FORM2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"TOPICAL FORMULATION CONTAINING ALCLOMETASONE AND MUPIROCIN"
2. APPLICANTS:
(a) NAME: LYKA LABS LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian 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.

Field of Invention:
The present invention relates to a topical skin care composition comprising a corticosteroid and a broad spectrum antibiotic, the invention more specifically relates to a topical composition comprising Alclometasone dipropionate and Mupirocin for treatment of infective bacterial eczema.
Background in invention:
"Infectious eczematoid dermatitis" is an eczema caused by the irritating effects on the skin of a purulent discharge from such a focus as a chronic otitis media, a draining sinus, or a boil. In pediatric practice before the days of antibiotics,eczema used to be fairly common in children whose ears ran all winter, as they often did.
Now, it is recognized that many eczemas which show no gross evidence of infection are kept active by low-grade infection and by allergic sensitivity to the infecting organism, and that treatment must be combined anti-eczematous and antibacterial. Cultures are of little use in diagnosis, for the organisms which cause the trouble are, as a rule, the same which can be recovered from normal skins (Staphylococcus aureus and occasionally beta hemolytic streptdococcus). Although the bacterial flora of the eczema lesions is not likely to be any different qualitatively from that of the normal skin, it is very different quantitatively; the number of bacteria is enormously greater.Bacterial eczema is likely to be chronic, thickened, often somewhat oozy and crusted in acute exacerbations, and usually rather sharply circumscribed. It is common behind the ears in combination with localized seborrheic dermatitis of the scalp, and on the face and backs of the hands in infants, although it may occur on any part of the body.
Psoriasis is a chronic, non-contagious autoimmune disease which affects the skin and joints. It commonly causes red scaly patches to appear on the skin. The scaly patches caused by psoriasis, called psoriatic plaques, are areas of inflammation and excessive skin production. Skin rapidly accumulates at these sites and takes on a silvery-white appearance. Plaques frequently occur on the skin of the elbows and knees, but can affect any area including the scalp and genitals. In contrast to eczema, psoriasis is more likely to be found on the extensor aspect of the joint.

The Koebner phenomenon, also called the "Koebner response" or the "isomorphic response", refers to skin lesions appearing on lines of trauma. The Koebner phenomenon may result from either a linear exposure or irritation.
Essentially, these skin diseases are characterized by itching and inflammation. The constant scratching of the inflamed region results in loss of barrier functions of the skin, which leads to invasion of the lower epidermal layers by pathogenic bacteria. Many patients resort to home remedies or OTC preparations which are inherently irritant, this complicates the clinical picture.
This is also the case in patients suffering from chronic eczema have thickened, damaged epidermis. This is also the problem in patients suffering from plaque psoriasis and they may present with Kobner's phenomena which indicates secondary bacterial infection.
A combination of corticosteroid with anti-bacterial agent takes cart of inflammation and infection ensuring a speedy recovery from bacterial eczema or psoriasis or Koebner's phenomenon. Hence, a combination of corticosteroid with antibacterial drug is advisable in such cases.
Alclometasone was first disclosed in US4I24707. Alclometasone is a synthetic glucocorticoid steroid for topical use in dermatological preparation as an antiinflammatory, anti-puritic agent, anti-allergic, anti-proliferative and vasoconstrictive agent.
Alclometasone dipropionate is chemically known as (7α-chloro-l 1(3, 17, 21-trihydroxy-16α-methylpregna-l, 4-diene-3, 20-dione 17, 21-dipropionate) having the following structural formula:


Alclometasone inhibits phospholipase A2 by inducing production of Iipocortins; inhibits synthesis of arachidonic acid, prostaglandins and leukotrienes; reduce release of cytokines from lymphocytes and other mediators of inflammation, Thereby reducing inflammation (including histamine).
Alclometasone cream and ointment are indicated for the relief of corticosteroid-responsive dermatoses. Alclometasone may be used on sensitive skin sites such as face, skinfolds.
Mupirocin was first disclosed in US3977943 granted to Beecham Group filed on July 7, 1975 and granted on August 31, 1976.
Mupirocin (Bactroban or Centany) is an antibiotic originally isolated from Pseudomonas fluorescens NCIMB 10586. Mupirocin is bacteriostatic at low concentrations and bactericidal at higher concentrations. It is used topically and is effective against Gram-positive bacterialike Proteus sp.t Enterobacter sp., Haemophilus sp. and Morexella catarrhalis, including MRSA Mupirocin is a mixture of several pseudomonic acids, with pseudomonic acid A (PA-A) constituting greater than 90% of the mixture. Also present in mupirocin are pseudomonic acid B with an additional hydroxyl group at C8, pseudomonic acid C with a double bond between CIO and C11, instead of the epoxide of PA-A, and pseudomonic acid D with a double bond at C4' and C5' in the 9-hydroxy-nonanoic acid portion of mupirocin.
Mupirocin is chemically known as 9-[(E)-4-[(2S,3R,4R,5S)-3,4-dihydroxy-5-[[(2S,3S)-3-[(2S,3S)-3-hydroxybutan-2-yl]oxiran-2-yl]methyl]oxan-2-yl]-3-methylbut-2-enoyl]oxynonanoic acid having the following structural formula:


Mupirocin is produced through fermentation of Pseudomonas fluorescens. Mupirocin inhibits isoleucyl transfer-RNA synthetase, thereby arresting bacterial protein synthesis. Due to this particular mode of action and its unique chemical structure, Mupirocin does not show any cross-resistance with other clinically available antibiotics. Mupirocin shows little risk of selection of resistant bacteria if used as prescribed.
Mupirocin is used as a topical treatment for bacterial skin infections, for example, furuncle, impetigo, open wounds etc, Mupirocin ointment shows in vivo activity against Staphylococcus aureus (including methicillin-resistant strains), S, epidermidis and beta-haemolytic Streptococcus species.
Further, Mupirocin has no cross resistance to other antibiotics which are used systemically or topically. Systemic allergic reactions are very rare due to topical use of Mupirocin.
European Patent No. EP0095897 discloses and claims a topical formulation comprising pseudomonic acid as sole therapeutic agent or a salt thereof and at least 1% by weight of a polyethylene glycol or derivative thereof.
European Patent No. EP0231621 Bl discloses a pharmaceutical composition comprising an intimate mixture of mupirocin with a corticosteroid for treatment of skin disorder. The said patent relates to a pharmaceutical composition for topical administration for treatment of skin disorders. The said composition comprises therapeutically effective amount of Mupirocin calcium and 0.001 to 5% of the hydrocortisone in topical formulationfor use in treatment of skin disorders. However, the patent does not teach use of the disclosed combination for any particular skin disorder.
In view of above, the current invention aims to provide synergistic combination of Alclometasone dipropionate and Mupirocin for treatment of Infectious Eczematoid Dermatitis, Psoriasis or Koebner's phenomenon.

Summary of the Invention:
This invention discloses the topical formulation comprising a corticosteroid, Alclometasone dipropionate along with a broad-spectrum anti-bacterial agent, Mupirocin; in form of ointment and cream having synergistic effect for treatment of Infectious Eczematoid Dermatitis, Psoriasis or Koebner's phenomenon.
Detailed Description of Invention:
The invention will now be described in details in connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated
The terms "infective bacterial eczema" and "Infectious Eczematoid Dermatitis" are used interchangeably to refer to a disorder characterized by eczema caused by the irritating effects on the skin of a purulent discharge from such a focus as a chronic otitis media, a draining sinus, or a boil.
The present invention provides a combination of Alclometasone dipropionate, a corticosteroid and Mupirocin, a broad spectrum antibiotic which is used for the treatment of infective bacterial eczema or 'Infectious Eczematoid Dermatitis' as well as secondary bacterial infection in patients suffering from chronic eczema or Psoriasis or Koebner's phenomenon. The formulation of present invention can be in form of topical ointment or cream.
In preferred embodiment the ointment of current invention comprises a therapeutically effective amount of a corticosteroid Alclometasone dipropionate in combination with Mupirocin a broad-spectrum antibiotic.
In preferred embodiment, the quantity of Alclometasone diporpionate in formulation of current invention is 0.05%.
In preferred embodiment, the quantity of Mupirocin in formulation of current invention is 2.0%.

The formulation of instant invention further, comprises Polyethylene glycol 400 in range of 50 - 75% w/w of the total composition as base for ointment.
The formulation of instant invention further, comprises Polyethylene glycol 3350 in range of 20 - 35% w/w of the total composition as base for ointment.
In further embodiment, the said ointment is prepared by process comprising of following steps:
(a) Melting polyethylene glycol 3350 with a small quantity of polyethylene glycol 400;
(b) Cooling of the clear molten mass of step (a) to temperature below 40°C;
(c) Dissolving Mupirocin in small quantity of Polyethylene glycol 400;
(d) Dissolving Alclometasone diporpionate in Polyethylene glycol 400, if required by warming;
(e) Adding Alclometasone dipropionate solution of step (d) in to melted base of step (b) followed by addition of Mupirocin solution of step (c); and
(f) Stirring properly and making up the final weight with Polyethylene Glycol.400.
In preferred embodiment, the present invention provides a cream formulation for topical administration of therapeutically effective amount of a corticosteroid Alclometasone dipropionate in combination with Mupirocin a broad-spectrum antibiotic.
The said cream formulation comprises 0.05% Alclometasone dipropionate in combination with 2.15% Mupirocin Calcium (equivalent to 2% Mupirocin).
Further, the formulation comprises an emulsifier selected from cetostearyl alcohol in range of 2-8%,cetomacrogol 1000 in range of 0.5-4% andcetyl alcohol in the range of 1 -12%.
An oil base selected from Light liquid paraffin in range of 2-8% white soft paraffin in range of 2-15%and stearyl alcohol in range of 2-30%.

A preservative selected from Methyl paraben in range of 0.05-0.25%, Propyl paraben in range of 0.01-0.1%, chlorocresol in range of 0.05-0.15% , benzyl alcohol in range of 1 -2% and phenoxy ethanol in range of 0.1 - 0.5%.
Formulation further comprises antioxidant, preferably butylated hydroxy toluene in range of 0.01-0.025%.
Furthermore the formulation comprises a penetration enhancer which also functions as a solubiliser, such as Propylene glycol in range of 5-25%, a Chelating agent,preferably disodium EDTA in range of 0.005-0.2%, a buffering agent selected from citric acid in range of 0.01-0.1%or disodium hydrogen phosphate in range of 0.01-0.1%.
Alternatively, the according to another embodiment the cream formulation as described above may contain a viscosity building agent preferably, Xanthan Gum inrange of 0.1-1%.
In further preferred embodiment, the invention discloses a process for manufacturing of the cream formulation comprises following steps:
(a) Melting Cetamacrogol 1000, Cetosteryl Alcohol, Light Liquid Paraffin, White soft paraffin and Butylated Hydroxy Toluene at 70°c~80°c;
(b) dissolving disodium EDTA in purified water by heating to 70°C~ 80°C;
(c) mixing oil phase from step (a) and water phase from step (b) under stirring to form a stable emulsion formation;
(d) adding Chlorocresol dissolved in Propylene Glycol to emulsion of step(c);
(e) dissolving Alclometasone Dipropionate in Propylene Glycol with the aid of heat;
(f) adding solution of step (e) to emulsion of step (d) under stirring at 40°C -50°C;
(g) dispersing Mupirocin Calcium in Propylene Glycol by sonication;
(h) adding dispersion of step (g) to emulsion of step (f) under stirring at 40°C; (i) cooling the bulk to form a stable cream formation; (j) adjusting the pH between 4.0 to 6.5 with the help of buffering agent, and (k) adjusting the final weight with purified water.
Alternatively, in another embodiment the process for manufacture of cream comprises:

(a) Melting Cetamacrogol 1000, Stearyl Alcohol, Cetyl Alcohol and Butylated Hydroxy Toluene at 70°C-80°C;
(b) dissolving Disodium EDTA and Xanthan Gum in Purified water by heating to 70°C- 80°C;
(c) adding solution of step (b) to solution of step (a) under stirring at 65°C;
(d) dispersing Mupirocin Calcium in Propylene Glycol and adding to step (c);
(e) dissolving Alclometasone Dipropionate in Propylene Glycol with the aid of heat;
(f) adding solution of step (e) to the bulk of step (d);
(g) adding Benzyl Alcohol and Phenoxy ethanol at 40°c under stirring to solution of step (f);
(h) cooling the bulk of step (g) to form a stable cream formation;
(i) adjusting the pH between 4.0 to 6.5 with the help of buffering agent, and
(j) adjusting the final weight with purified water.
The instant invention is more specifically explained by following example. However, it should be understood that the scope of the present invention is not limited by the example in any manner. It will be appreciated by any person skilled in this art that the present invention includes following example and further can be modified and altered within the technical scope of the present invention.
Examples EXAMPLE 1: Ointment Formulation:

Category Ingredients Concentration (%w/w)
Active Ingredients Alclometasone Dipropionate 0.05%

Mupirocin 2.0 %
Ointment Base Polyethylene Glycol 400 50% -75%

Polyethylene Glycol 3350 20% - 35%
The said ointment is prepared by process comprising melting polyethylene glycol 3350 with a small quantity of polyethylene glycol 400. The clear molten mass hence formed is cooled down to temperature below 40°C. Mupirocin is dissolved in small quantity of

Polyethylene glycol 400.Further, Alclometasone diporpionate is dissolved in Polyethylene glycol 400, if required by warming. The two solutions of Mupirocin and Alclometsone dipropionate are added, to the molten mass of PEG 3350 and PEG 400under continuous stirring in ointment mixer and cooling till mass start to solidify, and finally making up the weight usingPEG 400.
EXAMPLE 2: Cream Formulation:

Category Ingredients Concentration (% w/w)
Active Ingredients Alclometasone Dipropionate 0.05%

Mupirocin Calcium (Equivalent to 2% Mupirocin) 2.15%
Emulsifier Cetostearyl alcohol 2-8%

Cetomacrogol 1000 0.5-4%
Oil base Light liquid paraffin 2-8%

White soft paraffin 2-15%
Preservative Methyl paraben 0.05-0.25%

Propyl paraben 0.01-0.1%

Chlorocresol 0.05-0.15%
Antioxidant Butylated Hydroxy Toluene 0.01-0.025%
Penetration enhancer and Solubiliser Propylene glycol 5-25%
Chelating agent Disodium EDTA 0.005-0.2%
Buffering agent Citric acid 0.01-0.1%

Disodium hydrogen Phosphate 0.05-0.1%
Purified water q.s. q.s.
Process for manufacturing:
(a) Melting cetamacrogol 1000, cetosterylalcohol, light liquidparaffin, white soft paraffin and butylated hydroxy toluene at 70°c - 80°c;

(b) dissolving disodium EDTA in purified water by heating to 70°C~ 80°C;
(c) mixing oil phase from step (a) and water phase from step (b) under stirring to form a stable emulsion formation;
(d) addingchlorocresol dissolved in propylene glycol to emulsion of step(c);
(e) dissolving alclometasone dipropionate in propylene glycol with the aid of heat;
(f) adding solution of step (e) to emulsion of step (d) under stirring at 40°C-50°C;
(g) dispersing mupirocin calcium in propylene glycol by sonication;
(h) adding dispersion of step (g) to emulsion of step (f) under stirring at 40°c; (i) cooling the bulk to form a stable cream formation; (j) adjusting the pH between 4.0 to 6.5 with the help of buffering agent, and (k) adjusting the final weight with purified water.
EXAMPLE 3: Cream Formulation:

Category Ingredients Concentration (%w/w)
Active Ingredients Alclometasone Dipropionate 0.05%

Mupirocin Calcium (Equivalent to 2% Mupirocin) 2.15%
Emulsifier Cetyl Alcohol 1-12%

Cetomacrogol 1000 1-5%
Oil Base Stearyl Alcohol 2-30%
ViscosityBuilding agent Xanthan Gum 0.1-1%
Preservative Benzyl Alcohol 1-2%

Phenoxy ethanol 0.1-0.5%
Antioxidant Butylated Hydroxy Toluene 0.01-0.025%
Penetration enhancer Solubiliser Propylene glycol 2-25%
Chelating agent Disodium EDTA 0.01-0.2%
Buffering agent Citric acid 0.01-0.1%

Disodium hydrogen 0.01-0.1%

Phosphate
Purified water q.s. q.s.
Process for manufacturing:
(a) Melting Cetamacrogol 1000, Stearyl Alcohol, Cetyl Alcohol and Butylated Hydroxy Toluene at 70°C-80°C;
(b) dissolving Disodium EDTA and Xanthan Gum in Purified water by heating to 70°C-80°C;
(c) adding solution of step (b) to solution of step (a) under stirring at 65°C;
(d) dispersing mupirocin calcium in propylene glycol and adding to step (c);
(e) dissolving alclometasone dipropionate in Propylene Glycol with the aid of heat;
(f) adding solution of step (e) to the bulk of step (d);
(g) adding benzyl alcohol and phenoxy ethanol at 40°c under stirring to solution of step
(f);
(h) cooling the bulk of step (g) to form a stable cream formation;
(i) adjusting the pH between 4.0 to 6.5 with the help of buffering agent, and
(j) adjusting the final weight with purified water.
Overages of Alclometasone Dipropionateand Mupirocinor Mupirocin Calcium can be added for the long term stability purpose.
Stability study of the product is carried out as per lCH 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 pharmaceutical formulation comprising a combination of
a. alclometasone;
b. mupirocin, and
c. pharmaceutically acceptable excipients
for treatment of infectious eczematoid dermatitis.
2. The pharmaceutical composition as claimed in claim 1, wherein formulation comprises 0.5% alclometasone and 2% of mupirocin, as mupirocin calcium in an amount of 2.15%.
3. The pharmaceutical formulation as claimed in claim 1 is in form of topical ointment or cream.
4. The pharmaceutical formulation as claimed in claims 1 and 2, wherein ointment formulation comprises pharmaceutically acceptable excipients selected from ointment base selected form polyethylene glycol 400.in range of 50% -75%and polyethylene glycol 3350 in range of 20% - 35%.
5. The pharmaceutical formulation as claimed in claim 1 and 2, wherein cream formulation comprises pharmaceutically acceptable excipients selected form emulsifier, preservative, antioxidant, penetration enhancer, solubiliser, chelating agent, buffering agent and optionally a viscosity building agent or an oil base.
6. The pharmaceutical formulation as claimed in claim 4, wherein
a. the emulsifier is selected from cetostearyl alcohol in range of 1 - 12%,
cetomacrogol 1000 in range of 0.5 - 5% and cetyl alcohol in range of 1 - 12%;
b. the preservative selected from methyl paraben in range of 0.05-0.25%, propyl
paraben in range of 0.01-0.1%, chlorocresol in range of 0.05-0.15%, benzyl
alcohol in range of 1 - 2% and phenoxy ethanol in range of 0.1-0.5%;
c. the antioxidant is preferably butylated hydroxy toluene in range of 0.01-0.025%;
d. the penetration enhancer is preferably is propylene glycol in range of 2-25%;
e. the chelating agent is preferably disodium EDTA in range of 0.01-0.2%, and

f. the buffering agent is selected from citric acid in range of 0.01-0.1% and disodium hydrogen phosphate in range of 0.01 - 0.1%.
7. The pharmaceutical formulation as claimed in claim 4, wherein the optional viscosity building agent is selected from xanthan gum in range of 0.1 -1 %.
8. The pharmaceutical formulation as claimed in claim 4, wherein the optional oil base is selected from light liquid paraffin in range of 2-8%, white soft paraffin in range of 2-15% andstearyl alcohol in range of 2-30%.