WO2010086727A1 - Stable compositions for nail onychomycosis treatment - Google Patents

Abstract

Provided are novel stable and highly effective ethosomal antifungal compositions comprising acidic actives, such as terbinafme salts, processes for their preparation and methods of treatment of onychomycosis, wherein the pH of the compositions is raised by 1.0- 3.0 pH units by addition of a base, and the compositions further include one or more phospholipids.

Description

STABLE COMPOSITIONS FOR NAIL ONYCHOMYCOSIS TREATMENT

BACKGROUND OF THE INVENTION

[0001] Nail fungal infections are a widespread and hard to cure affliction. 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% amorolfine, 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[methylvinyl 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] US Patent No. 6,231,875 (to Johnson & Johnson Consumer Companies, Inc.) 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.

[0010] 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

[0011] The present invention successfully addresses unmet medical needs, providing innovative ethosomal topical compositions that allow for high concentrations of terbinafine or its salts and yet remain stable within the pH range that is desirable for optimum antimycotic activity, forming lacquers exhibiting enhanced substantivity of the terbinafine or its salts to the nail and skin, and exhibiting enhanced therapeutic activity. [0012] While the only FDA-approved 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). [0013] The pH of the composition is very important to its activity. Thus, G. Petranyi et al. (Antimicrobial Agents and Chemotherapy, Sept. 1987, p. 1365-1368) found that the terbinafine in vitro activity is pH dependent and rises with increasing pH value. However, 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.

[0014] The instant invention provides stable and highly effective topical compositions comprising high concentrations of terbinafine HCl, a base and a phospholipid in sufficient concentrations and ratios to form "soft" vesicles known as ethosomes. Ethosomes are known lipid vesicular systems containing one or more phospholipids, one or more alcohols, optionally in combination with one or more glycols, and water, in sufficient concentrations and ratios to form "soft" vesicles. Ethosomes and methods for preparing ethosomes are described in U.S. Patent No. 5,716,638.

[0015] 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. 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. Similar terbinafine HCl compositions lacking phospholipid are unstable, showing a high degree of precipitation of the drug at high concentrations. Without wishing to be bound by any particular theory, it is believed that 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.

[0016] These and other aspects of the invention will become apparent from the description of the invention which follows below.

DETAILED DESCRIPTION OF THE INVENTION [0017] This invention provides compositions for nail application. [0018] In one embodiment of this invention, liquid compositions containing terbinafine or a salt of terbinafine are provided, that can be applied on the nail, to form a film after the evaporation of the volatiles.

[0019] 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 terbinafine and/or one or more salts thereof, and pharmaceutically acceptable inactive ingredients.

[0020] The terbinafine salt can include, e.g., the hydrochloride salt or one or more other pharmaceutically acceptable terbinafine salts exhibiting an acidic pH value. [0021] We attempted to prepare compositions with high antifungal active content, using at first terbinafine HCl and a concentration of 10%. As 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. [0022] Thus, our first attempts at developing a highly concentrated terbinafine topical antifungal composition with a less acidic pH (higher than 4.0), by dissolving terbinafine hydrochloride at a concentration of 10% in a mixture of ethanol, water (with or without propylene glycol), and addition of an alkaline base that is, raising the pH value of the mixture by 1.0-3.0 pH units, preferably 1.0-2.5 pH units, by addition of a base (basification or alkalinization), resulted in a white cloudy suspension due to the precipitation of the active. Attempts to obtain solubilization by adding to the mixture Tween 20 (a known hydrophylic surfactant and a good solubilizer), propylene glycol or other solubilizers were unsuccessful. [0023] We have surprisingly found that the addition of a phospholipid to the above mixture, resulted in clear and stable compositions.

[0024] The phospholipid in the compositions of the invention may be selected from soy or egg phospholipids, synthetic phospholipids, PEG-ylated phospholipids, phosphorylated lipids, phosphorylated vitamin E, and mixtures thereof.

[0025] Throughout this application, "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. Typically, the pH of the compositions is raised by 1.0-3.0 pH units, preferably 2.0-2.5 pH units, thus obtaining compositions of higher antifungal activity. 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.

[0026] One preferred base used for basification is sodium hydroxide (NaOH), in the form of an aqueous solution, for example 0.5N or IN aqueous NaOH.

[0027] A literature search on other attempts at developing highly concentrated terbinafine topical antifungal uncovered US Patent No. 7,462,362 (to Nexmed Holdings Inc.). This patent uses 10% terbinafine hydrochloride (without basification) and a penetration enhancer.

[0028] In a further embodiment, 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 e.g., 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 and combinations thereof, d. 30-60% of volatile solvents selected from C2-C4 alkanols selected from ethanol, isopropanol, n-propanol and butanol (hereinafter "alcohol" or "alcohols"), and combinations thereof, e. 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 (hereinafter "glycol" or "glycols") and combinations thereof, f. 0.22-15% of 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. 15-40% 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 combinations thereof, according to need. [0029] We found that the 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.

[0030] In a preferred embodiment of this invention, there are provided stable and highly effective nail compositions which, after the evaporation of the volatiles, provide an occlusive film over the treated areas, thus improving the usefulness of the treatment.

[0031] In another embodiment, there are provided compositions that form an occlusive film over nail afflicted by nail afflictions, thus improving the treatment of said nail afflictions. The nail afflictions suitable for treatment by said method of treatment include fungal onychomycosis in its various forms, and nail infections.

[0032] The preferred concentration of the terbinafine or salt of terbinafine, e.g., terbinafine HCl, in the compositions of this invention preferably ranges from about 7% to about 15%, e.g., from 5-15%, from 7%-10%, or from 7%-12%, and most preferably is about

10%.

[0033] The terbinafine salts used in the compositions of the invention include terbinafine acid addition salts such as, e.g., terbinafine hydrochloride.

[0034] A preferred terbinafine topical solution comprises 10% terbinafine hydrochloride,

50% ethanol, 20% water, optionally 0-13% glycol, 5 % soy phospholipid, sodium hydroxide aqueous solution and 1% Klucel®, hydroxypropylcellulose sold in the U.S. by Hercules Inc.,

Wilmington, DE.

[0035] In an additional embodiment of this invention, there are provided methods of treatment of nail fungal infections by topical administration of the compositions of the present invention to the afflicted area of nail 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 a thin occlusive film comprising the active, which improves the effectiveness of the composition.

[0036] In a preferred embodiment of this invention, the 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. [0037] 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.

[0038] 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.

[0039] Removal of the unattached, infected nail, as frequently as monthly, by a healthcare professional may be needed. The effectiveness of said compositions is expected to enable a shortened period of treatment with superior results.

[0040] 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.

[0041] 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

[0042] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLE 1

Com osition

EXAMPLE 2

Composition

EXAMPLE 3

Com osition

EXAMPLE 4

Composition

Method of preparation of example no. 4 composition

[0043] The phospholipid was dissolved in ethanol, and vitamin E and glycol were added thereto. Terbinafine HCl was dissolved in the above ethanolic solution. The solution was mixed with a mechanical mixer until the drug was dissolved. Sodium hydroxide solution was added with continuous mixing. Hydroxypropyl cellulose was dispersed speedily on the surface of the above composition with continuous mixing. The composition was left for at least 12 hours for the dispersion of the polymer then mixed again until a homogenous liquid was obtained.

EXAMPLE 5

[0044] From the above examples it is evident that Composition from example no. 4 containing sodium hydroxide but for which phospholipid was absent, the drug precipitated. Thus the addition of phospholipid to a composition where the pH was increased prevented drug precipitation. Evaluation of the drug amount retained by the nail after application of 10% Terbinafine HCI formulations on clipped nails. [0045] Protocol of experiment

1. Weight 4 samples of about 10 mg nail pieces (clipped from an adult male).

2. Place each nails sample on a microscope glass slide and add on the nails about 80 mg of the Formulation.

3. Leave the slide uncovered for about 24h at Room Temperature.

4. By using tweezers introduce the nail samples in an Eppendorf and wash the nails with 1.5ml distilled water by vortexing twice for 5 minutes.

5. Remove the nail pieces, by using tweezers, place them on filter paper and wipe with Kim wipes 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 72h 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 0.45μ into a safe-lock Eppendorf.

10. Inject samples to HPLC.

[0046] Terbinafine amount extracted from nails after 24h application of about 8.4 mg Formulation /mg nail.

[0047] All 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.

[0048] 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.

[0049] 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 clear, stable and highly effective topical composition for the treatment of onychomycosis, comprising from about 7% to about 15% of terbinafine or a salt of terbinafine, 0.2-10% of a lipid, 50-60% of one or more volatile solvents selected from C2-C4 alcohols, 15-40% water, 0-30% of a glycol and 0.2-15% of a film-forming ingredient, a stabilizing effective amount of a phospholipid and base in an amount effective to increase the pH of the composition by about 1.0-3.0 pH units, to achieve a pH of from about 4.0 to about 6.0, forming an ethosome lipid vesicular system.

2. The composition of claim 1 , wherein the base used for raising the pH of the composition is selected from sodium hydroxide, potassium hydroxide, triethanolamine, tromethamine, borax and mixtures thereof.

3. The composition of claim 1 , wherein the lipid is selected from soy or egg phospholipids, phosphatidylcholine, synthetic phospholipids, PEG-ylated phospholipids, phosphorylated lipids, phosphorylated vitamin E and mixtures thereof.

4. The composition of claim 1, wherein the C2-C4 alcohols are selected from ethanol, isopropanol, n-propanol and butanol and combinations thereof.

5. The composition of claim 1 , comprising the following components: a. 5-10% terbinafine or a salt of terbinafine, b. 0.2-10% w/w of a lipid selected from phospholipids, phosphorylated lipids and combinations thereof, c. 50-60% of volatile solvents selected from ethanol, isopropanol, n-propanol and butanol 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, other pharmaceutically acceptable glycols, and combinations thereof, e. 0.2-10% of a polymer selected from cellulose derivatives, butyl monoesters of polymethylvinyl ether/maleic acid copolymer, PVP, PVA, Eudragits, other pharmaceutically acceptable polymers, and combinations thereof, f. 15-40% water, g. a base, selected from sodium hydroxide, potassium hydroxide, triethanolamine, tromethamine, ammonia, and combinations thereof, and h. 0-10% of pharmaceutically acceptable excipients, selected from plasticizers, emollients, sunscreens, pigments, antioxidants, stabilizers, perfumes, and combinations thereof.

6. The composition of claim 1, in the form of a topical solution or spray, wherein said solution or spray is capable of being applied to the nail with a brush, metered dose device, patch, bandage or as a spray, thereby forming a film.

7. A method of treating onychomycosis in a human in need thereof, the method comprising applying to the nail a therapeutically effective dose of the composition of claim 1, so as to form a film on the treated surface.

8. A method of treating onychomycosis, the method comprising contacting the afflicted nail area with the composition of claim 1, thereby forming an occlusive film over the afflicted nail area.

9. The composition of claim 1, containing 5-10% terbinafine HCl , an alkaline organic or inorganic base, 2-10% phospholipid, 15-40% water, 50-60% of one or more volatile solvents selected from C2-C4 alcohols, and 0.2-15% of film-forming ingredient.

10. The composition of claim 1 , wherein the one or more volatile solvents is ethanol.

1 1. The composition of claim 1 , wherein the base is selected from sodium hydroxide, potassium hydroxide, ammonia, triethanolamine, tromethamine and combinations thereof.

12. A clear, stable and highly effective topical composition for the treatment of nail fungal infections, comprising from about 7% to about 15% of terbinafine or a terbinafine salt, 0.2-10% of a phospholipid, 50-60% of one or more volatile solvents selected from C2- C4 alcohols, 15-40% water, 0-30% of a glycol, 0.2-15% of a film-forming ingredient, and sufficient base to increase the pH of the composition by about 1.0-3.0 pH units, and to achieve a pH of from about 4.0 to about 6.0, forming an ethosome lipid vesicular system.