DESC:FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising Efinaconazole with suitable pharmaceutically acceptable excipients, in particular the composition does not contain wetting agent. Such compositions can be administrated through topical route such that it can enhance the drug penetration for effective treatment of fungal diseases of the nail or nail bed. Further, the present invention relates to a process for the preparation of the said composition and its uses thereof.

BACKGROUND OF THE INVENTION

Efinaconazole chemically known as ((2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol) is a triazole antifungal. Currently it has been approved for the treatment of onychomycosis of the toenails.

Onychomycosis, also known as tinea unguium, is a fungal infection of the nails, and this condition may affect toenails or fingernails, but toenail infections are particularly common. It is the most common disease of the nails in the humans. The U.S. Patent No. 7,214,506 describes the use of Efinaconazole for the treatment of onychomycosis.

Several topical therapies have been suggested for treatment of nail disorders, such as onychomycosis. Nail lacquers, coating, polishes, enamels, and varnishes have been known in the art, particularly as containing a film-forming agent. The U.S. Patent No. 5,346,692 discloses a nail lacquer for treating onychomycosis, comprising a cellulose derivative as a film-forming agent, an active substance, and urea.

The U.S. Patent No. 6,143,794 discloses a topical formulation for the treatment of nail fungal infection that includes an antifungal agent, solvent, gelling agent, adhesion-promoting agent, film-forming agent, surfactant, and optionally a keratolytic agent.

The commercial topical antifungal product as approved by the FDA for treating onychomycosis is Ciclopirox Nail Lacquer 8% e.g. Penlac® containing butyl monoester of poly[methylvinyl ether/maleic acid], a copolymer, which results in formation of a dry film on the nail surface.

Efinaconazole (JUBLIA®) is commercially available as a 10% topical solution. The U.S. Patent No. 8,039,494; 8,486,978; 9,302,009; 9,566,272; 9,662,394; 9,861,698; 9,877,955 and 10,105,444, describes a stable topical composition comprising Efinaconazole, water, C12-15 alkyl lactate, diisopropyl adipate, cyclomethicone, ethanol, EDTA, butylated hydroxytoluene (BHT), and citric acid. In particular, the commercial efinaconazole product essentially comprises a wetting agent (i.e. cyclomethicone) to reduce the surface tension of the composition in order to achieve the desired spreadability for topical application in the treatment of Onychomycosis.

Cyclomethicone used in JUBLIA® is a polydimethylcyclosiloxane, which is composed of Decamethylcyclopentasiloxane. Cyclomethicone is clear, tasteless, essentially odorless and non-greasy. Due to its varying rates of evaporation, low surface tensions (high spreadability), and nongreasy feel, cyclomethicone is used as wetting agent. The volatile silicones, such as Cyclomethicone are generally considered as low hazard for humans; however it may be harmful to the environment. Moreover, the silicones can often be difficult to remove from the skin surface, and it can make the skin dull and dehydrated.

As a formulator, it has been very challenging to develop a novel pharmaceutical composition comprising Efinaconazole, wherein the composition does not contain wetting agents, specifically Cyclomethicone. Further, the inventors of present invention have developed a pharmaceutical composition in the form of a topical solution comprising Efinaconazole, wherein the composition does not contain film-forming polymers. There exists a need for the development of an improved pharmaceutical composition of Efinaconazole, which can achieve the desired spreadability along with enhanced penetration of the drug through the nails. Such compositions can be used for effective treatment of fungal diseases of the nail, particularly Onychomycosis.

OBJECTS OF THE INVENTION

The main object of the present invention is to provide a pharmaceutical composition comprising Efinaconazole with suitable pharmaceutically acceptable excipients, wherein the composition does not contain wetting agents.

Another object of the present invention is to provide a pharmaceutical composition comprising Efinaconazole, at least one vehicle, at least one solvent, and at least one antioxidant, wherein the composition does not contain wetting agents.

Another object of the present invention is to provide a method for the preparation of a pharmaceutical composition comprising Efinaconazole; wherein the method comprises the steps of:
a) Solubilizing the antioxidant(s) in the vehicle,
b) Dissolving Efinaconazole to the solution of step a),
c) Adding suitable solvent to the solution obtained in the step b),
d) Making up the final solution volume with vehicle to obtain a clear colourless to slightly yellow solution.

SUMMARY OF THE INVENTION

In a first embodiment, the invention relates to a pharmaceutical composition comprising Efinaconazole with suitable pharmaceutically acceptable excipients, wherein the composition does not contain wetting agents.

In another embodiment, the invention relates to a pharmaceutical composition comprising Efinaconazole as an active ingredient, at least one vehicle, at least one solvent, and at least one antioxidant, wherein the composition does not contain wetting agents.

In a preferred embodiment, the present invention is a pharmaceutical composition comprising Efinaconazole, ethanol, Citric acid (anhydrous), Butylated hydroxy toluene, C12-15 alkyl lactate, Diisopropyl adipate, Propylene Carbonate, and purified water, wherein the composition does not contain wetting agents.

In another embodiment, the invention relates to a method for the preparation of a pharmaceutical composition comprising Efinaconazole; wherein the method comprises the steps of:
a) Solubilizing the antioxidant(s) in the vehicle,
b) Dissolving Efinaconazole to the solution of step a),
c) Adding solvent(s) to the solution obtained in the step b),
d) Making up the final solution volume with vehicle to obtain clear colourless to slightly yellow solution.

DETAILED DESCRIPTION

The detailed description and the examples provided herein are exemplary and any modification or variation within the scope of the invention will be apparent to a person skilled in the art. Further, unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as understood by a person who is ordinarily skilled in the art.

In one aspect, the present invention provides a pharmaceutical composition comprising Efinaconazole with suitable pharmaceutically acceptable excipients, wherein the composition does not contain wetting agents.

In another aspect, the present invention provides a pharmaceutical composition comprising Efinaconazole with suitable pharmaceutically acceptable excipients, wherein the composition does not contain film-forming polymers.

In another aspect, the present invention provides a pharmaceutical composition comprising Efinaconazole, at least one vehicle, at least one solvent, and at least one antioxidant, wherein the composition does not contain wetting agents.

The drug of the present invention is Efinaconazole, which can be used in the range of about 1%W/W to about 30%W/W, preferably from about 8%W/W to about 12%W/W, and more preferably about 10%W/W.

The vehicle of the present invention dissolves or disperses the ingredients of the pharmaceutical composition, and further it evaporates from the nail surface upon application. Examples of suitable vehicles include one or more of water, alcohols, polyols, ethers, esters, aldehydes, ketones, fatty acids, fatty alcohols, and fatty esters. Preferably the vehicle of the present invention is selected from water, ethanol and mixtures thereof.

The solvent of the present invention is a non-aqueous solvent, which can be volatile or non-volatile. In a preferred embodiment, the solvent is miscible with the vehicle, and the drug of the present invention is solubilized to provide a clear colorless to slightly yellow solution. Preferably the solvent of the present invention is selected from C12-15 alkyl lactate, diisopropyl adipate, propylene carbonate, and mixtures thereof.

The antioxidant of the present invention maintains the stability of the pharmaceutical composition upon storage, for few days to several months or even years at suitable temperatures, about 20 °C and 40 °C, preferably about 20 °C to about 25 °C. Preferably the antioxidant is selected from citric acid, Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), and mixtures thereof.

The wetting agent for the purpose of the present invention refers to a chemical compound that reduces the surface tension of liquid compositions and that does not build viscosity. The wetting agent may be a surfactant, which may be anionic, cationic, or non-ionic. Preferably the wetting agent for antifungal topical composition is volatile silicone, such as Cyclomethicone. Other examples of suitable wetting agents are disclosed in U.S. Patent No. 9,566,272, which is incorporated herewith for reference purpose only. In a preferred embodiment, the compositions of the present invention does not contain wetting agents, especially cyclomethicone.

Generally the film-forming polymers are added into nail preparations, and they provide a solid or semi-solid film on the nail surface upon topical application. However, such conventional nail preparations create difficulty and irregularity in obtaining clinically effective treatment of onychomycosis by topical administration.

In a preferred embodiment, the composition of the present invention does not contain any film-forming polymers, but it provides unexpected results in terms of spreadability of the composition through the nail tissue.

In a preferred embodiment, the present invention is a pharmaceutical composition comprising Efinaconazole, ethanol, Citric acid anhydrous, Butylated hydroxy toluene, C12-15 alkyl lactate, Diisopropyl adipate, Propylene Carbonate, and purified water, wherein the composition does not contain wetting agents.

In addition to the above-mentioned ingredients, the pharmaceutical composition of the present invention may contain additional optional components, such as, chelating agents (e.g., EDTA), preservatives (e.g., benzyl alcohol), penetration enhancers (e.g., glycols), etc.

The efinaconazole compositions exhibit varying degrees of instability during storage, resulting in color variations such as dark yellow to orange red. Such color variations can discourage patients for self-administration of discolored compositions for the prescribed use. The compositions of the present invention remains clear colourless to slightly yellow, without any significant discoloration upon storage. In a preferred embodiment, the efinaconazole compositions of the present invention remains stable for at least 6 months, when stored at 40°C/ 75% RH and 25°C/ 60% RH, and the total impurities remained below 2%.

Another aspect of the invention is to provide a method for the preparation of a pharmaceutical composition comprising Efinaconazole; wherein the method comprises the steps of:
a) Solubilizing the antioxidant(s) in a vehicle,
b) Dissolving Efinaconazole to the solution of the step a),
c) Adding solvent(s) to the solution obtained in the step b),
d) Making up the final solution volume with vehicle, to obtain clear colourless to slightly yellow solution.

In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.

Example 1: Pharmaceutical composition of Efinaconazole
Sr. No. Ingredients %W/W
1 Efinaconazole 1-30%
2 Vehicle(s) q.s.
3 Solvent(s) 10-80%
4 Antioxidant(s) 0.01-5%
5 Chelating agent (optional) 0.0001-0.0005%
6 Preservative (optional) q.s.
7 Penetration enhancer (optional) q.s.

Method of preparation:
a) Solubilizing the antioxidant(s) in the vehicle,
b) Dissolving Efinaconazole to the solution of the step a),
c) Adding solvent(s) to the solution obtained in the step b),
d) Optionally the chelating agent, preservative or penetration enhancer can be added in the solution obtained in the step c),
e) Making up the final solution volume with vehicle, to obtain clear colourless to slightly yellow solution.

Example 2: Pharmaceutical composition of Efinaconazole
Sr. No. Ingredients %W/W
1 Efinaconazole 10%
2 Purified water 1%
3 Citric acid anhydrous 0.10%
4 Butylated hydroxy toluene (BHT) 0.10%
5 C12-15 alkyl lactate 10%
6 Diisopropyl adipate 12%
7 Alcohol 96% 53.80%
8 Propylene Carbonate 13%

Method of preparation:
a) Solubilizing the citric acid anhydrous and BHT in the Ethanol,
b) Dissolving Efinaconazole to the solution of the step a),
c) Adding C12-15 alkyl lactate, Diisopropyl adipate and Propylene Carbonate to the solution obtained in the step b),
d) Making up the final solution volume with water and ethanol, and stir well to obtain clear colourless to slightly yellow solution.

Example 3: Stability results for pharmaceutical composition of Efinaconazole.
Tests / condition Initial 40°C/ 75% RH 25°C/ 60% RH
6 Month, Inverted 6 Month, Horizontal 6 Month, Upright 6 Month, Inverted 6 Month, Horizontal 6 Month, Upright
Description A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution A clear colourless solution
pH 5.61 5.73 5.69 5.80 5.65 5.70 5.70
Water content 4.72% 5.28% 5.26% 5.28% 4.84% 4.74% 4.76%
Related substances (%)
Epoxide impurity 0.004% 0.005% 0.005% 0.005% 0.005% 0.005% 0.005%
Single maximum unknown impurity 0.071% 0.262% 0.260% 0.263% 0.111% 0.110% 0.110%
Total impurities 0.342% 0.720% 0.704% 0.717% 0.464% 0.442% 0.411%
Efinaconazole 99.9% 102.2% 102.3% 102.0% 101.4% 101.6% 101.3%
Ethanol content 96.5% 96.5% 96.3% 96.0% 97.8% 98.3% 98.1%

The stability study of the inventive composition shows that the Efinaconazole composition remains stable for at least 6 months, when stored at 40°C/ 75% RH and 25°C/ 60% RH, and the total impurities remained below 2%.

The pharmaceutical composition of the present invention remains clear colourless to slightly yellow solution upon storage. ,CLAIMS:We claim:

1. A pharmaceutical composition comprising Efinaconazole, at least one vehicle, at least one solvent, and at least one antioxidant, wherein the composition does not contain wetting agents.

2. The pharmaceutical composition according to any of the preceding claims, wherein Efinaconazole is present from about 1%W/W to about 30%W/W.

3. The pharmaceutical composition according to any of the preceding claims, wherein the vehicle is selected from water, ethanol and mixtures thereof.

4. The pharmaceutical composition according to any of the preceding claims, wherein the solvent is selected from C12-15 alkyl lactate, diisopropyl adipate, propylene carbonate, and mixtures thereof.

5. The pharmaceutical composition according to any of the preceding claims, wherein the antioxidant is selected from citric acid, Butylated hydroxy anisole, Butylated hydroxy toluene, and mixtures thereof.

6. The pharmaceutical composition according to any of the preceding claims, wherein the composition comprises Efinaconazole from about 1-30 %W/W, solvents from about 10-80 %W/W, antioxidants from about 0.01-5 %W/W, and vehicles.

7. A pharmaceutical composition comprising Efinaconazole, ethanol, Citric acid anhydrous, Butylated hydroxy toluene, C12-15 alkyl lactate, Diisopropyl adipate, Propylene Carbonate, and purified water, wherein the composition does not contain wetting agents.

8. A pharmaceutical composition comprising 10% Efinaconazole, 53.80% ethanol, 0.10% Citric acid anhydrous, 0.10% Butylated hydroxy toluene, 10% C12-15 alkyl lactate, 12% Diisopropyl adipate, 13% Propylene Carbonate, and 1% purified water.

9. A method for the preparation of a pharmaceutical composition comprising efinaconazole; wherein the method comprises the steps of:
a) Solubilizing the citric acid anhydrous and BHT in the Ethanol,
b) Dissolving Efinaconazole to the solution of the step a),
c) Adding C12-15 alkyl lactate, Diisopropyl adipate and Propylene Carbonate to the solution obtained in the step b),
d) Making up the final solution volume with with water and ethanol, and stir well to obtain clear colourless to slightly yellow solution.

10. The pharmaceutical composition according to any of the preceding claims, wherein the composition remains stable for at least 6 months when stored at 40°C/ 75% RH and 25°C/ 60% RH, and the total impurities remained below 2%.