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WO2010086732A1 - Compositions stables destinées au traitement des ongles et de la peau - Google Patents

Compositions stables destinées au traitement des ongles et de la peau Download PDF

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Publication number
WO2010086732A1
WO2010086732A1 PCT/IB2010/000179 IB2010000179W WO2010086732A1 WO 2010086732 A1 WO2010086732 A1 WO 2010086732A1 IB 2010000179 W IB2010000179 W IB 2010000179W WO 2010086732 A1 WO2010086732 A1 WO 2010086732A1
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WO
WIPO (PCT)
Prior art keywords
composition
nail
skin
combinations
salts
Prior art date
Application number
PCT/IB2010/000179
Other languages
English (en)
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
Publication of WO2010086732A1 publication Critical patent/WO2010086732A1/fr

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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
    • 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
    • A61K47/24—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

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% amorolfine, 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[methylvinyl 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.
  • US patent no. 6,231 ,875 describes topical antifungal compositions like topical lacquers comprising various actives, including terbinafine, which are acidified (by lowering the pH). However, formulating terbinafine at an acidic pH is not desirable for optimal efficacy.
  • the present invention successfully addresses unmet medical needs, providing innovative topical compositions that allow for high concentrations of acidic actives such as, e.g., terbinafine salts, and yet remain stable within the pH range that is desirable for optimum antimycotic activity, forming lacquers exhibiting enhanced substantivity of the active to the nail and skin, and exhibiting enhanced therapeutic activity.
  • acidic actives such as, e.g., terbinafine salts
  • terbinafine topical nail drug is Lamisil Solution Topical 1%
  • higher terbinafine concentrations are therapeutically needed.
  • Such compositions are being investigated in several products in development (Nexmed - 10% terbinafine nail lacquer).
  • the pH of the composition is very important to its activity.
  • G. Petranyi et al. Antimicrobial Agents and Chemotherapy, Sept. 1987, p. 1365-1368
  • formulating terbinafine in high concentrations within the pH range needed for optimal efficacy presents a formulation challenge, as the active has a tendency to precipitate from the composition at high concentrations.
  • the instant invention provides stable and highly effective topical compositions comprising high concentrations of terbinafine HCl, a base and a phospholipid.
  • the compositions of the invention can achieve terbinafine HCl concentrations as high as 7 wt% and greater (e.g., from about 7 wt% to about 15 wt%), while maintaining stability within a pH range that is desirable for optimal efficacy.
  • the compositions of the invention preferably include sufficient base to attain a pH which is 1.0-3.0 pH units higher than untreated compositions, and within the range for that is desirable for optimal antifungal activity.
  • compositions of the invention preferably have a pH of from about 4.0 to about 6.0, e.g., from about 4.0 to about 6.0, from about 4.5 to about 6.0, from about 4.5 to about 5.5, from about 5.0 to about 5.5, or from about 4.5 to about 5.0.
  • Similar terbinafine HCl compositions lacking phospholipid are unstable, showing a high degree of precipitation of the drug at high concentrations.
  • the phospholipid in the compositions of the invention may play a role in counteracting the tendency of terbinafine to precipitate out of the composition at high concentrations in this pH range.
  • compositions for a topical application [0017]
  • liquid compositions are provided, that can be applied on the nail or on the skin, to form a film after the evaporation of the volatiles.
  • the compositions of this invention are preferably liquid, in the form of solution, lotion, gel, spray, lacquer, foam or cream, containing a therapeutically effective amount of one or more antifungal agents and pharmaceutically acceptable inactive ingredients.
  • the antifungal agent may be a terbinafine salt (such as the hydrochloride), a ciclopirox salt, an amorolfine salt, a griseofulvine salt, a posaconazole salt, an itraconazole salt, an econazole salt, a butenaflne salt, or other topical antifungal drug exhibiting an acidic pH value.
  • compositions with high antifungal active content using at first terbinafine HCl and a concentration of 10%.
  • the initial pH of these concentrated compositions was very acidic (around 3.5-3.6), and based on the assumption than higher pH values are conducive to improved antifungal activity, we tried to basify these compositions.
  • the phospholipid in the composition of the invention may be selected from soy or egg phospholipids, synthetic phospholipids, PEG-ylated phospholipids, phosphorylated lipids, phosphorylated vitamin E, and mixtures thereof.
  • “basification” means treatment with a base, selected from, but not limited to, sodium hydroxide, potassium hydroxide, triethanolamine, tromethamine or ammonia and borax, to raise the pH value of the compositions.
  • a base selected from, but not limited to, sodium hydroxide, potassium hydroxide, triethanolamine, tromethamine or ammonia and borax.
  • the compositions of the invention preferably have a pH of from about 4.0 to about 6.0, e.g., from about 4.0 to about 6.0, from about 4.5 to about 6.0, from about 4.5 to about 5.5, from about 5.0 to about 5.5, or from about 4.5 to about 5.0.
  • a phospholipid is added to the compositions in order to obtain clear, stable compositions.
  • One preferred base used for basification is sodium hydroxide (NaOH), used as an aqueous solution, for example 0.5N or IN aqueous NaOH.
  • NaOH sodium hydroxide
  • this invention provides a composition that contains the following: a. 5-15%, more preferably 7- 10%w/w of terbinafine HCl, b.
  • a base selected from pharmaceutically acceptable bases, such as sodium hydroxide, potassium hydroxide or ammonia or basic salts like borax, in an amount sufficient to increase the pH value of the composition before the addition by about 2.0-2.5 pH units, c. 0.2-10%w/w of a lipid selected from phospholipids, phosphorylated lipids or combinations thereof, d. 61-95% of volatile solvents selected from C2-C4 alkanols selected from ethanol, isopropanol, n-propanol and butanol (hereinafter "alcohol” or “alcohols”), ethyl acetate or combinations thereof, e.
  • bases such as sodium hydroxide, potassium hydroxide or ammonia or basic salts like borax
  • 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 (hereinafter "glycol” or “glycols”) and combinations thereof, f.
  • 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 (hereinafter "glycol” or “glycols”) and combinations thereof, f.
  • a film-forming ingredient such as a polymer, selected from cellulose derivatives, butyl monoester of poly[methylvinyl ether/maleic acid] copolymer, PVP, PVA, Eudragits, other pharmaceutically acceptable film forming ingredients, polymers or combinations thereof, g. 10-40% water, and h. 0-10% of other pharmaceutically acceptable excipients selected from but not limited to, plasticizers, emollients, sunscreens, pigments, antioxidants, stabilizers, perfumes, etc., and combination thereof, according to need.
  • compositions of this invention comprising high concentrations of terbinafine hydrochloride (10%), which are stable, clear and less acidic compositions have improved substantive properties for the nails; more drug was found in the nail when the stable, less acidic composition was applied to the nail as compared to the more acidic composition.
  • the concentration of the active in the composition may range from 5% to 15%, more preferably from 7 to 10%.
  • stable and highly effective nail, skin and mucosal compositions which, after the evaporation of the volatiles, provide an occlusive film over the treated areas, thus improving the usefulness of the treatment.
  • compositions that form an occlusive 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 the method of the present invention include, e.g., fungal infections, onychomycosis, skin and nail infections and scalp fungal infections.
  • the preferred concentration of the acidic active, e.g., terbinafine HCl, in the compositions of this invention preferably ranges from about 7% to about 15%, e.g., from 5-
  • the terbinafine used in the compositions may include terbinafine acid addition salts such as, e.g., terbinafine hydrochloride.
  • a preferred terbinafine topical solution comprises 10% terbinafine hydrochloride
  • the nail and skin afflictions treated by the compositions of this invention include, e.g., fungi, yeasts and moulds.
  • compositions of the present invention 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 the volatiles in the composition evaporate, leaving on the nail or skin a thin occlusive film comprising the active, which improves the effectiveness of the composition.
  • compositions are topical solutions, to be applied evenly on the nail with a brush, a metered dosing device like a pipette or as a spray.
  • the application may be done once to twice daily and should be repeated until complete remission.
  • the effectiveness of said compositions is expected to enable a shortened period of treatment with superior results.
  • the topical solution 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 should be made on the previous coat.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne de nouvelles compositions antifongiques stables et très efficaces qui comprennent des actifs acides, des procédés de préparation de ces compositions et des procédés de traitement des infections fongiques des ongles et de la peau, le pH de la composition étant augmenté de 1,0 à 3,0 unités de pH par addition d'une base. La composition comprend en outre un ou plusieurs phospholipides.
PCT/IB2010/000179 2009-01-30 2010-01-30 Compositions stables destinées au traitement des ongles et de la peau WO2010086732A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14885009P 2009-01-30 2009-01-30
US61/148,850 2009-01-30

Publications (1)

Publication Number Publication Date
WO2010086732A1 true WO2010086732A1 (fr) 2010-08-05

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Family Applications (2)

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PCT/IB2010/000172 WO2010086727A1 (fr) 2009-01-30 2010-01-30 Compositions stables pour le traitement de l'onychomycose des ongles
PCT/IB2010/000179 WO2010086732A1 (fr) 2009-01-30 2010-01-30 Compositions stables destinées au traitement des ongles et de la peau

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Application Number Title Priority Date Filing Date
PCT/IB2010/000172 WO2010086727A1 (fr) 2009-01-30 2010-01-30 Compositions stables pour le traitement de l'onychomycose des ongles

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018044621A1 (fr) * 2016-08-29 2018-03-08 Schanbacher Carl L Procédés et compositions de traitement d'infections fongiques cutanées
US11554108B2 (en) 2016-08-29 2023-01-17 Xeropedix, Inc. Methods and compositions for treating cutaneous fungal infections

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE1300709A1 (sv) * 2013-11-14 2015-05-15 Lipidor Ab Komposition och metod för topikal behandling

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5716638A (en) * 1994-06-22 1998-02-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composition for applying active substances to or through the skin
US6231875B1 (en) * 1998-03-31 2001-05-15 Johnson & Johnson Consumer Companies, Inc. Acidified composition for topical treatment of nail and skin conditions
US20060160823A1 (en) * 2004-05-28 2006-07-20 Leonore Witchey-Lakshmanan Particulate-stabilized injectable pharmaceutical compositions of Posaconazole

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DE69907341T2 (de) * 1998-02-09 2004-01-22 Macrochem Corp., Lexington Antimykotischer nagellack
AR034813A1 (es) * 2001-07-20 2004-03-17 Novartis Ag Composiciones farmaceuticas y uso de las mismas
RU2358718C2 (ru) * 2003-03-21 2009-06-20 Нексмед Холдингс, Инк. Противогрибковое покрытие для ногтей и способ его применения
JP5435836B2 (ja) * 2003-07-03 2014-03-05 大正製薬株式会社 外用抗真菌剤組成物
DE502006000770D1 (de) * 2005-02-03 2008-06-26 Clariant Produkte Deutschland Konservierungsmittel
US20060246098A1 (en) * 2005-03-16 2006-11-02 Srinivasa Rao Stable aqueous-based emulsion formulation comprising urea and salicylic acid and method of using same
MX2008015599A (es) * 2006-06-14 2009-03-06 Reddys Lab Ltd Dr Composiciones topicas.
US20080261986A1 (en) * 2007-03-30 2008-10-23 Friden Phillip M Pharmaceutical formulations for iontophoretic delivery of an anti-fungal drug

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5716638A (en) * 1994-06-22 1998-02-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Composition for applying active substances to or through the skin
US6231875B1 (en) * 1998-03-31 2001-05-15 Johnson & Johnson Consumer Companies, Inc. Acidified composition for topical treatment of nail and skin conditions
US20060160823A1 (en) * 2004-05-28 2006-07-20 Leonore Witchey-Lakshmanan Particulate-stabilized injectable pharmaceutical compositions of Posaconazole

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018044621A1 (fr) * 2016-08-29 2018-03-08 Schanbacher Carl L Procédés et compositions de traitement d'infections fongiques cutanées
US10251822B2 (en) 2016-08-29 2019-04-09 Xeropedix, Inc. Methods and compositions for treating cutaneous fungal infections
CN109862882A (zh) * 2016-08-29 2019-06-07 卡尔·F·尚巴赫 用于治疗皮肤真菌感染的方法和组合物
US11554108B2 (en) 2016-08-29 2023-01-17 Xeropedix, Inc. Methods and compositions for treating cutaneous fungal infections

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