Nail lacquer composition containing ciclopirox

Abstract

The present invention relates to a nail lacquer composition containing at least one antifungal agent as a pharmacologically active ingredient. The present invention has an excellent penetrating effect of a drug in skin areas where the drug is applied because of needing treatment and, specifically, in fingernails by containing a polymer material which forms a specific film, and a penetration enhance, is convenient for management after locally applying the drug to a treatment site, and has excellent storage stability of the drug.

Claims

1. A nail lacquer composition comprising at least one antifungal agent, at least one film forming agent, at least one solvent and water, wherein the at least one antifungal agent is ciclopirox or a pharmaceutically acceptable salt thereof; the film forming agent is an octylacrylamide acrylate copolymer in an amount of 0.5 to 15 wt % relative to the total weight of the composition; the at least one solvent is ethanol in an amount of 60 to 85 wt % relative to the total weight of the composition; and wherein the amount of water is 5 to 20 wt %, relative to the total weight of the composition.

2. The composition according to claim 1, further containing at least one selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropylmethylcellulose.

3. The composition according to claim 1, further containing at least one selected from the group consisting of urea, cetostearyl alcohol, and N-methyl-2-pyrrolidone.

4. The composition according to claim 1, wherein the amount of ciclopirox or a pharmaceutically acceptable salt thereof is 0.5-10 wt. %, relative to the total weight of the composition.

5. The composition according to claim 2, wherein the amount of at least one selected from the group consisting of hydroxypropylmethylcellulose and hydroxypropylmethylcellulose is 0.001-10 wt. %, relative to the total weight of the composition.

6. The composition according to claim 3, wherein the amount of at least one selected from the group consisting of urea, cetostearyl alcohol, and N-methyl-2-pyrrolidone is 0.01-10 wt. %, relative to the total weight of the composition.

7. The composition according to claim 2, further containing at least one selected from the group consisting of urea, cetostearyl alcohol, and N-methyl-2-pyrrolidone.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows the comparison results of the amounts of the active ingredients remaining inside of toenail during the period after applying the test drug and the control drug.

(2) FIG. 2 shows the analysis results of the amounts of the active ingredients under the accelerated storage condition and the long storage condition of the test drug.

BEST MODE FOR EMBODIMENT OF INVENTION

(3) The present invention relates to a nail lacquer composition containing an antifungal agent as an active ingredient, wherein the composition contains an active ingredient, a specific film forming agent, a solvent and other additives, etc.

(4) [Antifungal Agent]

(5) The present invention contains at least one antifungal agent. The antifungal agent can be selected from any known antifungal agents of synthetic or natural origin. In addition, the active agent can be in the free form, and can also be in the form of free acid, free base or other salts.

(6) The examples of the known antifungal agents include, but are not limited to, 1-hydroxy-2-pyridone compounds, e.g., ciclopirox, rilopirox, piroctone, ciclopirox olamine or the compound disclosed U.S. Pat. No. 4,957,730; imidazole derivatives, e.g., clotrimazole, econazole, isoconazole, ketoconazole, miconazole, thioconazole, bifonazole, fenticonazole or oxiconazole; polyene derivatives, e.g., nystatin, natamycin or amphotericin; allylamine derivatives, e.g., niphtipine or terbinapine; triazole derivatives, e.g., fluconazole, itraconazole, terconazole or voriconazole; morpholine derivatives, e.g., amorolfine or the compound disclosed in U.S. Pat. No. 5,120,530; griseofulvin; acidic compounds, e.g. undecylenic acid; tolnaftate; or flucytosine, etc.

(7) In addition, as known antifungal agents, there is natural origin, in particular, plant extracts, for example, leaf extracts of tea-tree oil, lavender oil or neem tree, etc.

(8) The present invention can use the known antifungal agent alone or a mixture of two or more different antifungal agents. In particular, if the antifungal agent is of natural origin, the use of the mixture of two or more different antifungal agents is more preferable in the expression of the drug efficacy.

(9) In the aspect of the expression of the other effect as well as the expression of the drug efficacy, when using the antifungal agent alone or blending two or more different components, it is the most preferable to select ciclopirox basically. The amount of the antifungal agent may vary depending on structure, antimicrobial activity, release speed from nail lacquer film, spreading property and penetration into the nail, and this can be properly selected by a person skilled in the art. However, when containing ciclopirox as the antifungal agent, it is preferable to select ciclopirox in the amount of 0.001-30 wt. % relative to the total amount of the composition, and in particular, in the aspect of the expression of the targeted effect, it is the most preferable to select ciclopirox in the amount of 0.5-10 wt. %.

(10) [Film Forming Agent]

(11) The present invention contains at least one film forming agent. The film forming agent refers to a component of a binder essential to form a film such as a thin membrane or cover.

(12) There are several components as film forming agents known in this art. As aforementioned, in the commercially available medicine, Fenrakk™, an insoluble film forming agent was selected, and in Korean Patent No. 10-0530263, derivatives of chitosan, which are one kind of a water soluble film forming agent, were selected. However, the present inventors believed that the insoluble film forming agent has an excellent waterproof, but has a disadvantage that the formed film should be removed when applying the drug secondarily after applying the drug primarily to have a good penetrating power of the drug, but in order to remove the formed film, the use of an organic solvent, etc. is required, so the process is very inconvenient, and that the chitosan derivatives have a disadvantage that they are sensitive to the water, when applying the drug, the drug generally needs about 6 hours to be penetrated into the shell to sufficiently reach to a site to be treated, but the drug can be cleansed by being in contact with a small amount of water. Most of all, the film forming agent has unsatisfactory penetration of a drug into the nail.

(13) However, surprisingly, the present inventors have found that when selecting, as a film forming agent, at least one selected from the group consisting of an octylacrylamide acrylate copolymer, an acrylic acrylate copolymer, a styrene acrylate copolymer, an aminoalkyl methacrylate copolymer, an acrylate methacrylate copolymer, an ammonio methacrylate copolymer, an acrylate ammonium methacrylate copolymer, an acrylate dimethylaminoethyl methacrylate copolymer, and octylacrylamide acrylate butylaminoethyl methacrylate copolymer, the above disadvantages were all overcome, and discovered that the treatment of the disease has a surprising synergistic effect with an antifungal agent, in particular, ciclopirox, in the aspect of the targeted effect, and then the inventors completed the present invention.

(14) The film forming agent according to the present invention is a type that when applying the agent onto the nail together with a solvent, while the solvent is evaporated, a film is formed on the nail and maintained until it exposes to traditional typical hygienic cleaning cycles and then removed. This film forming agent is strong and flexible, has good waterproof, excellent in the easiness of cleaning, and most of all, can improve the penetration of a drug into the nail.
The film forming agent is preferably selected in the amount of 0.5-30 wt. %, relative to the total amount of the composition, and in particular, most preferably, selected in the amount of 1.0-15 wt. % in the aspect to the expression of the targeted effect.

(15) [Solvent]

(16) The present invention contains at least one physiologically acceptable solvent. As solvents, ethanol, isopropanol, ethyl acetate, butyl acetate, acetone or a mixture thereof, which are organic solvents that are physiologically acceptable and compatible with other components, including the drug and the film forming agent, of the composition, are preferred.

(17) Herein, the organic solvent is present in the composition in the amount sufficient to dissolve the components to be liquefied, e.g. a solid component, the film forming agent and other additives, and the organic solvent can be used in the amount of 40-90 wt. %, more preferably, 60-85 wt. %, relative to the total weight of the composition. In addition, as a solvent, water can be used because the penetration of the drug into hydration of the nail is easy and for the reduction of stimulus due to frequent and repeated exposures of the organic solvent to the nail and adjacent skin. Here, water can be used in the amount of 0-20 wt. %, preferably, 1-10 wt. %, relative to the total weight of the composition. However, in this case, it should be noted that the amount should be selected in the range that does not affect the problems of long term stability due to the degradation of the compatibility with other solvents and components, for example, phase separation, precipitation or the degradation of the content of the active component.

(18) [Other Additives]

(19) The present invention can further contain at least one ingredient selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, hydroxyalkyl cellulose and alkylcellulose, in order to improve the hydrophilic property of the film membrane.

(20) In addition, the present invention can further contain at least one ingredient selected from the group consisting of N-methyl-2-pyrrolidone, cetostearyl alcohol, cetanol, stearyl alcohol, urea, campa and salicylic acid, in order to improve nail penetration of the composition.

(21) Depending on cases, the present invention can contain antibiotic, anti-inflammatory agents, preservatives and/or local anesthetics, and can also contain other existing additives typically blended in nail lacquer for cosmetics or treatment, e.g., precipitation retarder, chelating agent, antioxidant, silicate, aroma component, wetting agent, lanolin derivatives, optical stabilizer or antibacterial component.

(22) [Preparation Method]

(23) The present invention can be prepared according to the general method typically used for the preparation of nail lacquers. For example, the present invention can be prepared by adding at least one antifungal agent, at least one film forming agent selected from the group consisting of an octylacrylamide acrylate copolymer, an aminoalkyl methacrylate copolymer and an alkyl acrylate methylmethacrylate copolymer, and other additives into a solvent or a mixture of solvents, respectively or simultaneously, and individually stirring the mixture with other liquid components simultaneously or by a typical mixing technique. Herein, there is no particular standard in the order of adding the individual components, and the order can be properly selected by a person skilled in the art. If any component is presented in the solid form, it is preferable to gradually add the ingredients into the liquid component in order to prevent clumping.

(24) Hereinafter, the present invention will be explained in more detail through specific examples. Please note that the following examples are only to exemplify the present invention, and the scope of the present invention is not limited to the following examples.

FORM FOR EMBODIMENT OF THE INVENTION

Example 1

(25) A nail lacquer composition was prepared by mixing the liquid components of Table 1 in a container provided with a stirrer, and then successively adding the components and stirring the mixture until the components were dissolved.

(26) TABLE-US-00001 TABLE 1 Wt. % relative to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 8% Hydroxypropylcellulose 0.2%.sup.  Ethanol 62.3%   Ethyl acetate 10%  Water 10%  Urea 0.5%.sup.  Setostearyle alcohol 1%

(27) The present nail lacquer composition was transparent for a long period, maintained the uniform phase, and maintained the uniform film membrane without disappearing until it was exposed to the cleaning cycle, so the drug could have exerted the continuous efficacy. In addition, as will be explained in Experimental Examples 1 and 2, the present nail lacquer composition was also excellent in the nail penetration and storage stability as shown in FIGS. 1 and 2.

Example 2

(28) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 2.

(29) TABLE-US-00002 TABLE 2 Wt. % relative to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 5% Hydroxypropylcellulose 0.3%.sup.  Ethanol 65.2%   Ethyl acetate 10%  Water 10%  Urea 0.5%.sup.  Setostearyle alcohol 1%

(30) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

Example 3

(31) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 3.

(32) TABLE-US-00003 TABLE 3 Wt. % relative to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 5% Hydroxypropylcellulose 0.2%.sup.  Ethanol 68.3%   Ethyl acetate 15%  Water 2% Urea 0.5%.sup.  Setostearyle alcohol 1%

(33) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

Example 4

(34) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 4.

(35) TABLE-US-00004 TABLE 4 Wt. % with respect to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 8% Hydroxypropylcellulose 0.2%.sup.  Ethanol 72.3%   Ethyl acetate 5% Water 5% Urea 0.5%.sup.  Setostearyle alcohol 1%

(36) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

Example 5

(37) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 5.

(38) TABLE-US-00005 TABLE 5 Wt. % with respect to the total Component amount of the composition Ciclopirox  8% Octylacrylamide acrylate copolymer  8% Hydroxypropylcellulose 0.2%  Ethanol 42.3%.sup.  Ethyl acetate 20% Water 10% Urea 10% Setostearyle alcohol 0.5% 

(39) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

Example 6

(40) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 6.

(41) TABLE-US-00006 TABLE 6 Wt. % with respect to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 8% Hydroxypropylcellulose 0.2%.sup.  Ethanol 67.3%   Ethyl acetate 10%  Water 5% Urea 0.5%.sup.  Setostearyle alcohol 1%

(42) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

Example 7

(43) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 7.

(44) TABLE-US-00007 TABLE 7 Wt. % with respect to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 8% Hydroxypropylcellulose 0.2%.sup.  Ethanol 72.3%   Ethyl acetate 5% Water 5% Urea 0.5%.sup.  Setostearyle alcohol 1%

(45) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

Example 8

(46) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 8.

(47) TABLE-US-00008 TABLE 8 Wt. % with respect to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 8% Hydroxypropylcellulose 0.2%.sup.  Ethanol 60.8%   Ethyl acetate 10%  Water 10%  Urea 2% Setostearyle alcohol 1%

(48) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

Example 9

(49) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 9.

(50) TABLE-US-00009 TABLE 9 Wt. % with respect to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 8% Hydroxypropylcellulose 0.2%.sup.  Ethanol 62.3%   Ethyl acetate 15%  Water 5% Urea 0.5%.sup.  Setostearyle alcohol 1%

(51) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

Example 10

(52) The nail lacquer composition was prepared according to the same method as in Example 1 using the components of Table 10.

(53) TABLE-US-00010 TABLE 10 Wt. % with respect to the total Component amount of the composition Ciclopirox 8% Octylacrylamide acrylate copolymer 8% Hydroxypropylcellulose 0.2%.sup.  Ethanol 60.8%   Ethyl acetate 15%  Water 5% Urea 2% Setostearyle alcohol 1%

(54) The present nail lacquer composition showed the phase and properties equivalent to the nail lacquer composition of Example 1.

[Experimental Example 1] Test for Nail Penetration of Active Ingredient Using Pig Tonail

(55) The comparison test was conducted by selecting, as a test drug, the composition of Example 1, and selecting, as a control drug, the commercially available product (Full Care Nail Lacquer™) consisting of the mixed ingredients of the following Table 11.

(56) TABLE-US-00011 TABLE 11 Mixed ingredients Ciclopirox Ethyl acetate Ethanol Setostearyle alcohol Hydroxypropyl Chitosan Water

(57) Example 1 (Ciclopirox 80 mg among about 1 g), which is the test drug, and the commercially available product (Full Care Nail Lacquer™) containing the same amount (Ciclopirox 80 mg among about 1 g) of the active ingredient as Example 1, which is the control drug, were applied onto the pig toenail having a diameter of 1.5 cm, in the amount of 1 mL (about 80 mg as Ciclopirox), respectively. After the application for 1 hour, 3 hours and 6 hours, the toenail was made into thin fragments using Microtome, and 10 mL methanol was put and subjected to ultrasonication for 1 hour at 50°, and then measured according to the high pressure liquid chromatography. The results are shown in FIG. 1.

(58) Upon comparing the total amount of the active ingredient penetrated into the toenail through FIG. 1, it can be figured out that the test drug showed relatively higher penetration as compared to the control drug, so the final penetration amount and the total penetration amount are similar or higher than those of the control drug. In other words, although the test drug has slightly lower waterproof property as compared to insoluble nail lacquers that use a large amount of pungent organic solvents, its waterproof property is not bad to the extent that the drug is disappeared when it is in a slight contact with water like the control drug, and the test drug can maintain the uniform film membrane until it is exposed to the hygienic cleaning cycles, and is excellent in the penetration of the active ingredient. Considering all of the above, the test drug is the most suitable antifungal nail lacquer as compared to prior art technologies known so far.

[Experimental Example 2] Stability Test of Active Ingredient

(59) The amount of the active ingredient of the test drug in Experimental Example 1 was measured according to high pressure liquid chromatography, and then stored for 3 months under the accelerated storage condition (Temperature 40° C., Relative humidity 75%) and the long storage condition (Temperature 25° C., Relative humidity 60%). Thereafter, after 1 month, 2 months and 3 months, the amount of the active ingredient was measured again according to high pressure liquid chromatography. The results are shown in FIG. 2

(60) It was confirmed that in the test drug, under the accelerated storage condition, even after the storage for 3 months, the amount of the active ingredient is maintained almost the same as that before the storage and that under the long storage condition.

(61) In other words, in the test drug, the composition of the nail lacquer is maintained stably in the active ingredient exerting the efficacy as well as in appearance and thus the test drug is suitable as an antifungal nail lacquer.