FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"TOPICAL FORMULATION CONTAINING HALOBETASOL PROPIONATE AND FUSIDIC ACID CREAM / OINTMENT"

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 Held of invention:
This invention relates to the topical composition containing corticosteroid Halobetasol Propionate along with bacteriostatic antibiotic Fusidic acid / sodium fusidate in the form of cream or ointment
Background of the invention:
Halobetasol propionate, a synthetic corticosteroid is used for topical dermatological use. The corticosteroids constitute a class of primarily synthetic steroids used topically as an anti-inflammatory, anti-pruritic agent and vasoconstrictive properties. Chemically Halobetasol propionate is 21-chloro-6a, 9-difluoro-ll B -methylpregna-1, 4-diene-3-20-dione, 17-propionate, C25H31ClF2O5, having structural formula as follows:

Halobetasol is a known synthetic corticosteroid for topical dermatological use. A cream containing 0.05% Halobetasol propionate is marketed under the brand name Ultravate and is used to treat swelling, inflammation, and itching associated with skin conditions such as eczema, dermatitis, rashes, insect bites, poison ivy, and allergies. It reduces the action of chemicals in the body that cause inflammation, redness, and swelling and itching caused by a number of skin conditions such as allergic reactions, eczema, and psoriasis.
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Fusidic acid is used in concentration of 2%, as a bacteriostatic antibiotic that is often used topically in creams and eyedrops, but may also be given systemically as tablets or injections. Chemically Fusidic acid is 2-(16-acetyloxy-3,l l-dihydroxy-4,8,10,14-tetramethyl- 2,3,4, 5,6,7, 9,11,12, 13,15,16- dodecahydro- lH-cyclopenta [a]phenanthren-17-ylidene) -6-methyl- hept-5-enoic acid,C31H48O6, having structural formula as follows:

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 and Sodium Fusidate are mainly used in treatment of Staphylococcal infections in single ingredient or multiple active ingredient dosage forms.
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.
The present invention provides a topical cream/ointment formulation comprising Halobetasol Propionate (a corticosteroid) alongwith Fusidic acid/Sodium Fusidate (a bacteriostatic antibiotic) as active ingredients, especially effective against treating dry, scaly, cracked or excoriated lesions.
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An article by Hengge UR, Ruzicka T, Schwartz RA and Cork MJ titled "Adverse effects of topical glucocorticosteroids" published in Journal of the American Academy of Dermatology, 2006 Vol: 54, pagesl-15, discloses that topical corticosteroids were introduced into medicine about 50 years ago. Cutaneous adverse effects occur regularly with prolonged treatment and are dependent on the chemical nature of the drug, the vehicle, and the location of its application. The most frequent adverse effects include atrophy, striae, rosacea, perioral dermatitis, acne, and purpura. Those that occur with lower frequency include hypertrichosis, pigmentation alterations, delayed wound healing, and exacerbation of skin infections. Of particular interest is the rate of contact sensitization against corticosteroids, which is considerably higher than generally believed. Systemic reactions such as hyperglycemia, glaucoma, and adrenal insufficiency have also been reported to follow topical application. Children are more prone to the development of systemic reactions to topically applied medication because of their higher ratio of total body surface area to body weight.
Halobetasol propionate cream/ointment is marketed under the brand name Ultravate and it has been observed that some of the medication used in Ultravate, is inevitably absorbed through the skin and into the bloodstream. If applied over a large area, or under an airtight dressing, the drug can cause a number of unwanted side effects, including increased sugar in the blood and urine, and a set of symptoms called Cushing's syndrome, characterized by a moon-shaped face, emotional disturbances, high blood pressure, weight gain, and growth of body hair in women.
"Fusidic acid-induced leukopenia and thrombocytopenia" published in the Journal of the Chinese Medical Association (ISSN 1726-4901) 2003, vol. 66, no7, 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. The major adverse effects are mild gastrointestinal discomfort and diarrhea. The hematological side effects such as granulocytopenia and thrombocytopenia have been rarely reported. The published literature regarding hematological adverse effects caused by fusidic acid is reviewed, and an immune-mediated mechanism possibly by
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drug-dependent antibody is speculated. Periodic complete blood count check in patients receiving long-term fusidic acid treatment to avoid serious hematological adverse effects is recommended.
Sodium fusidate is conventionally available for local treatment of skin infections at 2% concentration as an ointment, cream or gel. US Patent 4,323,558 describes sodium fusidate alone or in combination with tienes (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 pathogenic bacteria. Severely excoriated lesions causing secondary infection with Staphylococcus aureus or Streptococcus pyogenes may lead to edema, making the tracks less visible.
There is no known cure for eczema, therefore treatments aim to control the symptoms i.e. reduce inflammation and relieve itching, by using topical corticosteroids but prolonged use of topical corticosteroids for eczema is thought to increase the risk of possible side effects, the most common of which is the skin becoming thin and fragile (atrophy). When the normal protective barrier of the skin is disrupted (dry and cracked), it allows easy entry for 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) thus the need arises 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.
Antibiotics are not indicated in routine treatment of psoriasis. However, antibiotics should be employed to avoid an infection caused by the bacteria Streptococcus which triggers an outbreak of psoriasis, as in certain cases of guttate psoriasis (a type of
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psoriasis that looks like small, salmon-pink drops on the skin), thus necessitates the need to administer concomitantly an antibiotic along with the administration of topical corticosteroid.
Fucidin Tablets and Suspension can occasionally cause liver upsets which can produce jaundice (yellowing of a patient's skin and the whites of his or her eyes), rashes and irritation are the common side effects of this drug while other adverse effect includes blood disorders, disturbances of the gut such as diarrhoea, constipation, nausea, vomiting or abdominal pain, dark urine, lighter-than-usual feces. Therefore, the use of topical preparations containing fusidic acid is always preferred, however, the use of the same is strongly associated with the development of resistance to bacterial strains and hence there are voicing agitation against the continued use of fusidic acid as monotherapy in the community.
In view of the above draw backs involved in using halobetasol as well as fusidic acid/sodium fusidate as monotherapy, the present inventors have come up with a solution to overcome the above problems by providing a novel and rational pharmaceutical combination of halobetasol with fusidic acid/sodium fusidate in the form of cream/ ointment along with pharmaceutically accepted ingredients.
Object of the invention:
The main object of the invention is to provide the topical composition comprising a combination of Halobetasol Propionate and Fusidic acid/ Sodium fusidate useful for the management of corticosteroid responsive dermatoses, psoriasis or eczema.
Summary:
This invention discloses a topical synergistic composition containing corticosteroid Halobetasol Propionate along with bacteriostatic antibiotic agent Fusidic acid/ Sodium fusidate in the form of cream and ointment.
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Detailed description of the invention:
Many patients resort to home remedies or OTC preparations which are irritant 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. A combination of corticosteroid with anti-infective agent takes care of inflammation and infection ensuring speedy recovery.
Therefore, the present invention describes topical synergistic composition for treatment corticosteroid responsive dermatoses, psoriasis or eczema which comprises of therapeutically effective amounts of Halobetasol a synthetic corticosteroid in combination with Fusidic acid, a bacteriostatic antibiotic to a subject in need thereof, in the form of cream and ointment.
Halobetasol propionate along with sodium fusidate/ Fusidic acid, the combination is particularly used for the management of corticosteroid responsive dermatoses, psoriasis or eczema. The above combination is effective against treating dry, scaly, cracked or excoriated lesions.
According to a preferred embodiment, the present invention provides topical composition of Halobetasol with sodium fusidate/Fusidic Acid as a combination of high potency corticosteroid with broad spectrum topical anti-bacterial drug.
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 cream formation takes place. Further, adding preservatives, penetration enhancer, antifoaming agent etc for the stable cream formation. Active drug may be added before cream formation or while the cream formation is taking place.
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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

Halobetasol Propionate (0.05% w/w), 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 Halobetasol propionate and Fusidic acid/ Sodium Fusidate, is prepared using excipients selected from the group consisting of Cetostearyl alcohol, Cetomacrogol 1000, Microcrystalline wax, white soft paraffin, Light liquid paraffin, a - Tocopherol, Polysorbate 80, Glycerin, Disodium EDTA, Propylene glycol, citric acid and purified water .
According to another preferred embodiment, the ointment of Halobetasol propionate and Fusidic acid/ Sodium Fusidate is prepared using excipients selected from the group consisting of a-Tocopherol, β-hydroxy toluene, sorbitan sesquioleate, propylene glycol, white soft paraffin, cetyl alcohol, lanolin anhydrous, liquid paraffin and white bees wax.
Overages of Halobetasol Propionate 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:
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Example 1:
Composition for the Preparation of Cream:

Ingredients Concentration
Active Ingredients Halobetasol Propionate 0.05%
Fusidic Acid 2%
Emulsifier Cetostearyl alcohol 2-8%
Cetomacrogol 1000 0.5-4%
Microcrystalline wax 2-5%
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 Butylhydroxy anisole 0.005-0.02%
A - Tocopherol 0.01-0.05%
Humectant Glycerin -
Penetration enhancer Polysorbate 80 0.1-7%ss
Propylene glycol 10-24%
Chelating agent Disodium EDTA 0.005-0.2%
Buffering agent Citric acid 0.01-0.1%
Purified water
Example 2:
Composition for the Preparation of Ointment:

Ingredients Concentration
Active Ingredients Halobetasol Propionate 0.05%
Sodium Fusidate 2%
Antioxidant a-Tocopherol 0.01-0.15%
β-hydroxy toluene 0.1-0.5%
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Dated this 21st day of July 2008

Dr. Gopakumar G. Nair Agent for the Applicant
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