FORM 2
THE PATENTS ACT, l970
(39of l970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"HALOBETASOL MICROEMULSION BASED CREAM FORMULATION"
2. APPLICANTS:
(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.

Field of Invention
The present invention relates to field of topical formulations of Halobetasol. More particularly, the present invention relates to efficacious topical cream formulation containing microemulsion of Halobetasol cream formulation and the process for manufacturing thereof.
Background of Invention
Most pharmaceutical drug substances are lipophilic Compounds, which are practically insoluble in water. Researchers have developed drug delivery systems, such as tablets. capsules, ointments, creams, gels, suspensions, solutions and emulsions, in many dosage forms, to deliver these lipophilic substances to patients. A microemulsion, one of the pharmaceutical interests for new drug delivery, is normally composed of oil, water, surfactant, and co-surfactant. Hoar and Schulman were the first to introduce the word microemulsion, which they defined as a transparent solution obtained by titrating a normal coarse emulsion with medium-chain alcohols. The short to medium-chain alcohols are generally considered as co-surfactants in the microemulsion system.
Microemulsions are potential drug carrier systems for oral, topical and parenteral administration. They offer the advantage of spontaneous formation, ease of manufacturing and scale-up, thermodynamic stability, and improved drug solubilization and bioavailability. The droplet size of microemulsion is conventionally, considered to be less then l00nm. Microemulsions are conceived to be an ideal vehicle for drug deliverv since they provide a long shelf-life due to their thermodynamic nature and infinite physical stability.
Halobetasol, a synthetic topical corticosteroid, is generally applied in form of topical cream or ointment for treatment of various inflammatory reactions such as, dermatitis, eczema, insect bites, poison ivy, allergies, and other skin rashes. Halobetasol is used to reduce itching, inflammation and swelling associated with these skin conditions. Halobetasol was first disclosed in US Patent No. US4619921 assigned to Ciba-Geigy Corporation.

Chemically Halobetasol propionate is 21-chloro-6a, 9-difluoro-l 1(3, 17-dihydroxy-16β-methylpregna-1, 4-diene-3-20-dione, 17-propionate, C25H31CIF2O5. It has the following structural formula:

Halobetasol propionate has anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of the anti-inflammatory activity of the topical corticosteroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and Ieukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.
Halobetasol is a hydrophobic drug, that is, Halobetasol is not soluble in water or aqueous medium. The hydrophobicity of Halobetasol limits its usefulness if administered in an aqueous cream base. Further, the xenobiotic nature of Halobetasol prevents effective absorption through stratum corneum, which comprises keratin-rich dead cells embedded in a lipid matrix. As such, epidermal lipids are found in high concentrations in stratum corneum, therefore lipid carries which allow lipid exchange with the stratum corneum have proved to be promising for improving permeation rate as well as increasing solubalization and bioavailability of hydrophobic drugs. Microemulsions are conceived to be ideal vehicles for delivery of such drugs which are generally less soluble in water.
The presence of surfactant and co-surfactant in the microemulsion system reduces the interfacial tension. Therefore, the microemulsion is thermodynamically stable and forms spontaneously, with an average droplet diameter of 1 to 100 μm. Advantages of microemulsion over coarse emulsion include its ease of preparation due to spontaneous formation, thermodynamic stability, transparent and elegant appearance, increased drug

loading, enhanced penetration through the biological membranes, increased bioavailability and less inter- and intra-individual variability in drug pharmacokinetics.
The potency of topical steroid preparations is strongly correlated to their absorption through the skin. The therapeutic efficacy of the active ingredient mainly depends on such factors as the mixing state of active ingredient, e.g. dispersing or dissolving, the proportion of the active ingredient used and the affinity of the mixed composition to the skin and the like.
EP0211258 discloses a microemulsion composition for administration of glucocorticoids or corticotrophins comprising a pharmaceutically acceptable lipid in concentration from about 0.6% to 10%, an emulsifier and non-pyorgenic aqueous continuous phase. According to cited patent, less then 1% of droplets have a diameter of more the 125 nm. The patent teaches use of microemulsions for parenteral administration; wherein parenteral administration comprises administration of drug through any route other than oral or topical route of administration.
Indian Patent Application No. 2301/DELNP/2007 discloses a liposomal composition of glucocorticoid or glucocorticoid derivatives wherein the glucocorticoid derivative is selected from an amphipathic weak base glucocorticoid or glucocorticoid derivative having a pKa equal or below 11 and a logD at pH 7 in the range between -2.5 and 1.5; or an amphipathic weak acid GC or GC derivative having a pKa above 3.5 and a logD at pH 7 in the range between -2.5 and 1.5, but the patent application is silent over use of microemulsions and more specifically microemulsion based topical cream formulation for halobetasol.
In the preparation of cream formulations it is necessary to consider the rheological properties (viscosity, flowability. elasticity etc), mechanical properties, bioadhesion, absorption, providing moisture to the skin, preventing dryness to make it more effective.
It is thus the object of the invention to formulate a stable microemulsion based cream formulation for administration of Halobetasol with enhanced cutaneous permeation, and

good physical appearance, which is readily suitable to reduce itching, inflammation and swelling associated with these skin conditions.
Summary of invention
The instant invention provides a novel microemulsion based cream formulation for administration of a glucocorticoid namely, Halobetasol with a view of improving the permeation property of the topical glucocorticoid through the stratum corneum thereby resulting in increased bioavailability.
Description of Drawings
Fig. 1 depicts skin blanching profile after 2 hours of application of the formulation of invention and marketed formulation.
Fig. 2 depicts skin blanching profile after 4 hours of application of the formulation of invention and marketed formulation.
Fig. 3 depicts skin blanching profile after 6 hours of application of the formulation of invention and marketed formulation.
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 current invention describes a microemulsion based topical cream formulation for administration of Halobetasol.
In an embodiment, the current invention provides a microemulsion based topical cream formulation comprising a oleaginous vehicle for dissolution of Halobetasol as oil phase or discontinuous phase; a surfactant or emulsifying agent and an aqueous continuous phase

alongwith other pharmaceutically acceptable excipients. The said formulation shows improved permeation properties for Halobetasol, through skin.
In a preferred embodiment, the invention provides efficacious topical cream formulation comprising halobetasol in range of 0.025-0.05% solubilized in oleaginous vehicle in range of 0.05-5.0% as discontinuous phase, a surfactant or emulsifying agent and an aqueous continuous phase.
According to a preferred embodiment, the formulation of invention comprises Halobetasol in range of in range of 0.025-0.05% along with pharmaceutical excipients selected from emollient, oleaginous vehicle, emulsifying agent, oil base, preservative, surfactant, penetration enhancers, solubilizers and vehicles.
The microemulsion based topical cream formulation of invention further comprises at least one oleaginous vehicle, which also functions as emollient such as, isopropyl palmitate in an amount in range of 0.05-5.0%.
The formulation of instant invention comprises at least one emulsifying agent, which also function as emollient selected from cetostearyl alcohol, in range of 2-10% and/or cetomacrogol 1000 in range of 1-5%,
The formulation of instant invention further comprises an oil base such as white soft paraffin, in range of 2-15%.
The formulation of instant invention further comprises at least one preservative selected from chlorocresol, in range of 0.05-0.15%) and/or germaben HE in range of 0.05-0.1%.
The formulation of instant invention further comprises at least one surfactant selected from transcutol - P in range of 0.5-2% and/or polysorbate-80 in range of 1 -5%.
The formulation of instant invention further comprises at least one penetration enhancer, which also functions as a solubilizer, selected form propylene glycol in range of 2-25%

and/or butanol in range of 0.5-2% and/or isopropyl myristate in range of 1-10%, and aqueous vehicle to make up the volume.
According to another embodiment, the microemulsion based topical formulation is prepared by mixing of 10 parts of part I with 90 parts of part II of cream base under stirring and allowing the microemulsion to stand for 24 hrs before filling.
For preparation of Part I, Isopropyl myristate, polysorbate 80, butanol and transcutol P were mixed together on magnetic stirrer to form a clear solution. Halobetasol propionate was dissolved in a sufficient quantity of propylene glycol while heating. The solutions hence formed are mixed together by stirring and adding purified water under stirring.
For preparation of Part JJ, cetostearyl alcohol, cetomacrogol 1000, isopropyl myristate. isopropyl palmitate and white soft paraffin were melted in a stainless steel vessel. To this mixture water at 60°C - WC is added to and stirred. A solution of chlorocresol in propylene glycol is added and finally germaben HE is added to solution hence formed after cooling the solution below 40°C.
The instant invention is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes following examples and further can be modified and altered within the technical scope of the present invention.
Examples: EXAMPLE 1:
The compositions of the microemulsion based cream formulation of invention

Function Ingredients Concentration w/w
Active ingredient Halobetasol propionate 0.025-0.05%
Emollient, oleaginous vehicle Isopropyl palmitate 0.05-5.0%

Emulsifying agent, Emollient
Cetostearyl alcohol 2-10%

Cetomacrogol 1000 1-5%
Oil base White soft paraffin 2-15%
Preservative Chlorocresol 0.05-0.15%

Germaben HE 0.05-0.1%
Surfactant Transcutol - P 0.5-2%

Polysorbate 80 1-5%
Penetration enhancer, solubilizer Propylene glycol 2-25%%

Butanol 0.5-2%

Isopropyl myristate l-10%
Vehicle Purified water q. s.
The process for manufacturing above formulation comprises steps of:
Part I:
(a) Mixing isopropyl myristate, polysorbate 80, butanol and transcutol P on magnetic stirrer;
(b) dissolving Halobetasol propionate in some amount of propylene glycol with aid of heat;
(c) mixing solutions of step (b) with step (a) under stirring; and,
(d) mixing purified water with solution of step (c) under stirring.
Part II:
(a) Melting cetostearyl alcohol, cetomacrogol 1000, isopropyl myristate, isopropyl palmitate and white soft paraffin in a S. S vessel;
(b) heating water to 60°C - 70°C and mix with step (a) under stirring;

(c) dissolving Chlorocresol in propylene glycol and mix with solution of step (b) under stirring;
(d) adding germaben HE to step (c) at temperature below 40°C;
The process for manufacturing further comprises mixing of 10 parts of part 1 with 90 part of part II of cream base under stirring and allowing the microemulsion to stand for 24 hrs before filling.
Overages of Halobetasol propionate can be added for the long term stability purpose.
Stability study of the product is carried out as per ICH guidelines for 6 months under accelerated condition of 40°C / 75% RH and real time condition of 30°C / 65%RH and product was found to be stable.
Clinical Studies
Methodology:
A single blind skin blanching bioassay study on normal human volunteers was carried out for comparative evaluation of Halobetasol propionate formulations. The formulation A was plain Halobetasol propionate cream while the formulation B was microemulsion based Halobetasol propionate cream. The applied cream was removed from the application at different time periods such as, after 2 h, after 4 h, after 6 h and then recording the blanching response for further 24 hours after removal of cream.
Observations of single blind study for above formulation:
For drug removal at 2 h: after application of formulations under occlusion for 2 hours, they were removed and skin blanching profiling was done for the next 24 hours. The results from the observations are depicted graphically in Fig. 1.
For drug removal at 4 h: after application of formulations under occlusion for 4 hours, they were removed and skin blanching profiling was done for the next 24 hours. The results from the observations are depicted graphically in Fig. 2.

For drug removal at 6 h: after application of formulations under occlusion for 6 hours. they were removed and skin blanching profiling was done for the next 24 hours. The results from the observations are depicted graphically in Fig. 3.
Conclusion: The study showed that there is on an average 30% improvement in efficacy of the product when formulated as microemulsion based cream. The improvement was calculated from area under the Blanching Curve of the microemulsion based cream formulation which was 1.3 times that of normal cream formulation for different application time. The pharmacodynamic response was observed to elicit faster and higher in case of the nanotechnology based product. It was observed that the skin blanching was higher and lasted longer, suggesting an increased permeation and retention of the drug and hence, enhanced therapeutic efficacy of the product,

We Claim,
1. An efficacious topical cream formulation comprising halobetasol in range of 0.025-0.05% solubilized in oleaginous vehicle in range of 0.05-5.0% as discontinuous phase, a surfactant or emulsifying agent and an aqueous continuous phase.
2. The efficacious topical cream formulation as claimed in claim 1, wherein halobetasol is halobetasol propionate.
3. The efficacious topical cream formulation as claimed in claim 1. wherein the oleaginous vehicle is isopropyl palmitate.
4. The efficacious topical cream formulation as claimed in claim 1, wherein the surfactant is selected from transcutol - P in range of 0.5-2% or polysorbate 80 in range of 1-5% or combination thereof.
5. The efficacious topical cream formulation as claimed in claim 1, wherein emulsifying agent is selected from cetostearyl alcohol in range of 2-10% or cetomacrogol 1000 in range of 1-5% or combination thereof.
6. The efficacious topical cream formulation as claimed in claims 1 - 5 further comprises an oil base, a preservative and a penetration enhancer.
7. The efficacious topical cream formulation as claimed in claim 6, wherein the oil base is white soft paraffin in range of 2-15%.
8. The efficacious topical cream formulation as claimed in claim 6. wherein the preservative is selected from chlorocresol in range of 0.05-0.15% or germaben HE in range of 0.05-0.1% or combination thereof.
9. The efficacious topical cream formulation as claimed in claim 6, wherein the penetration enhancer is selected from propylene glycol in range of 2-25% or

Butanol in range of 0.5-2% or isopropyl myristate in range of 1-10% or combinations thereof.
10. The process for manufacture of the formulation as claimed in claims 1 - 9 comprises:
(a) Mixing isopropyl myristate, polysorbate 80. butanol and transcutol P on magnetic stirrer;
(b) dissolving Halobetasol propionate in desirable amount of propylene glycol with aid of heat;
(c) mixing solutions of step (b) with step (a) under stirring;
(d) mixing purified water with solution of step (c) under stirring;
(e) melting cetostearyl alcohol, cetomacrogol 1000, isopropyl myristate. isopropyl palmitate and white soft paraffin in a S. S vessel;
(f) heating water to 60°C - 70°C and mixing with bulk of step (e) under stirring:
(g) dissolving chlorocresol in propylene glycol and mixing with solution of step (f) under stirring:
(h) adding germaben HE to step (g) at temperature below 40°C;
(i) mixing 10 parts solution of step (d) with 90 part of base of step (h) under stirring; and,
(J) allowing the microemulsion of step (i) to stand for 24 hrs before filling.