k?to;m Calcium Smrnh, ComCarbaxymai cellu Sodium Stamh, Ftoto?Cart)«sy??sthy todks to® Warn 12 Swch< Tspimx?CArogoanan Stamh,CaikdcwDexifir: Xsfkhan Gu

[0046] In one embodiment, the pharmaceutically acceptable suspending or thickening agent is a cellulose thickener, which is an ether derivative. The cellulose ether derivative may be selectedfrom the group consisting of methyl cellulose, ethyl cellulose, methylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, ethyl hydroxyethyl cellulose, and carboxymethyl cellulose, or combinations thereof.

[0047] Other pharmaceutically acceptable suspending or thickening agents that can be used include honey, corn starch, flour, okra, karaya gum, mastic gum, tara gum, hyaluronic acid, polyvinyl alcohol.

[0048] Alternatively, in lotion and cream embodiments, as well as other topical dermatologic compositions such as shampoos and conditioners, the thickening agent may be an emulsion, such as an oil suspended in water, or water suspended in an oil. In some embodiments, the emulsifier may be selected from the group consisting of cocobetaine, ethoxylated alcohols, carboxylates, sodium isethionate, glycerol monostearate, cetyl alcohol, stearyl alcohol, and silicone emulsifiers such as dimethicones.

[0049] Alternatively, the thickening agent could also be the acid or the nitric oxide precursor.Pharmaceutically Acceptable Therapeutic Agent

[0050] The pharmaceutically acceptable agent as defined herein is a topical dermatologic agent that may be soluble or insoluble in water. In some embodiments, the pharmaceutically acceptable agent is a therapeutic dermatologic agent selected from the group consisting of agents to treat acne, topical anesthetics, topical anti-infectives including antibiotic, antimicrobials, and antivirals agents, topical anti-rosacea agents, topical antifungal agents, topical antihistamines, topical astringents, topical debriding agents, topical depigmenting agents, topical emollients, topical keratolytics, topical non-steroidal anti-inflammatory agents, topical rubefacient agents, topical steroid agents, topical antiseptic agents, topical agents that aid in angiogenesis, topical skin protectants, adhesives, topical skin cleansers, topical humectants, odor management agents as well as perfumes and fragrance oils, preservatives, emulsifiers, agents for moisture management, enzymes that can be used topically, excipients that can be used in topical skin compositions as well as wound dressings, as well as antineoplastics, antipsoriatics, photochemotherapeutics, topical steroids with anti-infectives, anorectal and thickeners or combinations thereof.

[0051] In one embodiment, the topical dermatologic agent may be soluble or insoluble in water and is selected from the group consisting of topical acne agents, topical anesthetics, topical anti-infectives, topical anti-rosacea agents, topical antibiotics, topical antifungals, topicalantihistamines, topical antineoplastics, topical antipsoriatics, topical antivirals, topical astringents, topical debriding agents, topical, depigmenting agents, topical emollients, topical keratolytics, topical non-steroidal anti-inflammatories, topical photochemotherapeutics, topical rubefacients, topical steroids, topical steroids with anti-infectives, and topical antiseptics, or a combination thereof. Examples of various topical dermatologic agents are provided in the definitions section of this application.

[0052] In another embodiment, the pharmaceutically acceptable agent may be soluble or insoluble in water and is a topical dermatologic composition disclosed herein that comprises a topical dermatologic antiseptic for first aid use to treat wounds including scrapes, cuts, and bums. In this and other embodiments, the topical dermatological antiseptic is selected from the group consisting of alcohol (ethanol and isopropanol), benzethonium chloride, benzalkonium chloride (BAC), camphorated metacresol, eucalyptol 0.091%, hexylresorcinol, hydrogen peroxide topical solution, iodine tincture, iodine topical solution, menthol, methylbenzethonium chloride, methyl salicylate, phenol, povidone-iodine, menthol, citric acid, sodium tetraborate, benzoic acid, polyaminopropyl biguanide, polyhexylmethylene biguanide, and thymol. BAC represents a mixture of N, N-dimethyl alkyl amines, which conform generally to the formula:. In another embodiment, the pharmaceutically acceptable agent is a topical dermatologic antiseptic is selected from the group consisting of ethanol, isopropanol, benzethonium chloride, benzalkonium chloride (BAC), camphorated metacresol, eucalyptol 0.091%, hexylresorcinol hydrogen peroxide topical solution, iodine tincture, iodine topical solution, menthol, hypochlorous acid, methylbenzethonium chloride, methyl salicylate, phenol, povidone-iodine, and thymol.

[0053] In another embodiment, two or more pharmaceutically acceptable agents are present in the first or second compositions. In one embodiment, one pharmaceutically acceptable agent is present in one of the compositions and another topical dermatologic agent is present in the other solution. In another embodiment, both pharmaceutically acceptable agents are present in one of the compositions and the other composition does not include one or both of the topical dermatologic agents. In another embodiment, both pharmaceutically acceptable agents arepresent in both solutions.

[0054] In another embodiment, three or more pharmaceutically acceptable agents are present in the first or second compositions. In one embodiment, one pharmaceutically acceptable agent is present in one composition, and the other two pharmaceutically acceptable agents are present in the other composition. In another embodiment, all three pharmaceutically acceptable agents are present in one of the compositions and the other composition does not include the topical dermatologic agents. In another embodiment, all pharmaceutically acceptable agents are present in both compositions.

[0055] In these and other embodiments, the first, second, and third topical dermatologic agents are selected from the group consisting of topical acne agents, topical anesthetics, topical anti-infectives, topical anti-rosacea agents, topical antibiotics, topical antifungals, topical antihistamines, topical antineoplastics, topical antipsoriatics, topical antivirals, topical astringents, topical debriding agents, topical depigmenting agents, topical emollients, topical keratolytics, topical non-steroidal anti-inflammatories, topical photochemotherapeutics, topical rubefacients, topical steroids, topical steroids with anti-infectives, and topical antiseptics, or a combination thereof. Examples of various topical dermatologic agents are provided in the definitions section of this application.

[0056] In these and the embodiments, the topical dermatologic agent is present based on the total weight of either the first solution, second solution, or both the first and second solutions, of 0.01 to 5 weight percent.

[0057] In another embodiment, the pharmaceutically acceptable therapeutic agent is not soluble or sparingly soluble in water and is selected from the group consisting of an anti-infective agent, an anti-inflammatory agent, a moisture manager, a topical cleanser, an emollient, an emulsifier, a biologic, an analgesic, a humectant, a preservative, a skin protectant, an odor manager, an acne treatment, a dandruff treatment, a wart treatment, a lubricant, an adhesive, a natural oil, and an oil / sebum manager, acne treatments, topical anesthetics, topical antifungals, topical antivirals, wart treatments, anti-rosacea treatments, antivirals, lice treatments, antibiotics, antihistamines, antineoplastics, anti -psoriatic agents, astringents, debriding agents, depigmenting agents, antiinflammatory agents, photochemotherapeutic agents, angiogenesis promoting agents, enzymes, or combinations thereof.

[0058] In some embodiments, the pharmaceutically acceptable therapeutic agent is a biologic. Ina further embodiment the biologic is collagen.

[0059] In some embodiments, the pharmaceutically acceptable therapeutic agent is a natural oil. In a further embodiment, the natural oil is tea tree oil.

[0060] In some embodiments, the pharmaceutically acceptable therapeutic agent is a topical anesthetic. In further embodiments, the topical anesthetic is selected from the group consisting of lidocaine, prilocaine, bupivacaine, ropivacaine, benzocaine, procaine, tetracaine, and mixtures thereof.

[0061] In a further embodiment, the pharmaceutically acceptable therapeutic agent is not soluble or sparingly soluble in water and is selected from the following table.Table of Pharmaceutically Acceptable Therapeutic Agents Not Soluble in Water

[0062] In another embodiment, the pharmaceutically acceptable therapeutic agent is selected from the following table.Table of Pharmaceutically Acceptable Therapeutic Agent Not Soluble in WaterAdditional Components

[0063] As noted above, at least one or both of the first and second compositions can further comprise an additional pharmaceutically acceptable excipient. The additional pharmaceutically acceptable excipient may be useful to stabilize the multiphasic composition. In one embodiment, the additional pharmaceutically acceptable excipient can be a surfactant or as summarized in the following table.Table of Additional ComponentsResultant Multiphasic Mixture

[0064] When mixed together, the first and second compositions produce a pharmaceuticallyacceptable resultant multi phasic composition. The multi phasic composition of the present invention is a composition that comprises multiple phases that are not miscible. Such multiphasic compositions include compositions comprising solids and fluids as well as multiple fluids, such as depicted in Figs 1 and 2. Upon mixing of the first and second compositions, the nitric oxide precursor reacts to produce nitric oxide and the resultant mixture containing nitric oxide provides nitric oxide and the at least one pharmaceutically acceptable agent.

[0065] In one embodiment, the resultant multiphasic mixture is selected from the group consisting of a spray, a shampoo, a lotion, a cream, a soap, a gel, and an ointment.

[0066] In one embodiment, the resultant multiphasic mixture is selected from the group consisting of a spray, a shampoo, a lotion, a cream, a soap, a gel, and an ointment, wherein the resultant multiphasic mixture is an extended release composition.

[0067] In a further embodiment, the resultant multiphasic mixture is an ointment. An ointment is known to the skilled person to be a suspension or emulsion semisolid formulation that typically comprises, in addition to the nitric oxide generating components and the additional therapeutic agent(s), 20 percent (w / w) or less of water and 50 percent (w / w) or more of hydrocarbons, waxes, or polyethylene glycols. Hydrocarbon-based ointments comprise petroleum, microcrystalline wax, ceresine, or the like. Absorption-based ointments comprise wool fat (lanolin), beeswax, or the like. Emulsion / water removable bases comprise an emulsifying wax. Water soluble bases comprise polyethylene glycols such as PEG 200 (average molecular mass 190-210), PEG 300 (average molecular mass 290-310), or PEG 400 (average molecular mass 390-410).

[0068] In a further embodiment, the resultant multiphasic mixture is a cream. A cream is known to the skilled person to be an emulsion semisolid formulation that typically comprises, in addition to the nitric oxide generating components and the additional therapeutic agent(s), 20 percent (w / w) or less of water and 50 percent (w / w) or more of hydrocarbons, waxes, or polyethylene glycols. Oily creams are water-in-oil emulsions comprising water or an aqueous solution in the dispersed phase and an oil in the continuous phase. Aqueous creams are oil-in-water emulsions comprising water or an aqueous solution in the continuous phase and an oil in the dispersed phase. Therapeutic agent(s) that are soluble in water are typically formulated in oil-in-water emulsions, while therapeutic agent(s) that are lipid-soluble in water are typically formulated in water-in-oil emulsions.

[0069] In a further embodiment, the resultant multiphasic mixture is a gel.

[0070] In a further embodiment, the resultant multiphasic mixture is a lotion. Lotions are emulsions of water and fat that typically comprise an aqueous base in which the nitric oxide generating components and / or the additional therapeutic agent(s) are finely divided, suspended, or dispersed.Additional Aspects and Embodiments

[0071] In a further aspect, the invention provides a topical dermatologic composition comprising:a first composition comprising a pharmaceutically acceptable acid;a second lipophilic composition comprising a nitric oxide precursor;wherein the first and second compositions upon mixing produce a pharmaceutically acceptable resultant suspension containing nitric oxide.

[0072] In one embodiment, the resultant mixture is selected from the group consisting of spray, a shampoo, a lotion, a cream, a soap, a gel, and an ointment or combinations thereof. In one embodiment, the resultant mixture is selected from the group consisting of a shampoo, a lotion, a gel, an ointment, a liniment, a cerate, an unguent, a balm, and a salve, or combinations thereof.

[0073] In another embodiment, the acid of the first composition is lipophilic.

[0074] In another embodiment, the first composition further comprises water and the acid of the first composition is dissolved in the water of the first composition.

[0075] In another embodiment, the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophilic acid. As noted previously, by "lipophilic acid" is meant an acid that is soluble in substances such as oils and other nonpolar liquids, as well as nonpolar substances such as fats, typically at standard temperature and pressure (298 K and 1 atmosphere of pressure).

[0076] In another embodiment, the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophilic acid selected from the group consisting of salicylic acid, an omega 3-fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, an omega-9 fatty acid, linolenic acid, caproic acid (C6), caprylic acid (C8), capric acid (CIO), undecyl acid (Cl 1), lauric acid (C12), myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16), heptadecanoic acid (C17), stearic acid (Cl 8), and a caprylic triglyceride, or combinations thereof.

[0077] In another embodiment, the second composition further comprises water and the nitric oxide precursor of the second composition is lipophobic and is dissolved in the water of thesecond composition. In a further embodiment, the lipophobic NO precursor is selected from the group consisting of sodium nitrite, potassium nitrite, or combinations thereof.

[0078] In a further embodiment, one of the first and second compositions comprises a pharmaceutically acceptable suspending or thickening agent and at least one pharmaceutically acceptable therapeutic agent that is not soluble in water, as well as optional additional components, all of which are described in previous paragraphs and tables.

[0079] In a further embodiment, one of the first and second compositions comprises a pharmaceutically acceptable suspending or thickening agent and at least one pharmaceutically acceptable therapeutic agent that is soluble in water, as well as optional additional components, all of which are described in previous paragraphs and tables.

[0080] In some embodiments the pharmaceutical compositions are extended release compositions, where the evolution rate of NO gas after the combination of the first and second composition occurs over extended time scales. In some embodiments the extended release profile of the drug may be attributable to increases in viscosity of the first and second compositions. In some embodiments, the extension of the release profile may be attributable to a decrease of the dissociation rate of the acid, which limits the rate of the NO gas evolution reaction. In some embodiments, the NO evolution reaction is slowed as a result of the reactive components being contained in separate immiscible phases, such that the reaction occurs primarily at the interface between the two layers. Because diffusion of the reactive species across the phase boundary is limited, the overall rate of reaction is reduced relative to a system in which the components are fully mixed, thereby limiting the rate of the NO evolution reaction. Additionally, the NO evolution reaction can be modulated by decreasing the mass transfer rate of the reactants. The NO evolution reaction rate can be decreased, at least in part, by the lowering effective porosity of the suspended reactants and / or lengthening the reactant diffusion pathways (i.e. increasing the tortuosity). By modulation of one of the particle size, packing density, crosslink density, excipient type, excipient identity, and pore size distribution, the effective porosity can be decreased and / or path length traveled by the reactants can be increased, thereby decreasing the rate of the NO-evolution reaction and extending NO gas release.

[0081] Extended release compositions are defined in the United States Pharmacopeia 35 <1151> as “a dosage form that is deliberately modified to protract the release rate of the API compared to that observed for an immediate-release dosage form.” Here, a comparable immediate releaseform would be, e.g., aqueous compositions of sodium nitrite and an aqueous acid that evolve NO when combined. The compositions herein may continue to release NO for an hour or more after mixing. In some examples the release of NO continues past 1, 1.5, 2, 2.5, 3, 6, or 12 hours. In some examples the release of NO continues past 24, 48, or 72 hours, or more.Method of Treatment

[0082] In one embodiment, the method of using the topical dermatologic composition disclosed herein comprises:providing the first and second compositions as recited herein;dispensing a portion of the first composition;dispensing a portion of the second composition;mixing the portion of the first composition and the portion of the second composition in a manner that produces a resultant mixed multiphasic medium comprising nitric oxide and additionally a pharmaceutically acceptable suspending or thickening agent, a pharmaceutically acceptable therapeutic agent, and optionally a pharmaceutically acceptable surfactant and other additional pharmaceutically acceptable components; andapplying the resultant mixed multiphasic medium to the site of the skin condition.

[0083] The first and second compositions are available in first and second plastic containers. A portion of the first composition is dispensed from the first container and then is mixed with a portion of the second composition which is dispensed from the second container. The two compositions are mixed, typically, by inline mixing immediately before application; or by mixing in a dish with a stirrer or finger immediately before application; or by mixing on the surface with a stirrer or finger concurrent with application. Such mixing produces a resultant multiphasic mixture for the in-situ generation of nitric oxide. The resultant multiphasic medium may be allowed to remain on the portion of skin for a period of time so that the resultant nitric oxide can be delivered to the site requiring treatment or an infection.

[0084] In one embodiment, the method employs a sealing layer that limits gas exchange, retaining NO within the system and prolonging its residence time. In one embodiments the gassealing layer is applied to the skin, e.g. via an adhesive. In one embodiment the sealing layer is applied to the dish or other container used to house the composition during use. In a further embodiment, the sealing layer is impermeable to NO gas or has low-to-moderate NO gas permeability. In still further embodiments, the sealing layer is a polymer selected from the groupconsisting of fluoropolymers, polyvinylidene chloride, ethylene-vinyl alcohol (EVOH), and multilayer barrier films comprising the same.Examples

[0085] Formulation Testing

[0086] Different compositions were formulated to test the effect of additional excipients on NOx production. The results show that NOx production remains robust in gel, lotion, and oil formulations containing additional excipients.

[0087] Formulation A: Acidic Gel Nitrite Gel

[0088] The acidic gel formulation is depicted in Table 1. Solution A was mixed with Solution B in the donor section of a Franz cell. NOx production is then measured over 10 minutes using a ThermoScientific® 42iQLS analyzer. The results are shown in Figure 1 tracking NOx production.Table A. Acidic Nitrite Gel

[0089] Solution A was mixed with Solution B in the donor section of a Franz cell. NOx production was then measured over 10 minutes using a ThermoScientific® 42iQLS analyzer. The results are depicted in FIG. 3.

[0090] Formulation B: Acidic Nitrite Lotion

[0091] Following the procedure for Composition A with the composition depicted in Table B.Table B. Acidic Nitrite LotionThe results are depicted in FIG. 4.

[0092] Formulation C-l: Acidic Nitrite Gel with 5% Lanolin

[0093] Following the procedure for Composition A with the composition depicted in Table A with 5 percent lanolin as summarized in Table Cl.Table Cl. Acidic Nitrite Gel with 5% LanolinThe results are depicted in FIG. 5-1.

[0094] Formulation C-2: Acidic Nitrite Lotion with 5% Lanolin

[0095] Following the procedure for Composition A with the composition depicted in Table B with 5 percent lanolin as summarized in Table C2.Table C2. Acidic Nitrite Lotion with 5% LanolinThe results are depicted in FIG. 5-2.

[0096] Composition DI: Acidic Nitrite Gel with 5% Shea

[0097] Following the procedure for Composition A with the composition depicted in Table A with 5 percent Shea as summarized in Table DI.Table DI. Acidic Nitrite Gel Formulation with 5% SheaThe results are depicted in FIG. 6-1.

[0098] Composition D2: Acidic Nitrite Lotion Formulation with 5% Shea

[0099] Following the procedure for Composition A with the composition depicted in Table B with 5 percent Shea as summarized in Table D2.Table D2. Acidic Nitrite Lotion Formulation with 5% SheaThe results are depicted in FIG. 6-2.

[0100] Composition E-l: Acidic Nitrite Gel Formulation with 5% Collagen

[0101] Following the procedure for Composition A with the composition depicted in Table A with 5 percent collagen as summarized in Table E-l.Table E-l. Acidic Nitrite Gel Formulation with 5% CollagenThe results are depicted in FIG. 7-1.

[0102] Composition E-2: Acidic Nitrite Lotion Formulation with 5% Collagen

[0103] Following the procedure for Composition A with the composition depicted in Table B with 5 percent collagen as summarized in Table E-2.Table E-2. Acidic Nitrite Lotion Formulation with 5% CollagenThe results are depicted in FIG. 7-2.Composition F: Acidic Nitrite Gel with 5% Benzalkonium Chloride (BZK)

[0104] Following the procedure for Composition A with the composition depicted in Table F with 5 percent benzalkonium chloride.Table F. Acidic Nitrite Gel with 5% Benzalkonium Chloride (BZK)The results are depicted in FIG. 8.Composition G: Acidic Nitrite Oil Formulation with 5% Collagen

[0105] Following the procedure for Composition A with the composition depicted in Table G with 5 percent collagen.Table G. Acidic Nitrite Oil Formulation with 5% CollagenormuaonThe results are depicted in FIG. 9.

[0106] Composition H: Acidic Nitrite Oil / Gel Formulation with 5% Stearic Acid and Collagen

[0107] Following the procedure for Composition A with the composition depicted in Table H with 5 percent stearic acid and collagen.Table H. Acidic Nitrite Oil / Gel Formulation with 5% Stearic Acid and CollagenThe results are depicted in FIG. 10.

[0108] Composition J: Acidic Nitrite Oil / Gel Formulation with 5% Stearic Acid and Benzalkonium Chloride

[0109] Following the procedure for Composition A with the composition depicted in Table H with 5 percent stearic acid and benzalkonium chloride.Table J. Acidic Nitrite Formulation with 5% Stearic Acid Oil / Benzalkonium Chloride / Nitrite OilThe results are depicted in FIG. 11.

[0110] Composition K: Acidic Nitrite Formulation with Stearic Acid Oil / Nitrite Oil / 5% Collagen

[0111] Following the procedure for Composition A with the composition depicted in Table K with 5 percent stearic acid and benzalkonium chloride.Table K. Acidic Nitrite Formulation with Stearic Acid Oil / Nitrite Oil / 5% CollagenThe results are depicted in FIG. 12.

[0112] Compositions L-Q: Acidic Nitrite Formulation with Hyaluronic Acid Gels and Xanthan Gum Gels

[0113] Gel Al, A2, and B are solutions formulated as depicted in Table L below. In Compositions L-Q, the amount of the two compositions measured is 1: 1 by weight. E.g., in Composition L, after collagen is suspended in Gel B in an amount of 1% w / w by total weight Gel B, 1 gram of Gel B and Gel Al are mixed, and NOx evolution is monitored.

[0114] Table L: Acidic Nitrite Formulation of Gel Al, Gel A2, and Gel B used in Compositions L-Q

[0115] Composition L: Citric Acid / Hyaluronic Acid with Nitrite / Xanthan Gum / Collagen

[0116] Following the procedure for Composition A with Gel Al and Gel B, where 1% w / w collagen is suspended in Gel B. The compositions of Gel Al and Gel B are given in Table L. The results are depicted in FIG. 13.

[0117] Surprisingly, it was found that the use of hyaluronic acid thickener extends the release profile compared to other thickeners. For example, when comparing a similar composition, Composition F as depicted in FIG. 9, the NOx production rate of Composition F decreases to <40% of the maximum NOx evolution rate at the 1 hour mark, while Composition L sustains a rate of approximately 80% of the maximum NOx evolution rate at the 1 hour mark. Without wishing to be bound by a theory, it is believed that this difference is attributable to the viscosity difference between the Composition F and Composition L.

[0118] Composition M: Citric Acid / Hyaluronic Acid / Lidocaine with Nitrite / Xanthan Gum

[0119] Following the procedure for Composition A with Gel Al and Gel B, where 1% w / w lidocaine is suspended in Gel Al. The compositions of Gel Al and Gel B are given in Table L. The results are depicted in FIG. 14.

[0120] Composition N: Citric Acid / Hyaluronic Acid / Tea Tree Oil with Nitrite / Xanthan Gum / Tea Tree Oil

[0121] Following the procedure for Composition A with Gel Al and Gel B, where 1% w / w tea tree oil is suspended in both Gel Al and Gel B. The compositions of Gel Al and Gel B are given in Table L. The results are depicted in FIG. 15.

[0122] Composition O: Hyaluronic Acid with Nitrite / Xanthan Gum / Collagen

[0123] Following the procedure for Composition A with Gel A2 and Gel B, where 1% w / w collagen is suspended in Gel B. The compositions of Gel A2 and Gel B are given in Table L. The results are depicted in FIG. 16.

[0124] Surprisingly, it was found that this composition has an extended release for NOx evolution. For example, Composition L as depicted in FIG. 13 reaches a peak NOx rate at ~15minutes and decreases to 80% of the maximum NOx evolution rate at the 1 hour mark.Composition O by comparison sustains a rate of approximately 95% of the maximum NOx evolution rate at the 1 hour mark.

[0125] Composition P: Hyaluronic Acid / Lidocaine with Nitrite / Xanthan Gum

[0126] Following the procedure for Composition A with Gel A2 and Gel B, where 1% w / w lidocaine is suspended in Gel A2. The compositions of Gel A2 and Gel B are given in Table L. The results are depicted in FIG. 17.

[0127] Composition Q: Hyaluronic Acid / Tea Tree Oil with Nitrite / Xanthan Gum / Tea Tree Oil

[0128] Following the procedure for Composition A with Gel A2 and Gel B, where 1% w / w tea tree oil is suspended in both Gel A2 and Gel B. The compositions of Gel A2 and Gel B are given in Table L. The results are depicted in FIG. 18.

[0129] Composition R: Citric Acid / Lidocaine / Shea Lotion with Sodium Nitrite / Standard Lotion

[0130] Following the procedure for Composition A, with Sodium Nitrite / Standard Lotion and Citric Acid / Shea Lotion, where 1% w / w lidocaine is suspended in the Citric Acid / Shea Lotion. Shea Lotion and Standard Lotion are provided as shown in Table R, below. Ten grams of citric acid are added to 100 g Shea lotion with 1% w / w lidocaine suspended in the mixture. Ten grams of sodium nitrite is added to 100 g Standard Lotion. The results are depicted in FIG. 19.

[0131] Table R: Shea Lotion and Standard Lotion Formulations Used in Composition R Ingredient Mass (g) Weight percentShea LotionDeionized Water 260 64% w / wShea Butter 120 30 % w / wEmulsifying Wax 16 4 % w / wVegetable glycerin 4 1 % w / wPhenoxy Ethanol 4 1 % w / wStandard LotionWhite Soft Paraffin 14.5% w / wLight Liquid Paraffin 12.6% w / wAnhydrous Lanolin l%w / wPurified water BalanceAdditional Standard Lotion IngredientsGlycerol MonostearateCetyl AlcoholSodium Cetostearyl Sulphate CarbomerMethyl HydroxybenzoatePropyl HydroxybenzoateSodium HydroxideCitric Acid MonohydrateOther Embodiments

[0132] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive.

[0133] The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

Claims1. A topical dermatologic composition comprising:a first composition comprising water and a pharmaceutically acceptable acid;a second composition comprising water and a nitric oxide precursor;wherein at least one of the first and second compositions comprises a pharmaceutically acceptable thickening agent and at least one pharmaceutically acceptable therapeutic agent that is not soluble in water; andwherein the first and second compositions, upon mixing, produce a pharmaceutically acceptable resultant multiphasic mixture containing nitric oxide and the at least one pharmaceutically acceptable agent that is not soluble in water.

2. The topical dermatologic composition of claim 1, wherein the composition further comprises a second pharmaceutically acceptable therapeutic agent that is soluble in water.

3. The topical dermatologic composition of claim 1, wherein the resultant multiphasic mixture is selected from the group consisting of a foam, a spray, a shampoo, a lotion, a cream, a soap, a gel, and an ointment, wherein the resultant multiphasic mixture is an extended release composition.

4. The topical dermatologic composition of claim 1, wherein the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophobic acid.

5. The topical dermatologic composition of claim 4, wherein the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophobic acid selected from the group consisting of citric acid, lactic acid, salicylic acid, phosphoric acid, ascorbic acid, hydrochloric acid, acetic acid, hyaluronic acid, hypochlorous acid, and medicinal honey, or combinations thereof.

6. The topical dermatologic composition of claim 4, wherein the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophobic acid is selected from the groupconsisting of citric acid, lactic acid, ascorbic acid, hyaluronic acid, hypochlorous acid, or honey, or combinations thereof.

7. The topical dermatologic composition of claim 1, wherein the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophilic acid.

8. The topical dermatologic composition of claim 4, wherein the pharmaceutically acceptable acid is a pharmaceutically acceptable lipophilic acid selected from the group consisting of an omega 3-fatty acid, an omega-6 fatty acid, an omega-7 fatty acid, an omega-9 fatty acid, linolenic acid, caproic acid (C6), caprylic acid (C8), capric acid (CIO), undecyl acid (Cl 1), lauric acid (C12), myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16), heptadecanoic acid (Cl 7), stearic acid (Cl 8), and a caprylic triglyceride, or combinations thereof.

9. The topical dermatologic composition of claim 7, wherein the nitric oxide precursor of the second composition is selected from the group consisting of nitrites, nitrates, diazeniumdiolates, NO-impregnated polymers, nano-crystalline NO particles, NO-metal complexes, nitroprusside, nitrosamine, nitrate esters, nitrosothiols, L-arginine, NO upregulators, and NO donors, or combinations thereof.

10. The topical dermatologic composition of claim 9, wherein the NO precursor is lipophobic.

11. The topical dermatologic composition of claim 10, wherein the NO precursor is lipophobic and is selected from the group consisting of sodium nitrite, potassium nitrite, or combinations thereof.

12. The topical dermatologic composition of claim 9, wherein the NO precursor is lipophilic.

13. The topical dermatologic composition of claim 12, wherein the NO precursor is lipophilic and is selected from the group consisting of diazeniumdiolates and nitrosothiols, or acombination thereof.

14. The topical dermatologic composition of claim 1, wherein the pharmaceutically acceptable agent is selected from the group consisting of an anti -infective agent, an antiinflammatory agent, a moisture manager, a topical cleanser, an emollient, an emulsifier, a debrider, a biologic, an analgesic, a humectant, a preservative, a skin protectant, an odor manager, an acne treatment, a dandruff treatment, a wart treatment, a lubricant, an adhesive, a natural oil, and an oil / sebum manager, acne treatments, topical anesthetics, topical antifungals, topical antivirals, wart treatments, anti -rosacea treatments, antivirals, lice treatments, antibiotics, antihistamines, antineoplastics, anti -psoriatic agents, astringents, debriding agents, depigmenting agents, anti-inflammatory agents, photochemotherapeutic agents, angiogenesis promoting agents, enzymes, or combinations thereof.

15. The topical dermatologic composition of claim 1, wherein the pharmaceutically acceptable agent is a topical anesthetic.

16. The topical dermatologic composition of claim 15, wherein the topical anesthetic is selected from the group consisting of lidocaine, prilocaine, bupivacaine, and ropivacaine.

17. The composition of claim 1, wherein at least one or both of the first and second compositions comprises a pharmaceutically acceptable excipient which is a pharmaceutically acceptable surfactant.

18. A topical dermatologic composition comprising:a first composition comprising a pharmaceutically acceptable acid;a second lipophilic composition comprising a nitric oxide precursor;wherein the first and second compositions upon mixing produce a pharmaceutically acceptable resultant suspension containing nitric oxide.

19. The topical dermatologic composition of claim 18, wherein the resultant mixture is selected from the group consisting of a shampoo, a lotion, a cream, a gel, an ointment, aliniment, a cerate, an unguent, a balm, and a salve, or combinations thereof.

20. The topical dermatologic composition of claim 18, wherein the acid of the first composition is lipophilic.

21. The topical dermatologic composition of claim 18, wherein the first composition further comprises water and the acid of the first composition is dissolved in the water of the first composition.

22. The topical dermatologic composition of claim 18, wherein the second composition further comprises water and the nitric oxide precursor of the second composition is dissolved in the water of the second composition.

23. The topical dermatologic composition of claim 18, wherein at least one of the first and second compositions further comprises at least one pharmaceutically acceptable agent.

24. The topical dermatologic composition of claim 23, wherein the at least one pharmaceutically acceptable agent is selected from the group consisting of an anti-infective agent, an anti-inflammatory agent, a moisture manager, a topical cleanser, an emollient, an emulsifier, a debriding agent, a biologic, an analgesic, a humectant, a preservative, a skin protectant, an odor manager, an acne treatment, a dandruff treatment, a wart treatment, a lubricant, an adhesive, a natural oil, an oil / sebum manager, acne treatments, topical anesthetics, topical antifungals, topical antivirals, wart treatments, anti-rosacea treatments, antivirals, lice treatments, antibiotics, antihistamines, antineoplastics, anti -psoriatic agents, astringents, debriding agents, depigmenting agents, anti-inflammatory agents, photochemotherapeutic agents, angiogenesis promoting agents, and enzymes, any of which may be soluble or insoluble in water, or combinations thereof.

25. The topical dermatologic composition of claim 23, wherein the pharmaceutically acceptable agent is not soluble in water.

26. The topical dermatologic composition of claim 23, wherein the pharmaceutically acceptable agent is soluble in water.

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