WO2007094999A2 - Compositions antifongiques pour les ongles - Google Patents

Compositions antifongiques pour les ongles Download PDF

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Publication number
WO2007094999A2
WO2007094999A2 PCT/US2007/003106 US2007003106W WO2007094999A2 WO 2007094999 A2 WO2007094999 A2 WO 2007094999A2 US 2007003106 W US2007003106 W US 2007003106W WO 2007094999 A2 WO2007094999 A2 WO 2007094999A2
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Prior art keywords
composition
antifungal agent
nail
group
weight
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PCT/US2007/003106
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English (en)
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WO2007094999A3 (fr
Inventor
Nigel Leeves
Gary Lawrence
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Stiefel Laboratories, Inc.
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Publication of WO2007094999A2 publication Critical patent/WO2007094999A2/fr
Publication of WO2007094999A3 publication Critical patent/WO2007094999A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q3/00—Manicure or pedicure preparations
    • A61Q3/02—Nail coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8129—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers or esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers, e.g. polyvinylmethylether

Definitions

  • the present subject matter relates generally to ungual antifungal compositions.
  • the present antifungal compositions comprise a therapeutically effective amount of an antifungal agent, an aqueous solvent, a pH adjuster, and a polymeric film forming agent having a degree of hydrolysis of about 80 to about 95%, a nominal viscosity of about 20-60 mPa s, and/or a degree of polymerization of about 500 to about 5000.
  • the compositions preferably do not contain penetration enhancers, but do exhibit significant penetration of the active agent.
  • These compositions are capable of temporarily or permanently reducing, inhibiting, treating, ameliorating, or preventing an ungual and/or subungual infection caused by microbes, such as fungi.
  • the present compositions are further capable of forming a film upon application to the nail and surrounding skin.
  • Fungal infections of the nail and surrounding skin are not only unsightly and socially embarrassing, but in certain cases they can result in lose of the nail and be very painful .
  • Fungal infections are caused by dermatophytes (i.e., fungi), which infect the nail and surrounding skin on a mammal and can cause inflammation, discoloration, and/or loss of the nail.
  • Dermatophyte infections i.e., fungal infections
  • Onychomycosis i.e. tinea unguium
  • the disease which can be caused by fungi, e.g., T. rubrum, T. mentagrophytes, Candida albicans and/or Candida parapsilosis, usually begins at the corner of the nail as a yellowish discoloration. As it spreads, the nail typically begins to separate from its bed distally, resulting in irregular nail dystrophy. Healthy individuals can contract such a condition through exposure to the afflicting fungi, which is at times present in unsanitary environments. However, individuals with compromised immune systems are at a higher risk of contracting the disease since these individuals lack the ability to fight off the fungi .
  • topical antifungal formulations have previously been developed in an attempt to decrease or eliminate microbes, in particular dermatophytes, from the nails of an infected mammal, and to decrease or eliminate infection, irritation, discoloration and/or loss of the nail associated with such dermatophyte infections.
  • Several of these previous topical antifungal formulations comprise an antifungal agent in a liquid composition which further includes a penetration enhancer and, upon drying, requires the use of an organic solvent to remove the composition from the nail.
  • a penetration enhancer a penetration enhancer
  • the use of such solvents can cause additional damage to the nail and skin through excessive drying and irritation of the tissues, as well as exposing the patient to unnecessary toxic and flammable substances, such as acetone.
  • U.S. Patent No. 6,455,592 to Laugier et al discloses the use of hydrophilic penetration agents, customarily used for the transcutaneous penetration of active ingredients, to improve the penetration of antifungal agents through the nails for the treatment of oncyhomycosis .
  • Laugier et al teach a composition comprising a pharmacologically- effective amount of terbinafine hydrochloride; a solvent medium comprising water and at least one straight- or branched-chain C 2 -C 8 alkanol ; and a hydrophilic penetration agent .
  • U.S. Published Patent Application No. 2003/0190340 to Bohn et al discloses a preparation comprising a hydrophilic gel-forming agent, water and a compound such as l-Hydroxy-4-methyl-6-cyclohexyl-2 (IH) pyridone .
  • the hydrophilic gel-forming agents may be substances such as gelatin, pectin, tragacanth, agar, carrageenan or alginate, semisynthetic compounds such as cellulose ethers, e.g.
  • gel-forming agents such as polyacrylates, polymethacrylates, polyvinyl alcohol or polyvinylpyrrolidones or mixtures of the hydrophilic gel forming agents.
  • the compositions described in this application are not very effective in use.
  • compositions present" a dual negative aspect, which can outweigh their potential treatment value, due to the necessity of their removal using drying and toxic organic solvents and the drying nature of the active ingredients themselves.
  • Humectants and/or moisturizers can mitigate certain of the negative symptoms and side effects associated with and caused by the topical application of an antifungal agent to the nail and surrounding skin of a mammal . Further, certain humectants and/or moisturizers can at times also aid in alleviating the negative symptoms caused by the disease being treated itself. In this regard, certain humectants and/or moisturizers can soften, smooth, and lubricate the infected nail and surrounding skin area ⁇ by increasing the amount of water retained intercellularly within the layers of these structures, and by reducing the amount of transepidermal water loss (TEWL) experienced by the nail and the skin layers. Accordingly, humectants and/or moisturizers can help reduce treatment and recovery time, and even leave the previously infected nail and surrounding skin area in better condition than before the infection.
  • TEWL transepidermal water loss
  • compositions containing a humectant and/or moisturizer and an antifungal agent have previously been attempted.
  • these compositions still required the use of organic solvents for removal of the dried composition from the nail and surrounding tissue, thereby diminishing or inactivating the advantageous properties of the humectant, the moisturizer, and/or the pharmaceutically active antifungal agent.
  • these known compositions oftentimes further require the incorporation of a penetration or diffusion enhancer to effectively treat a diseased nail bed.
  • the present subject matter relates generally to antifungal compositions, and more particularly to topical antifungal compositions for application to finger and toe nails and the surrounding skin tissues.
  • a preferred embodiment of the present subject matter relates to a composition effective for application to nails and surrounding skin, comprising: about 2 to about '20% by weight of a polymeric film forming agent having a degree of hydrolysis of about 80 to about 95%; at least about 35% by weight of an aqueous solvent; about 5 to about 15% by weight of an antifungal agent; and a sufficient amount of a pH adjuster to provide a pH of at least about 7.0 to said composition; wherein said composition forms a film upon application to said nails and surrounding skin, and wherein said composition does not contain a penetration enhancer.
  • Another preferred embodiment of the present subject matter relates to a method for treating onychomycosis in a mammal, comprising administering to nails and surrounding skin of a mammal in need thereof a composition comprising: about 2 to about 20% by weight of a polymeric film forming agent having a degree of hydrolysis of about 80 to about 95%; at least about 35% by weight of an aqueous solvent; about 5 to about .15% by weight of an antifungal agent; and a sufficient amount of a pH adjuster to provide a pH of at least about 7.0 to said composition; wherein said composition forms a film upon application to said nails and surrounding skin, and wherein said composition does not contain a penetration enhancer.
  • a further preferred embodiment of the present subject matter relates to a composition effective for application to nails and surrounding skin, comprising: about 2 to about 20% by weight of a polymeric film forming agent having a nominal viscosity of about 20-60 mPa s; at least about 35% by weight of an aqueous solvent; about 5 to about 15% by weight of an antifungal agent; and a sufficient amount of a pH adjuster to provide a pH of at least about 7.0 to said composition; wherein said composition forms a film upon application to said nails and surrounding skin, and wherein said composition does not contain a penetration enhancer.
  • Yet a further preferred embodiment of the present subject matter relates to a method for treating onychomycosis in a mammal, comprising administering to nails and surrounding skin of a mammal in need thereof a composition
  • a composition comprising: about 2 to about 20% by weight of a polymeric film forming agent having a nominal viscosity of about 20-60 mPa s; at least about 35% by weight of an aqueous solvent; about 5 to about 15% by weight of an antifungal agent; and a sufficient amount of a pH adjuster to provide a pH of at least about 7.0 to said composition; wherein said composition forms a film upon application to said nails and surrounding skin, and wherein said composition does not contain a penetration enhancer.
  • a further preferred embodiment of the present subject matter relates to a composition effective for application to nails and surrounding skin, comprising: about 2 to about 20% by weight of a polymeric film forming agent having a degree of polymerization of about 500 to about 5000; at least about 35% by weight of an aqueous solvent; about 5 to about 15% by weight of an antifungal agent; and a sufficient amount of a pH adjuster to provide a pH of at least about 7.0 to said composition; wherein said composition forms a film upon application to said nails and surrounding skin, and wherein said composition does not contain a penetration enhancer.
  • a further embodiment of the present subject matter is related to a method for treating onychomycosis in a mammal, comprising administering to nails and surrounding skin of a mammal in need thereof a composition comprising: about 2 to about 20% by weight of a polymeric film forming agent having a degree of polymerization of about 500 to about 5000; at least about 35% by weight of an aqueous solvent; about 5 to about 15% by weight of an antifungal agent; and a sufficient amount of a pH adjuster to provide a pH of at least about 7.0 to said composition; wherein said composition forms a film upon application to said nails and surrounding skin, and wherein said composition does not contain a penetration enhancer.
  • administering refers to any method which, in sound medical or cosmetic practice, delivers a composition to a subject in such a manner as to provide a net positive effect on a dermatological disorder, condition, or appearance.
  • the compositions are preferably .administered such that they cover the entire area to be treated.
  • Direct administration refers to any method which, in sound medical or cosmetic practice, delivers a composition to a subject without the use of another composition, delivery agent, or device.
  • Indirect administration refers to any method which, in sound medical or cosmetic practice, delivers a composition to a subject with the use of at least one other composition, delivery agent, or device.
  • the phrases “easy to remove” or “easily removable” refers to the ability of the presently described compositions, once they form a film in use, to be scrapable, capable of being washed off with a biologically innocuous solvent such as water, and/or peelable from a nail and/or skin to which they are applied.
  • an "effective amount” or a "therapeutically effective amount” of a pharmaceutically active antimicrobial agent or ingredient are synonymous and refer to an amount of the pharmaceutically active antimicrobial or antifungal agent sufficient enough to have a positive effect on the area of application. Accordingly, these amounts are sufficient to modify the skin/nail disorder, condition, or appearance to be treated but low enough to avoid serious side effects, within the scope of sound medical or dermatological advice.
  • a therapeutically effective amount of the pharmaceutically active antimicrobial agent will cause a substantial relief of symptoms when applied repeatedly over time. Effective amounts of the pharmaceutically active antimicrobial agent will vary with the particular condition or conditions being treated, the severity of the condition, the duration of the treatment, the specific components of the composition being used, and like factors.
  • salts refers to salts of certain ingredient (s) which possess the same activity as the unmodified compound (s) and which are neither biologically nor otherwise undesirable.
  • a salt can be formed with, for example, organic or inorganic acids.
  • Non- limiting examples of suitable acids include acetic acid, acetylsalicylic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, bisulfic acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfic acid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphoric acid, glycine, glucoheptanoic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hemisulfic acid, heptanoic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic acid, lactic acid, male
  • organic bases are used, poorly volatile bases are preferably employed, for example low molecular weight alkanolamines such as ethanolamine, diethanolamine, N- ethylethanolamine, N-methyldiethanolamine, triethanolamine, diethylaminoethanol, 2-amino-2-methyl-n-propanol , dimethylaminopropanol , 2-amino-2-methylpropanediol, and triisopropanolamine.
  • Ethanolamine is particularly preferred in this regard.
  • Salts of quaternary ammonium hydroxides such as trimethylbenzylammonium hydroxide, tetramethylammonium hydroxide, or tetraethylammonium hydroxide can also by used, as can guanidine and its derivatives, in particular its alkylation products.
  • salt-forming agents for example, low molecular weight alkylamines such as methylamine, ethylamine, or triethylamine .
  • Suitable salts for the components to be employed according to the present subject matter are also those with inorganic cations, for example alkali metal salts, in particular sodium, potassium, or ammonium salts, alkaline earth metal salts such as, in particular, the magnesium or calcium salts, as well as salts with bi- or tetravalent cations, for example the zinc, aluminum, or zirconium salts.
  • inorganic cations for example alkali metal salts, in particular sodium, potassium, or ammonium salts, alkaline earth metal salts such as, in particular, the magnesium or calcium salts, as well as salts with bi- or tetravalent cations, for example the zinc, aluminum, or zirconium salts.
  • organic bases such as dieyelohexylamine salts,- methyl-D- glucamine,- and salts with amino acids, such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl , and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; asthma halides, such as benzyl and phenethyl bromides; and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl , and diamyl sulfates
  • a preferred aspect of the subject matter expressed herein relates to various topical antifungal compositions.
  • the present subject matter preferably relates to a composition effective for application to nails and surrounding skin, comprising: about 2 to about 20% by weight of a polymeric film forming agent having a degree of hydrolysis of about 80 to about 95%, a nominal viscosity of about 20-60 mPa s, and/or a degree of polymerization of about 500 to about 5000; at least about 35% by weight of an aqueous solvent; about 5 to about 15% by weight of an antifungal agent; and a sufficient amount of a pH adjuster to provide a pH of at least about 7.0 to said composition; wherein said composition forms a film upon application to said nails and surrounding skin, and wherein said composition does not contain a penetration enhancer.
  • Such antifungal compositions are generally used to temporarily or permanently alleviate, reduce, inhibit, treat, ameliorate, or prevent antifungal infections such as onychomycosis and fungal infections of the nail and exhibit increased penetration of the active agent in-vitro.
  • the present compositions are uniquely formulated to increase the solubility of the antifungal agent contained therein.
  • the present compositions serve to hydrate the nail to which they are applied, resulting in increased penetration of the antifungal agent into the nail and through to the nail bed.
  • the present compositions are advantageous in that they form films which are easy to remove from the nail and/or skin to which they are applied.
  • the present compositions may be applied directly to skin or tissue alone for the treatment of, for example, tinea pedis or athlete's foot .
  • An essential component of the presently preferred compositions is a pharmaceutically active antifungal agent.
  • the antifungal agent is capable of destroying or inhibiting the growth of fungi and microorganisms, and reducing, inhibiting, treating, ameliorating, or . preventing discoloration, discomfort, itching, inflammation and/or nail loss associated with fungal infections of the ungual and subungual structures.
  • the antifungal agent includes pharmaceutically active antibacterial agents, antifungal agents, antiseptic agents, antipsoriatic agents, and derivatives and mixtures thereof.
  • the antimicrobial agent is an antifungal agent or a derivative thereof.
  • the antifungal agents used in the present compositions may possess anti-inflammatory properties. Accordingly, the present compositions may possess anti-inflammatory properties as well. In particular, the antifungal agents, and thus the antifungal compositions, may possess activity against microbes selected from the group consisting of gram positive bacteria, gram negative bacteria, funguses, molds, viruses, and combinations thereof.
  • the antifungal agent is preferably present in the instant compositions in a therapeutically effective amount.
  • the present compositions preferably contain about 0.1% to about 15% by weight, and more preferably from about 5% to about 15% by weight, of the antifungal agent.
  • the present compositions contain about 0.1 to about 4% by weight of the antifungal agent.
  • the present compositions contain about 7 to about 9% of the antifungal agent.
  • Non-limiting examples of preferred antifungal agents useful herein include N-pyridine oxides, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • Particularly preferred N-pyridone oxides useful in this regard are those having the formula I :
  • R-i/ R2/ and R 3 which are identical or different, are H or alkyl having 1 to 4 carbon atoms, and R 4 is a saturated hydrocarbon radical having 6 to 9 carbon atoms or a radical of formula II : where :
  • X is S or O
  • Y is selected from the group consisting of H, 1 or 2 identical halogen atoms, and a mixture of 2 different halogen atoms;
  • Z is selected from the group consisting of a single bond and a bivalent radical comprising O, S, CR 2 where R2 is H or
  • (Ci-C 4 ) -alkyl or from 2 to 10 carbon atoms linked in the form of a chain, which optionally further comprises one or more of the following:
  • Ar is an aromatic ring system having one or two rings that can be substituted by one, two, or three radicals, which may be identical or different, which are selected from the group consisting of halogen, methoxy, (Ci-C 4 ) -alkyl, trifluoromethyl , or trifluoromethoxy . These compounds are preferably present in the free or in the salt form.
  • the carbon chain members are preferably CH 2 groups. If the CH 2 groups are substituted by C 1 -C 4 alkyl groups, CH 3 and C 2 H 5 are preferred substituents .
  • Exemplary radicals U Z" are:
  • -OCH 2 CH CHCH 2 O-, -OCH 2 CH 2 O-, -OCH 2 CH 2 CH 2 O-, -SCH 2 CH 2 CH 2 S-,
  • the hydrocarbon radical R 4 is preferably an alkyl or cyclohexyl radical which can also be bonded to the pyridone ring via a methylene or ethylene group or can contain an endomethyl group.
  • R 4 can also be an aromatic radical which, however, is preferably bonded to the pyridone radical via at least one aliphatic carbon atom.
  • Preferred, non-limiting examples of the antifungal agent of formula I useful in the present compositions are those selected from the group consisting of: 6- [4- (4-chlorophenoxy) - phenoxymethyl] -l-hydroxy-4 -methyl -2 -pyridone, 6- [4- (2,4- dichlorophenoxy) phenoxymethyl] -l-hydroxy-4 -methyl -2 -pyridone, 6- (biphenyl-4-oxymethyl) -l-hydroxy-4-methyl-2 -pyridone, 6- (4- benzyl-phenoxymethyl) -1-hydroxy-4-methyl-2-pyridone, 6- [4- (4- chlorophenoxy) phenoxymethyl] -1-hydroxy-3 , 4-dimethyl-2- pyridone, 6- [4- (2 , 4-dichlorobenzyl) phenoxymethyl] -l-hydroxy-4- 3,4-dimethyl-2-pyridone, 6- [4-cinnamyloxyphenoxy methyl]
  • the antifungal agent of formula I useful in the present compositions is selected from the group consisting of: 6- [4- (4-chlorophenoxy) - phenoxymethyl] -l-hydroxy-4-methyl-2-pyridone, 1-hydroxy-4- methyl-6-cyclohexyl-2-pyridone, l-hydroxy-4-methyl-6- (2,4,4- trimethylpentyl) -2-pyridone, a pharmaceutically acceptable salt thereof, and a mixture thereof.
  • the antifungal agent of formula I used in the present compositions is l-hydroxy-4- methyl-6-cyclohexyl-2-pyridone (Ciclopirox) or a pharmaceutically acceptable salt thereof.
  • the ciclopiroxolamine salt is particularly preferred in this regard.
  • Antifungal agents other than those falling within formula I above are additionally contemplated as useful in the present antifungal compositions. Included among these other antifungal agents are those selected from the group consisting of imidazoles, allylamines, triazoles, glucan synthase inhibitors, chitin synthase inhibitors, polyenes, griseofulvin, morpholine derivatives, triazines, pyrimidines, any other antimicrobial azole, pharmaceutically acceptable salts thereof, and mixtures thereof. Other antifungal agents known in the art as effective upon topical administration to a patient are further contemplated as effective within the present compositions.
  • these other antifungal agents are those selected from the group consisting of amorolfine, amphotericin B, bacitracin, benzalkonium chloride, benzethonium chloride, bifonazole, butenafine, butoconazole, chloroxine, cilofungin, chlordantoin, chlortetracycline, clindamycin, clioqinol, clotrimazole, econazole, elubiol, faeriefungin, fezatione, fluconazole, flucytosine, fungimycin, gentamicin, griseofulvin, haloprogin, hexylresorcinol , itraconazole, ketoconazole, methylbenzethonium chloride, miconazole, mupirocin, naftifine, nikkomycin Z, nystatin, 1- ofloxacin, oxicon
  • preferred embodiments of the present compositions further comprise a polymeric film forming agent.
  • the polymeric film forming agent can enhance the effectiveness of the present compositions in temporarily or permanently reducing, inhibiting, treating, ameliorating, or preventing a nail and skin infection caused by fungi. Additionally, the polymeric film forming agent provides a flexible, protective film once the present compositions have been applied to the nail and surrounding skin of a mammal, or to skin or tissue alone, and can also serve as a release mechanism of the active agent from the dried film.
  • the presently preferred compositions are unique in that, once dried in use, they form films that are easily removable.
  • the present compositions are clear drying and exhibit a mechanical durability, as well as an efficient drying time and the ability to provide UV protection for the active and thereby enhanced composition stability. Accordingly, the present preferred compositions overcome the difficulties often previously observed since they require a reduced quantity of polymers . This permits the formation of compositions having the advantageous characteristics described herein, thereby increasing efficacy and patient compliance.
  • the present compositions preferably contain about 2% to about 20% by weight of the polymeric film forming agent. In a particularly preferred embodiment, the present compositions contain about 3 to about 10% by weight of the polymeric film forming agent .
  • the polymeric film forming agent has a degree of hydrolysis of about 80 to about 95%. More preferably, the degree of hydrolysis is about 85 to about 90%.
  • the polymeric film forming agent may also have a degree of polymerization of about 500 to about 5000. More preferably, the degree of polymerization is about 1500 to about 5000. Even more preferably, the degree of polymerization is about 1500 to about 3000. Most preferably, the degree of polymerization is about 2000 to about 2500. [49] Likewise, in the alternative to, or in addition to, these other properties, the polymeric film forming agent may also have a nominal viscosity of about 20 to about 60 mPa s. More preferably, the viscosity is about 25 to about 45 mPa s.
  • Non-limiting examples of preferred polymeric film forming agents useful in this regard include polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, methyacrylic acid polymer, derivatives thereof, and mixtures thereof.
  • the polymeric film forming agent is polyvinyl alcohol.
  • compositions comprise an aqueous solvent as an essential component.
  • This aqueous solvent is preferably present in an amount of at least about 35% by weight.
  • the aqueous solvent is preferably water and can' optionally include an additional solvent.
  • preferred aqueous solvents and additional solvents useful in this regard include lower alcohols, lower alkyl esters of lower carboxylic acids, lower carboxylic acids, lower alkyl esters, lower alkyl ketones, halogenated hydrocarbons, aromatic hydrocarbons, cyclic ethers, purified water, distilled water, sterilized water, derivatives thereof, and mixtures thereof.
  • the aqueous solvent is water and ethanol . pH Adjuster
  • compositions further comprise a pH adjuster.
  • pH modifiers useful in this regard include inorganic hydroxides, inorganic oxides, inorganic salts of weak acids, inorganic acids, organic acids, derivatives thereof, and mixtures thereof.
  • Preferred inorganic hydroxides useful herein include ammonium hydroxide, monovalent alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, divalent alkali earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, derivatives thereof, and mixtures thereof.
  • Preferred, non-limiting examples of inorganic oxides useful herein include magnesium oxide, calcium oxide, derivatives thereof, and mixtures thereof.
  • Preferred, non-limiting examples of inorganic salts of weak acids useful herein include ammonium phosphate (dibasic) , alkali metal salts of weak acids such as sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate (tribasic) , sodium phosphate (dibasic) , potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate (dibasic) , potassium phosphate (tribasic) , alkaline earth metal salts of weak acids such as magnesium phosphate and calcium phosphate, derivatives thereof, and mixtures thereof.
  • weak acids such as magnesium phosphate and calcium phosphate, derivatives thereof, and mixtures thereof.
  • inorganic acids useful herein include hydrochloric acid, hydrofluoric acid, hydrobromic acid, nitric acid, nitrous acid, hydrocyanic acid, perchloric acid, chlorous acid, sulfurous acid, hypochlorous acid, phosphoric acid, acetic acid, sulfuric acid, derivatives thereof, and mixtures thereof.
  • organic acids useful herein include lactic acid, citric acid, glutamic acid, methanoic acid, ethanoic acid, phenol, mon ⁇ chloroethanoic acid, dichloroethanoic acid, trichloroethanoic acid, butanoic acid, salicylic acid, glycolic acid, and mixtures thereof.
  • pH modifiers are also contemplated as within the scope of the present compositions.
  • the pH adjuster is added to the present compositions in an amount effective to adjust the pH of the composition to at least about 7.
  • the pH adjuster is used to provide the present compositions with a pH of at least about 7.7.
  • the pH adjuster is used to provide the present compositions with a pH of at least about 8.7.
  • the presently preferred compositions can contain one or more pH adjuster.
  • the pH adjuster is sodium hydroxide, hydrochloric acid, or a combination thereof .
  • compositions may optionally further contain a humectant .
  • the h ⁇ mectant may be added to the present compositions in a sufficient amount to, in part, improve flexibility and appearance of the films described herein.
  • Preferred, non-limiting examples of humectants useful in this regard include glycerol, sorbitol, sorbitol syrup, E965 maltitol, maltitol, maltitol syrup, E1200 polydextrose, E1518 glyceryl triacetate, triacetin, glyceryl triacetate, 1, 2 , 3 -propanetriyl triacetate, 1, 2, 3-propanetriol triacetate, triacetylglycerol, E1520 propylene glycol, 1, 2-propanediol , 1, 2-dihydroxypropane, methylethylene glycol, propane-1, 2 -diol , E420 sorbitol, propylene glycol, polyethylene glycol,
  • the present compositions can comprise about 0.1% to about 10% by weight of a humectant . In a more preferred embodiment, the present compositions can comprise about 0.5% to about 5% by weight of a humectant.
  • compositions discussed herein can additionally comprise at least one film extender.
  • film extenders useful in this regard include calcium carbonate, calcium phosphate, calcium stearate, magnesium stearate., zinc stearate, calcium sulfate, colloidal silicon dioxide, kaolin, magnesium carbonate, magnesium silicate, sodium stearyl fumarate, talc, titanium dioxide, zinc oxide, and mixtures thereof.
  • compositions may optionally further contain a chelator.
  • chelators useful in this regard include citric acid, isopropyl (mono) citrate, stearyl citrate, lecithin citrate, gluconic acid, tartaric acid, oxalic acid, phosphoric acid, sodium tetrapyrophosphate, potassium monophosphate, sodium hexametaphosphate, calcium hexametaphosphate, sorbitol, glycine (aminoacetic acid) , methyl glucamine, triethanolamine
  • NTA Nitrilotriacetic
  • HEDTA N- (hydroxyethyl) -ethylenetriaminetriacetic acid
  • aminocarboxylates aminocarboxylates
  • dimercaperol (BAL) dimercaperol
  • compositions may optionally further contain at least one antioxidant .
  • antioxidants useful in this regard include ascorbic acid, ascorbyl esters of fatty acids, magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate, tocopherol, tocopherol sorbate, tocopherol acetate, butylated hydroxy benzoic acid, thioglycolates, persulfate salts, 6-hydroxy-2 , 5 , 7, 8-tetramethylchroman-2- carboxylic acid, lipoic acid, gallic acid, propyl gallate, uric acid, sorbic acid, lipoic acid, amines, N,N- diethylhydroxylamine, N-acetyl-L-cysteine, amino-guanidine, sulfhydryl compounds, glutathione, dihydroxy fumaric acid, lycine pidolate, arginine pilolate, nordi
  • compositions may optionally further contain at least one moisturizer.
  • moisturizers useful in this regard include glycerin, pentylene glycol, butylene glycol, polyethylene glycol, sodium pyrrolidone carboxylate, alpha- hydroxy acids, beta-hydroxy acids, polyhydric alcohols, ethoxylated and propoxylated polyols, polyols, polysaccharides, panthenol , hexylene glycol, propylene glycol, octyldodecanol , dipropylene glycol, sorbitol, derivatives thereof, and mixtures thereof.
  • compositions may optionally further contain at least one preservative.
  • preservatives useful in this regard include propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, sorbitol, benzyl alcohol, parabens such as methyl paraben, ethyl paraben, propyl paraben, or butyl paraben, sorbitans, derivatives thereof, and mixtures thereof.
  • Dermatologically Acceptable Excipients [69]
  • the preferred compositions discussed herein can additionally comprise at least one dermatologically acceptable excipient commonly known to those of ordinary skill in the art as useful in topical compositions.
  • dermatologically acceptable excipients useful in these compositions are those selected from the group consisting of emollients, preservatives, gelling agents, colorants or pigments, radical scavengers, surfactants, emulsifiers, humectants, derivatives thereof, and mixtures thereof .
  • any other antifungal agent, polymeric film forming agent, aqueous solvent, moisturizer, preservative, antioxidant, humectant, pH adjuster, chelator, or other dermatologically acceptable excipient commonly known to those of ordinary skill in the art as useful in, topical compositions is contemplated as useful in the compositions described herein.
  • any non-toxic, inert, and effective topical carrier may be used to formulate the compositions described herein.
  • Such useful pharmaceutically acceptable excipients, carriers and diluents include purified water, physiological saline, Ringer's solution, dextrose solution, Hank's solution, and DMSO, which are among those preferred for use herein.
  • the presently preferred pharmaceutical compositions are formulated in a nail product, lacquer, enamel, gel paint, lotion, cream, ointment, gel, suspension, emulsion, foam, aerosol, or other pharmaceutically acceptable topical dosage form.
  • a nail product is particularly preferred in this regard.
  • Another preferred aspect of the present subject matter pertains to a method for treating onychomycosis in a mammal, comprising administering to nails and surrounding skin of a mammal in need thereof a composition comprising: about 2 to about 20% by weight of a polymeric film forming agent having a degree of hydrolysis of about 80 to about 95%, a nominal viscosity of about 20 to about 60 mPa S, and/or a degree of polymerization of about 500 to about 5000; at least about 35% by weight of an aqueous solvent; about 5 to about 15% by weight of an antifungal agent; and a sufficient amount of a pH adjuster to provide a pH of at least about 7.0 to said composition; wherein said composition forms a film upon application to said nails and surrounding skin, and wherein said composition does not contain a penetration enhancer.
  • the preferred compositions described herein can be used in methods for temporarily or permanently reducing, inhibiting, treating, ameliorating, or prophylactically treating nail and surrounding skin fungal infections, as well as- skin or tissue diseases or disorders. These methods can be achieved by topically applying the presently preferred compositions to the nail and surrounding skin of a patient, such as a mammal. In the alternative, these methods can be achieved by topically applying the presently preferred compositions to skin or tissue of a patient, such as a mammal. In this regard, the present compositions can be used in methods for preventing, inhibiting, or prophylactically treating a dermatophyte infection.
  • the present compositions are effective when applied to a patient either directly or indirectly.
  • the present compositions are directly applied to the area of nail and/or surrounding skin to be treated.
  • the present compositions are indirectly applied to the area of skin to be treated.
  • Such indirect application can occur via, for example, an article of clothing.
  • the article of clothing can be absorbent or non-absorbent .
  • the administration of the present compositions reduces the number of fungi, preferably pathogenic fungi, on the nail and/or skin of the mammal to which it is applied.
  • the fungi that can be acted on by the present topical compositions are selected from the group consisting of bacteria, funguses, molds, viruses, and combinations thereof .
  • Preferred examples of bacteria treatable with the present compositions are gram positive bacteria, gram negative bacteria, and combinations thereof.
  • Specific, non-limiting examples of such gram positive bacteria are those selected from the group consisting of Streptococcus sp., Micrococcus sp., Staphylococcus sp. , Bacillus sp., and combinations thereof .
  • Streptococcus sp are those selected from the group consisting of S. v ⁇ ridans, S. agalactiae, S. pyogenes, S. faecalis, S. durans,
  • Staphylococcus sp are those selected from the group consisting of S. aureus,
  • P. ovale P. versicolor
  • P. versicolor P. ovale, P. versicolor
  • Candida sp are those selected from the group consisting of C. albicans, C. cruzii, C. krusei, C, glabrata, C. guillermondii, C. inconspicua, C. parapsilosis, C. tropicalis, and combinations thereof .
  • Trichophyton sp are those selected from the group consisting of T. rubrum, T. mentagrophytes, T. tonsurans, T. violaceum, and combinations thereof .
  • Preferred, non-limiting examples of such molds are those selected from the group consisting of Aspergillus sp., B. dermatitidis, P. brasiliensis, and combinations thereof.
  • Preferred, non-limiting examples of such Aspergillus sp are those selected from the group consisting of A. flavus, A. fumigates, A. niger, and combinations thereof.
  • nail and/or skin disorders may also be treated according to the present inventive methods. Exemplary among these disorders are onychomycosis, tinea unguium and nonspecific fungal infections of the nail, and combinations thereof. Other nail and surrounding skin disorders known to those of ordinary skill in the art as effectively treatable by a topical composition are further contemplated as within the scope of the present subject matter.
  • the present inventive methods provide antimycotic activity against Pityrosporum strains, such as
  • compositions are particularly effective in treating the specific dermatophytes Tinea /and/or
  • Candida fungi such as Tinea pedis or athlete's foot.
  • the improved effectiveness of the present compositions may be a result of the hydrated film present in the preferred compositions.
  • the hydrated film imparts hydration to the nail and surrounding skin, which allows for an increased penetration of the active antifungal active agent into the nail and through to the nail bed, thereby enhancing the efficacy of the active agent and the ability of the antifungal agent to treat onychomycosis.
  • the present preferred compositions are expected to have the unique ability to allow for the increased in-vitro absorption of the active antifungal agent without the use or incorporation of a separate penetration enhancer. This increased penetration of the active agent can result in an improved therapeutic function and aids in reducing, inhibiting, treating, ameliorating or preventing fungal infections, such as onychomycosis .
  • the increased intercellular adhesion resulting from administration of the present compositions further reduces manifestations of fungal infections while enhancing the nail and skin repair.
  • This reduction of fungal manifestations is optimally achieved by daily topically applying the preferred compositions to the nail and surrounding skin of a mammal .
  • These compositions are superior to those compositions presently available for the reduction of fungal infections, and thus for the normalization of the nail and surrounding skin, due to their extended therapeutic characteristics. Accordingly, the presently preferred compositions can provide both an immediate therapeutic effect, as well as an extended therapeutic effect.
  • the present compositions provide a topical composition, which upon application to a surface of a nail or surrounding skin, allows a flexible, film to be deposited on the affected and surrounding area to help alleviate, reduce, inhibit, treat, ameliorate, or prevent a fungal infection and the symptoms and side effects of the same.
  • This flexible, film additionally protects the infected and surrounding area by acting as an intermediate layer between these areas and environmental stresses and/or clothing.
  • the flexible, film is initially deposited by the evaporation and/or absorption of the aqueous solvent and absorption of the active antifungal agent into the infected and surrounding area of the nail and skin.
  • the present compositions provide a therapeutically effective amount of an antifungal agent, along with a polymeric film forming agent, which forms a protective flexible film to cover the affected and surrounding areas of a fungal infection.
  • the present preferred compositions may be used in ⁇ combination with an additional pharmaceutical dosage form to enhance their effectiveness in treating an ungual, subungual and/or dermatological disease or disorder.
  • the present preferred compositions may be administered as part of a regimen additionally including any other pharmaceutical and/or pharmaceutical dosage form known in the art as effective for the treatment of an ungual, subungual and/or dermatological disorder.
  • a pharmaceutically active antifungal agent other than those specified herein can be added to the present preferred compositions to enhance their effectiveness in treating an ungual, subungual and/or dermat'ological disease or disorder. Accordingly, this additional antifungal agent or additional pharmaceutical dosage form can be applied to a patient either directly or indirectly, and concomitantly or sequentially, with the preferred compositions described herein.
  • the present preferred composition and the additional pharmaceutical dosage form can be administered to a patient at the same time.
  • one of the present preferred compositions and the additional pharmaceutical dosage form can be administered in the morning and the other can be administered in the evening.
  • the present compositions can be administered in combination with a separate oral composition containing another antifungal agent.
  • Another preferred aspect relates to a process for preparing a composition suitable for topical administration, said process comprising: hydrating a polymeric film forming agent; and adding a solution of an active antifungal agent to the hydrated polymeric film forming agent.
  • the hydration step is carried out in an aqueous humectant mix, wherein heating is maintained to a maximum of about 90 0 C during continuous mixing.
  • the active antifungal agent is dissolved in alcohol to form the active antifungal agent solution.
  • a solution of water and sodium hydroxide is prepared. The dissolved active antifungal agent solution is added to the hydrated polymeric film forming agent.
  • This particular preparation process is a non-limiting example of one possible process that can be used to prepare the preferred compositions. Other processes capable of preparing these compositions are further contemplated herein. Further, the individual phases of the preferred compositions (for example aqueous and alcoholic phases) can be prepared sequentially in any order or concurrently; it is not necessary to prepare the alcoholic phase before the aqueous phase is prepared in order to practice the present processes. Additionally, preferred compositions can be prepared according to either a batch process or continuously.
  • compositions produced according to the above-described process are pharmaceutical compositions produced according to the above-described process. If produced according to this process, these compositions exhibit chemical and physical stability suitable for topical administration.
  • the compositions produced according to these processes can be placed in a suitable containment vessel comprising a product contact surface composed of a material selected from the group consisting of glass, plastic, stainless steel, aluminum, Teflon, polymeric structure, ceramic structure, alloys, and mixtures thereof.
  • containment vessels are used to facilitate manufacturing, handling, processing, packaging, storage, and administration of said composition.
  • Preferred containment vessels in this regard can be selected from the group consisting of glass vessels and/or bottles.
  • Appropriate dosage levels for the pharmaceutically active antifungal agents contemplated in the preferred compositions and methods are well known to those of ordinary skill in the art and are selected to maximize the treatment of fungal skin infections and the above-mentioned nail and skin conditions. Dosage levels on the order of about 0.001 mg to about 5,000 mg per kilogram body weight of the pharmaceutically active antifungal agent are known to be useful in the treatment of the diseases, disorders, and conditions contemplated herein. Typically, this effective amount of the pharmaceutically active antifungal agent component will generally comprise from about 0.001 mg to about 100 mg per kilogram of patient body weight per day. Moreover, it will be understood that this dosage of ingredients can be administered in a single or multiple dosage units to provide the desired therapeutic effect .
  • compositions can be employed in conjunction with those provided in the above-described compositions.
  • amount of antifungal ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the antimicrobial ingredients.
  • the preferred pharmaceutical compositions may be given in a single or multiple doses daily.
  • the pharmaceutical compositions are given from one to three times daily. Starting with a low dose twice daily and slowly working up to higher doses if needed is a preferred strategy.
  • the amount of antifungal ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the antimicrobial ingredients.
  • a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific pharmaceutically active antifungal agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion,- possible drug combinations; the severity of the particular condition being treated; and the form of administration.
  • One of ordinary- skill in the art would ⁇ appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.
  • the optimal pharmaceutical formulations will be determined by one skilled in the art depending " upon considerations such as the particular skin protective ingredient and pharmaceutically active agent combination and the desired dosage. See, for example, "Remington's Pharmaceutical Sciences", 18th ed. (1990, Mack Publishing Co., Easton, PA 18042), pp. 1435-1712, the disclosure of which is hereby incorporated by reference. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the essential lipids .
  • a homogenous solution of glycerol and purified water is prepared in a suitable vessel. With stirring, sprinkle the polyvinyl alcohol into the aqueous solution. Upon completion of the polyvinyl alcohol addition, maintain stirring, cover and heat. Upon achieving 85-90 0 C, continue to stir for at least 60 minutes, ensuring full hydration is achieved. Cool the solution to approximately 15-25 0 C by mixing. In a separate vessel, dissolve the ciclopirox in the absolute alcohol . Add the alcohol/ciclopirox solution to the primary solution and mix until a homogenous suspension is achieved. In a separate vessel, . dissolve the sodium hydroxide in a portion of the purified water and cool to 15-25°C. Add the sodium hydroxide solution to the primary solution with mixing to the required pH. Continue mixing until a homogenous solution is formed. The resultant solution is placed in amber glass bottles having a plastic cap and fitted with a nylon brush . EXAMPLE 2
  • a patient is suffering from a fungal nail infection.
  • a preferred composition herein is topically administered to the patient. It would be expected that the patient would improve his/her condition or recover.
  • a patient is suffering from a Tinea infection of the nail and nail bed.
  • a preferred composition herein is topically administered to the patient. It would be expected that the patient would improve his/her condition or recover.
  • EXAMPLE 5 [xi2] A patient is suffering from a Candida infection of the nail and nail bed. A preferred composition herein is topically administered to the patient. It would be expected that the patient would improve his/her condition or recover.

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Abstract

La présente invention concerne de manière générale des compositions antifongiques pour les ongles. Dans un mode de réalisation préféré, les compositions antifongiques selon l'invention comprennent une quantité thérapeutiquement efficace d'un agent antifongique, un solvant aqueux, un agent d'ajustement du pH et un agent filmogéne polymère ayant un degré d'hydrolyse d'environ 80 à environ 95%, une viscosité nominale de 20 à 60 mPa s environ et/ou un degré de polymérisation d'environ 500 à environ 5000. Les compositions ne contiennent pas d'activateurs de pénétration. Ces compositions permettent de réduire, inhiber, traiter, améliorer ou prévenir de manière temporaire ou permanente une infection unguéale et/ou subunguéale provoquée par des microbes tels que des champignons. Les compositions selon l'invention permettent également de former un film lorsqu'elles sont appliquées sur les ongles et la peau avoisinante.
PCT/US2007/003106 2006-02-13 2007-02-07 Compositions antifongiques pour les ongles WO2007094999A2 (fr)

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RU2587064C2 (ru) * 2011-02-11 2016-06-10 Моберг Фарма Аб Новая противогрибковая композиция
US9561279B2 (en) 2011-02-11 2017-02-07 Moberg Pharma Ab Antifungal composition
US9433680B2 (en) 2013-01-31 2016-09-06 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US8778365B1 (en) 2013-01-31 2014-07-15 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9446131B2 (en) 2013-01-31 2016-09-20 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9452173B2 (en) 2013-01-31 2016-09-27 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US9161914B2 (en) 2013-01-31 2015-10-20 Merz Pharmaceuticals, Llc Topical compositions and methods for making and using same
US10166206B2 (en) 2013-01-31 2019-01-01 Sebela International Bermuda Limited Topical compositions and methods for making and using same
US10166205B2 (en) 2013-01-31 2019-01-01 Sebela International Bermuda Limited Topical compositions and methods for making and using same
US10695303B2 (en) 2013-01-31 2020-06-30 Sebela Ireland Limited Topical compositions and methods for making and using same
US10729667B2 (en) 2013-01-31 2020-08-04 Sebela Ireland Limited Topical compositions and methods for making and using same
US10925895B2 (en) * 2014-03-07 2021-02-23 Amy Dukoff Composition and method of using medicament for treatment of cancers and tumors
EP3346998A4 (fr) * 2015-08-17 2019-08-28 Sidmak Laboratories (India) PVT. Ltd. Système d'administration de film par voie topique
WO2019206389A1 (fr) * 2018-04-27 2019-10-31 Unigroup Aps Kit de pièces pour champignon des ongles

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