FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
PROVISIONAL SPECIFICATION
[See section 10]
'IMMUNO SUPPRESSANTS IN HAIR MOUSSE"

J (a) CIPLALTD.

7 (b) 8, Betlasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra,
India
ry (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:


Immunosuppressants in Hair Mousse
Technical Field
[001] The present invention relates to a stable, hair-styling mousse
formulation for immunosuppressants.
Background and Prior Art
[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 a hydrophobic macrolide immunosuppressant
produced by the soil fungus Streptomyces tsukubaensis. Chemically tacrolimus is 7-allyl-1,14-dihydroxy-12- [2-(4-hydroxy-3 -methoxycyclohexyl)-1 -methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0]octacos-18-ene-2,3,10,16-tetraone.
[004] 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.
[005] 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.
[006] 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.
[007] 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.

[008] US Patent Application 2002052407, US Patents 6187756 and
6184248 and WO9809523 describe the composition of tacrolimus to be used in neurological disorders and neurogenerative diseases.
[009] EP1092429 describes pharmaceutical compositions and methods
for treating immune response associated disorders.
[010] US Patent Applications 2002173516 and 2002013340 describe
pharmaceutical compositions and methods for treating immune response associated diseases of the surface and the anterior segment of the eye.
[011] EP 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.
[012] Surprisingly it was found that tacrolimus might be used for treating
topical immune therapy (relating to scalp conditions). Hence, various hair adornment care compositions were prepared comprising of immunosuppressants with an aim to treat topical immune disorders (relating to scalp conditions).
[013] Preparations for hair are well known from ages. All hair adornment
compositions aim to maintain the hair in a groomed position. Adornment compositions also provide conditioning, shine, body, and increased manageability. There are four categories of adornment compositions: sprays, shampoos, mousses, and gels. Hair sprays are composed of aerosolized copolymers such as polyvinylpyrrolidone, vinyl acetate etc. they are usually applied following hair styling, but may also function as a setting lotion. Hair gel preparations are similar to spray in composition but are in gel and alcohol-free form. They coat the hair shaft and restore shine.

[014] Hair mousse is foam released under pressure from an aerosolized
can of the same copolymer-containing hair styling aid as for hair gels. Mousses may contain glossening and conditioning agents and can be colored to provide either natural or unnatural highlights. Hair mousses can also be used to create natural appearing fullness more easily than hair gels due to their lower moisture content.
[015] The main ingredients for mousse includes petrolatum, waxes,
lanolin, and vegetable and mineral oils, plasticizers and propellant to enable the release of medicament as foam under pressure from an aerosolized can. These ingredients add shine to hair and moisturize it, aid in straightening of hair and decrease breakage in addition to topical immunotherapy. The formulation may additionally contain colorants 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 formulation can be formulated as hydrophobic or hydrophilic
cream or gel along with addition of propellant.
[017] The petrolatum and waxes are those commonly used in by a skilled
artisan in the cream 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.
[018] Mineral oils commonly used in mousse include fatty acids, fatty
alcohols, metallic stearates, monoalcohol esters, glycol esters, polyethylene glycol and its esters, sorbitran esters, etc.

Summary of the Invention
[019] The present invention describes a pharmaceutical composition for
topical immunotherapy of scalp and scalp conditions. More specifically, the invention relates to a composition comprising immunosuppressants in a pharmaceutically acceptable formulation, precisely suitable hair adornment composition such as hair-mousse. The mousse comprises of petrolatum, waxes, lanolin, and vegetable and mineral oils, plasticizers and propellant to enable the release of medicament-as foam under pressure from an aerosolized can. These ingredients add shine to hair and moisturize it, aid in straightening of hair and decrease breakage in addition to topical immunotherapy.
Detailed Description
[020] Preferably Hair-mousse formulations according to the present
invention comprise of formulations to be delivered from pressurized containers with the use of a suitable propellant as the carrier or excipient. Suitable propellants include 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3,-heptafluoropropane (HFA 227), or a combination of both, or mono-fluoro trichloromethane and dichloro difluoromethane or chloroflurocarbons and derivatives thereof, in particular 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), with HFA 134a being preferred.
[021] A mousse formulation according to the present invention
preferably further comprises a polar cosolvent such as C2-6 aliphatic alcohols and polyols, for example ethanol, isopropanol and propylene glycol, with ethanol being preferred. Preferably, the concentration of the cosolvent is in the range of about 5 to 50% by weight, of the total formulation.
[022] A formulation according to the present invention may further
comprise one or more surfactants. Such surfactants can be included to stabilize the formulations and for lubrication of a valve system. Some of the most commonly used surfactants in mousse formulations are 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.
[023] Preferably therapeutic agent (tacrolimus and functional derivatives thereof) present in mousse formulations according to the present invention is present at a concentration in the range of about 0.1% to 5 % of the total formulation.
[024] The present invention is further illustrated by the following
Examples, which do not limit the scope of the invention in any way.
Examples
[025] Example-I

Sr. No. Ingredients Quantity (%w/w)
I CREAM
1. Tacrolimus 0.1-5%
2. Polyethylene glycol 400 4.00
3. Polysorbate-80 0.80
4. Methyl paraben 0.20
5. Propyl paraben 0.02
6. Disodium edetate 0.10
7. Cetostearyl alcohol 1.50
8. Cetomacrogol 1000 0.50
9. Light liquid paraffin 5.00
10. Dimethicone 1.50
11. Propylene glycol 10.00
12. Triethanolamine q.s. to pH 6.0
13. Purified water q.s. to 90.0

14. Ethanol 5-50 %
15. Polyoxyl hydrogenated castor oil 2-20 %
n PROPELLANT
16. Tetrafluoroethane (HFC-134a) 10.00
[026] Example-II

Sr. No. Ingredients Quantity (%w/w)
I CREAM
1. Cyclosporin 0.1-5%
2. Polyethylene glycol 400 4.00
3. Polysorbate-80 0.80
4. Methyl paraben 0.20
5. Propyl paraben 0.02
6. Disodium edetate 0.10
7. Cetostearyl alcohol 1.50
8. Cetomacrogol 1000 0.50
9. Light liquid paraffin 5.00
10. Dimethicone 1.50
11. Propylene glycol 10.00
12. Triethanolamine q.s. to pH6.0
13. Purified water q.s. to 90.0
14. Ethanol 5-50 %
15. Polyoxyl hydrogenated castor oil 2-20 %
n PROPELLANT
16. Tetrafluoroethane (HFC-134a) 10.00

Claim
1. A pharmaceutical product comprising of immunosupprressants and functional derivatives thereof for use in topical immune disorders related to scalp and scalp conditions.
2. A pharmaceutical formulation according to claim 1, comprises of suitable hair adornment composition.
3. A pharmaceutical product according to any of claims 1 and 2, wherein the hair adornment composition preferably is a hair-mousse 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 immunosuppressants 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 hair-mousse preparation can be a cream, spray, gel, shampoo or as in the form of foam released under pressure from an aerosolized can containing hair-styling preparation.
7. A pharmaceutical product according to any of claims 1 to 6, wherein the Hair-mousse preparation preferably is in the form of foam released under pressure from an aerosolized can containing hair-mousse preparation.
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, surfactants, mineral oils, plasticizers, preservatives and propellant.
9. A pharmaceutical product according to any of claims 1 to 8, which also comprises of colorants, fragrances and antioxidants.

10. A pharmaceutical formulation according to any of claims 1 to 9, 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.
11. A pharmaceutical formulation according to claim 10, wherein said carrier or excipient comprises a propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3,-heptafluoropropane, a combination of 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3,-heptafluoropropane, mono-fluoro trichloromethane and dichloro difluoromethane or chloroflurocarbons and derivatives thereof.
12. A pharmaceutical formulation according to claim 11, wherein said propellant is 1,1,1,2-tetrafluoroethane.
13. A pharmaceutical formulation according to any of claims 8 to 12, 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.
14. A pharmaceutical formulation according to any of claims 8 to 13, wherein said mineral oils may include those commonly used in mousse i.e. fatty acids, fatty alcohols, metallic stearates, monoalcohol esters, glycol esters, polyethylene glycol and its esters, sorbitran esters, and derivatives thereof.
15. A pharmaceutical formulation according to any of claims 8 to 14, wherein said surfactants in mousse 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.
16. A pharmaceutical formulation according to any of claims 8 to 15, wherein said cosolvents comprises of C2-6 aliphatic alcohols and polyols, viz. ethanol, isopropanol and propylene glycol, with ethanol being preferred.

Preferably, the concentration of the cosolvent is in the range of about 5 to 50% by weight, of the total formulation. 17. A process of preparing a pharmaceutical product according to any of claims 1 to 16, which process comprises providing a hair-adornment preparation for the treatment of topical immunotherapy for scalp and scalp conditions.

rth
Dated this the 6m day of February 2003


DR. GOPAKUMAR G. NAIR
Agent for the Applicant GOPAKUMAR NAIR ASSOCIATES
Nair Baug, Akurli Road
Kandivli (East), Mumbai - 400 101