"A TOPICAL PHARMACEUTICAL COMPOSITION COMPRISING
LULICONAZOLE"
FIELD OF THE INVENTION:
The present invention relates to a topical pharmaceutical composition comprising Luliconazole or its pharmaceutically acceptable salts thereof. Further the present invention relates to topical compositions are free of chelating agents and a process for the preparation of said 10 pharmaceutical composition.
BACKGROUND OF THE INVENTION:
Luliconazole is an Imidazole antifungal and it is the R-enantiomer and contains one chiral center. The double bond adjacent to the dithiolane group is in the E configuration. The molecular formula is C14H9CI2N3S2 with a molecular weight of 354.28. Luliconazole is 15 chemically known as (2E)-2-[(4R)-4-(2, 4-dichlorophenyl)-l, 3-dithiolan-2-ylidene]-2-imidazol-1-ylacetonitrile and its structural formula is:
20 Luliconazole was first approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Apr 11, 2005, then approved by the U.S. Food and Drug Administration (FDA) on
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5 Nov 14, 2013. It was co-developed by Nihon Nohyaku, Pola and Medicis (acquired by valeant),
then marketed as Lulicon® by Pola in Japan and as Luzu® by Valeant in the US.
Luliconazole is a lanosterol demethylase inhibitor, which inhibits the synthesis of ergosterol by
inhibiting the enzyme lanosterol demethylase. This leads to decrease amounts of ergosterol, a
constituent of fungal cell membranes, and a corresponding accumulation of lanosterol.
10 Lulicon® is indicated for the treatment of cutaneous mycoses: tinea, candidiasis and tinea
versicolor.
Topical LUZU (luliconazole) Cream, 1% contains 10 mg of luliconazole per gram of cream in
a vehicle consisting of benzyl alcohol, butylated hydroxytoluene, cetostearyl alcohol, isopropyl
myristate, medium-chain triglycerides, methylparaben, polysorbate 60, propylene glycol,
15 purified water, and sorbitan monostearate.
Luliconazole is disclosed in US patent no. US 5900488 and Japanese patent application publication no. JP2002114680 covers luliconazole composition containing butylated hydroxytoluene, cetostearyl alcohol, isopropyl myristate, medium-chain triglycerides, methylparaben, polysorbate 60, propylene glycol, purified water, and sorbitan monostearate.
20 Japan patent no. JP5832451 (herein after refers to ‘451) relates to luliconazole compositions
comprising a polyhydric alcohol derivative selected from polyethylene glycol alkyl ether, polyoxyethylene alkyl ether, and polyoxyethylene-polyoxypropylene alkyl ether.
Japan patent no. JP5686874 (herein after refers to ‘874) covers a pharmaceutical composition
containing luliconazole and one component or two or more components selected from
25 carboxylic acid and derivative thereof, ketone, phosphoric acid and derivative thereof, local
anesthetic, antihistamine, and POE-based nonionic surfactant.
US patent no. US 8349882 (herein after refers to ‘882) discloses a pharmaceutical composition for external use comprising luliconazole and propylene carbonate at concentration of 0.1 to 40% by mass.
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5 International patent application no. WO2007102241 discloses pharmaceutical composition for
external use of luliconazole and α-hydroxycarboxylic acid and/or a salt thereof.
Japan patent no. JP5635075 B2 (herein after refered ‘075) invention relates to a pharmaceutical
composition comprising luliconazole, 10 to 80% by mass with respect to total amount of the
pharmaceutical composition of a ketone and a hydroxyalkylbenzene for excellent
10 solubilization.
Japan patent no. JP 5160409 (herein after refered ‘409) disclosed a pharmaceutical composition for external use comprising luliconazole and propylene carbonate and crotamiton and ethanol.
WO2017203456 (hereinafter referred ‘456) covered topical compositions comprising
combination of luliconazole with a corticosteroid such as betamethasone or clobetasol. The
15 compositions are free of an aliphatic alcohol and a ketone.
Luliconazole due to poor water solubility, is difficult to obtain a water soluble
formulations, for example, solutions and the like. Therefore the development of a stable
pressing luliconazole preparations, in particular topical formulation, the formulation studies
while focusing on drug formulations oxidation degradation and enhance skin penetration,
20 thereby greatly enhancing the stability and drug formulation effect.
The present inventors has developed a composition with provide stable product. Further the stable topical compositions are free of chelating agents and a process for the preparation of said pharmaceutical composition.
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5 SUMMARY OF THE INVENTION:
The present invention relates to stable topical composition comprising a Luliconazole as an active ingredient or a pharmaceutically acceptable salt thereof. The main object of the present invention provides topical compositions are free of chelating agents.
Accordingly, the object of the present invention composition comprises one or more
10 pharmaceutical excipients selected from a group consisting of a medium chain triglyceride, a
polyhydric alcohol, and an ester of a fatty acid, wherein composition is free of chelating agents.
Another object of the present invention provides, composition comprising the medium chain
triglyceride is selected from medium-chain triglycerides of the olive oil, coconut oil, or palm
kernel oil, caprylic /capric triglycerides. Preferably the medium-chain triglycerides is caprylic
15 /capric triglyceride.
The present invention is to provides, the composition comprising polyhydric alcohol is selected
from ethylene glycol, propylene glycol, hexylene glycol, glycerol, erythritol or sorbitol.
Preferably the polyhydric alcohol is propylene glycol and the ester of fatty acids is selected
from higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic
20 acid, stearic acid, behenic acid, and undecylenic acid. Preferably ester of fatty acid is isopropyl
myristate and vehicle is purified water.
The stable topical cream composition comprising luliconazole of the present invention further
comprises one or more additional pharmaceutical excipients selected from a group consisting
a polysorbate 60, butylated hydroxyl toluene, sorbitan monostearate and a preservatives,
25 wherein composition is free of chelating agents.
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5 Another object of the present invention relates to method of manufacturing process of
Luliconazole topical composition is as follows.
i. Preparation of water phase with purified water, methyl paraben and polysorbate 60
and maintain the phase temperature at 70- 75ºC to get homogeneous mixture,
ii. Preparation of wax phase with materials like sorbiton monostearate, cetostearyl
10 alcohol, MCT oil and isopropyl myristate added in vessel and heating at 70 -75ºC,
followed by addition of BHT mix,
iii. Step (ii) is added to step (i) at 70-75 º C and stir for 30 minutes, and then cooled to
45 – 50o C, and
iv. Added drug slurry at 50ºC and homogenized for 20 minutes, further added Benzyl
15 alcohol at 45°C and stir for 20 minutes to get desired composition.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to stable topical compositions comprising Luliconazole. The
present invention is also relates to Luliconazole topical compositions without using chelating
20 agents.
The object of the present invention provides pharmaceutical composition comprising
Luliconazole or a salt thereof as an active ingredient with suitable excipients like benzyl
alcohol, methyl paraben, butylated hydroxyl toluene, sorbitan monostearate, medium chain
triglycerides, cetostearyl alcohol, polysorbate 60, propylene glycol, isopropyl myristate and
25 purified water, wherein compositions are free of chelating agents.
The term "active" as used herein means Luliconazole or its salts, or some additional actives as described herein or combination thereof.
The term "stable topical composition" is used to refer to a pharmaceutical composition for
application to body surfaces such as the skin or mucous membranes to treat ailments. The
30 "stable topical composition" refers to cream.
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5 The term ‘stable’ refers to formulations that substantially retain the label amount of the
therapeutically active ingredient during storage for commercially relevant times. Further, the term ‘stable’ also optionally refers to formulations that contain polymorphically stable active ingredient.
As used herein, the term ‘active ingredient’ includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for the corresponding disease state. The most preferred active ingredient is Luliconazole.
As used herein, the term ‘therapeutically effective amount’ means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, lessening in severity or amelioration of disease.
As used herein, the term ‘treating’ or ‘treatment’ refers to the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by Luliconazole in a mammal.
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", “having”, “containing” "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The stable topical composition may be epicutaneous, meaning that it is applied directly to the
25 skin or mucosa. The effect of the stable topical composition in the pharmacodynamics sense,
may be local and primarily address condition of the skin including either or both of the
epidermis and underlying dermal layers and/or tissue such as muscles, bones, ligaments and
internal organs covered by the skin rather than systemic, or be systemic or provide both local
and systemic effects. Stable topical compositions can be used for both stable topical and
30 transdermal administration of substances.
The term “MCT” as used herein medium chain triglycerides to a pharmaceutical composition.
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5 The term “BHT” as used herein butylated hydroxyl toluene to a pharmaceutical composition.
In one embodiment, the chelating agents selected from a group consisting of ethylene diamine tetra-acetic acid (EDTA), disodium edetate and or any combination thereof.
In one embodiment, the present invention relates to stable topical composition comprising luliconazole wherein; the compositions are free of a chelating agents.
10 In one embodiment, the present invention composition comprises one or more pharmaceutical
excipients selected from a group consisting of a medium chain triglyceride, a polyhydric alcohol, and an ester of a fatty acid.
In another embodiment, the medium chain triglyceride is selected from medium-chain
triglycerides of the olive oil, coconut oil, or palm kernel oil, caprylic /capric triglycerides.
15 Preferably the medium-chain triglycerides is caprylic /capric triglyceride.
In further embodiment, the polyhydric alcohol is selected from ethylene glycol, propylene glycol, hexylene glycol, glycerol, erythritol or sorbitol. Preferably the polyhydric alcohol is propylene glycol.
In yet further embodiment, the stable topical composition comprising luliconazole of the
20 present invention further comprises one or more additional pharmaceutical excipients selected
from a group consisting a polysorbate 60, butylated hydroxyl toluene, sorbitan monostearate and a preservatives.
In yet another embodiment, the ester of fatty acids is selected from higher fatty acids such as
oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid,
25 and undecylenic acid. Preferably ester of fatty acid is isopropyl myristate.
In one embodiment, the stable topical composition of the present invention may comprise from about 30%-95% by weight of purified water.
In another embodiment, the preservatives selected from a group consisting of phenoxyethanol, parabens such as methyl paraben and propyl paraben, propylene glycols, sorbates, benzyl
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5 alcohol, butylated hydroxyl toluene, urea derivatives such as diazolindinyl urea, and the like or
any combinations thereof.
In another embodiment of the present invention, relates to method of manufacturing process of Luliconazole topical composition is as follows.
i. Preparation of water phase with purified water, methyl paraben and polysorbate 60
10 and maintain the phase temperature at 70- 75ºC to get homogeneous mixture.
ii. Preparation of wax phase with materials like sorbiton monostearate, cetostearyl
alcohol, MCT oil and isopropyl myristate added in vessel and heating at 70 -75ºC,
followed by addition of BHT mix;
iii. Step (ii) is added to step (i) at 70-75ºC and stir for 30 minutes, and then cooled to
15 45 – 50oC, and
iv. Added drug slurry at 50ºC and homogenized for 20 minutes, further added Benzyl
alcohol at 45°C and stir for 20 minutes to get desired composition.
In one embodiment, the stable topical composition of the present invention is in the form of any of the dosage form creams and Ointment, preferably dosage form is cream.
20 In one embodiment, the present invention relates to method of treating fungal infections with
stable topical composition of the invention.
The stable topical composition of this invention may be used treating fungal infections like, Tinea pedis, tinea corporis, tinea cruris, tinea versicolor, cutaneous mycoses and candidiasis.
In further embodiment of the present invention, a topical cream qualitative composition
25 comprising Luliconazole, benzyl alcohol, methyl paraben, butylated hydroxyl toluene, sorbitan
monostearate, medium chain triglycerides, cetostearyl alcohol, polysorbate 60, propylene glycol, isopropyl myristate and purified water.
The process details of the invention are provided in the examples given below, which are
provided by way of illustration only and therefore should not be construed to limit the scope of
30 the invention.
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5 Manufacturing Process:
i. Aqueous Phase:
Aqueous phase was prepared with purified water, methyl paraben and polysorbate 60 and maintain the phase temperature at 70- 75ºC to get homogeneous mixture.
ii. Wax Phase:
10 Wax phase was prepared with materials like sorbiton monostearate, cetostearyl alcohol,
MCT oil and isopropyl myristate added in vessel and heating at 70 -75ºC, followed by addition of BHT mix; ensure the complete solubilisation and maintain the temperature at 70-75ºC.
iii. Emulsification:
15 Wax Phase was added to water phase, stir for 30 minutes at 70-75ºC, and then cooled to
45 – 50o C.
iv. Drug slurry:
Propylene glycol was heated to 50ºC and then added Luliconazole to disperse in it. The
dispersion passed through colloid mill.
20 v. Addition:
Drug slurry added to emulsification step (iii) at 50ºC and homogenized for 20 minutes, further added Benzyl alcohol at 45°C and stir for 20 minutes to get desired composition.
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5
We Claim:
1. A stable topical cream composition comprising Luliconazole, where in the composition is
free of a chelating agents; cream is prepared by following steps.
i. Preparation of water phase with purified water, methyl paraben and polysorbate 60
10 and maintain the phase temperature at 70- 75ºC to get homogeneous mixture,
ii. Preparation of wax phase with materials like sorbiton monostearate, cetostearyl
alcohol, MCT oil and isopropyl myristate added in vessel and heating at 70 -75ºC,
followed by addition of BHT mix,
iii. Step (ii) is added to step (i) at 70-75 º C and stir for 30 minutes, and then cooled to
15 45 – 50o C, and
iv. Added drug slurry at 50ºC and homogenized for 20 minutes, further added Benzyl
alcohol at 45°C and stir for 20 minutes to get desired composition.
2. The pharmaceutical composition as claimed in claim 1, where in the drug slurry was
20 prepared by adding Luliconazole to propylene glycol at 50ºC.
3. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises
one or more of 1% of Luliconazole, 4 % of medium chain triglycerides, 5% of propylene
glycol, 3 % of isopropyl myristate, 0.05%-2% of a preservative by weight of the
composition, wherein composition is free of a chelating agents.
25 4. The pharmaceutical composition as claimed in claim 2, wherein the medium chain
triglyceride is selected from medium-chain triglycerides of the olive oil, coconut oil, or
palm kernel oil, caprylic /capric triglycerides. Preferably, the medium-chain triglycerides
is caprylic /capric triglyceride.
5. The pharmaceutical composition as claimed in claim 1, wherein any of the dosage form
30 such as creams and ointments, preferably dosage form is cream.
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5 6. The pharmaceutical composition as claimed in claim 1, wherein Luliconazole is indicated
for the topical treatment of fungal infections like interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum.
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Dated this Twenty eighth (28)th day of January, 2019.

Sridhar. Prasangi
15 (IN/PA 2608)
General Manager-IPM
Optimus Pharma Private Limited
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