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EP-4734963-A1 - NITRIC OXIDE CONTAINING FOAM FORMULATION FOR TOPICAL MEDICAL USE

EP4734963A1EP 4734963 A1EP4734963 A1EP 4734963A1EP-4734963-A1

Abstract

Disclosed herein are topical nitric oxide (NO) formulations containing a surfactant and methods that deliver NO to treat skin wounds, burns, infections, site of inflammations, or other skin conditions requiring treatment, as well as to eradicate and degrade biofilms on the skin surface. The NO formulations can be modified to prolong the time of NO exposure by modulating the surfactant concentration.

Inventors

  • MILLER, C. MICHAEL
  • BELL, DAVID A.

Assignees

  • Noxy Health Products, Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A method of treating a topical site on a patient requiring treatment, comprising contacting the site with a NO topical foam formulation comprising NO, water, and a surfactant, wherein the concentration of the surfactant is 0.1 weight/weight (w/w) to 50% w/w.
  2. 2. The method of claim 1, wherein the site is a skin wound, burn, infection, site of inflammation, or other skin condition requiring treatment.
  3. 3. The method of claims 1-2, wherein the surfactant is a cationic surfactant and the NO comes from a source of NO.
  4. 4. The method of claims 1-3 further comprising an acid.
  5. 5. The method of claims 1 to 4, wherein the formulations employed to make the NO topical foam formulation comprises two formulations, wherein the first formulation comprises water, acid, and the surfactant; and the second formulation comprises water, the surfactant, and a nitrite salt.
  6. 6. The method of claims 1 to 5, wherein the acid concentration (w/w%) of the first solution is 1 to 30 percent and the surfactant concentration of the first solution is 0.1 to 50 percent (w/w).
  7. 7. The method of claims 1 to 5, wherein the nitrite concentration (w/w%) of the second solution is 1 to 30 percent and the surfactant concentration of the second solution is 0.1 to 50 percent (w/w).
  8. 8. The method of claims 1-7, wherein: the surfactant is selected from the group consisting of cetyl trimethyl ammonium bromide, cetrimonium bromide, dodecylbenzenesulfonic acid, cetylpyridinium chloride, stearalkonium chloride, polyquaternium-7, cocamidopropyl betaine, coco betaine, lauryl dimethyl ammonium chloride, polyquaternium-10, behentrimonium chloride, and cetrimonium chloride or combinations thereof; the NO comes from a source comprising one or more of a NO gas, nitrite salt, NONOate, NO-polymer, nano-crystalline NO, NO-metal, NO silica particles, nitrate esters, nitroprusside, nitrosamine, L-arginine, L-citrulline, nitrosothiols, NO synthase or synthase upregulators; and the acid is selected from the group consisting of citric acid, lactic acid, salicylic acid, phosphoric acid, ascorbic acid, hydrochloric acid, acetic acid, hyaluronic acid, and hypochlorous acid or combinations thereof.
  9. 9. The method of claim 8, wherein the NO comes from a source selected from the group consisting of sodium nitrite, calcium nitrite, potassium nitrite, and ammonium nitrite or combinations thereof.
  10. 10. The method of claim 9, wherein the surfactant is cocobetaine, the nitrite is sodium nitrite, and the acid is citric acid.
  11. 11. The method of claims 1 to 10, further comprising one or more additional topical dermatological agents.
  12. 12. The method of claims 1-11, wherein the rate of NO release is decreased by increasing the surfactant concentration, increasing the shear rate, or lowering the temperature.
  13. 13. The method of claims 1-11, wherein NO exposure times are increased from 10 seconds to 72 hours by increasing the surfactant concentration, increasing the shear rate, r lowering the temperature of the NO topical foam formulation.
  14. 14. The method of claims 1-13, wherein the site is a skin infection selected from the group consisting of a bacterial infection, a viral infection, and a fungal infection, and wherein the skin infection exists on a wound, a bum, or site of another condition requiring treatment.
  15. 15. The method of claim 14, wherein the infection is a planktonic infection, or an infection caused in conjunction with a biofdm.
  16. 16. The method of claim 15, wherein the formulation of claims 1-12 is administered prior to, concurrent with, or subsequent to antibiotic treatment.
  17. 17. A method of: (i) treating, inhibiting, or eradicating an infection on a topical site of a patient requiring such treatment, or of (ii) disrupting, degrading, or removing a biofilm on the topical site of a patient requiring such treatment, or of (iii) reducing or removing the bioburden on the topical site of a patient requiring such treatment, or of (iv) removing or loosening foreign material from a topical site; or of (v) disinfecting a topical site of a human or animal comprising: applying the NO topical foam formulation foam as recited in claims 1-13 to the topical site; and allowing the NO topical foam formulation to remain on the topical site for a period of time to allow the NO to be absorbed to provide a therapeutic effect; wherein the therapeutic effect is an antimicrobial effect, vasodilatory effect, or healing effect.
  18. 18. A method of: (i) treating, inhibiting, or eradicating an infection on a topical site of a patient requiring such treatment, or of (ii) disrupting, degrading, or removing a biofilm on the topical site of a patient requiring such treatment, or of (iii) reducing or removing the bioburden on the topical site of a patient requiring such treatment, or of (iv) removing or loosening foreign material from a topical site; or of (v) disinfecting a topical site of a human or animal comprising: applying the NO topical foam formulation foam as recited in claims 1-13 to the topical site; and allowing the NO topical foam formulation to remain on the topical site for a period of time to allow the NO to treat, inhibit, or eradicate the infection or to disrupt, degrade, or remove the biofilm, or to reduce or remove the bioburden, or to remove or loosen the foreign material, or to disinfect; wherein the infection, biofilm, or bioburden is caused by a bacteria, a virus, or a fungus.
  19. 19. A method of prolonging a therapeutic effect of the NO topical foam formulation recited in claims 1-13, the method comprising increasing the surfactant concentration of the NO topical foam formulation and decreasing the rate of NO delivery, wherein the therapeutic effect is an antimicrobial effect, a vasodilatory effect, or a wound healing effect.
  20. 20. A therapeutic covering for an application site on the skin of a patient requiring such treatment, wherein the covering is the NO topical formulation foam as recited in claims 1-13, wherein the covering protects the application site on the skin or tissue from ambient interference and environmental contaminants such as air- or waterborne pathogens.

Description

Nitric Oxide Containing Foam Formulation for Topical Medical Use Cross-Reference to Related Applications [001] This application claims priority to U.S. Provisional Application Serial Number 63/511,243, filed June 30, 2023, the entire contents of which are incorporated by reference herein. Background [002] Nitric oxide (NO) is a known antimicrobial, vasodilator, and signaling molecule that can be used to treat humans and animals suffering from a range of medical afflictions, particularly those associated with the skin. For example, in 2004, Miller reported the use of NO gas to treat leg abscesses. According to the report, gaseous NO was applied to the leg of a patient using a “single patient use” plastic boot. The boot was equipped with a delivery system that administered 200 ppm NO gas for an average of 8.1 hours. After 14 consecutive nights of treatment, the lesion was significantly reduced in size. Miller, J Cutan Med Surg, 2004 Jul- Aug;8(4):233-8. doi: 10.1007/sl0227-004-0106-8. In US 2005/0191372, Miller further discloses NO gas bathing units, including an inflatable bag-like bathing units in the shape of a boot or mitten or glove that can be placed over a patient’s foot or hand, respectively. Other reports relating to the use of NO to treat skin conditions abound. [003] Miller illustrates the real-world challenges of using NO gas for wound treatment. NO gas is reported to be toxic at higher concentration (greater than exposures of 200 ppm). In Miller’s bathing units, it is impossible to control the directionality of NO gas diffusion to just the site on the skin requiring treatment. Treatment effects are thus due to serendipitous absorption of NO. As a result, Miller’s method and device requires long treatment times and high concentrations of NO gas, increasing the risk of toxic exposure. [004] To avoid the issues posed by NO gas treatment, therapeutic media such as creams and ointments have been developed that generate NO in situ from the reaction of nitrite with acid. These creams and ointments are two-part formulations. The first formulation contains the nitrite, and the second formulation contains the acid. When the two formulations are mixed, for instance on skin that requires treatment, the acid and nitrite react to form NO gas, which then diffuses to the skin. Zhu H, Ka B, Murad F, World J. Surg. 2007, 31 , 624. Zhu H, Wei X, Bian K, Murad F, J. Burn Care Res. 2008, 29, 804. [005] Researchers have also utilized foams for NO delivery to skin requiring treatment. In US 10,751,365 Miller, Hill and Bell disclose a two-part liquid formulation that is to provide NO to the skin. The first formulation contains nitrite and a surfactant, and the second formulation contains acid and a surfactant. The two formulations can be agitated to produce foams. When the two foamed formulations are mixed, the acid and nitrite react to form NO which is present as NO-containing bubbles in the foam, which then can be placed on skin requiring treatment. [006] However, challenges remain in using NO-containing foam as a delivery medium, particularly for treating infections on the skin that are caused by microbial pathogens including bacteria, viruses, and fungi, as well as for treating inflammatory dermal conditions. Summary [007] These and other needs are met by the present invention, which harnesses the antimicrobial, vasodilator, and cell signaling properties of NO to treat a variety of topical skin infections and conditions using a NO foam formulation. We have surprisingly found that modifying the NO foam formulations by adjusting the surfactant concentration makes it possible to modify the foam collapse rate and thus the rate of NO delivery to a site on the skin that requires treatment, so that longer or shorter treatment times can be achieved as needed. Prolonged exposure times for the NO topical foam formulation means prolonged times for NO to exert its therapeutic effect and/or antimicrobial effect, for the foam to serve as a protective covering, and for the foam to exert its moistening quality. [008] Thus, in one aspect, what is provided is an NO topical foam formulation, comprising NO, water, and a surfactant, wherein the concentration of the surfactant is 0.1% weight/weight (w/w) to 50% w/w. A further embodiment of this aspect is a formulation comprising additional components, which are described herein below. [009] In another aspect, what is provided is a method of treating an infection, site of inflammation, or skin condition with NO in a patient requiring such treatment, comprising contacting the skin with the NO topical foam formulation as disclosed herein for an extended or specified period of time. In this aspect, the site requiring treatment is a skin wound, burn, infection, site of inflammation, or other condition requiring treatment. [010] In another aspect, what is provided is a method of treating, inhibiting, or eradicating an infection on the skin of a patient requiring such treatment, comprising: