FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION
[See section 10]
"LOTIONS AND TOPICAL COMPOSITIONS OF IMMUNO SUPPRESSANTS"
(a) CIPLA LTD.
(b) 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of the invention and the manner in which
it is to be performed:

LOTIONS AND TOPICAL COMPOSITIONS OF IMMUNO SUPPRESSANTS
Technical field:
[001] This invention relates to a pharmaceutical composition for the treatment of
topical immune disorders and those related to recalcitrant facial erythema with atopic dermatitis, dermatophyte sis and other related disorders.
More specifically, the invention relates to a composition comprising immunosuppressants in a pharmaceutically acceptable formulation, precisely suitable topical composition such as lotion or a solution or suspension.
Background of invention:
[002] Topical immunotherapy can be used to describe any topical agent with
immunomodulatory properties. More recently, topical formulations of a different class of compounds with direct immunosuppressive actions have been tested in diseases believed to have an immunologic basis, especially atopic dermatitis and psoriasis. These topical immunosuppressive agents include tacrolimus and the structurally related ascomycin derivatives.
[003] Tacrolimus is hydrophobic macrolide immunosuppressant produced by the
soil fungus Streptomyces tsukubaensis. Chemically tacrolimus is 7-allyl-l,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1 -methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-azatricyclo[22.3.1.0]octacos-18-ene-2,3,10,16-tetraone. Tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This effect has been shown to prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon). Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-(alpha), all of which are involved in the early stages of T-cell activation. Tacrolimus

inhibits proliferation and selective cytokine expression in antigen stimulated T cells in culture. The drug inhibits B cell proliferation at similar concentrations. To elaborate, Tacrolimus inhibits T-lymphocytes activation, i.e. has a direct effect on T-lymphocytes so as to inhibit IL-2 transcription, which decreases responsiveness of T-lymphocytes to foreign antigens. Its action on atopic dermatitis may be related to alteration of antigen-presenting cells, suppression of IL-2 and co stimulatory molecule expression, impairment of phenotypic and functional differentiation of epidermal Langerhans' cells, and suppression of Thl and Th2 cytokine induction in nymph node cells. The effect of tacrolimus on pruritis may be related to inhibition of histamine release from skin mast cells and impairment of de novo mast cell prostaglandin D2 synthesis along with diminished release of histamine from basophiles. Immunosuppression with tacrolimus in humans prevents allograft rejection. Tacrolimus is also reported as used in the treatment of rejection in transplantation and autoimmune diseases, i.e. routinely used in transplantation of kidney, liver, heart, etc.
[004] Tacrolimus is available in both intravenous and oral formulation for the
prevention of organ rejection after allogeneic liver or kidney transplantation. Oral tacrolimus has been found useful in the treatment of psoriasis, but potentially serious side effects, such as nephrotoxicity and hypertension, limits its use for dermatologic indications by this route. Topical formulations (ointments) have been extensively studied and reported to show positive effects in treatment of inflammatory skin diseases such as atopic dermatitis and psoriasis. Tacrolimus administered topically (as ointment) is reported to be safe and effective in the treatment of skin diseases. It reported that in atopic dermatitis patients, tacrolimus does not alter collagen synthesis and is not atrophogenic.
[005] The following prior art patent documents describe known tacrolimus
formulations (patent nos. US2002173516, US2002052407, US2002013340, EP1092429, US6187756, US6184248, EP1067926, HU0000587, WO9809523, etc.)

[006] US patent 2002052407, US6187756 and US6184248 and WO9809523
describe the composition of tacrolimus to be used in neurological disorders and neurogenerative diseases.
[007] EP1092429 Pharmaceutical compositions and methods for treating
immune response associated disorders.
[008] US patent 2002173516 and US2002013340 describes Pharmaceutical
compositions and methods for treating immune response associated diseases of the surface and the anterior segment of the eye.
[009] EP patent 1067926 and W09951215 describe the use of tacrolimus as
showing inhibitory activity on the production of nitric oxide, for increasing an effect caused by IL-2 inhibitor.
Surprisingly it was found that tacrolimus might be used in the treatment of recalcitrant
facial erythema with atopic dermatitis and for topical immune therapy.
[010] It is reported that Tacrolimus ointment gives good results in treating
recalcitrant facial erythema in most patients with moderate to severe atopic dermatitis.
Yet, one reason for unresponsiveness to the treatment with ointment may be contact
sensitivity to white petrolatum and waxes.
[011] Hence, lotion compositions were prepared comprising of
immunosuppressants with an aim to treat recalcitrant facial erythema with atopic
dermatitis and other topical immune disorders.
[012] Lotions are aqueous solutions or suspensions intended for application to
the skin surface.
On application to the skin, the water evaporates leaving a residue of the medicament on
the skin surface. The evaporation causes cooling and lotions are applied to the specified
area. The cooling effect may be enhanced by the inclusion of alcohol. Other humectants
like glycerin, propylene glycol, polyethylene glycols, and etc. may be included to
promote adherence of the residual powder or particles to the skin.

Lotions may also take the form of dilute emulsions, usually of the oil-in-water type (where water is the dominant phase) or water-in-oil type (where oil is the dominant phase) emulsions. Oil-in-water type lotions are generally used as facial moisturizers, and water-in-oil type lotions are generally used as night creams and facial replenishing creams. Oil-in-water type lotions impart cool feel and nonglossy appearance, while water-in-oil emulsions impart warm feel and glossy appearance. They should contain a preservative to inhibit the growth of microorganisms.
The medicament (Immunosuppressants) should be either dissolved or dispersed in the vehicle.
Summary of Invention:
[013] The present invention describes a pharmaceutical composition for the
treatment of topical immune disorders and those related to recalcitrant facial erythema with atopic dermatitis, dermatophyte sis and other related disorders. More specifically, the invention relates to a composition comprising immunosuppressants in a pharmaceutically acceptable formulation, precisely suitable topical composition such as lotion or a solution. The lotion comprises of petrolatum, waxes, lanolin, and vegetable and mineral oils, plasticizers, glycols, sorbitol and derivatives thereof, alcohol, preservatives, stearic acid and derivatives thereof, water-soluble gums, emulsifiers like triethanolamine.
[014] These lotions are aqueous solutions or suspensions intended for
application to the skin surface. On application to the skin, the water evaporates leaving a residue of the medicament on the skin surface. The evaporation causes cooling in addition to topical immunotherapy.
Detailed Description:
[015] The present invention describes a stable, lotion formulation for
immunosuppressants having a therapeutic effect against immune disorders related to recalcitrant facial erythema with atopic dermatitis, dermatophytosis and related disorders and other topical immune disorders.

The main ingredients for lotion includes petrolatum, waxes, lanolin, and vegetable and mineral oils, plasticizers, glycols, sorbitol and derivatives thereof, alcohol, preservatives, stearic acid and derivatives thereof, water-soluble gums, emulsifiers like triethanolamine, etc. It may also contain silicone derivatives that might render the lotion water-resistant through four to six washings The formulation may additionally contain flavors and silicone and functional derivatives thereof to add lubricity, castrol oil and derivatives thereof to aid in manageability and soluble glycoprotein to maintain proper moisture balance and enhance shine.
[016] The petrolatum and waxes are those commonly used in by a skilled artisan
in the lotion formulation and may include all petroleum bases and waxes obtained from natural and synthetic origin such as beeswax, carnauba wax, cetomacrogol waxes, paraffin waxes, etc.
[017] Mineral oils commonly used in lotion include fatty acids, fatty alcohols,
metallic stearates, monoalcohol esters, glycol esters, polyethylene glycol and its esters, sorbitran esters, etc.
[018] A lotion formulation according to the present invention preferably further
comprises of alcohols such as C2-6 aliphatic alcohols and polyols, for example ethanol,
isopropanol, with ethanol being preferred. Preferably, the concentration of the alcohol is
in the range of about 5 to 50% by weight, of the total formulation.
[019] A lotion formulation according to the present invention preferably further
comprises of oils derived from natural sources, such as corn oil, olive oil, cottonseed oil and sunflower seed oil. Castor oil, Cocoa butter, Coconut oil, Evening Primrose oil, Jojoba oil, Linseed oil, olive oil, Palm oil, Palm kernel oil, Peanut oil, etc. and derivatives thereof.
[020] Preferably therapeutic agent (tacrolimus and functional derivatives
thereof) present in lotion formulations according to the present invention is present at a
concentration in the range of about 0.1% to 5 % of the total formulation.
[021] The present invention will now be further illustrated by the following
Examples, which do not limit the scope of the invention in any way.

Examples:
[022] Example-I:

Sr. No. Ingredients Quantity (%w/w)
A.
1. Cetostearyl alcohol 5.50
2. Cetomacrogol 1000 0.30
3. Light liquid paraffin 5.00
4. Dimethicone 2.0
5. Arlamol CP 1.0
B.
6. Methyl paraben 0.20
7. Propyl paraben 0.02
8. Disodium edetate 0.10
9. Propylene glycol 8.00
10. Purified water q.s.
C.
11. Tacrolimus 0.1-5.0
12. Polyoxy hydrogenated caster oil 0.5-5.0
13. Ethanol 5 - 50 %
[023] Procedure: Heat (A) to 70-75°C. Heat (B) to 70-75X. Mix these with
homogenization. Homogenize for 10 minutes. Dissolve drug in ethanol and add Polyoxy hydrogenated caster oil, mix. Add drug solution to lotion base and mix. Check pH. Make up the volume by water.
[024] Example-II:
Topical solution

Sr. No. Ingredients Quantity (%w/w)
1. Tacrolimus 0.1-5.0

2. Ethanol q.s. to 100%
3. Polyoxy hydrogenated caster oil 2-20 %
[025] Procedure; Dissolve the drug in ethanol. Add and mix into it Polyoxy
hydrogenated caster oil and make up the volume with ethanol.
[026] Example-Ill:
Topical solution

Sr. No. Ingredients Quantity (%w/w)
1. Tacrolimus 0.1-5.0
2. Ethanol q.s. to 100%
3. Polyoxy hydrogenated caster oil 2-20 %
4. Purified water 5-50
5. Methyl paraben 0.20
6. Propyl paraben 0.02
[027] Procedure; Dissolve parabens in ethanol followed by the drug. Add and
mix into it Polyoxy hydrogenated caster oil. Add and mix into above purified water.

Claims:
1. A pharmaceutical product comprising of immunosupprressants and functional derivatives thereof for use in topical immune disorders and those related to recalcitrant facial erythema with atopic dermatitis, dermatophyte sis and other related disorders.
2. A pharmaceutical formulation according to claim 1, comprises of suitable topical composition.
3. A pharmaceutical product according to any of claims 1 and 2, wherein the topical composition preferably is a lotion or a solution preparation.
4. A pharmaceutical product according to any of claims 1 to 3, wherein said immunosupprressants are selected from the group consisting of cyclosporins, tacrolimus or a pharmaceutically acceptable salt, solvate or functional derivatives thereof.
5. A pharmaceutical product according to claims 1 and 2, wherein the preferred immunosupprressants is tacrolimus or tacrolimus coated with the surfactant (with 0.1 - 10 % of the surfactant) or a pharmaceutically acceptable salt, solvate or functional derivatives thereof
6. A pharmaceutical product according to any of claims 1 to 5, wherein the topical lotion preparation can be a cream, spray, gel, suspension and solution.
7. A pharmaceutical product according to any of claims 1 to 6, wherein the topical preparation preferably is in the form of lotion or solution or suspension.
8. A pharmaceutical product according to any of claims 1 to 7 which comprises of immunosuppressants or pharmaceutically acceptable salts, solvate or functional derivatives thereof, petrolatum, waxes, lanolin, and vegetable and mineral oils, plasticizers, glycols, sorbitol and derivatives thereof, alcohol, preservatives, stearic acid and derivatives thereof, water-soluble gums, emulsifiers like triethanolamine.
9. A pharmaceutical formulation according to any of claims 1 to 8, wherein the concentration of said immunosupprressant present in said formulation is in the range of about 0.1% to 5% by weight, based on the weight of the total formulation.

10. A pharmaceutical formulation according to any of claims 8 and 9, wherein said petroleum bases and waxes may include all petroleum bases and waxes obtained from natural and synthetic origin such as beeswax, carnauba wax, cetomacrogol waxes, paraffin waxes, lanolin, wool fat, ozocerite, etc
11. A pharmaceutical formulation according to any of claims 8 to 10, wherein said surfactants may include those commonly used in lotion i.e. fatty acids, fatty alcohols, metallic stearates, monoalcohol esters, glycol esters, polyethylene glycol and its esters, sorbitran esters, and derivatives thereof.
12. A pharmaceutical formulation according to any of claims 8 to 11, wherein said oils in lotion formulations may include oils derived from natural sources, such as corn oil, olive oil, cottonseed oil and sunflower seed oil, Castor oil, Cocoa butter, Coconut oil, Evening Primrose oil, Jojoba oil, Linseed oil, olive oil, Palm oil, Palm kernel oil, Peanut oil, etc.
13. A pharmaceutical formulation according to any of claims 8 to 12, wherein said alcohols comprises of C2-6 aliphatic alcohols and polyols, viz. ethanol, isopropanol and propylene glycol, with ethanol being preferred. Preferably, the concentration of the alcohols is in the range of about 5 to 50% by weight, of the total formulation.
14. A process of preparing a pharmaceutical product according to any of claims 1 to 13, which process comprises providing a topical preparation (lotion or a solution) for the treatment of topical immune disorders and those related to recalcitrant facial erythema with atopic dermatitis, dermatophytosis and related disorders.