WO2019079150A1 - Compositions et procédés pour traiter la dermatite atopique - Google Patents

Compositions et procédés pour traiter la dermatite atopique Download PDF

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Publication number
WO2019079150A1
WO2019079150A1 PCT/US2018/055807 US2018055807W WO2019079150A1 WO 2019079150 A1 WO2019079150 A1 WO 2019079150A1 US 2018055807 W US2018055807 W US 2018055807W WO 2019079150 A1 WO2019079150 A1 WO 2019079150A1
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Prior art keywords
gel
based formulation
gml
oil
group
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PCT/US2018/055807
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English (en)
Inventor
Patrick M. Schlievert
Marnie L. Peterson
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Hennepin Life Sciences, Llc
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Publication of WO2019079150A1 publication Critical patent/WO2019079150A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • This invention relates to treating and preventing atopic dermatitis in, for example infants, children, and adults.
  • Glycerol monolaurate (GML) and GML-related compositions, together with suitable accelerants, in gel-based formulations may be applied to biological surfaces (skin and/or mucous membranes) to kill pathogenic microorganisms, inhibit production of exotoxins by pathogenic microorganisms, prevent inflammation and stabilize human cells to interfere with toxic reactions or infections, and select for beneficial bacteria such as lactobacilli and bifidobacteria.
  • Atopic dermatitis is a chronic relapsing, highly pruritic, inflammatory skin disease that is often the prelude to development of food allergy, asthma, and allergic rhinitis. Nearly 10% of the U.S. population has ADS. S. aureus skin infections are important in maintenance of skin disease in patients with ADS and such infections can modify the host response to environmental allergens and various pathogens. Recent studies suggest that host- pathogen interactions stemming from the production of S. aureus derived virulence factors, such as super antigens and a-toxin, contribute greatly to the skin inflammation seen in ADS.
  • ADS so far requires a multi-pronged approach that includes improvement in skin barrier function, reduction of skin inflammatory response, and control of S. aureus infection with use of antibiotics.
  • Overuse of antibiotics in managing ADS can result in methicillin-resistant S. aureus (MRSA) infections with organisms that complicate control of skin disease.
  • MRSA methicillin-resistant S. aureus
  • the use of a non-aqueous gel containing GML would be a desirable addition to therapy due to role that S. aureus super antigens and a-toxin play in contributing to skin inflammation in ADS,.
  • GML gel-based formulations comprising GML that may be used to treat atopic dermatitis.
  • These formulations may include GML at concentrations from 10 ug/ml up to 100,000 ug/ml dissolved in any of a variety of gels or ointments.
  • GML dissolved in any type of plant-derived or vegetable oil, petroleum jelly, or petroleum.
  • GML is broadly antibacterial, anti-viral, anti-fungal, and anti-protozoan.
  • One embodiment of the present invention is a gel-based formulation comprising a composition that kills, or inhibits the growth of, one or more pathogenic microorganisms that may be associated with atopic dermatitis, where the composition comprises about 10-100 mg/mL of an active compound selected from the group consisting of Formula 1, Formula 2, and a combination of Formulas land 2:
  • the gel-based formulation includes GML that may be present in an amount of about 10-100 mg/mL, preferably about 30-70 mg/mL.
  • the gel-based formulation may also include a glycol glycerol, a cellulose derivative, a plant-derived oil, and/or petroleum jelly. Further, the gel-based formulation may include about 0.0001-0.05 M of an accelerant selected from lactic acid, ascorbic acid, citric acid,
  • the gel-based formula may include an additional active ingredient selected from an antibacterial, anti-viral, anti-fungal, anti-protozoan, or combinations thereof.
  • the active compound is combined with a topical solution comprising the following components:
  • the active compound is combined with a topical solution comprising substantially pure or about 100% w/w% plant-derived oil, petroleum jelly or derivatives thereof.
  • the plant-derived oil is selected from the group consisting of palm oil, olive oil, corn oil, and combinations thereof.
  • the gel-based formulation has a pH of about 4-4.5
  • a particular embodiment of the present invention is a gel-based formulation composition that kills, or inhibits the growth one or more pathogenic microorganisms associated with atopic dermatitis, wherein the formulation comprises about 10-100 mg/mL of a compound selected from the group consisting of Formula 1, Formula 2, and a combination of Formulas 1 and 2:
  • R1 is: and optionally about 0.0001-0.05 M of an accelerant
  • lactic acid ascorbic acid, citric acid
  • the optional accelerant and compound are combined with a topical solution comprising a) about 73.55 w/w% propylene glycol; b) about 25 w/w% polyethylene glycol 400; c) about 1.25 w/w% hydroxyethyl cellulose or hydroxypropyl cellulose; and d) about 1- 25 w/w% saline, water.
  • the optional accelerant and compound are combined with a topical solution comprising plant-derived or vegetable oil, petroleum jelly, or a derivative thereof.
  • the plant-derived oil may be selected from the group consisting of palm oil, olive oil, com oil, and combinations thereof, and the gel-based formulation has a pH of about 4-4.5.
  • Another embodiment of the present invention is a method of treatment or prophylaxis, the method comprising:
  • (ii) comprises an optional accelerant and a compound selected from the group consisting of
  • the optional accelerant may be lactic acid, ascorbic acid, citric acid, ethylenediaminetetraacetic acid, or other chelating ingredients
  • the compound may GML
  • the gel-based formulation may include a plant-derived oil selected from the group consisting of palm oil, olive oil, corn oil, and combinations thereof, a cellulose derivative selected from the group consisting of hydroxy ethyl and hydroxypropyl cellulose, a glycol derivative selected from the group consisting of polyethylene, and propylene glycol, a petroleum jelly derivative, as well as water and/or saline.
  • Such embodiments may also include an additional active ingredient selected from the group consisting of antibacterial, anti-viral, anti-fungal, anti-protozoan ingredients, and
  • Alternative embodiments of the present invention include a gel-based formulation that contains compound (either together with or in place of Formulas 1 and 2), that are either Formula 3 or Formula 4 or both Formula 3 and Formula 4:
  • the gel-based formulations of the present invention may be administered either before, simultaneous with, or after the administration of one or more supplementary ingredients.
  • Supplementary ingredients can include, for example, anti-fungal ingredients, modulators of immune function, or antibiotics.
  • compositions containing one or more pharmaceutical excipients and one or more gel- based formulations may also be included in various types of gels, creams, or foams.
  • Figure 1 is a line graph showing the inhibitory growth effects when a GML Gel (5% GML) formulation of the present invention is mixed with pathogenic microorganisms, and then allowed to grow when added to suitable media.
  • Figures 2-4 are graphs showing the effect of various concentrations of GML in olive, palm, and corn oil on the growth of several microorganisms (measured as CFU/mL). Bars represent the following microorganisms, from left: Staphylococcus aureus MNPE (methicillin sensitive strain), S. aureus MW2 (methicillin resistant strain), Candida albicans,
  • Streptococcus agalactiae Streptococcus agalactiae, and Gardnerella vaginalis.
  • Figure 5 is a series of graphs showing the measured CFU/mL from biofilms formed from S. aureus strains MN8 (methicillin sensitive strain, top panels), MNWH (methicillin resistant strain, middle panels), and MW2 (methicillin resistant strain, bottom panels) cultured in 96 well plastic microtiter plates, in the presence or absence of the indicated concentrations of GML for 24 or 48 hours.
  • Figure 6 is a series of graphs showing the measured biofilm absorbance at 595 nm after crystal violet staining of biofilms, formed from S. aureus strains MN8 (methicillin sensitive strain, top panels), MNWH (methicillin resistant strain, middle panels), and MW2 (methicillin resistant strain, bottom panels) cultured in 96 well plastic microtiter plates, for 24 or 48 hours, in the presence or absence of the indicated concentration of GML.
  • the present invention provides topical GML gel-based formulations and methods of treating atopic dermatitis with these formulations.
  • ADS patients have various systemic and skin immune abnormalities, including elevated total serum IgE and sensitization to allergens, elevated T helper (Th2)-type cytokine expression in acute lesions, and increased numbers of T cells expressing the skin homing receptor, cutaneous lymphocyte-associated antigen. These patients also have a defect in terminal differentiation of their keratinocytes leading to reduced expression of barrier proteins such as filaggrin, as well as decreased expression of epidermal antimicrobial peptides needed for innate immune responses against invading pathogens. Loss of filaggrin has been linked to enhanced antigen penetration into the skin, increased S. aureus and viral growth in the skin as well as susceptibility to the cytotoxic effects of staphylococcal toxins.
  • Th2 T helper
  • ADS patients with more polarized Th2-type disease with allergies and asthma and increased biomarkers have been reported to have more severe skin disease complicated by microbial infections. These observations suggest that filaggrin mutations and Th2 responses enhance S. aureus colonization and create a niche for S. aureus infection in ADS skin. Once S. aureus has colonized ADS skin, it perpetuates its survival by increasing Th2 mediated responses that suppress antimicrobial responses in atopic skin.
  • GML alone and as a non-aqueous gel is highly antimicrobial against S. aureus, including MRS A. Additionally, GML is anti-inflammatory. Both of these properties would be highly advantageous in management of S. aureus infections in ADS.
  • antimicrobial means effective in preventing, inhibiting, or arresting the growth or pathogenic effects of a microorganism.
  • Microorganism is used herein to mean any bacteria, virus, or fungus.
  • the formulations of the invention are used to prevent, inhibit, or arrest the growth, for example, of one or more of the following microorganisms: S. aureus, P. aeruginosa, E. coli or K. pneumoniae.
  • antibacterial refers to inhibition or arrest of the growth of a bacterium, fungus, or protozoans, or a reduction in the severity of or likelihood of developing a bacterial, fungal, or protozoan disease, inducing death of the bacterium, fungus, or protozoans, or reduction or inhibition of the pathogenic effects of the respective bacterium, fungus, or protozoans.
  • Bactericidal is used interchangeably with "antibacterial.”
  • anti-viral refers to inhibition of viral infection or virus replication, a reduction in the likelihood that a patient exposed to a virus will contract the viral disease or a reduction in the severity of the viral disease.
  • an effective amount refers to an amount that is sufficient to affect a beneficial or desired antimicrobial activity, including, without limitation, killing the microorganism or inhibiting microbial infection, growth or toxicity.
  • An effective amount of GML is about up to 1 mg/mL, about up to 10 mg/mL, about up to 50 mg/mL, or about up to 100 mg/mL.
  • beneficial or desired results may include inhibiting or suppressing the growth of a microorganism or killing a microorganism; inhibiting one or more processes through which a microorganism infects a cell or patient; inhibiting or ameliorating the disease or condition caused by a microbial infection; or a combination thereof.
  • beneficial or desired results may include inhibiting or suppressing the growth of a microorganism or killing a microorganism; inhibiting one or more processes through which a microorganism infects a cell or patient; inhibiting or ameliorating the disease or condition caused by a microbial infection; or a combination thereof.
  • the terms “treat”, “treatment”, or “treating” also refer to prophylaxis treatment.
  • “Prophylaxis” refers to prevention of an infection or disease, or prevention of the development of symptoms of that infection or disease, a delay in the onset of an infection or disease or its symptoms, or a decrease in the severity of a subsequently developed infection or disease or its symptoms.
  • skin surface refers to the protective outer covering of the body of a vertebrate, generally comprising a layer of epidermal cells and a layer of dermal cells.
  • a “mucosal surface,” as used herein, refers to a tissue lining of an organ or body cavity that secretes mucous.
  • pharmaceutically acceptable topical carrier refers to a material, diluent, or vehicle that can be applied to skin or mucosal surfaces without undue toxicity, irritation, or allergic reaction.
  • pharmaceutically acceptable excipient means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • pharmaceutically acceptable excipient as used in the present application includes both one and more than one such excipient.
  • plant-derived oil means a substance extracted from a plant or seed that exists in liquid form at room temperature. Suitable plant-derived oils include, without limitation, palm, olive, corn, canola, coconut, soybean, wheat germ, jojoba, sunflower, sesame, peanut, cottonseed, safflower, soybean, rape seed, almond, beech nut, cashew, hazelnut, macadamia, mongongo nut, pecan, pine nut, pistachio, walnut, grapefruit seed, lemon, orange, bitter gourd, bottle gourd, buffalo gourd, butternut squash seed, egusi seed, pumpkin seed, watermelon seed, acai, black seed, blackcurrant seed, borange seed, evening primrose, flaxseed, eucalyptus, amaranth, apricot, apple seed, argan, avocado, babassu, coriander seed, grape seed, mustard, poppyseed, rice bran, castor, or mixtures thereof.
  • Mixtures can be, by way of example and without limitation, a combination of olive oil and soybean oil, a combination of coconut oil and wheat germ oil, or a combination of jojoba oil, palm oil, and castor oil.
  • Mixtures of suitable oils can be binary, ternary, quaternary, or higher mixtures.
  • the term “accelerant” refers to a compound, substance, liquid, powder, or mixture that, when added to GML or GML-derivative has the effect of enhancing or contributing to the antimicrobial properties of the composition.
  • active ingredient means an antibacterial ingredient, anti-fungal ingredient, anti-viral ingredient, anti-protozoan ingredient, or combination thereof.
  • Antibacterials for use with the invention include aminoglycosides, carbacephems, cephalosporins, glycopeptides, lincosamides, lipopetides, macrolides, monobactams, nitrofurans, penicillins, polypetides, quinolones, sulfurarnides, and tetracyclines.
  • Anti-fungal ingredients include, without limitation, those of the azole class, polyene class, or echinocanins class, nucleoside analogues, allylamines, griseofulvin, tolnaftate, or selenium compounds.
  • Anti-viral ingredients include, for example and without limitation, acyclovir, ganciclovir,
  • valganciclovir abacavir, enofovir, larnivudine, emtricitabine, zidovudine, tenofovir, efavirenz, raltegravir, enfuvirdide, maraviroc, ribavirin, amantadine, rimantadine, interferon, oseltamivir, and zanamivir.
  • cellulose derivative refers to any a cellulose-based compound and may include, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, or cellulose acetate.
  • ''biofilnr' means an aggregate of microorganisms, usually bacterial, adhered to one another and growing on a surface.
  • the microbial cells in the biofilm typically produce an extracellular matrix known as an extracellular polymeric substance. Often, this matrix and the density of the aggregate itself significantly increase the antibiotic resistance of the bacteria in the biofilm.
  • Biofilms can be involved in ear infections and dental diseases such as gingivitis.
  • isolated compound refers to a compound (e.g., GML or a related compound) that either has no naturally-occurring counterpart or has been separated or purified from components which naturally accompany it, e.g., in tissues such as pancreas, liver, spleen, ovary, testis, muscle, joint tissue, neural tissue, gastrointestinal tissue or tumor tissue, or body fluids such as blood, serum, or urine.
  • a naturally occurring biological compound is considered “isolated” when it is at least 70%, by dry weight, free from other naturally-occurring organic molecules with which it is naturally associated.
  • a preparation of a compound for use in the invention is at least 80%, more preferably at least 90%, and most preferably at least 99%, by dry weight, that compound.
  • the degree of isolation or purity can be measured by any appropriate method, e.g., column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis. Since a compound (e.g., GML) that is chemically synthesized is, by its nature, separated from the components that naturally accompany it, the synthetic compound is by definition "isolated".
  • Isolated compounds, and supplementary ingredients useful for the invention can be obtained, for example, by: (i) extraction from a natural source (e.g., from tissues or bodily fluids); (ii) where the compound or supplementary ingredients are proteins, by expression of recombinant nucleic acids encoding the proteins; or (iii) by standard chemical synthetic methods known to those in the art.
  • a natural source e.g., from tissues or bodily fluids
  • the compound or supplementary ingredients are proteins, by expression of recombinant nucleic acids encoding the proteins
  • composition provided herein comprises the monoglyceride
  • GML is a fatty acid ester of glycerol, derivative of lauric acid, with the chemical formula C15H30O4. GML is also known in the art as glyceryl laurate or monolaurin. GML is found naturally in breast milk and some plants, and is used as a food and cosmetic additive. GML and other glycerides are listed in the Generally Recognized as Safe Substances database by the US Food and Drug Administration. GML and related compounds have been previously disclosed in U.S. Patent Publication No. 2007/0276049 (filed November 10, 2004), U.S Patent No. 8,796,332, and U.S. Publication Number 2013/0281532, the disclosures of which are herein incorporated by reference for all purposes.
  • GML can be obtained or synthesized in multiple forms including both R and S optical isomers, as well as forms with lauric acid in the 1/3-position and in the 2-position.
  • the gel- based formulation provided herein comprises the R isomer of GML.
  • the formulation comprises the S isomer of GML.
  • the formulation comprises a racemic mixture of isomers.
  • the formulation may comprise GML with lauric acid ester at the 1/3 position, GML with lauric acid ester at the 2-position, or a combination thereof.
  • R and S isomers of each form and racemic mixtures thereof, are amenable for use with the present invention.
  • GML glycerol monolaurate
  • GML Glycerol monolaurate
  • the gel-based formulation comprises a GML derivative, for example a compound selected from one of Formulae A-F.
  • GML derivative for example a compound selected from one of Formulae A-F.
  • examples of such compounds include, by way of example and without limitation, glycerol monocaprylate, glycerol monocaprate, glycerol monomyristate, glycerol monopalmitate, and dodecyl glycerol.
  • X is independently -O- or -S-; and n is an integer from 5 to 20 (inclusive).
  • the gel-based formulation comprises at least one derivative of GML, and the at least one derivative is a compound of either Formula E or Formula F.
  • Examples of such compounds include, but are not limited to, glycerol dilaurate, glycerol dicaprylate, glycerol dimyristate, glycerol trilaurate, and glycerol tripalmitate.
  • a compound of Formula A, B, C, or D is present in a formulation of the invention, and at least one -X- is -S-. In one embodiment, one occurrence of -X- is -S- and the remaining occurrences of -X- are -0-.
  • a compound of Formula E or F is present in the formulation of the invention, each occurrence of n is 10, and at least one -X- is -0-.
  • the gel-based formulation provided herein comprises GML and a GML derivative.
  • the gel-based formulation provided herein comprises GML and a compound of Formula F.
  • each occurrence of n is 10 and at least one -X- is -0-.
  • the gel-based formulation comprises GML or derivative thereof at a concentration of about 10 ug/mL to about 100 mg/mL. In a further embodiment, the gel-based formulation comprises GML or derivative thereof at a concentration of about 50
  • the gel-based formulation comprises GML or derivative thereof at a concentration of about 10 Mg/mL, about 50 Mg/mL, about 100 Mg/mL, about 500 Mg/mL, about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 50 mg/mL, or about 100 mg/mL.
  • the amount of GML or derivative thereof in the composition can be tailored accordingly to the extent of the atopic dermatitis being treated as well as the characteristics of the patient being treated.
  • the amount of GML in the composition may vary depending on, for example, the nature of the infection or illness; the site of administration; the patient's medical history, patient weight, age, sex, and surface area being treated; and whether the patient is receiving any other medications.
  • the present invention is directed to a gel-based formulation comprising GML or a derivative thereof.
  • the gel-based formulation comprises at least one glycol.
  • the gel-based formulation comprises propylene glycol, polyethylene glycol, or a combination thereof.
  • the polyethylene glycol has a molecular weight (MW) range from about 300 to about 10,000.
  • the polyethylene glycol has a molecular weight of about 300 to about 1,000.
  • the polyethylene glycol has a molecular weight of about 400.
  • polyethylene glycol is present in the gel-based formulation.
  • the polyethylene glycol has a MW of about 400, about 500 or about 1,000.
  • the polyethylene glycol is present in the gel-based formulation at a concentration (w/w) of about 15% to about 50%, about 20% to about 40%, or about 25% to about 35%, for example, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%.
  • both propylene glycol and polyethylene glycol are present in the gel-based formulation.
  • propylene glycol is present at a concentration of about 70% to about 80% and polyethylene glycol is present at a concentration of about 20% to about 30%. In even a further
  • the polyethylene glycol is polyethylene glycol 400.
  • propylene glycol is present in the composition.
  • propylene glycol is present in the composition at a concentration of about 60% to about 80%, for example, about 60%, about 65%, about 70%, about 71 %, about 72%, about 73%, about 74%, about 75%, or about 80%.
  • a gel-based formulation comprising GML or a derivative thereof.
  • the gel-based formulation comprises at least one cellulose derivative.
  • the composition comprises one cellulose derivative or two cellulose derivatives.
  • the cellulose derivative is hydroxypropyl cellulose.
  • the cellulose derivative is hydroxyethyl cellulose, carboxymethyl cellulose or hydroxymethyl cellulose.
  • the composition comprises a combination of hydroxyethyl cellulose and hydroxypropyl cellulose.
  • the cellulose derivative is present at a concentration of about 0.1% (w/w) to about 5.0% (w/w).
  • multiple cellulose derivatives are present in the composition at the same concentration.
  • two cellulose derivatives are present, and each is present at a concentration of about 1.25% (w/w).
  • Cellulose derivatives include, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, or cellulose acetate.
  • the gel-based formulation provided herein comprises GML or a derivative thereof, at least one cellulose derivative, propylene glycol and polyethylene glycol.
  • a gel-based formulation comprising GML or a derivative thereof is provided.
  • the composition comprises at least one plant- derived oil, for example, at least one of the oils described above (e.g., palm oil, olive oil, or corn oil).
  • the plant-derived oil is present in the composition at a concentration of as much as about 100 w/w%.
  • the gel-based formulation provided herein comprises a plant- derived oil and at least one cellulose derivative.
  • the gel- based formulation comprises hydroxypropyl cellulose and a plant-derived oil, or hydroxyethyl cellulose and a plant-derived oil, or a combination of hydroxy propyl cellulose, hydroxyethyl cellulose, and a plant-derived oil.
  • the cellulose derivative and the plant-derived oil e.g., palm oil, corn oil, or plant oil
  • the gel-based formulation comprises petroleum jelly.
  • the composition comprises a plant-derived oil and two cellulose derivatives.
  • the two cellulose derivatives are hydroxypropyl cellulose and hydroxyethyl cellulose, and the total concentration of cellulose derivatives in the composition is about 1.25% (w/w).
  • Cellulose derivatives include, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose, or cellulose acetate.
  • the gel-based formulation provided herein comprises one or more accelerants.
  • the accelerant is an organic acid, a chelator, or a combination thereof.
  • the accelerant is a chelator.
  • the accelerant is EDTA.
  • the accelerant in one embodiment, is EDTA.
  • the GML composition provided herein comprises EDTA at a concentration of about 0.00005 M, about 0.0005 M, about 0.005 or about 0.05 M.
  • a chelator is present in the composition at a concentration of about 0.00005 M to about 0.05 M, about 0.0005 M to about 0.005 M, or about 0.005 to about 0.05 M.
  • the gel-based formulation comprises both a plant-derived oil and an accelerant, for example palm oil and EDTA.
  • the accelerant is an organic acid and is present in the formulation with a plant-derived oil.
  • the gel-based formulation provided herein comprises an accelerant and a non-aqueous gel, for example a gel comprising a cellulose derivative.
  • the gel-based formulation comprises GML or a derivative thereof, a plant-derived oil, a non-aqueous gel (e.g., a gel comprising one or more cellulose derivatives) and an accelerant.
  • the composition contains at least one pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipients are well known to those skilled in the art and may include buffers (e.g., phosphate buffer and citrate buffer), amino acids, alcohols, proteins such as serum albumin, parabens (e.g., methylparaben), or mannitol.
  • the pH of the composition is from about 3.5 to about 7.0. In a further embodiment, the pH of the composition is from about 4.0 to about 6.0. In a still further embodiment, the pH of the composition is from about 4.0 to about 4.5.
  • the composition provided herein comprises GML or a derivative thereof and a pharmaceutically acceptable topical carrier.
  • the pharmaceutically acceptable topical carrier is a mix of hydrocarbons such as, for example, paraffin wax or petroleum jelly. Petroleum jelly is any water-insoluble, hydrophobic, semi- solid mixture of hydrocarbons.
  • the pharmaceutically acceptable topical carrier can be added to any of the formulations described herein.
  • the gel-based formulation comprises an additional active ingredient.
  • Additional active ingredients include, for example, antibacterial, anti-viral, antifungal, and anti-protozoan ingredients.
  • Antibacterials include, without limitation, aminoglycosides, carbacephems, cephalosporins, glycopeptides, lincosamides, lipopetides, macrolides, monobactams, nitrofurans, penicillins, polypetides, quinolones, sulfuramides, or tetracyclines.
  • Anti-fungal ingredients include, without limitation, those of the azole class, polyene class, or echinocanins class, nucleoside analogues, allylamines, griseofulvin, tolnaftate, or selenium compounds.
  • Anti-viral ingredients include, for example and without limitation, acyclovir, ganciclovir, valganciclovir, abacavir, enofovir, lamivudine, emtricitabine, zidovudine, tenofovir, efavirenz, raltegravir, enfuvirdide, maraviroc, ribavirin, amantadine, rimantadine, interferon, oseltamivir, or zanamivir.
  • the composition is a solid, semi-solid, foam, wax, cream, or lotion.
  • the GML gel-based formulations described herein may be less irritating than currently approved antimicrobial compositions, therefore resulting in a more favorable patient compliance rate, as compared to other antimicrobial compositions presently used in the art.
  • the method comprises administering to the patient a gel-based formulation comprising GML or a derivative thereof, as described herein.
  • a gel-based formulation comprising GML or a derivative thereof, as described herein.
  • the method comprises topically administering to the patient an effective amount of a composition comprising GML or a derivative thereof, a plant-derived oil, and a pharmaceutically acceptable topical carrier.
  • the method comprises topically administering an effective amount of a composition comprising GML, a non- aqueous gel, and a pharmaceutically acceptable topical carrier.
  • the composition may be given twice per day for 3-4 days, or 6-7 days.
  • the composition may be given once per day for 7-10 days or 12-14 days.
  • the method of treating a microbial infection comprises applying an effective amount of one or more of the GML compositions described herein to at least one skin or mucosal surface of a patient.
  • the gel-based formulation is applied to or impregnated in a wipe, sponge, swab, or other material, and then applied to the skin or mucosal surface of the patient using the respective material.
  • the term "swab" refers to a material suitable for applying a liquid, gel, wax, cream, or lotion to a skin or mucosal surface, or the act of applying a liquid, gel, wax, cream, or lotion to the skin or mucosal surface, or the act of collecting a liquid, gel, wax, cream, lotion, or fluid from the skin or mucosal surface.
  • the material is attached to a holder, for example a stick, wire, rod, or applicator.
  • the material attached to a holder is attached at one or both ends thereof.
  • the wipe, sponge, swab, or other material is pre-loaded or packaged together with the composition.
  • GML compositions inhibit microbial infection through one or more of several mechanisms that include, but are not limited to, direct microbial toxicity; inhibiting entry of the infectious microorganism into the vertebrate cell; inhibiting growth of the microorganism; inhibiting production or activity of virulence factors such as toxins; stabilizing the vertebrate cells; or inhibiting induction of inflammatory or immunostimulatory mediators that otherwise enhance the infectious process.
  • direct GML-mediated interruption of bacterial membranes includes interference with the localization of signaling proteins within the membrane, or interference with ligand binding to signaling proteins.
  • GML has an indirect effect on a two-component signal transduction system and the effect is selected from modifications to membrane structure that interfere with the ability of transmembrane proteins to perform signaling functions; dissipation of the bacterial plasma membrane potential; and alterations of pH gradients across the membranes.
  • GML Similar to GML's putative effects on bacterial plasma membranes, GML has been shown to inactivate certain viruses by disrupting viral lipid envelopes.
  • a method is provided to remove or kill a biofilm comprising one or more microorganisms.
  • the method comprises administering the gel- based formulation by applying it directly to the biofilm.
  • the methods of the invention comprise administering a second active ingredient, along with GML or a derivative of GML.
  • the additional active ingredient may be present in the compositions described herein, or may be administered separately.
  • the one or more additional active ingredients prior to, or after, the topical GML composition is administered.
  • the two active ingredients may be topically administered serially, or administered serially by different routes of administration.
  • the additional active ingredient(s) is administered before, during, or after administration of the composition of the invention.
  • the additional active ingredients) is administered by the same route as the composition or by a different route.
  • the additional active ingredients in one embodiment, is administered by one of the following routes of administration: topical, intranasal, intradermal, intravenous, intramuscular, oral and subcutaneous.
  • the dose of additional active ingredients depends on, for example, the nature of the infection or illness; the site of administration; patient weight, age, sex, and surface area; concomitant medications; and medical judgment.
  • 5% w/v GML nonaqueous gel is bactericidal for 54 strains of S. aureus, including highly antibiotic resistant organisms and multiple clonal groups. GML is antimicrobial on contact, killing the organisms in only a few minutes. The estimated chance of S. aureus developing resistance to GML is ⁇ 1/10; thus resistance is highly unlikely. 5% GML nonaqueous gel is also a stronger anti-staphylococcal ingredient than GML alone.
  • This example demonstrates the ability of GML in olive, palm, or corn oil to inhibit the growth of several bacterial or fungal microorganisms in vitro.
  • GML in olive ( Figure 2, palm ( Figure 3), or corn (figure 4) oil was pre-warmed to 37 °C. to melt the GML and was then added to 1 mL of Todd Hewitt (Difco, Detroit Mich.) broth in round bottom tubes at concentrations ranging from 10 Mg/mL to 5000 pg/mL.
  • the following microbes were added to the tubes at the indicated concentrations: Staphylococcus aureus MNPE (methicillin sensitive, lxl07/mL); Staphylococcus aureus MW2 (methicillin resistant, 1 ⁇ 107/mL); Streptococcus agalactiae (1 ⁇ 107/mL); Gardnerella vaginalis
  • the tubes were shaken at 37° C. at 200 revolutions per minute (RPM) in standard air for 18 hours. Plate counts were performed to determine colony-forming units/mL (CFU/mL).
  • G. vaginalis CFU/mL were reduced in all three oils; growth of both G. vaginalis and S. agalactiae was completely or nearly completely inhibited at levels of 20 Mg/mL GML or higher in all 3 oils. Additionally, the growth of C. albicans and both strains of S. aureus was inhibited at 100 pg/mL GML and growth was completely inhibited by GML at 500 pg/mL and 5000 pg/mL GML, in all 3 oils. GML was effectively anti-microbial when mixed with olive, palm, or corn oil.
  • 96 well plastic microtiter plates were inoculated with approximately 10 6 /mL of one of three strains of S. aureus (MN8, a methicillin sensitive strain; MNWH, a methicillin resistant strain; or MW2, a methicillin resistant strain).
  • MN8 methicillin sensitive strain
  • MNWH methicillin resistant strain
  • MW2 methicillin resistant strain
  • Wells were cultured stationary at 37 °C for 24 and 48 hours.
  • the wells were agitated 3 times by pipetting up and down.
  • the bactericidal activity of GML was determined by measuring CFU/mL in supernatants.

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Abstract

L'invention concerne le traitement et la prévention de la dermatite atopique. Le monolaurate de glycérol (GML) et/ou des compositions associées au GML conjointement avec des accélérateurs appropriés dans une formulation à base de gel peuvent être utilisés pour traiter la dermatite atopique. Une telle formulation à base de gel tue ou inhibe la croissance d'un ou plusieurs micro-organismes pathogènes qui causent la dermatite atopique.
PCT/US2018/055807 2017-10-18 2018-10-15 Compositions et procédés pour traiter la dermatite atopique WO2019079150A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013103556A1 (fr) * 2012-01-05 2013-07-11 The Trustees Of Columbia University In The City Of New York Composition antimicrobienne
US20130281532A1 (en) * 2012-04-20 2013-10-24 Hennepin Life Sciences Compositions for topical treatment of microbial infections

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013103556A1 (fr) * 2012-01-05 2013-07-11 The Trustees Of Columbia University In The City Of New York Composition antimicrobienne
US20130281532A1 (en) * 2012-04-20 2013-10-24 Hennepin Life Sciences Compositions for topical treatment of microbial infections

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