FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION:
"TOPICAL FORMULATION CONTAINING ALCLOMETASONE DIPROPIONATE IN COMBINATION WITH FUSIDIC ACID OR SODIUM
FUSIDATE"


2, APPLICANT:
(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:


Technical field of the invention:
This invention relates to the topical corticosteroid along with broad spectrum topical anti¬bacterial drug. Particularly, this invention relates to a composition containing Alclometasone Dipropionate and Fusidic acid or Sodium Fusidate in topical formulation in the form of cream, ointment, gel, lotion etc.
Background of the invention:
Alclometasone is synthetic glucocorticoid steroid for topical use in dermatology as anti¬inflammatory, antipruritic, antiallergic, antiproliferative and vasoconstrictive agent. Alclometasone Dipropionate marketed as medication 'Aclovate' by GlaxoSmithKline.
Alclometasone cream and ointment are indicated for the relief of corticosteroid-responsive dermatoses, including atopic dermatitis, eczema, psoriasis, allergic dermatitis, contact dermatitis, actinic dermatitis, kiss-type allergy, skin itch.
Alclometasone may be used on sensitive skin sites (face, skinfolds); in pediatric patients 1 year or older and in geriatric patients. Alclometasone as 'Aclovate' is supplied as cream and ointment.
Aclovate Cream and Ointment contain alclometasone dipropionate (7a-chloro-l 1(3, 17, 21 -trihydroxy-16a-methylpregna-l ,4-diene-3,20-dione 17,21 -dipropionate), a synthetic corticosteroid for topical dermatologic use.
Chemically, alclometasone dipropionate is C28H37CIO7. It has the following structural formula:
2.


Alclometasone dipropionate has molecular weight of 521. It is a white powder, insoluble in water, slightly soluble in propylene glycol, and moderately soluble in hexyiene glycol.
WO/2006/059152 relates to pharmaceutical aerosol formulations comprising mixtures of first composite particles that include a first pharmaceuticalIy active agent and second composite particles that include a second pharmaceutically active agent. In a preferred embodiment of the invention, wherein the formulation includes a plurality of pharmaceutically active agents, at least one such agent is a p2-agonist and another is a steroid. WO '152 further discloses steroid agent such as Alcometasone and antibiotic/antibacterial agents such as metronidazole, sulphadiazine, etc.
US 2006/0188449 discloses a topical foam aerosol formulation comprising an active agent or agents selected from the group consisting of anti-inflammatory agents, topical anesthetics, topical antibiotics, anti-fungal agents, and combinations thereof, solubilized or dispersed in an oil and water emulsion; wherein anti-inflammatory agent is selected from the group consisting of alclometasone dipropionate, amcinonide and the antifungal agent selected from the group consisting of clotrimazole, econazole etc.
Chemically Fusidic acid is 2-(16-acetyloxy-3,l l-dihydroxy-4,8,10,14- tetramethyl- 2,3,4, 5,6,7, 9,] 1,12, 13,15,16- dodecahydro- I H-cyclopenta [a]phenanthren-17-ylidene) -6-methyl- hept-5-enoic acid,C3]H4806, having structural formula as follows:
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Fusidic acid is a bacteriostatic antibiotic, often used topically in creams and eye drops, but may also be given systemically as tablets or injections. Fusidic acid works by interfering with bacterial protein synthesis, specifically by preventing the translocation of the elongation factor G (EF-G) from the ribosome. Fusidic acid is only effective on gram-positive bacteria such as Staphylococcus species and Corynebacterium species. Fusidic acid inhibits bacterial replication and does not kill the bacteria, and is therefore termed "bacteriostatic".
"Fusidic acid-induced leukopenia and thrombocytopenia" published in the Journal of the Chinese Medical Association (ISSN 1726-4901) 2003, vol. 66, no 7, pp. 429-432, discloses that Fusidic acid is an active agent against a wide variety of Gram-positive bacteria, and it has been increasingly used in methicillin-resistant Staphylococcus aureus infection.
As quoted in Martindale 32nd edition 1 g of Sodium Fusidate is equivalent to about 0.98 g of Fusidic acid. In recent years, Sodium Fusidate has been increasingly used as an anti-infective. It is also used as an agent to treat strains resistant to antibiotics.
US Patent 4,323.558 describes sodium fusidate alone or in combination with trienes (triethylenetetramine) in form of gel, ointment or lotion in 1% concentration for treatment of inflammation.
Majority of skin diseases present with itching and inflammation resulting into loss of barrier functions of the skin. This leads to invasion of the epidermis layers of skin by
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pathogenic bacteria. Scratching by the patient both introduces infection and spreads it from one area to another. Any skin infection further irritates the skin and a rapid deterioration in the condition may ensue (to strive to attain).
Many patients resort to home remedies or OTC preparations, which are irritants in nature. This complicates the clinical picture. The treating physician needs to control signs and symptoms of inflammation and at the same time control associated bacterial infection. Failure to treat the bacterial infection while the patient is recommended a topical corticosteroid preparation leads to 'flare' of bacterial infection.
Thus the need aroused to create a combination of antibiotic along with corticosteroid (particularly having super-high range of potency as compared with other topical corticosteroids) to overcome both, the side effects of using topical corticosteroid alone and causing of skin infection due to scratching.
"Co-operative double-blind trial of an antibiotic/ corticoid combination in impetiginized atopic dermatitis''' by Gerald N. Wachs et al published in British Journal of Dermatology; Volume 95 Issue 3, Pages 323-328 discloses double-blind study of an antibiotic corticosteroid combination, the antibiotic alone and the corticosteroid alone in infected atopic dermatitis (Atopic eczema). Combination therapy found to be more effective than monotherapy and reduced the mean scores for infection, inflammation and overall severity to a greater extent than the antibiotic or corticosteroid alone.
Fucidin® H Cream is used in inflammatory skin conditions, where bacterial infection is also present. Fucidin H Cream contains hydrocortisone 1% and fusidic acid 2%. It is marketed by LEO Laboratories Limited.
The article "The Antibacterial-Corticosteroid Combination: What is its Role in Atopic Dermatitis?" by Williams. Richard E.A.; in American Journal of Clinical Dermatology. 1(4):211-215, July/August 2000; discloses antibacterial, whether topical or systemic, in combination with topical corticosteroids, may produce a more rapid decrease in S. aureus colonization than topical corticosteroids alone. Topical antibacterial-corticosteroid combinations can be useful when treating small areas of skin for a limited period of time
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but are accompanied by the risk of sensitization and the emergence of resistant strains of bacteria. Systemic antibacterial in combination with topical corticosteroid are more appropriate when larger areas are involved.
Another article "Topical betamethasone /fusidic acid in eczema: efficacy against and emergence of resistance in Staphylococcus aureus''' by Menday A. et al; Journal of Dermatological Treatment, Volume 11, Number 3, 1 September 2000 , pp. 143-149(7); discloses the bacteriological implications of treating eczema, infected with Staphylococcus aureus with topical betamethasone/fusidic acid. When betamethasone/fusidic acid treatment is given for short periods there is little selection pressure on the development of resistance to fusidic acid.
A simple cream formulation (Fucicort®, also known as Fucibet® (Fusidic Acid 2% w/w and betamethasone 0.1% w/w (as betamethasone valerate) Leo Pharma) in some European countries combining the two drug substances has been used in clinically infected Atopic Dermatitis (AD) for more than a decade.
"An Efficient New Formulation of Fusidic Acid and Betamethasone 17-Valerate (Fucicort® Lipid Cream) for Treatment of Clinically Infected Atopic Dermatitis" by Finn Schult z Larsen et al published in Acta Derm Venereol 2007; 87: 62-68 describes a lipid formulation of fusidic acid and betamethasone 17-valerate (Fucicort® Lipid cream) to relieve the dryness of atopic dermatitis skin as an additional treatment option to the established Fucicort® cream. The new lipid composition offers an efficient, safe and well tolerated alternative for the short term treatment of clinically infected atopic dermatitis.
In the management of skin infections, it is important to offer alternate treatment to control bacterial infections, which provide effective treatment that relieves the dryness of the eczematous skin and satisfy the different needs and preferences of the patients.
Therefore, the present inventors have come up with a valuable alternative in the management of corticosteroid responsive dermatoses, psoriasis, eczema and edema and provide a solution to overcome the problems mentioned in the prior art by providing a novel, efficient and rational pharmaceutical combination of alclometasone dipropionate
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with fusidic acid or Sodium Fusidate in the form of cream, ointment, gel, lotion etc. along with pharmaceutical^ accepted ingredients.
Object of the invention:
The main object of the invention is to provide the topical composition comprising a combination of Alclometasone propionate and.Fusidic acid or Sodium Fusidate, useful for the management of corticosteroid responsive dermatoses, psoriasis, eczema or edema.
Description of the invention:
The present invention describes topical composition of Alclometasone with Fusidic Acid or Sodium Fusidate, which is a combination of high potency corticosteroid with broad spectrum topical anti-bacterial drug.
According to a preferred embodiment, the present invention provides a combination of Alclometasone Dipropionate along with Fusidic acid or Sodium Fusidate for the management of corticosteroid responsive dermatoses, psoriasis, eczema and edema of groin or armpits. The above combination is effective against treating dry, scale, cracked orenoriated lesions.
A combination of corticosteroid with anti-bacterial agent takes care of inflammation and bacterial infection, ensuring speedy recovery.
The present invention describes topical synergistic composition for the treatment of corticosteroid responsive dermatoses, psoriasis, eczema and edema, which comprises therapeutically effective amounts of alclometasone, a synthetic corticosteroid in combination with Fusidic acid or Sodium Fusidate, a bacteriostatic antibiotic in the form of cream , ointment, gel,lotion etc.
The cream can be prepared in a customary manner, for example, by mixing oil phase and water phase under stirring for the emulsion formation at 60-70°C; followed by cooling till
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cream formation takes place. Further, adding preservatives, penetration enhancer, antifoaming agent etc for the stable cream formation.
While the ointment is prepared by melting and mixing the oil base excipients, active ingredient is either dissolved or suspended in oil base and added under constant stirring, followed by adding penetration enhancer, surfactant, antioxidant, etc for stable ointment formation.
According to the invention, the topical cream/ointment formulation comprises Alclometasone Dipropionate (0.05% w/w) and Fusidic Acid / Sodium Fusidate (2% w/w) along with commonly used pharmaceutical excipients selected from the group comprising ointment/cream base like waxes, preservatives, antioxidants, buffering agent, chelating agent, penetration enhancer, humectant, surfactant, solubilizer, emulsifier and mixture thereof.
According to a preferred embodiment, the topical cream of Alclometasone dipropionate and Fusidic acid, is prepared using excipients selected from the group consisting of Cetostearyl alcohol, Cetomacrogol 1000, white soft paraffin, Light liquid paraffin, a -Tocopherol, Butylated Hydroxy toluene, Butylated Hydroxy anisole, Polysorbate 80, Glycerin, Disodium EDTA, Propylene glycol, Hexylene Glycol, citric acid and purified water.
According to another preferred embodiment, the ointment of Alclometasome dipropionate and Sodium Fusidate is prepared using excipients selected from the group consisting of a-Tocopherol, Butylated-hydroxy toluene, Butylated hydroxy anisole, sorbitan sesquioleate, propylene glycol, hexylene glycol, white soft paraffin, cetyl alcohol, lanolin anhydrous, liquid paraffin and white bees wax.
Overages of Alclometasone Dipropionate and Fusidic Acid / Sodium Fusidate may be added for the long term stability of the product.
The invention is further illustrated by following non-limiting examples of this combination product: