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WO2009054992A1 - Compositions antimicrobiennes comprenant du docusate - Google Patents

Compositions antimicrobiennes comprenant du docusate Download PDF

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Publication number
WO2009054992A1
WO2009054992A1 PCT/US2008/012056 US2008012056W WO2009054992A1 WO 2009054992 A1 WO2009054992 A1 WO 2009054992A1 US 2008012056 W US2008012056 W US 2008012056W WO 2009054992 A1 WO2009054992 A1 WO 2009054992A1
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WO
WIPO (PCT)
Prior art keywords
formulation
polar lipid
urea
article
infection
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2008/012056
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English (en)
Inventor
Christopher N. Hensby
Robert A. Kaster
Seth Lederman
Seth Orlow
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IVREA Pharmaceuticals Inc
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IVREA Pharmaceuticals Inc
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Filing date
Publication date
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Publication of WO2009054992A1 publication Critical patent/WO2009054992A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the skin is the largest organ in the body and serves important functions that are necessary to life.
  • the skin acts as a barrier to the invasion of various pathogens and toxic substances.
  • Skin is composed of the two layers: the epidermis is the first layer; and the dermis is the layer below the epidermis.
  • the skin is highly impermeable. It must be impermeable to preserve its own integrity while at the same time maintaining the delicate dynamic electrolyte balance of the body.
  • the skin must serve a containment function; it must also function as a microbial, chemical, radiation and thermal barrier. A good deal of this impermeability of the skin results from the nature of one very thin layer created by normal developmental and physiological changes in the skin. After cells are formed in the basal layer, they begin to migrate toward the skin surface, until they are eventually sloughed off. As they undergo this migration, they become progressively more dehydrated and keratinized.
  • stratum corneum When they reach the surface, just prior to being discarded, they form a thin layer of dense, metabolically inactive cells approximately ten microns (10-15 cells) thick. This layer is called the stratum corneum or the "cornified layer". As a result of the high degree of keratinization of the cells which comprise the stratum corneum, a daunting barrier is created. Therefore, penetration via the nonpolar route, i.e., across the membrane of these cells, remains most difficult. The problem is even more difficult when trying to deliver an antimicrobial composition through the unguis, the horny cutaneous plates on the dorsal surface of the distal end of the terminal phalanx of a finger or toe (fingernails and toenails).
  • the composition should be easy to apply topically in a quantitative amount, rapidly permeate the skin to get where needed, have a pleasant odor and appearance, and not require cleansing to remove the composition.
  • compositions that does not rely on a traditional active agent for its antimicrobial activity.
  • traditional active agents are associated with the development of resistant organisms.
  • certain traditional active agents, particularly antifungals are associated with a relatively high incidence of side effects.
  • the invention includes a method for treating or inhibiting a microbial infection in a subject, comprising administering to the subject a therapeutically effective amount of a formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant wherein the surfactant is a docusate salt, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent.
  • the invention includes a method for reducing or inhibiting growth of microbes on an inanimate surface, comprising applying an effective amount of a disinfectant formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant wherein the surfactant is a docusate salt, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent.
  • a disinfectant formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant wherein the surfactant is a docusate salt, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent.
  • the invention includes a method for improving the appearance or health of nails, claws, hooves and other epithelial stratum lucidum, comprising applying to the bed of a nail, claw, hoof or other epithelial stratum lucidum an effective amount of a formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant wherein the surfactant is a docusate salt, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent.
  • the invention includes a method for treating or inhibiting the enlargement of soft tissue wounds or infected external mucosal tissues, comprising applying a therapeutically effective amount of a formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant wherein the surfactant is a docusate salt, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent.
  • the invention also includes containers containing and articles partially or completely impregnated with an antimicrobial formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant wherein the surfactant is a docusate salt, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent.
  • an antimicrobial formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant wherein the surfactant is a docusate salt, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent.
  • the invention includes the use of a formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent, in the manufacture of a medicament or disinfectant for the treatment or inhibition of microbial infection.
  • a formulation comprising a mixture of a polar lipid, a biocompatible organic solvent, a surfactant, water, and urea, at a pH of between about 5.5 and 8.0, provided that said formulation does not include an effective amount of an additional antimicrobial agent, in the manufacture of a medicament or disinfectant for the treatment or inhibition of microbial infection.
  • the advantages of compositions of the invention include, but are not limited to: avoidance of the risks associated with parenteral treatment; elimination of the inconveniences of parenteral treatment; avoidance of the variable rates of absorption and metabolism inherent in oral treatment; and elimination of gastrointestinal irritation resulting from exposing the
  • compositions of the invention comprise a mixture of a polar lipid, a biocompatible organic solvent, a surfactant, water, and urea, at a pH of between about 5.5 and 8.0 and preferably between 6.0 and 7.0. Such compositions preferably do not include an effective amount of an additional antimicrobial agent.
  • the composition may optionally include cholesterol or a preservative such as benzyl alcohol.
  • compositions of the invention comprise a polar lipid, such as lecithin or phosphotidylcholine, and two biocompatible organic solvents, one chosen from the group of esters and one chosen from the group of liquid dihydric and polyhydric alcohols, a preservative, water, a thickener and urea, at a pH of between about 5.5 and 7.5 and preferably between 6.0 and 7.0.
  • the compositions may additionally contain other optional components that reduce skin irritation, or enhance their cosmetic appeal or acceptability, e.g, pigments, fragrances, perfumes, and the like.
  • the compositions of the present disclosure typically contain about 10 to 30% by weight of the polar lipid (e.g., 10-15%, 15- 20%, 20-25%, or 25-30%).
  • the polar lipid is lecithin or phosphatidylcholine.
  • the lecithin or phosphatidylcholine is of a high quality, pharmaceutical grade.
  • Appropriate lecithin and phosphatidylcholine may be obtained as commercially available soya lecithin or soya phosphatidylcholine.
  • soya lecithin is used in the composition of this invention.
  • the biocompatible organic solvent may be any non-toxic solvent in which the polar lipid and urea are soluble.
  • the biocompatible organic solvent includes both an ester and a di- or polyhydric alcohol.
  • the esters are fatty mono esters having a structure, obtainable by replacing the active hydrogen of a fatty acid having 4 to 22 carbon atoms and more typically having 8 to 18 carbon atoms by the alkyl group of a monohydric alcohol, particular example being 12 carbon atoms.
  • the fatty acid can be saturated or unsaturated and more typically is saturated.
  • the monohydric alcohol typically contains 2 to 8 carbon atoms and more typically 2 to 5 carbon atoms, a particular example being 3 carbon atoms.
  • Acceptable esters for this purpose include, but are not limited to isopropyl esters.
  • the ester is isopropyl myristate or isopropyl palmitate, with isopropyl myristate being preferred.
  • the biocompatible organic dihydric and polyhydric alcohol solvents may be any non-toxic di- or polyalcohol in which the polar lipid is soluble.
  • Acceptable dihydric and polyhydric alcohols for this purpose include, but are not limited to di- and tri-alcohol alkanes.
  • the alcohols contain 3 to 8 carbon atoms and more typically 3 to 5 carbon atoms and are saturated alcohols.
  • the polyalcohol is propylene glycol or glycerol, with propylene glycol being particularly preferred.
  • compositions of the present disclosure typically contain about 2 to 30% by weight and more typically 4 to 10% by weight of the ester and, when present, about 0.5 to about 20% by weight, more typically 1 to about 20% weight, and even more typically 1 to about 10% weight of the alcohol. Many of the compositions contain about 2 to about 20% by weight or, 2 to about 10% weight of the alcohol. Compositions according to the present disclosure exhibit reduced skin irritation.
  • the polar lipid is typically dissolved in the organic solvent at mass ratios anywhere from 5:1 to 1 :5.
  • the polar lipid and organic solvent are mixed in even mass ratios.
  • soya lecithin and isopropyl myristate are mixed in equal mass ratios and mixed until the lecithin is evenly distributed in the isopropyl myristate.
  • This mixture called lecithin organogel (L.O.), is stable and may be used even after prolonged storage without loss of activity.
  • the polar lipid is dissolved in the organic ester solvent and di- or polyhydric alcohol solvent at mass ratios from about 5:1 : 1 to about 1 :5:5.
  • the polar lipid and organic ester solvent and polyalcohol solvent are mixed in equal mass ratios.
  • soya lecithin, isopropyl myristate, and propylene glycol are mixed in equal mass ratios and mixed until the lecithin is evenly distributed.
  • a surfactant can be included in the formulation at a concentration of between about 0.5 or 1-20% (e.g.,0.5 or 1-5%, 5-10%, 10-15% or 15-20%) of the final composition mass.
  • the surfactant is one which is compatible with administration in vivo without elicitation of undesirable side effects.
  • One preferred surfactant is a docusate salt, such as docusate sodium or docusate calcium, and its more water soluble form, docusate sodium benzoate.
  • Other appropriate ionic or non-ionic surfactants that are optionally present in combination with the docusate salt include polysorbate 80 (e.g., TweenTM 80), tetradecyltrimethyl ammonium bromide, pentaoxyetylene glycol monododecyl ether, poloxamer 407 and triethanolamine laureth sulfate.
  • an amount of urea preferably as an aqueous solution, is typically added to the solvent-polar lipid mixture.
  • the urea is added so that the urea concentration will be between about 1% and 20% by mass (e.g., 1% to 15% or 5% to 10%) of the final composition mass.
  • a 20% aqueous solution of urea about 10 grams is added to about 100 grams of the solvent-polar lipid mixture.
  • the thickener is advantageously selected from common National Formulary or United States Pharmacopeia thickening agents including, but not limited to appropriate polymer weights of polyethylene glycol, polyvinylpyrrolidone, a polyacrylic acid (e.g., carbomer) and methylcellulose.
  • the amount of thickener is typically about 0.05 to about 5% by weight.
  • a 10% aqueous solution of urea, containing 0.7% Carbomer 934 is added to about 100 grams of the surfactant- solvent-polar lipid mixture.
  • one or more preservatives may be included in a composition of the present invention.
  • the preservative protects the composition from microbial contamination and/or oxidation.
  • the preservative can include an antioxidant.
  • Preservatives such as methyldibromo-glutaronitrile, methylchloroisothiazolinone, phenoxyethanol, diazolidinyl urea, imidazolidinyl urea, iodopropynyl butylcarbamate, chloromethylisothiazolinone, methylisothiazolinone, sodium benzoate, chloracetamide, EDTA, DMDM- hydantoin, quaternium-15, vitamin E and its derivatives including vitamin E acetate, vitamin C, butylated hydroxytoluene, methylparaben, ethylparaben, propylparaben, butylparaben, essential oils including tea tree, neem seed, and thyme, extracts including grapefruit seen and rosemary, or any mixtures thereof, may be included as a preservative in a composition of the present invention.
  • a composition of the present invention may have a combination of
  • preservative When present, about 0.01 wt. % to about 1 wt. % of preservative may be included in a composition of the present invention. In some embodiments, the present composition has one or more preservatives in an amount that totals about 0.05 wt. % to about 0.50 wt. % of the total weight of the composition.
  • the formulation comprises a biocompatible organic solvent, a polar lipid, a docusate salt water, urea, at a pH of about 5.5 to 8.0, wherein the polar lipid is lecithin or phosphatidylcholine, the biocompatible organic solvent is an isopropyl ester selected from the group consisting of isopropyl myristate and isopropyl palmitate, and the urea is present at a concentration of about 5 to 20% by mass of the final composition.
  • the formulation comprises two biocompatible organic solvents, a polar lipid, a docusate salt and optionally one or more additional surfactants, water, urea and thickener; wherein the organic solvents comprise an ester and a dihydric alcohol and/or polyhydric alcohol.
  • the formulation comprises about 2 to about 30% of the ester and about 0.5 to about 20% of the dihydric alcohol and/or polyhydric alcohol.
  • a preferred ester is isopropyl myristate
  • a preferred alcohol is propylene glycol
  • a preferred polar lipid is lecithin
  • a preferred thickener is methyl cellulose and/or polyacrylic acid (e.g. Carbopol).
  • One or more of these preferred components may be present in a formulation.
  • the formulation consists essentially of two biocompatible organic solvents, a polar lipid, a docusate salt and optionally one or more additional surfactants, water, urea and thickener; wherein the organic solvents comprise an ester and a dihydric alcohol and/or polyhydric alcohol; and wherein the composition comprises about 2 to about 30% of the ester and about 0.5 to about 20% of the dihydric alcohol and/or polyhydric alcohol.
  • Such formulations optionally comprise a preservative.
  • the formulation comprises about 10 to about 30% by weight of the polar lipid; about 0.5 to about 15% by weight of the docusate salt, about 40 to about 65% by weight of water, about 1 to about 15% by weight of the urea and about 0.05 to about 5% of weight of the thickener.
  • the formulation consists essentially of isopropyl myristate, lecithin, docusate sodium, propylene glycol, polysorbate 80, water, urea, methylcellulose, polyacrylic acid and triethanolamine.
  • the pH is adjusted to about a pH of 5.5 to 8.0, such as 5.5 to 7.5, 6.0 to 8.0 or 6.0 to 7.0. This is easily accomplished, for example, by addition of aqueous sodium hydroxide, as the compositions initially tend to have an acid pH. However, if the composition is alkaline, addition of acid to reduce the pH would be desirable.
  • aqueous hydrogen choloride citric acid or a biological buffer such as sodium carbonate or triethanolamine, as in trolamine salicylate.
  • a biological buffer such as sodium carbonate or triethanolamine
  • the formulation thickens and forms a gel for topical administration.
  • it is convenient to prepare a first gel composition which can be used to add to other components in the formulation of a final composition for topical administration.
  • a speed-gel may be prepared by mixing lecithin organogel (L.O.), as a 1 :1 (m/m) mixture of lecithin and isopropyl myristate, with LID oil (a 1 :1 [m/m] mixture of L. O. and docusate sodium), dissolving additional docusate sodium powder into this mixture, and then adding aqueous urea.
  • L.O. lecithin organogel
  • LID oil a 1 :1 [m/m] mixture of L. O. and docusate sodium
  • dissolving additional docusate sodium powder into this mixture and then adding aqueous urea.
  • the speed- gel may then be added to solubilized active ingredients and other excipients which may be useful in solubilizing the active ingredient, such as DMSO, peppermint oil, glycerin, and/or polyethylene glycol. An homogenous mixture is then made by carefully blending the various components.
  • a composition is prepared by mixing lecithin organogel (L.O.), as a 1 :1 :1 (m/m/m) mixture of lecithin, isopropyl myristate and propylene glycol, with LID oil (a 1 :1 [m/m] mixture of L.O. and docusate sodium), dissolving additional surfactant and/or docusate sodium powder into this mixture, and then adding thickened aqueous urea.
  • L.O. lecithin organogel
  • LID oil a 1 :1 [m/m] mixture of L.O. and docusate sodium
  • Excipients that may be useful include L.O., propylene glycol, isopropyl myristate, peppermint oil, glycerin, and/or polyethylene glycol. A homogenous mixture is then made by carefully blending the various components.
  • a composition is prepared by mixing lecithin organogel (L.O.), as a mixture of lecithin, isopropyl myristate, and propylene glycol, with docusate sodium and optionally an additional surfactant (e.g., polysorbate 80), and then adding to this mixture a homogenous composition of aqueous urea, thickener (e.g., polyacrylic acid), one or more preservatives (e.g., methylparaben, propylparaben, butylparaben), and optionally additional surfactant (e.g., a polyethylene glycol-polypropyelene glycol copolymer such as poloxamer 407). Trolamine is added to this combined mixture to adjust the pH, and a homogenous composition is then made by carefully blending the various components.
  • lecithin organogel L.O.
  • docusate sodium e.g., polysorbate 80
  • an additional surfactant e.g
  • the components be compounded in the order: L.O., then surfactant, then aqueous urea, then pH adjustment. Varying the approach to mixing the gel slightly but maintaining the integrity of the appropriate ratios of the components and the order of addition, still allows for the formation of an acceptable gel. Alteration of the ratios beyond the limits described herein, may interfere with product consistency and gel formation. Additional details on preparation of compositions useful in the invention can be found, for example, in U.S. Patent No. 5,654,337 and U.S. Patent Publication Nos. 2006/0078579, 2006/0078580, 2006/01 10342 and 2006/0122279, the contents of which are incorporated herein by reference.
  • compositions of the invention have activity against a wide variety of microbes.
  • the microbes are selected from Gram negative bacteria, Gram positive bacteria, anaerobic bacteria, fungi and viruses, particularly fungi or one or more of the types of bacteria listed above. All microbes have the ability to resist or become tolerant to chemotherapeutic agents, antimicrobial agents, or antibiotics.
  • Antimicrobial resistance may be innate to the microoganism, the result of genetic mutation within the microbial genome, or acquired through the lateral or vertical transfer of resistance genes or genetic elements from other organisms.
  • Antibiotic resistance is the ability of a microorganism to survive and/or reproduce in the presence of a antimicrobial agent(s) that was previously effective at killing or retarding reproduction of the microorganism.
  • compositions of the present invention can have activity against a variety of microorganisms resistant to one or more antimicrobial agents.
  • the microbes may be resistant to one or more antimicrobial (e.g., antibacterial, antifungal, and antiviral) agents.
  • antimicrobial e.g., antibacterial, antifungal, and antiviral
  • compositions of the invention can have against fungi that are resistant to at least one allylamine (e.g., naftifine, terbafine).
  • Microbes can be treated using compositions of the invention on essentially any area of the body, including the scalp, face, axilla, arms, trunk, mucosal membranes, hands, fingernails, groin, legs, toenails and feet.
  • compositions of the invention are effective against both infections and microbes present on the surface (e.g., those removed by a surgical scrub or other skin disinfectant).
  • compositions of the invention are effective in reducing the number of microbes or treating a microbial infection on or in epithelial cells, such as stratified squamous epithelial cells and epidermal appendages (e.g., keratinized or non-keratinized), stratified cuboidal cells (e.g., sweat glands, follicles), pilosebaceous glands, and the junction of epithelium and mucous membranes.
  • epithelial cells such as stratified squamous epithelial cells and epidermal appendages (e.g., keratinized or non-keratinized), stratified cuboidal cells (e.g., sweat glands, follicles), pilosebaceous glands, and the junction of epithelium and mucous membranes.
  • an effective amount of a composition of the invention is an amount sufficient to partially or completely achieve the desired objective.
  • an amount effective to treat or inhibit an infection is an amount that reduces the infection, inhibits the continued growth of an infection, reduces the symptoms resulting from an infection or maintains an infection-free or substantially infection- free (e.g., asymptomatic) state.
  • an amount effective to reduce or inhibit growth on a surface is an amount sufficient to reduce the number of microbes or to reduce the rate of growth of microbes.
  • An effective amount of antimicrobial agents is also an amount effective to treat or inhibit an infection is an amount that reduces the infection, inhibits the continued growth of an infection, reduces the symptoms resulting from an infection or maintains an infection-free or substantially infection- free (e.g., asymptomatic) state.
  • Examples of fungal infections that can be treated by administering a composition of the invention include onychomycosis (also known as tinea unguium) and dermatophytosis (also known as ringworm), which includes tinea pedis, tinea cruris, tinea versicolor, tinea corporis and tinea capitis.
  • Fungal infections include those infections caused by organisms classified generically as yeast (e.g., single celled organisms) and molds (e.g., organisms that grow with hyphae).
  • Such infections may be caused by, for example, one or more fungi selected from Trichophyton rubrum, Trichophyton mentagrophytes , Trichophyton inter digitale, Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum, Microsporum canis, Microsporum audouinii, Trichophyton tonsurans, Trichophyton soudanense, Trichophyton capitis, Scytalidium, Scopulariopsis and Aspergillus, particularly for onychomycosis.
  • Fungi that are advantageously treated with a composition of the invention include Trichophyton rubrum, Trichophyton mentagrophytes, and Trichophyton capitis.
  • Other fungal infections that can be treated using a composition of the invention include diaper dermatitis, thrush and candidal vaginitis.
  • vaginitis a microbial infection (or conditions related to a microbial infection) that can be treated using a composition of the invention
  • vaginitis a microbial infection (or conditions related to a microbial infection) that can be treated using a composition of the invention
  • vaginitis a microbial infection (or conditions related to a microbial infection) that can be treated using a composition of the invention
  • vaginitis or conditions related to a microbial infection
  • vaginitis a microbial infections (or conditions related to a microbial infection) that can be treated using a composition of the invention
  • vaginitis a composition of the invention
  • vulvovaginitis a composition of the invention
  • periodontal plaque gingivitis
  • acne rosacea
  • folliculitis infected eczema
  • impetigo a a angular cheilitis
  • paronychia a keratolysis
  • Bacterial infections that can be treated with compositions of the invention includes Streptococcus and Staphylococcus infections, particularly antibiotic- resistant Staphylococcus infections such as methicillin-resistant S. aureus.
  • Viral infections that can be treated with compositions of the invention include warts, HPV, herpes simplex 1 and 2, along with viral lesions.
  • compositions of the invention are also useful for preventing superinfection of a wound or lesion caused by or associated with a first microbial infection (e.g., HIV transmission via a herpes lesion).
  • a first microbial infection e.g., HIV transmission via a herpes lesion
  • compositions of the invention can also be used to sterilize surfaces, such as kitchen, bathroom and hospital floors, walls, cabinets and counter tops, medical devices and other inanimate objects in general.
  • the compositions can be used as a surgical scrub and skin disinfectant.
  • a physician can determine the appropriate amount based on, for example, the condition to be treated, its severity and the age, weight and sex of the subject to be treated.
  • Subjects include humans, companion animals (e.g., cats, dogs), livestock animals (e.g., horses, cows, sheep, goats, deer) and research animals (e.g., mice, rats, monkeys).
  • compositions of the invention can be applied to the location where desired, such as topically (e.g., skin or nails) or on a mucosal membrane.
  • the improvements include one or more of the nail color, the nail clarity, the nail smoothness and the nail integrity.
  • improving the appearance of a nail involves improving the health of a nail where the nail is broken or damaged.
  • the improvement in the nail includes, for example, decreasing the roughness of the nail surface, reducing any discoloration or opaqueness of the nail or reducing any splitting of a nail.
  • Wounds that can be treated using compositions of the invention include fungating tumors, bed sores, pressure ulcers, venous ulcers and arterial ulcers. It is contemplated that the compositions of this invention are administered as frequently as required as long as local reactions or toxicity do not become a problem.
  • compositions of the invention can be packaged in any appropriate container or impregnated (partially or completely) into an article.
  • impregnated articles include articles that are coated with a composition as well as those where the composition is present on more than surfaces (e.g., the composition has to some degree penetrated into the article).
  • Suitable containers include an aerosol can, an atomizer, ajar having a pump, a rollette and a tube container.
  • Suitable articles include medical devices, gauze pads, bandages, wound dressings, packages and packaging materials, tissues, towels and towelettes.
  • non-woven substrates such as wet-creped hand towels and spunbonded and meltblown polymeric web commonly used in disposable hospital items such as surgical drapes, gowns, bedsheets, pillow cases and textile materials and the like can be impregnated with compositions of the invention.
  • Hygienic face masks used by persons suffering from respiratory illness or by persons working in a dusty environment where the dust is contaminated with pathogenic fungal spores can be impregnated with an anti-fungally effective amount of compositions of the invention.
  • disposable diapers can be impregnated with compositions of the invention as well as tampons and intravaginal sponges and the like.
  • Compositions of the invention may also be provided in an appropriate carrier as a vaginal douche.
  • Vessel #3 To a clean 6 qt SS beaker (vessel #3) were added 13.0 g of isopropyl myristate, NF. Vessel #3 was placed on a hot plate and a stirrer was added. The speed was adjusted so that a vortex was created while stirring. To vessel #3 was added 14.6-14.7 g of lecithin, NF portionwise. Vessel #3 was heated to 40-45 °C. When the lecithin was dispersed, 1.05 g of Docusate sodium, USP was added to vessel #3. Next, 1.9 g of propylene glycol, USP was added to vessel #3, followed by 0.6 g of polysorbate 80, NF. Stirring was continued until all solids were dissolved. Vessel #3 was cooled to 25 0 C in a water/ice bath.
  • vessel #3 The contents of vessel #3 were slowly added to vessel #2 while stirring continued. Once all of the vessel #3 contents had been added, the mixture was stirred for an additional 30 min. To a clean, tared 2 qt SS beaker (vessel #4) was added the combined contents of vessels #2 and #3 with sufficient purified water, USP to bring the total mass in vessel #4 to 200 g.
  • the final formulation contained 0.5% docusate sodium w/w and is referred to below as Formulation A.
  • Formulations B-I were prepared according to the method described above, but with a weight percentage of docusate sodium of 1 %, 1.5%, 3%, 5%, 7.5%, 10%, 15% and 20%, respectively.
  • a control formulation included no docusate sodium.
  • a clean SS beaker (vessel #2) were added 35.915 g of Isopropyl Myristate, NF. Vessel #2 was placed on a hot plate and a stirrer #2 was added. The speed was adjusted so that a vortex was created while stirring. While maintaining a temperature of 60 ⁇ 5°C, 40.205 g of lecithin, NF was added portionwise to vessel #2. With constant stirring and maintaining temperature, 27.5 g of docusate sodium, USP was added portionwise to the mixture and continuously stirred until all solids were dissolved. Next, 5.39 g of propylene glycol, USP was added to vessel #2, followed by 1.65 g of polysorbate 80, NF. Stirring was continued with the internal temperature being maintained at 60 ⁇ 5°C until the mixture was homogeneous.
  • the pH of the mixture can be adjusted using a IN NaOH or IN HCl solution. After pH adjustment, the contents were mixed for five minutes and then pH was measured again. The procedure was repeated until the content were stably measured at pH 6.5. The final formulation contained 5.0% docusate sodium w/w.
  • Formulations A-I were assessed by placing an amount of the formulations on an agar plate inoculated with a dermatophyte.
  • the inoculum was prepared from the 7-day-old cultures of dermatophyte isolates grown on potato dextrose agar slant. Briefly, 3 mL of sterile saline was added on the slant and rubbed gently with the help of sterile swab tip. The inoculum was collected into a sterile tube and kept for 20-30 minutes to settle down the heavy conidia and hyphal fragments.
  • the upper homogenous phase containing conidia and small hyphal fragments was collected into the new sterile glass tube and adjusted to 0.5 McFarland density standards.
  • Saboraurd dextrose agar plates 150 mm size were inoculated by dipping a sterile cotton swab two times into the respective inoculum suspension and evenly streaking the swab in three directions over the entire surface.
  • the inoculated agar surface was allowed to dry for 10-15 min.
  • To determine the zone of inhibition 6 mm well was made into the centre of the inoculated agar using sterile Pasteur pipette (Fisher Scientific, Nepean, Canada) and 100 ⁇ l of drug formulation loaded in the well.
  • Inhibition zone diameter was measured in millimeter (mm) using a dial caliper after 6-days of incubation at 28°C.
  • Formulations containing 5% w/w or more of docusate demonstrated activity against both dermatophytes.
  • Table 1 Antifungal activity of Formulations A-I against T. rubrum and T. mentagrophytes isolates using agar diffusion method.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Dermatology (AREA)
  • Oncology (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention porte sur des compositions antimicrobiennes qui conviennent pour le traitement d'états comprenant l'onychomycose, un aspect d'ongle médiocre et un tissu infecté et qui conviennent également pour désinfecter des surfaces qui contiennent un lipide polaire, un solvant organique biocompatible, un sel de docusate, de l'eau et de l'urée. De telles compositions ne comptent pas sur un agent pharmaceutiquement actif séparé pour leurs propriétés antimicrobiennes.
PCT/US2008/012056 2007-10-25 2008-10-23 Compositions antimicrobiennes comprenant du docusate Ceased WO2009054992A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US62807P 2007-10-25 2007-10-25
US61/000,628 2007-10-25
US19603308P 2008-10-14 2008-10-14
US61/196,033 2008-10-14

Publications (1)

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WO2009054992A1 true WO2009054992A1 (fr) 2009-04-30

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8778365B1 (en) 2013-01-31 2014-07-15 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
WO2014121048A3 (fr) * 2013-01-31 2014-10-23 Merz Pharmaceuticals, Llc Compositions topiques et procédés de préparation et d'utilisation correspondants
US9446131B2 (en) 2013-01-31 2016-09-20 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9452173B2 (en) 2013-01-31 2016-09-27 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
WO2022138565A1 (fr) * 2020-12-22 2022-06-30 ライオン株式会社 Agent anti-inflammatoire

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Publication number Priority date Publication date Assignee Title
US4717737A (en) * 1985-06-05 1988-01-05 Gerald N. Kern Anti-bacterial methods and agent
US4885310A (en) * 1985-05-09 1989-12-05 Gerald N. Kern Anti-fungal methods and agent
US5654337A (en) * 1995-03-24 1997-08-05 II William Scott Snyder Topical formulation for local delivery of a pharmaceutically active agent
US20060110342A1 (en) * 2004-10-08 2006-05-25 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US4885310A (en) * 1985-05-09 1989-12-05 Gerald N. Kern Anti-fungal methods and agent
US4717737A (en) * 1985-06-05 1988-01-05 Gerald N. Kern Anti-bacterial methods and agent
US5654337A (en) * 1995-03-24 1997-08-05 II William Scott Snyder Topical formulation for local delivery of a pharmaceutically active agent
US20060110342A1 (en) * 2004-10-08 2006-05-25 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8778365B1 (en) 2013-01-31 2014-07-15 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
WO2014121048A3 (fr) * 2013-01-31 2014-10-23 Merz Pharmaceuticals, Llc Compositions topiques et procédés de préparation et d'utilisation correspondants
US9161914B2 (en) 2013-01-31 2015-10-20 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9433680B2 (en) 2013-01-31 2016-09-06 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9446131B2 (en) 2013-01-31 2016-09-20 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9452173B2 (en) 2013-01-31 2016-09-27 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US10166206B2 (en) 2013-01-31 2019-01-01 Sebela International Bermuda Limited Topical compositions and methods for making and using same
US10166205B2 (en) 2013-01-31 2019-01-01 Sebela International Bermuda Limited Topical compositions and methods for making and using same
US10695303B2 (en) 2013-01-31 2020-06-30 Sebela Ireland Limited Topical compositions and methods for making and using same
US10729667B2 (en) 2013-01-31 2020-08-04 Sebela Ireland Limited Topical compositions and methods for making and using same
WO2022138565A1 (fr) * 2020-12-22 2022-06-30 ライオン株式会社 Agent anti-inflammatoire

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