FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and ruleI3)
1. TITLE OF THE INVENTION:
"TOPICAL FORMULATION OF HALOMETASONE MONOHYDRATE IN I COMBINATION WITH ANTIFUNGAL DRUG"
2. APPLICANT:
(a) NAME: Lyka Labs Limited
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: 101, Shivshakti Industrial Estate, Andheri-Kurla Road,
Andheri (East), Mumbai - 400059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
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 combination of therapeutically effective amount of potent topical corticosteroid such as Halometasone monohydrate along with broad-spectrum antifungal drug such as Miconazole nitrate or Clotrimazole in the form of cream and lotion, for the treatment of infective eczema and eradicating fungal infections. The invention further relates to process for preparation of the said topical composition.
BACKGROUND OF THE INVENTION:
Halometasone belongs to the class of potent (group III) corticosteroids. It is a potent steroid and recommended as an alternative to Betamethasone dipropionate and Mometasone furoate. Halometasone monohydrate has anti-inflammatory action with significant safety and tolerability profile.
The anti-inflammatory action attributed by corticosteroids is due to the induction of lipocortins that prevent the formation of prostaglandins and leukotrienes which are mediators leading to inflammation. Halometasone, a corticosteroid acts by inhibiting the release (or blocking production) of various cytokines like prostaglandins and leukotrienes.
The anti-inflammatory effects of Halometasone can be demonstrated in test animals, which show that it is comparable in potency to fluocinolone acetonide. Epidermo-hyperplasia-inhibition-test shows that the anti-epidermoplastic effect of halometasone is only slightly weaker than that of fluocinolone acetonide, indicating that it is likely to exert therapeutically beneficial effects on dermatological disorders characterized by epidermal hyperplasia, e.g. psoriasis and chronic eczema.
Chemically, Halometasone is (6α, 1 lβ, 16α)-2-chloro-6, 9-difluoro-11, 17, 21-tri hydroxy-16-methylpregna-l, 4-diene-3, 20-dione. It has the following structural formula:


Miconazole is an imidazole antifungal agent and commonly applied topically (to the skin) or mucus membranes to cure fungal infections. It works by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes. It can also be used against certain species of Leishmania protozoa (which are a type of unicellular parasite), as these also contain ergosterol in their cell membranes. In addition to its antifungal and antiparasitic actions, it also has some limited antibacterial properties.
Miconazole is mainly used externally for the treatment of athlete's foot, ringworm and jock itch. Internal application is used for oral or vaginal thrush (yeast infection). In addition the oral gel may also be used for the lip disorder angular cheilitis.
Chemically, Miconazole nitrate is 1 -(2-(2,4-dichlorobenzyloxy)-2-(2.4-dichlorophenyl)ethyl) imidazolium nitrate. It has the following structural formula:

Clotrimazole is an antifungal medication commonly used in the treatment of fungal infections of both humans and animals such as vaginal yeast infections, oral thrush, and ringworm. It is also used to treat athlete's foot and jock itch.

It is commonly available as an over-the-counter substance in various dosage forms, such as a cream, and also (especially in the case of ear infection) as a combination medicine. It is also available as a troche (prescription only). For ear infection it is often applied in liquid form, as ear drops. Fungal infections can be slow to clear up, so the usual course for an anti-fungal agent is generally longer than the typical 3-7 days of an antibiotic. Clotrimazole is a potent, specific inhibitor of cytochrome P450 oxidase and may alter the metabolism of other drugs.
Chemically, Clotrimazole is l-[(2-chIorophenyl)(diphenyl)methyl]-lH-imidazole. It has the following structural formula:

US4298604 relates to an antifungal compositions comprising clotrimazole and betamethasone dipropionate in the form of lotion, ointment and cream.
US4512987 relates to topical administration which comprising the anti-inflammatorily active glucocorticoid - halometasone and the antimicrobial agent - triclosan.
US5002938 relates to an antifungal gel composition comprising an imidazole antifungal agent selected from the group consisting of miconazole, miconazole nitrate, clotrimazole, clotrimazole nitrate, enconazole, econazole nitrate, sulconazole, sulconazole nitrate along with corticosteroid anti-inflammatory agent selected from the group consisting of acetate. butyrate, valerate and propionate 17-esters of hydrocortisone, betamethasone, cortisone and prednisone for topical administration.

US6656928 relates to a composition for topical administration comprising a corticosteroid, a drying agent and a broad spectrum anti-fungal agent that treats both dermatophytes and yeast infections.
An article titled, "Efficacy of Antifungal Agents in the Cornea" by Denis M. O'Day et al., published in Investigative Ophthalmology & Visual Science, Vol. 25, March 1984, pp. 331-335, relates to the study of the effects of combining corticosteroid with antifungal therapy in a quantitative rabbit model of Candida keratitis to evaluate the influence of corticosteroid therapy on the efficacy of various antifungal agents.
An article titled, "Potency Ranking of Two New Topical Corticosteroid Creams Containing 0.1 % Desonide or 0.05 % Halometasone Utilizing the Human Skin Blanching Assay" by E. Meyer et al., published in Arzneim.-Forsch./Drug Res. 38 (II), 12, Year 1988, pp. 1840-1843, relates to the study of investigating the blanching activities and, by inference, the clinical anti-inflammatory efficacies of two corticosteroid containing 0.1 % desonide or 0,05 % halometasone, were released onto the market without reference having been made to clinical efficacy, especially as compared to already available proprietary topical corticosteroid preparations.
The relentless increase of invasive fungal infections and poor outcomes associated with available medications prompted the search for better therapeutic strategies. Combining corticosteroids with antifungal drugs is recommended as a means to enhance efficacy in a variety of invasive infections including infective eczema and eradicating fungal infections. Therefore, the present inventors have come up with a topical pharmaceutical composition comprising a specific combination of Halometasone monohydrate along with antifungal drug such as Miconazole nitrate or Clotrimazole, in a single formulation, which shows enhanced effects that lead to more rapid clearing and are notably effective for the treatment of infective eczema and eradicating fungal infections.
OBJECT OF THE INVENTION:
In accordance with the above, the main object of the current invention is to provide the topical composition comprising Halometasone monohydrate along with antifungal drug

such as Miconazole nitrate or Clotrimazole, for the treatment of infective eczema and eradicating fungal infections.
Another object of the present invention is to provide the process for preparation of said topical composition in the form of cream and lotion.
SUMMARY OF THE INVENTION:
The present invention discloses the topical composition comprising corticosteroid such as Halometasone monohydrate along with antifungal drugs such as Miconazole nitrate or Clotrimazole in the form of cream and lotion, for the treatment of infective eczema and eradicating fungal infections and further it discloses the process for preparation of said topical compositions.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Therapeutic Justification:
The most striking feature of combination of powerful corticosteroid with broad spectrum anti-fungal drug is the necessity to control eczema and eradicate fungal infection.
Patients suffering from infective eczema, psoriasis or dermatitis usually suffer from itching as a common symptom; moreover, repeated itching and scratching of the skin leads to damage of the epidermis, a natural protective barrier which in turn results into secondary fungal infection.
On the other side, patients suffering from dermotophyte or Candida infection easily get sensitized to fungal invasion and have secondary eczematous reaction. They are diagnosed as suffering from infective eczema. This condition occurs more often in the

folds of the skin like axilla, under the breast or inguinal region where fungal infection are very common.
Therefore, use of corticosteroid without anti-fungal drug not only delays therapeutic response but also the immunosuppressive action of corticosteroid that interferes in the body defense mechanism to tackle fungal infection.
Thus, there is a need to provide a combination of an antifungal drug with a corticosteroid to effectively control immunosuppressive action of corticosteroid that interferes in the body defense mechanism thereby tackling the fungal infection.
Hence, the present inventors have come up with the invention that describes a topical composition useful for the treatment of infective eczema and eradicating fungal infections which comprises combination of corticosteroid such as Halometasone monohydrate along with antifungal drugs such as Miconazole nitrate or Clotrimazole.
The term "topical" as employed herein relates to the use of the active ingredient incorporated in a suitable pharmaceutical carrier, and applied at the site of the disease for exertion of local action.
In the preferred embodiment, the present invention provides the topical composition which comprises combination of therapeutically effective amount of Halometasone monohydrate and antifungal drug such as Miconazole nitrate or Clotrimazole along with pharmaceutically accepted excipients.
In another embodiment, the present invention provides the topical composition comprising combination of Halometasone monohydrate and antifungal drug such as Miconazole nitrate or Clotrimazole along with pharmaceutically acceptable excipients in the form of cream and lotion.
In an embodiment of the present- invention, the topical cream/lotion formulation comprises combination of Halometasone monohydrate (0.05% w/w) and Miconazole nitrate or Clotrimazole (1.0-2.0% w/w or w/v) along with the pharmaceutical excipients

selected from the group comprising of cream/lotion base like emulsifier, oil base, preservative, antioxidant, penetration enhancer and solubilizer, chelating agent, buffering agent, surfactant and combinations thereof.
According to another embodiment of the present invention, the topical cream of Halometasone monohydrate and Miconazole nitrate or Clotrimazole, is prepared using excipients selected from the group consisting of Cetostearyl alcohol, Cetomacrogol 1000, Light liquid paraffin, White soft paraffin, Methyl paraben, Propyl paraben, Chlorocredo], Butylated hydroxy toluene, Propylene glycol, Disodium EDTA, Citric acid and Disodium hydrogen phosphate.
According to another preferred embodiment of the present invention, the topical composition of Halometasone monohydrate and Miconazole nitrate or Clotrimazole in the form of cream is prepared by following steps:
1. Melting oil base excipients, emulsifier and antioxidant by heating at 70-80°C;
2. dissolving chelating agent, buffering agent in sufficient quantity of purified water by heating at 70-80°C;
3. mixing oil phase and water phase under stirring for the emulsion formation at 60°-70°C;
4. dissolving or dispersing active ingredients in solubilizer and adding to bulk of step
3;
5. dissolving preservatives in propylene glycol and adding to bulk emulsion of step 4 under stirring; or dissolving preservatives in oil phase and water phase separately;
6. cooling and stirring of the bulk emulsion till cream formation takes place; and
7. adjusting the weight with purified water.
According to another embodiment of the invention, the lotion of Halometasone monohydrate and Miconazole nitrate or Clotrimazole is prepared using excipients selected from the group consisting of PEG 400, Butylated hydroxy toluene, Propylene glycol, White soft paraffin, Cetyl alcohol, Methyl paraben, Propyl paraben, Sodium lauryl sulphate.

According to another preferred embodiment of the present invention, the topical composition of Halometasone monohydrate and Miconazole nitrate or Clotrimazole in the form of lotion is prepared by following steps:
1. Melting emulsifier and oil base by heating at 70-80°C;
2. dissolving preservatives in oil phase and water phase separately;
3. mixing oil phase and sufficient water phase under stirring for the emulsion formation at 60°-70°C;
4. dissolving or dispersing active ingredients in solubilizer;
5. adding active drug either before emulsion formation or during emulsion formation;
6. dissolving surfactant in sufficient purified water and then adding to bulk; and
7. cooling and stirring the bulk till lotion formation takes place and then making up the volume with purified water.
Alternately, lotion is also prepared by dissolving Halometasone in hot Propylene Glycol and dissolving Miconazole nitrate or Clotrimazole in Propylene glycol in separate beakers. Simultaneously, dissolving Butylated hydroxy toluene in PEG 400; and then adding all the solutions into one vessel followed by mixing, till clear solution is obtained.
The invention is further illustrated by following non-limiting examples of this combination product:
EXAMPLES:
Example 1: Composition for the Preparation of Cream:
Table 1:

Ingredients Concentration
% w/w
Active Ingredients Halometasone monohydrate 0.05% w/w
Miconazole nitrate 2.0% w/w
Emulsifier Cetostearyl alcohol 2-8%
Cetomacrogol 1000 0.5-4%
Oil base Light liquid paraffin 2-8%

White soft paraffin 2-8%
Preservative Methyl paraben 0.05-0.25%
Propyl paraben 0.01-0.1%
Chlorocresol 0.05-0.15%
Antioxidant Butylated Hydroxy toluene 0.005-0.02%
Penetration enhancer And solubaliser Propylene glycol 6-24%
Chelating agent Disodium EDTA 0.005-0.2%
Buffering agent Citric acid 0.01-01%
Disodium hydrogen phosphate 0.001-0.1%
Purified water q.s q.s.
Table 2:

Ingredients Concentration
% w/w
Active Ingredients Halometasone monohydrate 0.05% vv/w
Clotrimazole 1.0% w/w
Emulsifier Cetostearyl alcohol 2-8%
Cetomacrogol 1000 0.5-4%
Oil base Light liquid paraffin 2-8%
White soft paraffin 2-8%
Preservative Methyl paraben 0.05-0.25%
Propyl paraben 0.01-0.1%
Chlorocresol 0.05-0.15%
Antioxidant Butylated hydroxy toluene 0.005 - 0.02%
Penetration enhancer And solubaliser Propylene glycol 6-24%
Chelating agent Disodium EDTA 0.005-0.2%
Buffering agent Citric acid 0.01-0.1%
Disodium hydrogen phosphate 0.001-0.1%
Purified water q.s q.s.

Process for preparing cream formulation is as follows:
1. Melting oil base excipients, emulsifier and antioxidant by heating at 70-80oC;
2. dissolving, chelating agent in sufficient quantity of purified water by heating at 70-80°C;
3. mixing oil phase and water phase under stirring for the emulsion formation at 60°-70°C
4. dissolving or dispersing active ingredients in Solubilizer and adding to bulk of step 3;
5. dissolving preservatives in propylene glycol and adding to bulk emulsion of step 4 under stirring: or dissolving preservatives in oil phase and water phase separately;
6. cooling and stirring of the bulk til! cream formation takes place; and
7. adjusting the weight with purified water.
Example 2: Composition for the Preparation of Lotion:
Table 3:

Ingredients Concentration
Active Ingredients Halometasone monohydrate 0.05% w/v
Miconazole nitrate 2% w/v
Inactive Ingredients PEG 400 40 - 75%
Butylated hydroxy toluene 0.01-0.03%
Propylene glycol q.s
_
Table 4:

Ingredients Concentration
Active Ingredients Halometasone monohydrate 0.05% w/v
Miconazole nitrate 2% w/v
Oil Phase White soft paraffin 1.5-1.0%
Emulsifier Cetyl alcohol 1-2.5%
Propylene glycol 5-10%
Preservative Methyl paraben 0.2-0.5%

Propyl paraben 0.03-0.07%
Surfactant Sodium lauryl sulphate 0.2-0.4%
Vehicle Water q.s
Table 5:

Ingredients Concentration
Active Ingredients Halometasone monohydrate 0.05% w/v
Clotrimazole 1]%w/v
Inactive Ingredients PEG 400 40 - 75%
Butylated hydroxy toluene 0.01-0.03%
Propylene glycol q.s
Table 6:

Ingredients Concentration
Active Ingredients Halometasone monohydrate 0.05% w/v
Clotrimazole l%w/v
Oil Phase White soft paraffin 0.5-1.0%
Emulsifier Cetyl alcohol 1-2.5%
Propylene glycol 5-10%
Preservative Methyl paraben 0.2-0.5%
Propyl paraben 0.03-0.07%
Surfactant Sodium lauryl sulphate 0.2 - 0.4%
Vehicle Water
i q.s
Process for preparing lotion formulation is as follows:
1. Dissolving Halometasone in hot Propylene glycol;
2. in a separate beaker dissolving Miconazole nitrate or Clotrimazole in hot Propylene glycol;
3. dissolving Butylated hydroxy toluene in PEG 400; and
4. adding all the solutions into one vessel and mixing well till clear solution is obtained.

Another process for preparing lotion formulation is as follows:
1. Melting emulsifier and oil base by heating at 70-80°C;
2. dissolving preservatives in oil phase and water phase separately;
3. mixing oil phase and sufficient water phase under stirring for the emulsion
formation at 60°-70°C;
4. dissolving or dispersing active ingredients in solubilizer;
5. adding active drug either before emulsion formation or during emulsion formation;
6. dissolving surfactant in sufficient purified water and then adding to bulk; and
7. cooling and stirring the bulk till lotion formation takes place and then making up the volume with purified water.
Appropriate overages of active ingredients are added for long term stability purpose.
STABILITY DATA:
Stability study of the product is carried out as per ICH guideline for 6 months at accelerated condition of 40°c / 75% RH and real time condition of 30°c / 65%RH. Product is stable.

We Claim,
1. A topical pharmaceutical composition comprising combination of therapeutically effective amount of Halometasone monohydrate and antifungal drug along with pharmaceutically acceptable excipients, for the treatment of infective eczema and eradicating fungal infections.
2. The topical pharmaceutical composition as claimed in claim 1, wherein said antifungal drug is selected from Miconazole nitrate or Clotrimazole.
3. The topical pharmaceutical composition as claimed in claim I, wherein said Halometasone monohydrate is present in an amount of 0.05% w/w.
4. The topical pharmaceutical composition as claimed in claim 1, wherein said antifungal drug is present in an amount of 1.0-2.0% w/w.
5. The topical pharmaceutical composition as claimed in claim I, wherein said pharmaceutically acceptable excipients are selected from emulsifier, oil base, preservative, antioxidant, penetration enhancer and solubilizer. chelating agent, buffering agent, surfactant and combinations thereof.
6. The topical pharmaceutical composition as claimed in claim 1, wherein said composition is in the form of cream and lotion.
7. The topical pharmaceutical composition as claimed in claim 6, wherein the cream contains pharmaceutically acceptable excipients selected from the group consisting of Cetostearyi alcohol. Cetomacrogol 1000, Light liquid paraffin, White soft paraffin, Methyl paraben, Propyl paraben, Chlorocresol, Butylated hydroxy toluene, Propylene glycol, Disodium EDTA, Citric acid and Disodium hydrogen phosphate.
8. The topical pharmaceutical composition as claimed in claim 6, wherein the lotion contains pharmaceutically acceptable excipients selected from the group

consisting of PEG 400, Butylated hydroxy toluene, Propylene glycol, White soft paraffin, Cetyl alcohol, Methyl paraben, Propyl paraben, Sodium lauryl sulphate.
9. The process for preparation of cream as claimed in claim 6, comprising.
a) Melting oil base excipients, emulsifier and antioxidant by heating at 70-80°C;
b) dissolving chelating agent, buffering agent in sufficient quantity of purified water by heating at 70-80°C;
c) mixing oil phase and water phase under stirring for the emulsion formation at 60°-70°C;
d) dissolving or dispersing active ingredients in solubilizer and adding to bulk of step (c):
e) dissolving preservatives in propylene glycol and adding to bulk emulsion of step (d) under stirring; or dissolving preservatives in oil phase and water phase separately;
f) cooling and stirring of the bulk emulsion till cream formation takes place; and
g) adjusting the weight with purified water.
10.The process for preparation of lotion as claimed in claim 6, comprising,
a) Melting emulsifier and oil base by heating at 70-80°C;
b) dissolving preservatives oil phase and water phase separately;
c) mixing oil phase and sufficient water phase under stirring for the emulsion formation at 60°-70°C;
d) dissolving or dispersing active ingredients in solubilizer;
e) adding active drug either before emulsion formation or during emulsion formation;
f) dissolving surfactant in sufficient purified water and then adding to bulk; and
g) cooling and stirring the bulk till lotion formation takes place and then making up the volume with purified water..
11. Process for preparation of lotion as claimed in claim 10, optionally prepared by
following steps;
a) dissolving active ingredients separately in hot Propylene glycol;
b) dissolving antioxidant in PEG 400;

c) adding all the solutions into one vessel and mixing well till clear solution is obtained.