FORM 2
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:
"ALCLOMETASONE MICROEMULSlON 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 corticosteroid formulation for treating inflammation of the skin. More particularly, the present invention relates to stable alclometasone microemulsion based topical cream formulation and the process for manufacturing thereof.
Background of Invention
Microemulsions are thermodynamically-stable, optically-clear emulsions having submicron-sized droplets suspended in a continuous phase. These emulsions form spontaneously and typically consist of an aqueous phase, an organic phase, and a surfactant/co-surfactant component. Micro emulsions are conceived to be an ideal vehicle for drug delivery since they provide a long shelf-life due to their thermodynamic nature and infinite physical stability.
AIclometasone[7-chloro-l l-hydroxy-10,13,16-trimethyl-3-oxo-17-(2-propanoyloxyacetyl)-7,8,9,11,12,14,15,16-octahydro-6H-cycIopenta[a]phenanthren-17-yl] propanoate, is a synthetic glucocorticoid steroid for topical use in dermatology as antiinflammatory, antipruritic, antiallergic, antiproliferative and vasoconstrictive asent. Alclometasone dipropionate has following chemical structure:

Alclometasone inhibits phospholipase A2 by inducing production of lipocortins; inhibits synthesis of arachidonic acid, prostaglandins and leukotrienes acid, reduce release of cytokines from lymphocytes and others mediators 0f inflammation (inclusive of histamine).

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.
Alclometasone is a hydrophobic drug, that is, Alclometasone is not soluble in water or aqueous medium. The insolubility of Alclometasone in water limits its usefulness if administered in an aqueous cream base. Further, the xenobiotic nature of Alclometasone 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 amounts 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 solubulization and bioavailability of Alclometasone.
EP0097374 discloses corticosteroid topical preparation which comprises a monoglyceride of a C6-C10 medium-chain fatty acid together with the active ingredient Alclometasone dipropionate, but the said patent does not disclose or teach preparation of microemulsions for improving permeation rate as well as increasing solubulization and bioavailability of Alclometasone
EP0211258 discloses a microemulsion composition comprising glucocorticoids or crticotropins, a pharmaceutically acceptable lipid in concentration form 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 Alclometasone.
1N209289 provides a pre-concentrate for production of microemulsions for water-insoluble drugs along with C8 to C20 fatty acid mono-, di-, or tri-glycerides from a vegetable oil or any mixture of two or more thereof or from synthetic origin and Surfactant and co-surfactants and process for preparation thereof. The patent discloses use of the microemulsions hence formed for filling in soft-gelatin capsule.
Another Indian Patent Application No. 17707MUM/2008 discloses a microemulsion based formulation for administration of a drug, but the said application does not teach or motivate a person skilled in art to prepare micremulsion based formulation for topical application of drug, more specifically, a glucocorticoid.
In view of above, the present inventors have come up with a microemulsion based topical cream formulation for effective delivery of alcolmetasone
Object of Invention:
It is thus the objective of the present invention to develop a topical formulation wherein the solubility or dispersion of the active ingredient is efficiently balanced so as to impart safety, stability and a good feeling when applied to the skin.
Summary of invention:
in accordance with the above objective, the instant invention provides a microemulsion based cream formulation for topical application of glucocorticoid, particularly Alclometasone (as Alclometasone dipropionate), with improved stability.

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 present invention describes a stable microemulsion based topical cream for administration of glucocorticoid, more particularly Alclometasone.
In an embodiment, the invention discloses a microemulsion based topical formulation for administration of alclometasone comprising an emollient an oleaginous vehicle, an emulsifying agent and an oil base.
In an embodiment the formulation of invention comprises alclometasone (as alclometasone dipropionate) in range of 0.025-0.05% an emollient, an oleaginous vehicle, an emulsifying agent and an oil base.
The formulation of invention further comprises other pharmaceutically acceptable excipients such as, preservative, surfactant, penetration enhancer, solubilizer and an aqueous continuous phase.
In a preferred embodiment the formulation of invention comprises an oleaginous vehicle, which also acts as emollient, is preferably isopropyl palmitate in range of 0.05 - 5.0%.
In further preferred embodiment, the emulsifying agent, which also acts as emollient, selected from cetostearyl alcohol in range of 2- 10% or cetomacrogol 1000 in range of 1 - 5% or combination thereof.
In further preferred embodiment, the oil base, is white soft paraffin in range of 2- 15%.
The formulation of invention, further comprises a preservatives selected from chiorocresol in range of 0.05 - 0.15% or germaben HE in range of 0.05 - 0.1% or combinations thereof.

The formulation further comprises a surfactant selected from transcutol-P in range of 0.5 - 2% or polysorbate 80 in range of 1 -5% or combination thereof.
Furthermore, the formulation comprises a penetration enhancer 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 in an aqueous vehicle-
In a preferred embodiment, the invention provides a process for manufacturing the formulation of invention that comprises mixing 10 parts of part I with 90 parts of part I! under stirring and further allowing the mixture to stand for 24 hrs before filling.
The process for manufacturing Part I comprises mixing isopropyl myristate, polysorbate 80, butanol, and transcutol-P using magnetic stirrer to form a clear solution. The Alclometasone dipropionate was dissolved in sufficient amount of propylene glycol aided by heating. The solutions hence formed are mixed together by stirring and adding purified water under stirring.
The process for manufacturing Part 11 comprises melting cetostearyl alcohol, cetomacrogol 1000, isopropyl myristate, isopropyl palmitate and white soft paraffin in a stainless steel vessel. The solution hence formed is mised with water at 60° - 70°C under stirring. To the solution hence formed, a solution of chlorocresol in propylene glycol is added under stirring. To the solution formed germaben HE is added after cooling the solution to 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 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.

Example: EXAMPLE 1
Microemulsion based topical cream formulation:

Ingredients Concentration w/w
Active ingredient Alclometasone dipropionate 0.025-0.05%
Emollient, oleaginous vehicle Isopropyl palmitate 0.05-5.0%
Emulsifying agent. Emollient Cetostearyl alcohol Cetomacrogol 1000 2-10%
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, Propylene glycol 2-25%%
solubilizer Butanol 0.5-2%
Isopropyl myristate 1-10%
Vehicle Purified water q.s.
Process for manufacturing:
Part:1
(a) Mixing isopropyl myristate, polysorbate 80, butanol and transcutol P on magnetic
stirrer;
(b) dissolving Alclometasone dipropionate in some amount of propylene glycol with aid of heat:
(c) mixing ingredients of step (b) with step (a) under stirring; and.
(d) mixing purified water with ingredients of step (c) under stirring.
Part II: (a) Melting cetostearyl alcohol, Cetomacrogol 1000, isopropyl myristate, isopropyl palmitate and white soft paraffin in a stainless steel vessel;

(b) heating water to 60 C - 70 C and mixing it with solution of step (a) under stirring;
(c) dissolving chlorocresol in propylene glycol and mixing it with solution of step (b) under stirring; and,
(d) adding germaben IIE to solution of step (c) at temperature below 40°C.
Preparation of the final microemulsion solution:
(a) Mixing 10 parts of part I with 90 parts of part II of cream base under stirring; and,
(b) allowing the mixture to stand for 24 hrs before filling.
Overages of Alclometasone Dipropionate 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 the product is found to be stable under aforesaid condition.

We claim,
1. A stable microemulsion based topical formulation for administration of alclometasone comprising an emollient, an oleaginous vehicle, an emulsifying agent and an oil base.
2. The stable microemulsion based topical formulation as claimed in claim 1, wherein alclometasone is in range of 0.025 - 0.05%.
3. The stable microemulsion based topical formulation as claimed in claim 2, wherein alclometasone is alclometasone dipropionate.
4. The stable microemulsion based topical formulation as claimed in claim 1. wherein the oleaginous vehicle is isopropyl palmitate in range of 0.05 - 5%.
5. The stable microemulsion based topical 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%.
6. The stable microemulsion based topical formulation as claimed in claim 1, wherein oil base is white soft paraffin in range of 2-15%.
7. The stable microemulsion based topical formulation as claimed in claim 1. further comprises a preservative, a surfactant and a penetration enhancer.
8. The stable microemulsion based topical formulation as claimed in claim 7, wherein
a. 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;
b. the surfactant is selected from transcutol - P in range of 0.5-2% or polysorbate 80
in range of 1-5% or combination thereof;
c. 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
combination thereof.

9. The process for manufacturing of the stable microemulsion based topical formulation according to claims 1 - 8 comprises:
(a) Mixing isopropyl myristate, polysorbate 80, butanol and transcutol P on magnetic stirrer;
(b) dissolving Alclometasone dipropionate in some amount of propylene glycol with aid of heat;
(c) mixing ingredients of step (b) with step (a) under stirring;
(d) mixing purified water with ingredients of step (c) under stirring;
(e) melting cetostearyl alcohol, cetomacrogol 1000, isopropyl myristate, isopropyl palmitate and white soft paraffin in a stainless steel vessel;
(f) heating water to 60°C - 70°C and mixing it with solution of step (e) under stirring;
(g) dissolving chlorocresol in propylene glycol and mixing it with solution of step (f) under stirring;
(h) adding germaben HE to solution of step (g) at temperature below 40°C:
(i) mixing 10 parts of solution of step (d) with 90 parts of cream base of step step (h) under stirring; and.
(j) allowing the mixture to stand for 24 hrs before filling.