DESC:FORM 2
THE PATENTS ACT, 1970
(39 Of 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule13)
1. TITLE OF THE INVENTION: TOPICAL PHARMACEUTICAL COMPOSITIONS OF LULICONAZOLE
2. APPLICANT(S)
(a) Name: GLENMARK PHARMACEUTICALS LIMITED
(b) Nationality: INDIAN
(c) Address: B/12 MAHALAXMI CHAMBERS 22, BHULABHAI DESAI ROAD, MUMBAI 400026
3. PREAMBLE TO THE DESCRIPTION
PROVISIONAL COMPLETE
The following specification describes the invention The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to a topical pharmaceutical composition comprising luliconazole, or a pharmaceutically acceptable salt thereof. The topical compositions described herein are useful for the treatment of skin disorders, such as onychomycosis.
BACKGROUND OF THE INVENTION
Onychomycosis is a fungal infection occurring in the nails and may affect the adjacent skin. Typically, it manifests as discoloration of the nail, nail plate thickening, and onycholysis. It is the most common nail pathology and accounts for about 90% of toenail infections worldwide. This infection presents several problems for affected populations, including local pain, paresthesia, and reduced quality of life as its appearance may impair social interactions and daily activities Most onychomycoses are caused by the dermatophytes Trichophyton, Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton Infections often initiate from tinea pedis, a fungal infection on the surrounding skin of the feet. Factors that contribute to disease progression are humidity, occlusive footwear, nail trauma, and genetic predisposition. Patients with diabetes, poor peripheral circulation, HIV, and immunosuppression are also more susceptible, as are elderly patients.
Luliconazole is an imidazole antifungal that has been approved first in Japan for topical treatments of fungal infections. Luliconazole is represented by a structural formula (I)

Formula (I)
Luliconazole 1% Cream and Luliconazole 5% solution are indicated for the treatment of cutaneous mycosis Tinea: Tinea pedis, tinea corporis and tinea cruris; Candidiasis: Intertrigo and interdigital erosion, Tinea versicolor.
Luliconazole is disclosed in International patent application no. WO9702821. International patent application no. WO2011155640 disclose luliconazole compositions comprising a polyhydric alcohol derivative. International patent application no. WO2007102242 discloses a composition comprising luliconazole dissolved in propylene carbonate at a concentration of 0.1 to 40% by mass. International patent application no. WO2007102241 relates to a composition of luliconazole and a-hydroxycarboxylic acid/salt. International patent application nos. WO2014041708 and WO2014136282 relates to specific crystal habit of Luliconazole that helps to improve the solubilization of luliconazole. International patent application nos. WO2010117091 and WO2010117089 provide luliconazole composition comprising a higher alcohol and/or a diester of a dibasic acid excluding a diester carbonate, and a polyoxyethylene alkyl ether and/or a polyoxyethylene alkenyl ether. WO2007102242 discloses luliconazole composition comprising one or two or more members selected from among N-methyl-2-pyrrolidone, propylene carbonate, and crotamiton. WO2011024620 discloses pharmaceutical compositions of luliconazole with a ketone and a hydroxyalkylbenzene for excellent solubilization and suppressing stereo-isomerization of luliconazole.
Luliconazole formulation as disclosed being highly chemical unstable wherein compound may not be dissolved sufficiently, and hence time-dependently gets precipitated Further, Luliconazole on storage leads to formation of different stereoisomers depending on the solvent system used which leads to poor efficacy and therefore there is a still need to develop chemically stable topical pharmaceutical composition of luliconazole.

SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol.
In one aspect, the present invention relates to a chemically stable topical pharmaceutical composition, wherein the composition is a solution.

In one aspect, the present invention relates to a chemically stable topical pharmaceutical composition comprising luliconazole, wherein the penetration enhancer is lactic acid and film forming polymer is selected from diethylene glycol monoethyl ether (Transcutol P) and methylvinyl ether-maleic anhydride (Gantrez).

In one aspect, the present invention relates to a chemically stable topical pharmaceutical composition comprising luliconazole and a pharmaceutically acceptable excipient wherein the compositions provided herein comprises about 1% to about 5% dimethyl sulfoxide, about 40% to about 75% ethanol, about 1% to about 5% lactic acid and about 1% to about 30% diethylene glycol monoethyl ether (Transcutol P) and about 0.5% to about 1% methylvinyl ether-maleic anhydride (Gantrez).

In one aspect, the present invention relates to a chemically stable topical pharmaceutical composition comprising luliconazole and a pharmaceutically acceptable excipient wherein the compositions provided herein comprises about 5% luliconazole, about 2% dimethyl sulfoxide, about 45% to about 70% ethanol, about 4% lactic acid and about 25% diethylene glycol monoethyl ether and about 1% methylvinyl ether-maleic anhydride.
In one aspect, the topical pharmaceutical compositions of the present invention is chemically stable as a function of time i.e. contains greater than about 85%, such as greater than about 90%, greater than about 92.5%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99% or greater than about 99.5% of the initial amount of the luliconazole or a pharmaceutical acceptable salt thereof, after storage for 1, 3, 6, 12, 18, or 24 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH..
In one more aspect, the topical pharmaceutical compositions of the present invention is chemically stable as a function of time i.e. contains not more than 0.01 to 0.1 weight percent of any of the isomer 1, 2 or 3 of luliconazole after storage for 1, 3, 6, 12, 18, or 24 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.
In certain embodiments, any of the pharmaceutical topical compositions described herein has a pH between about 2 and about 8.

In certain embodiments, any of the topical compositions described herein comprise luliconazole, or a pharmaceutically acceptable salt thereof, as the sole active ingredient in the composition.
Yet another aspect, the present invention relates to a process for the preparation of a topical composition comprising luliconazole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present invention relates to a method of treating onychomycosis. The method comprises topically administering to a subject in need thereof a pharmaceutical composition according to any of the embodiments described herein. Preferably, the composition is topically applied to the area of the subject to be treated.
In a further embodiment, the present invention relates to a kit comprising a pharmaceutical composition for topical administration according to any of the embodiments described herein contained in a container, and a package insert containing instructions about the use of the pharmaceutical topical composition.
In another aspect, the present invention relates to at least once daily, such as once a day or twice a day, topical administration of topical composition according to any of the embodiments described herein. Preferably, the composition is topically applied to the area of the subject to be treated.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION
The details of one or more embodiments of the present invention are described herein. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom.

Luliconazole 1% Cream and Luliconazole 5% solution are available in the market and approved for the treatment of cutaneous mycosis Tinea: Tinea pedis, tinea corporis and tinea cruris; Candidiasis: Intertrigo and interdigital erosion, Tinea versicolor.
Development of Luliconazole formulation particularly in solution form is challenging due to chemically unstable nature of Luliconazole, since it may not get dissolved sufficiently, and may lead to time-dependent precipitate formation. Further, geometrical and optical isomerism is possible in luliconazole. Geometrical isomerism is observed due to the presence of a double bond and optical isomerism due to chiral center and therefore it exhibits 4 isomers such as RE, RZ, SE and SZ. Luliconazole RE is biologically active substance, while the remaining three are biologically inactive isomers.
Luliconazole on storage leads to formation of different stereoisomers depending on the solvent system used which leads to poor efficacy and therefore selection of right solvent system is very critical for the solution formulation, which is also chemically stable.
The present invention intends to develop a chemically stable pharmaceutical composition with a solvent system which provides improved stability over the period of its shelf life.
In one embodiment, the present invention relates to a chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol.

In another embodiment, the present invention relates to a chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol wherein the penetration enhancer agent is lactic acid and one or more film forming polymer is selected from diethylene glycol monoethyl ether (Transcutol P) and methylvinyl ether-maleic anhydride (Gantrez).

In another embodiment, the present invention relates to a chemically stable topical pharmaceutical composition comprising luliconazole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient wherein the compositions provided herein comprises wherein the composition comprises about 1% to about 5% dimethyl sulfoxide, about 40% to about 75% ethanol, about 1% to about 5% lactic acid and about 1% to about 30% diethylene glycol monoethyl ether (Transcutol P) and about 0.5% to about 1% methylvinyl ether-maleic anhydride(Gantrez).
In another embodiment, the present invention relates to a chemically stable topical pharmaceutical composition comprising luliconazole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient wherein the compositions provided herein comprises wherein the composition comprises comprises about 5% luliconazole, about 2% dimethyl sulfoxide, about 45% to about 70% ethanol, about 4% lactic acid and about 25% diethylene glycol monoethyl ether and about 1% methylvinyl ether-maleic anhydride.
In another embodiment, the topical pharmaceutical compositions of the present invention is chemically stable as a function of time i.e. contains greater than about 85%, such as greater than about 90%, greater than about 92.5%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99% or greater than about 99.5% of the initial amount of the luliconazole or a pharmaceutical acceptable salt thereof, after storage for 1, 3, 6, 12, 18, or 24 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH..
In another embodiment, the topical pharmaceutical compositions of the present invention is chemically stable as a function of time i.e. contains not more than 0.01 to 0.1 weight percent of any of the isomer 1, 2 or 3 of luliconazole after storage for 1, 3, 6, 12, 18, or 24 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.
Luliconazole after storage under a severe condition or an accelerated condition is converted to their different stereoisomers such as the SE form, E form or the Z form. Isomer I described herein is chemically 2(Z)-[4R-(4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene)-2-imidazol-1-yl)acetonitrile. Isomer II described herein is chemically 2(Z)-[4S-(4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene)-2-imidazol-1-yl)acetonitrile, Isomer III described herein is chemically 2(E)-[4R-(4-(2,4-Dichlorophenyl)-1,3-dithiolan-2-ylidene)-2-imidazol-1-yl)acetonitrile.
In another embodiment, the topical pharmaceutical compositions of the present invention is chemically stable as a function of time i.e. contains not more than 0.01 to 0.1 weight percent of total impurities of luliconazole after storage for 1, 3, 6, 12, 18, or 24 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.
In another embodiment, the topical compositions described herein is in the form of a solution.

In certain embodiments, any of the pharmaceutical topical compositions described herein has a pH between about 2 and about 8.

Suitable solvents for use in any of the pharmaceutical topical compositions described herein include, but are not limited to, water, ethanol, butylene glycol, propylene glycol, polyethylene glycol, propylene carbonate, caproyl 90, DMSO, ethyl acetate and diethylene glycol monoethyl ether, and any combination of the foregoing.

Suitable penetration enhancers for use in any of the compositions described herein may include, but are not limited to, lactic acid, dimethyl sulphoxide (DMSO), dimethyl formamide (DMF),dimethyl acetamide (DMAC), Azones, Pyrrolidones, .oxizolidinones (i.e. 4-decycloxazolidine-2-one), Surface active agents (i.e. sodium lauryl sulphate, Benzalkonium chloride), urea, Terpens (i.e. Menthol, Linalool, Limonene, Carvacrol), essential oils (i.e. Basil oil, Neem oil, Eucalyptus, Chenopodium, Ylang- Ylang), diethylene glycol menoethyl ether (transcutol P), and any combination of any of the foregoing.

Suitable film forming polymer for use in any of the compositions described herein may include, but are not limited to diethylene glycol monoethyl ether (Transcutol P) methylvinyl ether-maleic anhydride (Gantrez) .

In certain embodiments, any of the topical compositions described herein comprise luliconazole, or a pharmaceutically acceptable salt thereof, as the sole active ingredient in the composition.
Yet another embodiment, the present invention relates to a process for the preparation of a topical composition comprising luliconazole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another embodiment, the present invention relates to a method of treating onychomycosis. The method comprises topically administering to a subject in need thereof a pharmaceutical composition according to any of the embodiments described herein. Preferably, the composition is topically applied to the area of the subject to be treated.
In a further embodiment, the present invention relates to a kit comprising a pharmaceutical composition for topical administration according to any of the embodiments described herein contained in a container, and a package insert containing instructions about the use of the pharmaceutical topical composition.
In another embodiment, the present invention relates to at least once daily, such as once a day or twice a day, topical administration of topical composition according to any of the embodiments described herein. Preferably, the composition is topically applied to the area of the subject to be treated.
The term "comprising" as used herein is meant to be open ended and used in the inclusive sense of "having" or "including" and not in the exclusive sense of "consisting only of" The term "consists essentially of," as used herein means the claimed elements and others, but is meant to exclude things that are inconsistent with the basic and novel characteristics of the inventions.

The terms "a" “an” "the" and “(s)” as used herein are understood to encompass the plural as well as the singular or otherwise clearly mentioned wherever needed. For example, reference to "the solvent" includes reference to one or more of such solvents.

As used herein, the term “about” when used to refer to weight percent in a composition refers to ± 5% of the reported weight percentage.
The term "topical composition" as used herein refers to a composition suitable for application directly to the scalp, skin, nail, or mucosal tissue, either by hand or through a suitable applicator. In one embodiment, the term "topical composition" as used herein refers to a composition suitable for application directly to the skin, e.g., in the form of a cream, a gel, an ointment or a spray.
The term “chemically stable” means a composition comprising luliconazole which is stable and doesn’t convert to other isomers of luliconazole over the period of time preferably for the period of its shelf life.
As used herein, the terms “treatment” or “treating” relate to curing or substantially curing a condition, as well as ameliorating, delaying, relieving, inhibiting, or reducing at least one symptom of the condition, and are inclusive of prophylactic treatment and therapeutic treatment. As would be recognized by one or ordinary skill in the art, treatment that is administered prior to clinical manifestation of a condition is prophylactic (i.e., it protects the subject against developing the condition). If the treatment is administered after manifestation of the condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, control, or maintain the existing condition and/or side effects associated with the condition).

EXAMPLES

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1

Sr. No. Ingredient %w/w
1. Luliconazole 5.00
2. Absolute alcohol (Ethanol 99.9%) 45.00
3. Lactic acid 90% 4.00
4. Dimethyl sulfoxide 2.00
5. Diethylene glycol monoethyl ether (Transcutol-P) 25.00
6. Methylvinyl ether-maleic anhydride (Gantrez ES-425) 1.00

Manufacturing Process:
1. Weigh all ingredients as per weighing record.
2. Take Ethanol in SS vessel & add Gantrez under stirring.
3. In step-2 add Transcutol-P, Dimethyl sulfoxide and lactic acid the solution was mixed until uniform clear solution.
4. Add Luliconazole in step-3 to the solvent mixture and the container is rinse with ethanol add into the bulk.
5. The bulk is mixed until Luliconazole gets visually dissolved to obtain a clear, pale yellow to dark yellow solution, free of particles with a characteristic ethanoic odor.
6. Fill the Bulk 2.5/10ml in glass bottle with PET cap.

TABLE 1: Result of Stability studies of Example 1 after 6 months

Condition Assay of Luliconazole Impurity-A (0.5%) Single Max (0.2%) Total IMP (3.%) Isomer – I (0.5%) Isomer – II (0.5%) Isomer – III (0.5%) pH (3.5-7.0)
Initial 100.40 0.002 0.003 0.02 0.002 0.003 0.004 4.50
40/75 6M (I) 101 ND 0.02 0.04 0.07 0.05 0.06 5.04
40/75 6M (U) 99.4 ND 0.02 0.08 0.07 0.05 0.06 4.36
30/65 6M (I) 99.9 ND 0.02 0.03 0.03 0.02 0.03 5.05
30/65 6M (U) 99.6 ND 0.02 0.03 0.03 0.02 0.02 4.41
25/60 6M (I) 98.8 NP NP NP 0.02 0.01 0.02 5.04
25/60 6M (U) 99.1 ND 0.02 0.02 0.02 0.01 0.02 4.30

Note: ND-Not detectable; NP-Not Present; (I)- Inverted position; (U)- Upward position.

Results: Table 1 shows that formulation described in Example 1 is chemically stable for 6 months at different stability conditions at the pH range of 3.5-7.

TABLE 2: Result of % weight loss study were conducted at RT of Example 1 using different solvents

Solvent Pack Initial assay Assay after 24hr OE initial Wt. after 24hr OE % loss
Acetone +
TP 25% 2.5ml 101.30 137.20 27.46 26.824 7.23
10ml 111.00 43.75 43.459 3.31
MEK +
TP 25% 2.5ml 103.20 133.70 26.602 26.087 5.85
10ml 110.80 44.041 43.459 6.61
DMSO 20% 2.5ml 100.50 109.20 26.205 25.653 6.27
10ml 104.00 42.431 42.032 4.53
DMSO 20% +TP 25% 2.5ml 101.70 114.10 26.854 26.627 2.58
10ml 105.00 43.954 43.667 3.26
DMSO 45% +TP 25% 2.5ml 101.00 103.80 26.6 26.374 2.57
10ml 105.20 41.963 41.75 2.42

Note: OE-Open exposure; DMSO-Dimethyl sulfoxide; MEK-Methyl ethyl ketone; TP- Transcutol-P

Results: Table 2 shows % weight loss with different solvents. The table shows that Combination of DMSO with Transcutol P exhibits less amount of weight loss compared to that of Acetone with Transcutol P or Methyl ethyl ketone with Transcutol P DMSO alone.

In Vitro Permeation Test
1. Human cadaver Nails (Science Care, Arizona (USA)) were used to perform the IVPT. The study was performed using custom-designed Franz diffusion cells.

2. Before starting an experiment, nails were removed from -20° C freezer and let them thaw at room temperature for 15 min. Then they were submerged in PBS for the hydration for 30 min.

3. Nail adaptors having a 0.2 cm2 active diffusion area were used to mount the nails on the Franz diffusion cells.

4. Nail adaptors were sandwiched between donor and receptor chambers of Franz cells. A buffer contained Phosphate buffered saline (PBS) with 2% w/v HPßCD and 0.01% w/v gentamicin was used as a receptor fluid. Receptor fluid was degassed before filling in the receptor chamber through a sampling tube using a transfer pipette. A magnetic stir bar (3mm) was placed in each cell for proper distribution of the drug in the receptor chamber.

5. Cells were tilted a bit to remove the bubble sitting under the active diffusion area of the nail adaptor.

6. Custom modified dry block heaters were used to run this study. After assembling the cell, they were placed in the dry block. The temperature of the block was maintained at 32°C (the nail surface temperature was ~ 32°C in each case).
7. Formulations; 1) Example 1 2) control, each had 5 replicates (based on the availability of nails from one donor).

8. Each nail was dosed with a 5 µl formulation each day for 15 days. At each sampling time point, nails were washed with ethanol-soaked Q tips to remove the previously dosed formulation. Then nails were dosed with a fresh formulation.

9. A 300 µl receptor fluid sample was withdrawn from the sampling tube of the Franz cells at designated time points. Then cells were refilled with a 300 µl of a fresh receptor fluid.

10. At the completion of the flux studies, Franz cells and nail adaptors were disassembled to remove nails from the cells. Each nail was cleaned with a 1ml ethanol three times.

11. Nails were completely wiped with Kimwipes®. The active diffusion area of the nails was cut using matric punch (0.2 cm2). Active clipping of nails was placed in a 5ml glass vials which were filled with a 3ml of DMSO for the extraction of luliconazole.

12. Nails’ active clippings were incubated and shaken in DMSO for 48 hours. After the incubation period, a 500 µl sample was collected in the HPLC vial. In this study, all the samples were analyzed using HPLC.

Glenmark Formulation: Luliconazole 5%, Dimethyl sulfoxide, ethanol, lactic acid and diethylene glycol monoethyl ether ( Transcutol P) and Methylvinyl ether-maleic anhydride (Gantrez ES-425)

Control Formulation: Luliconazole 5%, N-methyl-2-pyrrolidone, benzyl alcohol, diixopropyl adipate, acetic acid, povidone, and anhydrous ethanol

Results:
Figure 1. The cumulative amount of drug permeated in the receptor fluid
Figure 1. Shows the amount of luliconazole permeated across the nail into the receptor fluid. The cumulative amount of luliconazole quantified in the receptor fluid for Glenmark formulation was found to be similar to the control formulation at each time point. The cumulative amount was represented in µg/cm2 unit.

Figure 2. The total amount of drug retained in the active diffusion area of nail palate

Figure 2. Shows the amount of luliconazole extracted from the active diffusion area of the nail plate. The cumulative amount was represented in µg/cm2 unit.
The total amount of Luliconazole extracted from the active diffusion area of the nails was found to be higher in case of Glenmark formulation (32.33 ± 4.28 µg/cm2) compared to control formulation (18.43 ± 5.11 µg/cm2).

Figure 3. Luliconazole flux graph

Figure 3. Shows the luliconazole flux graph.
Luliconazole flux across the nail was found to be the same in the cases of both formulations. Flux was represented in µg/cm2 /day unit.

Figure 4. The total percentage delivery of luliconazole.

Figure 4. The sum of the cumulative amount of luliconazole found in the receptor fluid after 15 days and the total amount of luliconazole retained in the active diffusion area of the nail was used to calculate the percentage delivery of luliconazole. The total dosed amount of luliconazole for 15 days was 3.75 mg which was considered as 100% in the calculation. The total % delivery of luliconazole was found to be higher in the case of Glenmark formulation compared to control formulation.

Claims

1. A chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol.

2. A chemically stable topical pharmaceutical composition as claimed in claim 1, wherein the composition is a solution.

3. A chemically stable topical pharmaceutical composition as claimed in claim 1, wherein the penetration enhancer is lactic acid and film forming polymer is selected from diethylene glycol monoethyl ether and methylvinyl ether-maleic anhydride.

4. A chemically stable topical pharmaceutical composition as claimed in claim 1, wherein the composition comprises about 1% to about 5% dimethyl sulfoxide, about 40% to about 75% ethanol, about 1% to about 5% lactic acid and about 1% to about 30% diethylene glycol monoethyl ether and about 0.5% to about 1% methylvinyl ether-maleic anhydride.

5. A chemically stable topical pharmaceutical composition as claimed in claim 1, comprises about 5% luliconazole, about 2% dimethyl sulfoxide, about 45% to about 70% ethanol, about 4% lactic acid and about 25% diethylene glycol monoethyl ether and about 1% methylvinyl ether-maleic anhydride.

6. A chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol,

wherein the composition contains greater than about 85% of the initial amount of the luliconazole or a pharmaceutical acceptable salt thereof, after storage for atleast 6 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.

7. A chemically stable topical pharmaceutical composition as claimed in claim 6, Wherein the composition contains greater than about 95% of the initial amount of the luliconazole or a pharmaceutical acceptable salt thereof, after storage for at least 6 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.

8. A chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the composition contains not more than 0.1 weight percent of any of the isomer 1, 2 or 3 of luliconazole after storage for at least 6 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.

9. A chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the composition exhibits about more than 85% of drug retention in the nail palate.
10. A chemically stable topical pharmaceutical composition as claimed in claim 8 or 9, wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol.

11. A chemically stable topical pharmaceutical composition as claimed in claim 8 or 9, wherein the penetration enhancer is lactic acid and film forming polymer is selected from diethylene glycol monoethyl ether and methylvinyl ether-maleic anhydride.

12. The topical pharmaceutical compositions as per claim 1 comprising luliconazole, or a pharmaceutically acceptable salt thereof wherein the composition has a pH between about 2 and about 8.

Dated this 25th day of January 2022

On behalf of Glenmark Pharmaceuticals Limited

Digitally signed by

Pramod Sagar
Deputy General Manager,
Intellectual Property Management
,CLAIMS:1. A chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol.

2. A chemically stable topical pharmaceutical composition as claimed in claim 1, wherein the composition is a solution.

3. A chemically stable topical pharmaceutical composition as claimed in claim 1, wherein the penetration enhancer is lactic acid and film forming polymer is selected from diethylene glycol monoethyl ether and methylvinyl ether-maleic anhydride.

4. A chemically stable topical pharmaceutical composition as claimed in claim 1, wherein the composition comprises about 1% to about 5% dimethyl sulfoxide, about 40% to about 75% ethanol, about 1% to about 5% lactic acid and about 1% to about 30% diethylene glycol monoethyl ether and about 0.5% to about 1% methylvinyl ether-maleic anhydride.

5. A chemically stable topical pharmaceutical composition as claimed in claim 1, comprises about 5% luliconazole, about 2% dimethyl sulfoxide, about 45% to about 70% ethanol, about 4% lactic acid and about 25% diethylene glycol monoethyl ether and about 1% methylvinyl ether-maleic anhydride.

6. A chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol,

wherein the composition contains greater than about 85% of the initial amount of the luliconazole or a pharmaceutical acceptable salt thereof, after storage for atleast 6 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.

7. A chemically stable topical pharmaceutical composition as claimed in claim 6, Wherein the composition contains greater than about 95% of the initial amount of the luliconazole or a pharmaceutical acceptable salt thereof, after storage for at least 6 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.

8. A chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the composition contains not more than 0.1 weight percent of any of the isomer 1, 2 or 3 of luliconazole after storage for at least 6 months at about 25 °C and about 60% relative humidity (RH), or about 30 °C and about 65% RH, or about 40 °C and about 75% RH.

9. A chemically stable topical pharmaceutical composition comprising luliconazole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient comprising one or more solvent, one or more penetration enhancer and one or more film forming polymer wherein the composition exhibits about more than 85% of drug retention in the nail palate.
10. A chemically stable topical pharmaceutical composition as claimed in claim 8 or 9, wherein the solvent is selected from group comprising of dimethyl sulfoxide and ethanol.

11. A chemically stable topical pharmaceutical composition as claimed in claim 8 or 9, wherein the penetration enhancer is lactic acid and film forming polymer is selected from diethylene glycol monoethyl ether and methylvinyl ether-maleic anhydride.

12. The topical pharmaceutical compositions as per claim 1 comprising luliconazole, or a pharmaceutically acceptable salt thereof wherein the composition has a pH between about 2 and about 8.