WO2010086726A1 - Compositions for nail and skin treatment - Google Patents

Compositions for nail and skin treatment Download PDF

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Publication number
WO2010086726A1
WO2010086726A1 PCT/IB2010/000171 IB2010000171W WO2010086726A1 WO 2010086726 A1 WO2010086726 A1 WO 2010086726A1 IB 2010000171 W IB2010000171 W IB 2010000171W WO 2010086726 A1 WO2010086726 A1 WO 2010086726A1
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WO
WIPO (PCT)
Prior art keywords
composition
nail
film
skin
combinations
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Application number
PCT/IB2010/000171
Other languages
French (fr)
Inventor
Elka Touitou
Original Assignee
Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd.
Priority to JP2011546993A priority Critical patent/JP2012516320A/en
Priority to EP10735529.9A priority patent/EP2391344B1/en
Publication of WO2010086726A1 publication Critical patent/WO2010086726A1/en
Priority to US13/137,259 priority patent/US9668987B2/en
Priority to US15/413,987 priority patent/US20170224629A1/en

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    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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    • 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
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    • 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
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    • 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
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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Definitions

  • Nail fungal infections are a widespread and hard to cure affliction, and so are some other skin afflictions. While several systemic and topical treatments are commercially available, none is completely satisfactory, as evidenced by the continuous effort to find new therapeutic methods.
  • the nail fungal infection known as onychomycosis caused mainly by the dermatophyte trichphyton rubrum, is particularly difficult to treat, and while some treatments prove effective, there are significant side-effects and the infection is recurrent.
  • the most prominent drugs for nail fungal infections are terbinafine and ciclopirox. Other antifungal drugs in use or development include griseofulvin, posaconazole, amorolfine, itraconazole, econazole and butenafine.
  • Terbinafine (Lamisil®), a very effective drug for the treatment of onychomycosis (tinea unguium), is mainly administered systemically, despite the known side-effects like liver toxicity.
  • Terbinafine is commercially available also as the 1% Lamisil® OTC topical cream, but the indications for the cream are different.
  • Penlac® nail lacquer is a 8% ciclopirox topical solution which is applied once daily and repeatedly to the nail and to the skin beneath it to form a lacquer layer.
  • Another commercial nail lacquer is 5% amorolf ⁇ ne, commercially available as OTC in the UK as Loceryl or Curanail.
  • Penlac® composition includes the following ingredients: each gram of PENLAC® NAIL LACQUER (ciclopirox) Topical Solution, 8%, contains 80 mg ciclopirox in a solution base consisting of ethyl acetate, NF; isopropyl alcohol, USP; and butyl monoester of poly [methyl vinyl ether/maleic acid] in isopropyl alcohol. Ethyl acetate and isopropyl alcohol are solvents that vaporize after application.
  • the activity of the topical lacquers like Penlac® depends in large measure on the composition of the film that forms on the nail after the evaporation of the solvents.
  • the film is formed by ciclopirox in butyl monoester of poly[methylvinyl ether/maleic acid (Gantrez® ES-435), a copolymer.
  • Conventional antifungal compositions exhibit poor to marginal efficacy against nail fungal infections, and there is clearly an unmet need for antifungal compositions with improved efficacy in the treatment of nail fungal infections.
  • the present invention successfully addresses unmet medical needs, providing innovative drug delivery systems that result in structured films having as main elements the active(s), phospholipids and a film-forming ingredient.
  • the compositions of the present invention exclude terbinafine and salts thereof, and preferably are liquid compositions comprising at least one active agent, at least one volatile solvent, at least one film-forming ingredient, at least one phospholipid and, optionally, other pharmaceutically acceptable ingredients.
  • the compositions of the invention preferably are applied to the nail or skin treated surfaces as solutions that are in the form of a lacquer.
  • compositions of the invention After the compositions of the invention are applied, rapid drying of the volatiles results in a film on the treated surface, which film exhibits a web-like structure containing the active(s), the phospholipid(s), other pharmaceutically acceptable ingredients, which may include residual solvents.
  • These structured arrangements exhibit sustained and improved delivery of the active to the treated nail or skin. While we do not wish to be bound by any specific theory, we believe that the improved delivery is due to the reservoir effect of the web-like structures.
  • the film formed adheres to the skin or nail surface, is substantive to it, and contains the drug incorporated mainly in the web-structure which probably acts as a reservoir for the active.
  • the compositions of this invention contain a sufficiently high concentration of volatile solvent(s) to afford a rapid formation of a continuous, cohesive film on the treated nail or skin surface.
  • the structures in the film are formed due to the presence of phospholipids and film-forming ingredient in the composition. In the absence of phospholipids, no such web-like structure as are observed. The presence of volatile solvents in the composition allows for quick formation of stable and continuous films.
  • This system allows for improved and sustained drug delivery and drug retention into the tissue, which is believed to be due to the reservoir effect and the phospholipid's presence and effect.
  • compositions of the present invention may be applied once to multiple times per day and repeated until complete remission.
  • effectiveness of the compositions of the present invention enables a shortened period of treatment with superior results..
  • Figure 1 depicts a fluorescence micrograph image of film obtained from Formulation No. I —Olympus Fluoview IXLO Confocal Laser Scanning Microscope.
  • the probe used - Fluorescein DHPE (iV-(fluorescein-5-thiocarbamoyl)--l,2-dihexadecanoyl-,5'ft- glycero-3-phosphoethanolamiiie, triethylamnionium salt) InvitrogenTM'
  • the web structure incorporating the probe is evident in the micrograph.
  • Figure 2 depicts a fluorescence micrograph image of the film obtained from Formulation No. I —Olympus Fluoview IXLO Confocal Laser Scanning Microscope.
  • the probe used - Fluorescein DHPE (iV-(fluorescein-5-thiocarbamoyl)--l,2-dihexadecanoyl-,5'ft- glycero
  • Figure 3 depicts a light micrograph image of the film obtained from Formulation
  • No. I - Axioscope Zeiss microscope connected by a C-mount to a video camera, a TV screen and a PC.
  • Figure 4 depicts a light micrograph image of the film formed by Formulation No.
  • the formulation contains polymer but not phospholipid.
  • Figure 5 depicts a light micrograph image of the film obtained from Formulation
  • Figure 6 depicts a light micrograph image of the film obtained from Formulation
  • No. XIV - Axioscope Zeiss microscope connected by a C-mount to a video camera, a TV screen and a PC.
  • Figure 7 depicts a light micrograph image of the film obtained from Formulation
  • No. XV - Axioscope Zeiss microscope connected by a C-mount to a video camera, a TV screen and a PC.
  • Figure 8 depicts a light micrograph image of the film obtained from Formulation
  • No. XVI - Axioscope Zeiss microscope connected by a C-mount to a video camera, a TV screen and a PC.
  • Figure 9 depicts a light micrograph image of the film obtained from Formulation
  • Figure 10 depicts a light micrograph image of the film obtained from Formulation
  • Figure 11 depicts a light micrograph image of the film obtained from Formulation
  • Figure 12 depicts a light micrograph image of the film obtained from Formulation
  • Figure 13 depicts a light micrograph image of the film obtained from Formulation
  • Figure 14 depicts a light micrograph image of the film obtained from Formulation
  • Figure 15 depicts a light micrograph image of the film obtained from Formulation
  • Figure 16 depicts a light micrograph image of the film obtained from Formulation
  • No. XXIV - Axioscope Zeiss microscope connected by a C-mount to a video camera, a TV screen and a PC.
  • compositions for topical application resulting in structured continuous, cohesive films following evaporation of volatiles in the composition, said films containing web-like structures serving as drug reservoirs.
  • the present invention also provides liquid compositions, that can be applied on the nail or skin, to form a structured webbed film after application.
  • the present invention additionally provides liquid compositions, that can be applied on the nail or skin for medical use, cosmetic use or veterinary use.
  • compositions comprising a phospholipid, a film- forming ingredient and high concentration of volatile solvents, result in films exhibiting novel and hitherto unknown web-like structures. When the compositions comprise one or more actives, these actives become part of the web, which is acting like a reservoir for the active(s).
  • compositions comprising an active, a phospholipid, at least one volatile solvent, optionally water and/or a glycol and at least one film-forming ingredient, wherein a cohesive film exhibiting a web-like structure is formed on application on the treated nail or skin and rapid subsequent evaporation of the volatiles.
  • the film-forming ingredient, the phospholipid, other ingredients, residual solvent(s) and the active are part of the novel webbed structures.
  • compositions of this invention are preferably liquid, in the form of solution, lotion, low viscosity gel, spray, lacquer, foam, emulsion, patch, drug reservoir, suspension or cream.
  • compositions of the present invention comprise a therapeutically effective amount of drug or agent (e.g., an antifungal agent), excluding terbinafine and salts thereof, and pharmaceutically/cosmetically acceptable inactive ingredients.
  • drug or agent e.g., an antifungal agent
  • terbinafine and salts thereof e.g., terbinafine and salts thereof, and pharmaceutically/cosmetically acceptable inactive ingredients.
  • the agent can be selected from the group comprising antimicrobials, anti aging, antivirals, anti-mycotics, anti-parasitics, antiinflammatory, anthelminic drugs, anti hirsutism, anti wrinkle, pain management drugs, anti-worms, anti-ringworms, anti-warts, anti-yeast, erectile dysfunction drugs, vasodilators, vasoconstrictors, vitamins, colors, impetigo treatments, albinos treatment drugs, immuno suppressing agents, psoriasis drugs, melanin, pigments, peptides, amino-acids, hormones, anti cancer, analgesic, anesthetics, antihistamines, steroids, retinoids, seborrhea treatment drugs, acne drugs, atopic dermatitis drugs, rosacea drugs, vitiligo drugs, keratosis pilaris drugs treatment, alopecia drugs treatment, dermatitis drugs, eczema drugs, hyper
  • Exemplary agents can include, e.g., 5-fluorouracil, 19-nortestosterone, acetaminophen, acyclovir, alitretinoin, polypeptides, alprostadil, anti histamines, azatadine, azelaic acid, bacitracin, becaplermin, benzocaine, benzophenone, benzoyl peroxide, betamethasone, betamethasone dipropionate, betamethasone valerate, botox, botox like compounds, caffeine, capsaicin, ceramides, cetirizine, cimetidine, clindamycine, clobetasol propionate, clobetasone butyrate, clotrimazole, copper peptides, cortisone, corticosteroids, crotamiton, cyclizine, cyproheptadine, dexamethasone Na sulphate
  • the nail or skin fungal infections can include, for example, onychomycosis, dermatomycosis, hyperkeratotic skin diseases, seborrheic eczema, thickened skin and chapped skin.
  • the antifungal agent can include ciclopirox, amorolfine, griseofulvine, posaconazole, itraconazole, econazole, butenafine, or other regulatory approved topical antifungal drug, as well as borax, geraniol (3,7-dimethylocta-2,6-dien-l-ol), or any combination of the foregoing.
  • the compositions of this invention comprise: a. 0.01 -20% of at least one drug/active agent, b. 0.2-15 % w/w of at least one film-forming ingredient, c. 0.2-20% w/w of at least one phospholipid, d.
  • At least one volatile solvent e. 0-40% w/w water
  • f. 0-10% of an alkaline (basic) molecule g. 0-30% of a hydrophilic agent such as glycols, trehalose, PCA, NaPCA, h. 0-10% of a base, selected from pharmaceutically acceptable bases, like but not limited to sodium hydroxide, potassium hydroxide, triethanolamine, tromethamine and ammonia.
  • pharmaceutically acceptable bases like but not limited to sodium hydroxide, potassium hydroxide, triethanolamine, tromethamine and ammonia.
  • other pharmaceutically acceptable excipients like but not limited to, plasticizers, emollients, sunscreens, pigments, antioxidants, stabilizers, perfumes, etc. according to need.
  • the phospholipid may be selected from, e.g., soy lecithin, egg lecithin, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, synthetic phospholipids, PEG-ylated phospholipids, phosphorylated lipids, phosphorylated vitamin E and mixtures thereof.
  • the concentration of the phospholipid in the compositions of the present invention preferably ranges from 0.2-10%.
  • the film-forming ingredient may be selected from, e.g., ethyl cellulose, esters of polyfmethylvinyl ether/maleic acid] copolymer, PVP, PVA, PVP/PVA combinations, cationic cellulose polymers, chitosan, chitosan derivatives, polyacrylates, Eudragits, other pharmaceutically acceptable polymers or combinations thereof.
  • the film-forming ingredient in the compositions of the present invention can range from 0.2-15%, and preferably ranges from 0.5-5%, and more preferably from 0.5-2%.
  • the composition comprises a hydrophilic film-forming ingredient selected from cellulose derivatives, hydroxypropylcellulose, hydroxyethylcellulose, PVP and others.
  • the film-forming ingredient includes a non-ionic, water-soluble cellulose ether such as, for example, hydroxypropylcellulose, an example of which includes Klucel®, e.g., Klucel® HF, a hydroxypropylcellulose that is sold in the United States by Hercules Inc., Wilmington, DE.
  • the volatile solvents preferably are selected from ethyl acetate, C2-C4 alcohols, ethanol, isopropanol, n-propanol and butanol (hereinafter “alcohol” or “alcohols”), and combinations thereof.
  • the glycol which can be used in the compositions of the invention, is preferably selected from ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, tetraglycol, butylene glycol, hexylene glycol and glycol esters or ethers like ethylene glycol monomethyl ether, diethylene glycol monoethyl ether, or other pharmaceutically acceptable glycols (hereinafter "glycol” or "glycols”) and combinations thereof.
  • glycol ethylene glycol monomethyl ether
  • diethylene glycol monoethyl ether diethylene glycol monoethyl ether
  • glycol esters or ethers like ethylene glycol monomethyl ether, diethylene glycol monoethyl ether, or other pharmaceutically acceptable glycols (hereinafter "glycol" or "glycols") and combinations thereof.
  • Propylene glycol is among the preferred glycols.
  • the glycol concentration (e.g., the propylene glycol concentration) is preferably from about 5 wt% to about 20 wt%, e.g., from about 5 wt% to about 15 wt% (e.g., about 13 wt%).
  • a total high concentration of all the volatiles in the compositions is desirable, being conducive to a rapid drying time and film formation.
  • the concentration of volatiles in the composition can range, e.g., from 50-95%, and is preferably from 60-90%, and more preferably from 65-85%.
  • compositions comprise a phospholipid, ethanol, and water, a film forming ingredient, at least one active and optionally sodium hydroxide or potassium hydroxide.
  • the composition of the invention comprises a phospholipid, ethanol, glycol, and water, a film forming ingredient, an active, optionally sodium hydroxide or potassium hydroxide.
  • the composition of the invention comprises a phospholipid, ethanol, water, a hydrophilic film forming polymer, at least one active and optionally a base like sodium hydroxide or potassium hydroxide.
  • the composition of the invention comprises a phospholipid, ethanol, and water, a hydrophilic film forming polymer, an active, optionally glycol and optionally sodium hydroxide or potassium hydroxide.
  • the concentration of the active in the composition of the invention can range from 0. 01% to 20%.
  • the present invention provides nail and skin lacquers, providing a film containing phospholipid web-like structures over the treated nail and skin areas, thus improving the usefulness of the treatment.
  • the present invention provides compositions that form an occlusive structured film over skin and mucosal areas afflicted by various skin afflictions, thus improving the treatment of said skin afflictions.
  • the skin afflictions suitable for treatment by said method of treatment are selected from psoriasis, eczema, acne, fungal infections, atopic dermatitis, immune system diseases, antimicrobial infections, viral infections, warts, impetigo, skin discoloration, cancer, dermatitis, inflammation, hyperhidrosis, alopecia, onychomycosis, rosacea, pain, allergy or varicose veins.
  • the nail or skin fungal infections suitable for treatment include, e.g., onychomycosis, dermatomycosis, hyperkeratotic skin diseases, seborrheic eczema, viral infections, impetigo, inflammation, warts, thickened skin and chapped skin.
  • a preferred active in the instant compositions islidocaine, or Lidocaine HCl.
  • a preferred lidocaine topical composition comprises 5% lidocaine, 2% phospholipid, 0.5-1.5% Klucel® HF 5 65% ethanol 96, 0-30% ethyl acetate, 0-10% propylene glycol , and water to 100%
  • lidocaine topical composition comprises 7% lidocaine HCl, 3- 6% phospholipid, 0.3-1.5% Klucel® HF, 60-85% ethanol, 0.3% vitamin E 5 0-20% propylene glycol and water to 100%
  • a preferred tizanidine HCL topical composition comprises 5% tizanidine HCl, 4% phospholipid, 0.5-1.5% hydroxypropylethyl cellulose, 60-75% ethanol 96, 0-13% Isopropyl alcohol and water to 100%.
  • the concentration of ciclopirox in the compositions of this invention preferably ranges from 0.1% to 20% and more preferably 1% to 15%.
  • the concentration of griseofulvine in the compositions of this invention preferably ranges from 0.1% to 20% and more preferably 1% to 15%.
  • the concentration of amorolfme in the compositions of this invention preferably ranges from 0.1% to 20% and more preferably 1% to 15%.
  • the concentration of posaconazole in the compositions of this invention preferably ranges from 0.1% to 20% and more preferably 1% to 15%.
  • the nail and skin afflictions treated by the compositions of this invention are fungi, yeasts and moulds.
  • compositions of the present invention are topical solutions, to be applied evenly on the skin or nail with a brush, spatula, pipette, applicator, metered spray or mist, sponge or patch.
  • the volatiles in the composition preferably evaporate rapidly after application, leaving on the nail a thin cohesive film substantive to the applied surface containing phospholipid structured reservoirs that release the drug(s) to the site of application.
  • the application may be done once to multiple times daily and repeated as per physician's instructions.
  • the composition should be applied evenly over the entire nail plate and 5 mm of surrounding skin. If possible, it should be applied to the nail bed, and the under surface of the nail plate when it is free of the nail bed. The next day, an additional application is done on the previous coat or on the cleaned nail plate.
  • Removal of the unattached, infected nail, as frequently as monthly, by a healthcare professional may be needed. The effectiveness of said compositions could enable a shortened period of treatment with superior results.
  • compositions of Formulation No. I and comparison Formulation No. II are detailed in Table No. 1 below:
  • Hydroxypropyl cellulose was dispersed speedily to the above composition with continuous mixing at 700 RPM by Heildolph RZR-2000 Stirrer equipped with Pitched
  • composition was mixed thoroughly at 700 RPM by Heildolph RZR-2000
  • Fluorescence imagining was performed by means of Olympus Fluoview IXLO
  • phospholipid, lidocaine and vitamin E were dissolved in ethanol-propylene glycol mixture with continuous mixing at 700 RPM. Water was added with continuous mixing. Hydroxypropylcellulose was dispersed to the above composition with continuous mixing at 700 RPM for 15 minutes. The composition left rest for about until next day and then mixed again for ten minutes. A clear homogenic formulation was obtained.
  • a drop of the above formulation was applied and spread on a slide glass and left at room temperature for to allow evaporation of the solvents and film formation.
  • the slides were observed by light microscopy.
  • Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
  • a film containing web-like structures is observed ( Figure 5).
  • phospholipid and vitamin E were dissolved in ethanol- propylene glycol mixture with continuous mixing at 700 RPM.
  • Lidocaine HCl was dissolved in water and the aqueous solution was added with continuous mixing to the above solvents mixture.
  • Hydroxypropylcellulose was dispersed to the above composition with continuous mixing at 700 RPM for 15 minutes. The composition was left to rest until next day and then mixed again for ten minutes. A clear homogeneous formulation was obtained.
  • Formulation No. XIV was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed ( Figure 6). EXAMPLE 14
  • Formulation No. XV was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed ( Figure 7).
  • Formulation No. XVI was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed ( Figure 8). EXAMPLE 16
  • Formulation No. XVII was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed ( Figure 9).
  • Formulation No XVIII was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed ( Figure 10). EXAMPLE 18
  • Formulation No. XIX was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed ( Figure 11).
  • Formulations Nos. XX and XXI were prepared according to the methods described above. A drop of the above formulations was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed for Formulation XX ( Figure 12) and Formulation XXI ( Figure 13). EXAMPLE 20
  • Formulation No XXII was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed ( Figure 14).
  • This example illustrates a protocol for evaluating the drug amount retained by the nail after application of a composition of the present invention on clipped nails.

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Abstract

Novel topical compositions for the treatment of nail and skin afflictions comprising at least one active, excluding terbinafine, at least one volatile solvent, at least one film-forming ingredient and at least one phospholipid, processes for their preparation and methods of treatment of nail and skin afflictions. Following application of the compositions and evaporation of volatile solvents, the composition produces a film, which has web-like structures containing the active(s).

Description

COMPOSITIONS FORNAIL AND SKIN TREATMENT
BACKGROUND OF THE INVENTION
[0001] Nail fungal infections are a widespread and hard to cure affliction, and so are some other skin afflictions. While several systemic and topical treatments are commercially available, none is completely satisfactory, as evidenced by the continuous effort to find new therapeutic methods. The nail fungal infection known as onychomycosis, caused mainly by the dermatophyte trichphyton rubrum, is particularly difficult to treat, and while some treatments prove effective, there are significant side-effects and the infection is recurrent. [0002] The most prominent drugs for nail fungal infections are terbinafine and ciclopirox. Other antifungal drugs in use or development include griseofulvin, posaconazole, amorolfine, itraconazole, econazole and butenafine.
[0003] Terbinafine (Lamisil®), a very effective drug for the treatment of onychomycosis (tinea unguium), is mainly administered systemically, despite the known side-effects like liver toxicity. Terbinafine is commercially available also as the 1% Lamisil® OTC topical cream, but the indications for the cream are different.
[0004] The significant side-effects are the main reason why topical treatments, likely to diminish the systemic effects, are being coveted, and attempts are being made to develop efficient topical drugs, with minimal side-effects.
[0005] The FDA www.ClinicalTrials.gov site lists 15 clinical studies with terbinafine, mostly topical treatments against onychomycosis, including terbinafine nail lacquer. Higher concentrations of terbinafine and alternative actives, like posaconazole and 5% amorolfine nail lacquer are being investigated as possible treatment for nail fungal infections, which evidences the fact that there is still an unmet medical need for safe and effective topical treatments of nail fungal infections. Only four clinical studies are listed on this site for ciclopirox, out of which none for onychomycosis or other nail infections, which shows that ciclopirox is not considered a preferred treatment, while terbinafine is. [0006] Another antifungal drug, ciclopirox, of limited antifungal activity, is administered only topically. The commercial product Penlac® nail lacquer is a 8% ciclopirox topical solution which is applied once daily and repeatedly to the nail and to the skin beneath it to form a lacquer layer. Another commercial nail lacquer is 5% amorolfϊne, commercially available as OTC in the UK as Loceryl or Curanail.
[0007] The nail application of Penlac® results in formation of a dry film, after evaporation of the liquid components of the composition. Penlac® composition includes the following ingredients: each gram of PENLAC® NAIL LACQUER (ciclopirox) Topical Solution, 8%, contains 80 mg ciclopirox in a solution base consisting of ethyl acetate, NF; isopropyl alcohol, USP; and butyl monoester of poly [methyl vinyl ether/maleic acid] in isopropyl alcohol. Ethyl acetate and isopropyl alcohol are solvents that vaporize after application.
[0008] The activity of the topical lacquers like Penlac® depends in large measure on the composition of the film that forms on the nail after the evaporation of the solvents. In the Penlac® case, after the evaporation of the solvents, the film is formed by ciclopirox in butyl monoester of poly[methylvinyl ether/maleic acid (Gantrez® ES-435), a copolymer. [0009] Conventional antifungal compositions, however, exhibit poor to marginal efficacy against nail fungal infections, and there is clearly an unmet need for antifungal compositions with improved efficacy in the treatment of nail fungal infections.
SUMMARY OF THE INVENTION
[0010] The present invention successfully addresses unmet medical needs, providing innovative drug delivery systems that result in structured films having as main elements the active(s), phospholipids and a film-forming ingredient. The compositions of the present invention exclude terbinafine and salts thereof, and preferably are liquid compositions comprising at least one active agent, at least one volatile solvent, at least one film-forming ingredient, at least one phospholipid and, optionally, other pharmaceutically acceptable ingredients. The compositions of the invention preferably are applied to the nail or skin treated surfaces as solutions that are in the form of a lacquer. After the compositions of the invention are applied, rapid drying of the volatiles results in a film on the treated surface, which film exhibits a web-like structure containing the active(s), the phospholipid(s), other pharmaceutically acceptable ingredients, which may include residual solvents. These structured arrangements exhibit sustained and improved delivery of the active to the treated nail or skin. While we do not wish to be bound by any specific theory, we believe that the improved delivery is due to the reservoir effect of the web-like structures.
[0011] The film formed adheres to the skin or nail surface, is substantive to it, and contains the drug incorporated mainly in the web-structure which probably acts as a reservoir for the active. The compositions of this invention contain a sufficiently high concentration of volatile solvent(s) to afford a rapid formation of a continuous, cohesive film on the treated nail or skin surface. The structures in the film are formed due to the presence of phospholipids and film-forming ingredient in the composition. In the absence of phospholipids, no such web-like structure as are observed. The presence of volatile solvents in the composition allows for quick formation of stable and continuous films.
[0012] After the evaporation of solvents, a thin and continuous film containing structures resembling a web is formed on the treated surface.
[0013] Microscopy study of the films obtained from the compositions of the present invention show that a unique structure is formed and maintained in the film. Fluorescence
Microscopy (Figure 1) shows web-like arrangement structures dispersed throughout the film.
[0014] This system allows for improved and sustained drug delivery and drug retention into the tissue, which is believed to be due to the reservoir effect and the phospholipid's presence and effect.
[0015] The composition may be applied once to multiple times per day and repeated until complete remission. The effectiveness of the compositions of the present invention enables a shortened period of treatment with superior results..
[0016] These and other aspects of the invention will become apparent from the description of the invention, which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 depicts a fluorescence micrograph image of film obtained from Formulation No. I —Olympus Fluoview IXLO Confocal Laser Scanning Microscope. The probe used - Fluorescein DHPE (iV-(fluorescein-5-thiocarbamoyl)--l,2-dihexadecanoyl-,5'ft- glycero-3-phosphoethanolamiiie, triethylamnionium salt) Invitrogen™' The web structure incorporating the probe is evident in the micrograph. [0018] Figure 2 depicts a fluorescence micrograph image of the film obtained from
Formulation No. II - Olympus Fluoview IXLO Confocal Laser Scanning Microscope. The probe used Fluorescein DHPE (N-(fluorescein-5-thiocarbamoyl)-l,2-dihexadecanoyl-.s7"z- glycero-3-phosphoethanolamine triethylammonium salt) Invitrogen™ .
[0019] Figure 3 depicts a light micrograph image of the film obtained from Formulation
No. I - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0020] Figure 4 depicts a light micrograph image of the film formed by Formulation No.
II - Axioscope Zeiss light microscope, connected by a C-mount to a video camera, a TV screen and a PC. The formulation contains polymer but not phospholipid.
[0021] Figure 5 depicts a light micrograph image of the film obtained from Formulation
No. Ill - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0022] Figure 6 depicts a light micrograph image of the film obtained from Formulation
No. XIV - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0023] Figure 7 depicts a light micrograph image of the film obtained from Formulation
No. XV - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0024] Figure 8 depicts a light micrograph image of the film obtained from Formulation
No. XVI - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0025] Figure 9 depicts a light micrograph image of the film obtained from Formulation
No. XVII - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0026] Figure 10 depicts a light micrograph image of the film obtained from Formulation
No. XVIII - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0027] Figure 11 depicts a light micrograph image of the film obtained from Formulation
No. XIX - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. [0028] Figure 12 depicts a light micrograph image of the film obtained from Formulation
No. XX - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0029] Figure 13 depicts a light micrograph image of the film obtained from Formulation
No. XXI - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0030] Figure 14 depicts a light micrograph image of the film obtained from Formulation
No. XXII - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0031] Figure 15 depicts a light micrograph image of the film obtained from Formulation
No. XXIII - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0032] Figure 16 depicts a light micrograph image of the film obtained from Formulation
No. XXIV - Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
DETAILED DESCRIPTION OF THE INVENTION
[0033] This invention provides compositions for topical application, resulting in structured continuous, cohesive films following evaporation of volatiles in the composition, said films containing web-like structures serving as drug reservoirs. [0034] The present invention also provides liquid compositions, that can be applied on the nail or skin, to form a structured webbed film after application. [0035] The present invention additionally provides liquid compositions, that can be applied on the nail or skin for medical use, cosmetic use or veterinary use. [0036] We have surprisingly found that compositions comprising a phospholipid, a film- forming ingredient and high concentration of volatile solvents, result in films exhibiting novel and hitherto unknown web-like structures. When the compositions comprise one or more actives, these actives become part of the web, which is acting like a reservoir for the active(s).
[0037] In an embodiment of this invention, there are provided compositions comprising an active, a phospholipid, at least one volatile solvent, optionally water and/or a glycol and at least one film-forming ingredient, wherein a cohesive film exhibiting a web-like structure is formed on application on the treated nail or skin and rapid subsequent evaporation of the volatiles.
[0038] The film-forming ingredient, the phospholipid, other ingredients, residual solvent(s) and the active are part of the novel webbed structures.
[0039] The compositions of this invention are preferably liquid, in the form of solution, lotion, low viscosity gel, spray, lacquer, foam, emulsion, patch, drug reservoir, suspension or cream.
[0040] The compositions of the present invention comprise a therapeutically effective amount of drug or agent (e.g., an antifungal agent), excluding terbinafine and salts thereof, and pharmaceutically/cosmetically acceptable inactive ingredients.
[0041] The agent can be selected from the group comprising antimicrobials, anti aging, antivirals, anti-mycotics, anti-parasitics, antiinflammatory, anthelminic drugs, anti hirsutism, anti wrinkle, pain management drugs, anti-worms, anti-ringworms, anti-warts, anti-yeast, erectile dysfunction drugs, vasodilators, vasoconstrictors, vitamins, colors, impetigo treatments, albinos treatment drugs, immuno suppressing agents, psoriasis drugs, melanin, pigments, peptides, amino-acids, hormones, anti cancer, analgesic, anesthetics, antihistamines, steroids, retinoids, seborrhea treatment drugs, acne drugs, atopic dermatitis drugs, rosacea drugs, vitiligo drugs, keratosis pilaris drugs treatment, alopecia drugs treatment, dermatitis drugs, eczema drugs, hyperhidrosis drugs, skin discoloration drugs, overactive bladder syndrome drugs, anti rheumatic pain drugs vaccines, antigens, sun screeners, as well as other drugs or combinations thereof
[0042] Exemplary agents can include, e.g., 5-fluorouracil, 19-nortestosterone, acetaminophen, acyclovir, alitretinoin, polypeptides, alprostadil, anti histamines, azatadine, azelaic acid, bacitracin, becaplermin, benzocaine, benzophenone, benzoyl peroxide, betamethasone, betamethasone dipropionate, betamethasone valerate, botox, botox like compounds, caffeine, capsaicin, ceramides, cetirizine, cimetidine, clindamycine, clobetasol propionate, clobetasone butyrate, clotrimazole, copper peptides, cortisone, corticosteroids, crotamiton, cyclizine, cyproheptadine, dexamethasone Na sulphate, diclofenac, diflucortolone valerate, dihydroxyacetone, diphenhydramine, docosanol, doxepin, eflornithine, erythromycin, estradiol, famotidine, famotidine, fatty acids, fexofenadine, flumethasone pivalate, glycyrrhizic acid, halobetasol, hormones, hydrocortisone, hydrocortisone 17- butyrate, hydroxyzine, ibuprofen, imiquimod, immunosuppressive agents, ivermectin, ketorolac, kojic acid, lidocaine, lindane, loratidine, mafenide acetate, masoprocol, melanin, melatonin, methylprednisolone aceponate, metronidazole, minoxidil, mometasone furoate, mupirocin, mycosinate, nabumetone, nadolol, neomycin, niacinamide, nicotine, octyl- methoxycinnamate, omega acids, oxybutynin, penciclovir, permethrin, peroxicam, phenothiazines, pimecrolimus, piperazine, piperonyl butoxide, podofliox, podophyllin, polymyxin, prilocaine, propylamine derivatives, prostaglandins, pyrethrins, ranitidine, retinoic acid, retinoid, RNA, DNA, salicylic acid, selenium sulfide, silver sulfadiazine, sodium sulfacetamide, steroids, sterols, sulfacetamide, sulfur, tacrolimus, testosterone, tetracyclin, tizanidine tolterodine, triamcinolone acetonide, vancomycin, vitamins, vitamin A, vitamin D, vitamin D3 derivatives, vitamin E, whitening agents, other drugs and their salts or derivatives, and combinations thereof.
[0043] The nail or skin fungal infections can include, for example, onychomycosis, dermatomycosis, hyperkeratotic skin diseases, seborrheic eczema, thickened skin and chapped skin.
[0044] The antifungal agent can include ciclopirox, amorolfine, griseofulvine, posaconazole, itraconazole, econazole, butenafine, or other regulatory approved topical antifungal drug, as well as borax, geraniol (3,7-dimethylocta-2,6-dien-l-ol), or any combination of the foregoing. [0045] In a further embodiment, the compositions of this invention comprise: a. 0.01 -20% of at least one drug/active agent, b. 0.2-15 % w/w of at least one film-forming ingredient, c. 0.2-20% w/w of at least one phospholipid, d. 50-85% w/w of at least one volatile solvent, e. 0-40% w/w water, f. 0-10% of an alkaline (basic) molecule, g. 0-30% of a hydrophilic agent such as glycols, trehalose, PCA, NaPCA, h. 0-10% of a base, selected from pharmaceutically acceptable bases, like but not limited to sodium hydroxide, potassium hydroxide, triethanolamine, tromethamine and ammonia. i. 0-5% of other pharmaceutically acceptable excipients, like but not limited to, plasticizers, emollients, sunscreens, pigments, antioxidants, stabilizers, perfumes, etc. according to need.
[0046] The phospholipid may be selected from, e.g., soy lecithin, egg lecithin, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, synthetic phospholipids, PEG-ylated phospholipids, phosphorylated lipids, phosphorylated vitamin E and mixtures thereof. [0047] The concentration of the phospholipid in the compositions of the present invention preferably ranges from 0.2-10%.
[0048] The film-forming ingredient may be selected from, e.g., ethyl cellulose, esters of polyfmethylvinyl ether/maleic acid] copolymer, PVP, PVA, PVP/PVA combinations, cationic cellulose polymers, chitosan, chitosan derivatives, polyacrylates, Eudragits, other pharmaceutically acceptable polymers or combinations thereof.
[0049] The film-forming ingredient in the compositions of the present invention can range from 0.2-15%, and preferably ranges from 0.5-5%, and more preferably from 0.5-2%. [0050] In one embodiment the composition comprises a hydrophilic film-forming ingredient selected from cellulose derivatives, hydroxypropylcellulose, hydroxyethylcellulose, PVP and others. In some embodiments, the film-forming ingredient includes a non-ionic, water-soluble cellulose ether such as, for example, hydroxypropylcellulose, an example of which includes Klucel®, e.g., Klucel® HF, a hydroxypropylcellulose that is sold in the United States by Hercules Inc., Wilmington, DE. [0051] The volatile solvents preferably are selected from ethyl acetate, C2-C4 alcohols, ethanol, isopropanol, n-propanol and butanol (hereinafter "alcohol" or "alcohols"), and combinations thereof.
[0052] The glycol, which can be used in the compositions of the invention, is preferably selected from ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, tetraglycol, butylene glycol, hexylene glycol and glycol esters or ethers like ethylene glycol monomethyl ether, diethylene glycol monoethyl ether, or other pharmaceutically acceptable glycols (hereinafter "glycol" or "glycols") and combinations thereof. Propylene glycol is among the preferred glycols. The glycol concentration (e.g., the propylene glycol concentration) is preferably from about 5 wt% to about 20 wt%, e.g., from about 5 wt% to about 15 wt% (e.g., about 13 wt%). [0053] A total high concentration of all the volatiles in the compositions is desirable, being conducive to a rapid drying time and film formation.
[0054] The concentration of volatiles in the composition can range, e.g., from 50-95%, and is preferably from 60-90%, and more preferably from 65-85%.
[0055] In another embodiment, the compositions comprise a phospholipid, ethanol, and water, a film forming ingredient, at least one active and optionally sodium hydroxide or potassium hydroxide.
[0056] In yet another embodiment, the composition of the invention comprises a phospholipid, ethanol, glycol, and water, a film forming ingredient, an active, optionally sodium hydroxide or potassium hydroxide.
[0057] In still another embodiment, the composition of the invention comprises a phospholipid, ethanol, water, a hydrophilic film forming polymer, at least one active and optionally a base like sodium hydroxide or potassium hydroxide.
[0058] In still yet another embodiment, the composition of the invention comprises a phospholipid, ethanol, and water, a hydrophilic film forming polymer, an active, optionally glycol and optionally sodium hydroxide or potassium hydroxide.
[0059] The concentration of the active in the composition of the invention can range from 0. 01% to 20%.
[0060] In some embodiments, the present invention provides nail and skin lacquers, providing a film containing phospholipid web-like structures over the treated nail and skin areas, thus improving the usefulness of the treatment.
[0061] In other embodiments, the present invention provides compositions that form an occlusive structured film over skin and mucosal areas afflicted by various skin afflictions, thus improving the treatment of said skin afflictions. The skin afflictions suitable for treatment by said method of treatment are selected from psoriasis, eczema, acne, fungal infections, atopic dermatitis, immune system diseases, antimicrobial infections, viral infections, warts, impetigo, skin discoloration, cancer, dermatitis, inflammation, hyperhidrosis, alopecia, onychomycosis, rosacea, pain, allergy or varicose veins. [0062] The nail or skin fungal infections suitable for treatment include, e.g., onychomycosis, dermatomycosis, hyperkeratotic skin diseases, seborrheic eczema, viral infections, impetigo, inflammation, warts, thickened skin and chapped skin. [0063] A preferred active in the instant compositions islidocaine, or Lidocaine HCl. [0064] A preferred lidocaine topical composition comprises 5% lidocaine, 2% phospholipid, 0.5-1.5% Klucel® HF5 65% ethanol 96, 0-30% ethyl acetate, 0-10% propylene glycol , and water to 100%
[0065] Another preferred lidocaine topical composition comprises 7% lidocaine HCl, 3- 6% phospholipid, 0.3-1.5% Klucel® HF, 60-85% ethanol, 0.3% vitamin E5 0-20% propylene glycol and water to 100%
[0066] A preferred tizanidine HCL topical composition comprises 5% tizanidine HCl, 4% phospholipid, 0.5-1.5% hydroxypropylethyl cellulose, 60-75% ethanol 96, 0-13% Isopropyl alcohol and water to 100%.
[0067] The concentration of ciclopirox in the compositions of this invention preferably ranges from 0.1% to 20% and more preferably 1% to 15%.
[0068] The concentration of griseofulvine in the compositions of this invention preferably ranges from 0.1% to 20% and more preferably 1% to 15%.
[0069] The concentration of amorolfme in the compositions of this invention preferably ranges from 0.1% to 20% and more preferably 1% to 15%.
[0070] The concentration of posaconazole in the compositions of this invention preferably ranges from 0.1% to 20% and more preferably 1% to 15%. [0071] The nail and skin afflictions treated by the compositions of this invention are fungi, yeasts and moulds.
[0072] In an additional embodiment of this invention, there are provided methods of treatment of nail and skin fungal infections by topical administration of the compositions of the present invention to the afflicted area of nail or skin as a solution, lotion, gel, foam, cream, spray or spray lacquer, whereby after the application a film is formed on the nail or skin exhibiting phospholipid-polymer structvires, generating a drug reservoir in the film. [0073] In a preferred embodiment of this invention, the compositions are topical solutions, to be applied evenly on the skin or nail with a brush, spatula, pipette, applicator, metered spray or mist, sponge or patch.
[0074] The volatiles in the composition preferably evaporate rapidly after application, leaving on the nail a thin cohesive film substantive to the applied surface containing phospholipid structured reservoirs that release the drug(s) to the site of application. [0075] The application may be done once to multiple times daily and repeated as per physician's instructions. The composition should be applied evenly over the entire nail plate and 5 mm of surrounding skin. If possible, it should be applied to the nail bed, and the under surface of the nail plate when it is free of the nail bed. The next day, an additional application is done on the previous coat or on the cleaned nail plate. [0076] Removal of the unattached, infected nail, as frequently as monthly, by a healthcare professional may be needed. The effectiveness of said compositions could enable a shortened period of treatment with superior results.
[0077] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
[0078] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.
EXAMPLES
[0079] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
EXAMPLE 1
[0080] The compositions of Formulation No. I and comparison Formulation No. II are detailed in Table No. 1 below:
Table No. 1
Figure imgf000012_0001
[0081] Comparison between Formulation No. I (Fluorescence Microscopy Figure 1 and light microscopy Figure 3) which comprises phospholipid and hydroxypropylcellulose (Klucel HF) and Formulation No. II (Fluorescence Microscopy Figure 2 and light microscopy Figure 4) that did not contain phospholipid. It can be seen that only Formulation No. I, containing phospholipid, produced a film containing web-like structures, while Formulation No. II, lacking phospholipid, did not.
Formulation No. I - Method of preparation
[0082] In a closed vessel, the phospholipid was dissolved in ethanol. Water was added to the above solution while mixing at 700 RPM with a Heidolph RZR-2000 Mechanical
Overhead Stirrer equipped with "in house made" Pitched Propeller Blade Impeller from stainless steel (6cm diameter).
[0083] Hydroxypropyl cellulose was dispersed speedily to the above composition with continuous mixing at 700 RPM by Heildolph RZR-2000 Stirrer equipped with Pitched
Propeller Blade. The composition was left to rest for 12 hours.
[0084] The composition was mixed thoroughly at 700 RPM by Heildolph RZR-2000
Stirrer equipped with Pitched Propeller Blade.
[0085] The solution obtained applied to the nail or skin produces a film adherent to the applied area.
[0086] A drop of the above formulations was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy and CLSM.
[0087] Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC.
[0088] Fluorescence imagining was performed by means of Olympus Fluoview IXLO
Confocal Laser Scanning Microscope with the probe Fluorescein DHPE (N-(fiuorescein-5- thiocarbamoy^-l^-dihexadecanoyl-sn-glycero-S-phosphoethanolamine, triethylammonium salt) InvitrogenTM. EXAMPLE 2
Table No. 2
Figure imgf000014_0001
Preparation method of Formulation No. HI
[0089] In a closed vessel, phospholipid, lidocaine and vitamin E were dissolved in ethanol-propylene glycol mixture with continuous mixing at 700 RPM. Water was added with continuous mixing. Hydroxypropylcellulose was dispersed to the above composition with continuous mixing at 700 RPM for 15 minutes. The composition left rest for about until next day and then mixed again for ten minutes. A clear homogenic formulation was obtained.
[0090] A drop of the above formulation was applied and spread on a slide glass and left at room temperature for to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures is observed (Figure 5).
EXAMPLE 3
Table No. 3
Figure imgf000014_0002
Preparation method of formulations No. IV and No. V
[0091] In a closed vessel, phospholipid and vitamin E were dissolved in ethanol- propylene glycol mixture with continuous mixing at 700 RPM. Lidocaine HCl was dissolved in water and the aqueous solution was added with continuous mixing to the above solvents mixture. Hydroxypropylcellulose was dispersed to the above composition with continuous mixing at 700 RPM for 15 minutes. The composition was left to rest until next day and then mixed again for ten minutes. A clear homogeneous formulation was obtained.
EXAMPLE 4
Table No. 4
Figure imgf000015_0001
EXAMPLE 5
Table No. 5
Figure imgf000015_0002
EXAMPLE 6
Table No. 6
Figure imgf000016_0001
EXAMPLE 7
Table No. 7
Figure imgf000016_0002
EXAMPLE 8
Table No. 8
Figure imgf000016_0003
EXAMPLE 9
Table No. 9
Figure imgf000017_0001
EXAMPLE 10
Table No. 10
Figure imgf000017_0002
EXAMPLE 11
Table No. 11
Figure imgf000017_0003
EXAMPLE 12
Table No. 12
Figure imgf000018_0001
EXAMPLE 13
Table No. 13
Figure imgf000018_0002
[0092] Formulation No. XIV was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed (Figure 6). EXAMPLE 14
Table No. 14
Figure imgf000019_0001
[0093] Formulation No. XV was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed (Figure 7).
EXAMPLE 15
Table No. 15
Figure imgf000019_0002
[0094] Formulation No. XVI was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed (Figure 8). EXAMPLE 16
Table No. 16
Figure imgf000020_0001
[0095] Formulation No. XVII was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed (Figure 9).
EXAMPLE 17
Table No. 17
Figure imgf000020_0002
[0096] Formulation No XVIII was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed (Figure 10). EXAMPLE 18
Table No. 18
Figure imgf000021_0001
[0097] Formulation No. XIX was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed (Figure 11).
EXAMPLE 19
Table No. 19
Figure imgf000021_0002
[0098] Formulations Nos. XX and XXI were prepared according to the methods described above. A drop of the above formulations was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed for Formulation XX (Figure 12) and Formulation XXI (Figure 13). EXAMPLE 20
Table No. 20
Figure imgf000022_0001
[0099] Formulation No XXII was prepared according to the methods described above. A drop of the above formulation was applied and spread on a slide glass and left at room temperature to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed (Figure 14).
EXAMPLE 21
Table No. 21 - Water-free formulations
Figure imgf000022_0002
Preparation method of Formulations No. XXII and XXIV
[0100] In a closed vessel, phospholipid was dissolved in ethanol and propylene glycol if present with continuous mixing at 700 RPM by Heildolph RZR-2000 stirrer equipped with
Pitched Propeller Blade. Klucel was dispersed speedily to the above composition with continuous mixing at 700 RPM. The composition was left to rest for about 12 hours, then mixed thoroughly.
[0101] A drop of the above formulations was applied and spread on a slide glass and left at room temperature for to allow evaporation of the solvents and film formation. The slides were observed by light microscopy. Light microscope imaging was assessed using an Axioscope Zeiss microscope, connected by a C-mount to a video camera, a TV screen and a PC. A film containing web-like structures was observed (Figure 15 for formulation XXIII and Figure 16 for Formulation XXIV).
EXAMPLE 22
[0102] This example illustrates a protocol for evaluating the drug amount retained by the nail after application of a composition of the present invention on clipped nails.
Protocol of experiment
1. Weigh 4 samples of about 10 mg nail pieces (clipped from a healthy adult male).
2. Place each nails sample on a microscope glass slide and add on the nails about 30 mg of each formulation tested.
3. Leave the slide uncovered for about 24 hours at Room Temperature.
4. By using tweezers, introduce the nail samples in an Eppendorf and wash the nails with 1.5 ml 50% ethanol by vortexing than remove and wash again in 1.5 ml distilled water by vortexing.
5. Remove the nail pieces, using tweezers, place them on filter paper and wipe with Kimwipes until they look dry.
6. Insert each sample to 0.5 ml safe-lock Eppendorf by using tweezers and add 0.5 ml ACN: MeOH: Water mixture.
7. Shake for 24 hours for extraction.
8. Withdraw the nails by using tweezers and centrifuge the extract at 5000 RPM for 15 min. Remove 400 μl of supernatant and place it in a 0.5 ml Eppendorf.
9. Filtrate through Acrodisk GHP 0.45 μ into a safe-lock Eppendorf.
10. Inject samples to HPLC.
[0103] AU references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. In addition, the citation or identification of any reference in this application shall not be construed as an admission that such reference qualifies as prior art with respect to the present invention.
[0104] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
[0105] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:
1. A topical composition for the treatment of nail or skin afflictions in a human or animal, comprising 0.01-20% of at least one active, excluding terbinafine and salts thereof, 0.2-20% of one of more phospholipids, 50-85% of volatile solvents selected from ethyl acetate, C2-C4 alcohols or combinations thereof, 0-40% water, 0-30% of a glycol, 0.2-15% of a film-forming ingredient and optionally 0-5% other pharmaceutically acceptable ingredients, wherein following the evaporation of volatiles, a continuous film is formed on the nail or skin surface treated, said film exhibiting a web-like structure comprising the actives(s).
2. The composition of claim 1, wherein the said glycol is selected from ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, tetraglycol, butylene glycol, hexylene glycol and glycol esters or ethers like ethylene glycol monomethyl ether, diethylene glycol monoethyl ether, or other pharmaceutically acceptable glycols and combinations thereof.
3. The composition of claim 1, wherein the at least one active is selected from antimicrobials, antivirals, anti-mycotics, anti-parasitics, anti-worms, anti-ringworms, anti- warts, anti-yeast, vasodilators, vasoconstrictors, vitamins, impetigo treatments, immuno suppressing agents, anti-psoriasis drugs, melanin, pigments, peptides, amino-acids, hormones, anti-cancer, analgesic, anesthetic, antihistamines, steroids, retinoids, anti-acne drugs, atopic dermatitis drugs, rosacea drugs, keratosis pilaris drugs, deπnatitis drugs, anti- eczema drags, anti-hyperhidrosis drugs, skin discoloration drugs and combinations thereof.
4. The composition of claim 1, wherein the at least one active is selected from, ciclopirox, amorolfine, griseofulvine, posaconazole, itraconazole, econazole, butenafine, borax, geraniol, and combinations thereof.
5. The composition of claim 1 wherein the nail or skin fungal infections are selected from onychomycosis, dermatomycosis, hyperkeratotic skin diseases, seborrheic eczema, viral infections, impetigo, inflammation, warts, thickened skin, chapped skin, and combinations thereof.
6. The composition of claim 1 wherein the nail or skin fungal infections are caused by dermatophytes, non-dermatophytic molds, yeast fungi, moulds or bacteria, including micro-organisms selected from Candida, trychophyton rubrum, trichophyton interdigitale, epidermophyton floccosum, trichophyton violaceum, microsporum gypseum, trichophyton tonsurans, trichophyton soudanense, trichophyton verrucosum, neoscytalidium, scopulariopsis, aspergillus, or a combination thereof.
7. The composition of claim 1, wherein the phospholipid is selected from soy lecithin, egg lecithin, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, synthetic phospholipids, PEG-ylated phospholipids, phosphorylated lipids, phosphorylated vitamin E and mixtures thereof.
8. The composition of claim 1, wherein the optional other pharmaceutically acceptable ingredients are selected from glycols, trehalose, PCA, NaPCA, a base, selected from pharmaceutically acceptable bases, like but not limited to sodium hydroxide, potassium hydroxide, triethanolamine and ammonia, borax, plasticizers, emollients, sunscreens, pigments, antioxidants, stabilizers, perfumes and combinations thereof.
9. The composition of claim 1, wherein the film structure is as exemplified in Fig. 1 , Fig. 3 or Fig. 5.
10. The composition of claim 1 , wherein the film-forming ingredient is selected from hydrophilic film-forming ingredients selected from cellulose derivatives, hydroxypropylcellulose, hydroxyethylcellulose, PVP, and combinations thereof.
11. The composition of claim 1 , wherein the film-forming ingredient is selected from ethyl cellulose, esters of poly [methyl vinyl ether/maleic acid] copolymer, PVA, PVP/PVA combinations, cationic cellulose polymers, chitosan, chitosan derivatives, polyacrylates, Eudragits, and combinations thereof.
12. The composition of claim 1 , in the form of a pharmaceutically acceptable form of administration, selected from a solution, a lotion, a gel, a foam, a patch, a cream, a spray and a spray lacquer.
13. The composition of claim 1, comprising the following components: a. 0.01-20% of an antifungal drug selected from, ciclopirox, amorolfme, griseofulvine, posaconazole, butenafine, itraconazole or other approved antifungal drug and combinations thereof, b. 0.2-20% w/w of one or more phospholipids, c. 50-85% of a volatile solvent selected from ethanol, isopropanol, n-propanol, butanol, ethyl acetate and combinations thereof, d. 0-30% of a glycol selected from ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, tetraglycol, butylene glycol, hexylene glycol and glycol esters or ethers like ethylene glycol monomethyl ether, diethylene glycol monoethyl ether or other pharmaceutically acceptable glycols and combinations thereof, e. 0.2-15% of a film-forming ingredient selected from cellulose derivatives, butyl monoester of poly [methyl vinyl ether/maleic acid] copolymer, PVP, PVA, Eudragits, other pharmaceutically acceptable polymers and combinations thereof, f. 0-40% water, g. 0-10% of a 0.5N to 1.0N aqueous solution of a base selected from sodium hydroxide, potassium hydroxide, ammonia borax and combinations thereof, and h. 0-5% of other pharmaceutically acceptable excipients selected from plasticizers, emollients, sunscreens, pigments, antioxidants, stabilizers, perfumes, and combinations thereof.
14. The composition of claim 1, in the form of a topical solution or spray, whereby said solution or spray is capable of being applied to a nail or skin surface with a brush or a metered dose device, thereby forming a film when allowed to dry.
15. A method of treating a nail or skin fungal infection in a human in need thereof, the method comprising applying to the nail or skin a therapeutically effective dose of the composition of claim 1, and allowing the composition to dry, thereby forming a film.
16. A method of treating nail or skin afflictions, the method comprising contacting the afflicted nail or skin with the composition of claim 1, thereby forming an occlusive film over the nail or skin.
17. An article of manufacture comprising a dispensing device and the composition of any one of claims 1-14 contained therein.
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US20170224629A1 (en) 2017-08-10
US20120114574A1 (en) 2012-05-10
EP2391344B1 (en) 2017-07-12
US9668987B2 (en) 2017-06-06
JP2012516320A (en) 2012-07-19
EP2391208A4 (en) 2012-09-12
EP2391344A4 (en) 2012-08-08
EP2391208A1 (en) 2011-12-07
WO2010086723A1 (en) 2010-08-05
EP2391344A1 (en) 2011-12-07

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