Claims:We claim:
1. A topical pharmaceutical composition of apremilast.
2. A method of treating psoriasis, comprising steps of: administering a topical pharmaceutical composition comprising apremilast or pharmaceutically acceptable salts thereof to a subject prone to psoriasis.
3. A method of treating psoriatic arthritis, comprising steps of: administering a topical pharmaceutical composition comprising apremilast or pharmaceutically acceptable salts thereof to a subject prone to psoriatic arthritis.
4. A topical pharmaceutical composition of claim 1, wherein the topical pharmaceutical composition is a gel.
5. A topical pharmaceutical composition of claim 1, wherein the topical pharmaceutical composition is a cream.
6. A topical pharmaceutical composition of claim 1, wherein the topical pharmaceutical composition is an ointment.
7. A topical pharmaceutical composition of claim 1, wherein the topical pharmaceutical composition is a spray.
8. A topical pharmaceutical composition of claim 1, wherein the topical pharmaceutical composition comprises apremilast and dimethyl sulfoxide (DMSO).
9. The composition of claim 1, wherein said apremilast is present in the range of 1% to 25% by weight.
10. The composition of claim 7, wherein said apremilast to DMSO ratio is between 1:100 to 100:1.
, Description:Field of invention
The present invention provides topical pharmaceutical composition of drugs used for the treatment of psoriasis and/or psoriatic arthritis.

Background of invention
This invention relates to topical pharmaceutical composition of apremilast, a method of use thereof and a method of manufacture.

Apremilast is a phosphodiesterase4 (PDE4) inhibitor. Apremilast is known chemically as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide. Its empirical formula is C22H24N2O7S and the molecular weight is 460.5. It is an inhibitor of phosphodiesterase 4 (PDE4), is indicated for the treatment of psoriatic arthritis.

Use of apremilast containing compositions for oral administration in tablet form is known. However a topical pharmaceutical composition may be suitable for patients who have difficulty in swallowing or whose gastro intestinal side effects are not reduced even after suggested oral dose titration. Swallowing or oral treatment complexities like dose titration or gastric side effects are expected to be lower by administering apremilast in the form of current topical pharmaceutical composition.

Detailed description
The present invention relates to the use of medicines for the treatment of psoriasis or psoriatic arthritis, for preparing pharmaceutical compositions in the form of topical formulations.

Accordingly the present invention provides a topical pharmaceutical composition suitable for topical application, comprising apremilast and/or pharmaceutically acceptable excipients thereof.
It has been surprisingly been found that pharmaceutical compositions in the form of topical formulations of apremilast provide desired pharmacological actions and fewer side effects.

In one embodiment of the invention, apremilast is provided in the pharmaceutical compositions in the form of topical gel.

In another embodiment of the invention, apremilast is provided in the pharmaceutical composition in the form of topical cream or topical ointment.

In yet another embodiment of the invention, apremilast is provided in the pharmaceutical composition in the form of topical solution or topical spray.

In another embodiment of the invention, apremilast is provided in the pharmaceutical composition in the form of topical gel or cream or ointment or solution or spray along with dimethyl sulfoxide.

In an embodiment of the invention, topical gel or cream or ointment or solution or spray comprises excipients that are hydrophilic in nature.

In another embodiment of the invention, topical gel or cream or ointment or solution or spray comprises excipients that are hydrophobic in nature.

In an embodiment of the invention, topical gel or cream or ointment or solution or spray comprises excipients that are hydrophilic and/or hydrophilic in nature.

In yet another embodiment of the invention, topical pharmaceutical composition comprises excipients to provide better feel to the skin.

In another embodiment of the invention, topical pharmaceutical composition comprises excipients to provide better feel to the skin and lower irritation to the skin.

In yet another embodiment of the invention, topical pharmaceutical composition comprises excipients to provide better feel to the skin, lower irritation and low or non-staining to the skin or the clothes.

In one of the embodiment of the invention, topical pharmaceutical composition comprises fragrance.

In an embodiment of the invention, topical composition of present invention has excipients that help deep penetration of apremilast in to the skin and provide ease of application, spreadability and cleaning.

Topical pharmaceutical compositions of the invention include but not limited to cream, ointment, gel, solution or spray.

Topical pharmaceutical compositions of the invention include apremilast in the concentration of 1% to 25% by weight.

Topical pharmaceutical compositions of the invention include apremilast and DMSO in the ration of 1:100 to 100:1 or 1:10 to 10:1 or 1:1.

Topical pharmaceutical compositions of the invention have a pH in the physiological range between 1 to 8 or 2 to 7 or 3 to 6.

Excipients used in the composition are,

Natural polymers: Collagen, gelatin, agar, alginates, tragacanth, pectin, xanthan gum and others.

Semi synthetic polymers: Carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and others.

Synthetic polymers: Carbomers, poloxamer, polyacrylamide, polyvinyl alcohol, polyethylene and others.

Inorganic substances: Aluminum hydroxide, bentonite and others

Surfactants: Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80, sorbitanlaurate, sorbitan oleate, sorbitanstearate, polyoxyethylene stearate, sodium lauryl sulfate, Sebrotearyle alcohol, Brij-96 and others.

Water miscible solvents: Ethanol, propylene glycol, glycerin, polyethylene glycol and others.
Preservatives such as not limited to methylparaben, propylparaben, butyl paraben, Sorbic acid chlorocresol, benzoic acid, benzyl alcohol, phenyl mercuric nitrate, benzalkonium chloride, chlorhexidine and others.

Stabilizers such as not limited to chelating agents.

Anti-oxidants such as but not limited to BHA, BHT, ascorbic acids and others.

In an embodiment of the invention, topical composition of present invention has excipients that help adjusting the pH of the composition. The pH of the topical compositions may be adjusted between from about 3 to about 8 to provide a non-irritating composition. Such agents include many pharmaceutically acceptable acids, bases and buffers. Suitable acids may include one or more of hydrochloric acid, phosphoric acid and lactic acid. Suitable bases may include one or more of diethanolamine, triethanolamine and sodium hydroxide. Suitable buffers may include phosphates, such as monobasic sodium phosphate, dibasic sodium phosphate, lactates and citrates.

Hydrocarbons: Petrolatum, microcrystalline wax, paraffin wax, plastibase (jelene), liquid paraffin, ceresi and others.

Vegetable oils and Animal fat: Coconut oil, bees wax, olive oil, lanolin,peanut oil, spermaceti wax, sesameoil, almond oil and others.

Hydrogenated and Sulphated oils: Hydrogenated castor, cotton seed,soyabeen corn oils, hydrogenated sulphated caster oils and others.

Alcohols, Acids and Esters: Cetyl alcohol, stearic acid, stearylalcohol, oleic acid, oleyl alcohol, palmitic acid, lauryl alcohol, lauraic acid,myristylalcohol, ethyl oleate, isopropylmyristicate, ethylene glycol and others.

Silicones: Dimethylpropylsiloxanes, methylphenyl polysiloxanes, steryl esters of dimethyl polysiloxanes and others.

Example 1
Component % w/w
Ap01 0.5
DMSO 10
PEG 400 5
Propylene glycol 12.9
Carbopol® 941 1.2
pH adjusting agents QS pH 5 to 6
Glycerin QSAD 100

Manufacturing process
a) Weigh approximately 100% of DMSO into a stainless steel vessel. Add propylene glycol and polyethylene glycol 400. Stir with a propeller mixer.
b) While continuing to mix, add Ap01 to Step a). Mix until dissolved.
c) While continuing to mix, add Carbopol® 941 slowly to Step b), avoiding clumping. Mix vigorously at room temperature until a uniform and lump free dispersion is achieved.
d) While continuing to mix, add 80% of glycerin slowly to Step c). Mix the contents at room temperature until a uniform dispersion is achieved.
e) While mixing, add sufficient pH adjusting agent to achieve a pH of 5.0 to 6.0.
f) Add the remaining glycerin to make 100% and mix until uniform.
g) Transfer to a storage vessel and fill.

Example 2
Component % w/w
Ap01 0.5
DMSO 30
PEG 400 5
Propylene glycol 13.3
Carbopol® 941 1.2
pH adjusting agents QS pH 5 to 6
Glycerin QSAD 100

Manufacturing process
a) Weigh approximately 100% of DMSO into a stainless steel vessel. Add propylene glycol and polyethylene glycol 400. Stir with a propeller mixer.
b) While continuing to mix, add Ap01 to Step a). Mix until dissolved.
c) While continuing to mix, add Carbopol® 941 slowly to Step b), avoiding clumping. Mix vigorously at room temperature until a uniform and lump free dispersion is achieved.
d) While continuing to mix, add 80% of glycerin slowly to Step c). Mix the contents at room temperature until a uniform dispersion is achieved.
e) While mixing, add sufficient pH adjusting agent to achieve a pH of 5.0 to 6.0.
f) Add the remaining glycerin to make 100% and mix until uniform.
g) Transfer to a storage vessel and fill.

Example 3
Component % w/w
Ap01 0.5
White Soft Paraffin 90
Liquid Paraffin 7
Sorbitan sesquioleate 0.5
Menthol 1
DMSO 1

Manufacturing Process:
a) Add white soft paraffin and sorbitan sesquioleate into a melting vessel and melt the contents at 75°C.
b) Transfer to Becomix, and mix the contents at 10rpm. Cool the contents to 50°C.
c) Dissolve Ap01 in DMSO in a separate vessel. Disperse this solution in liquid paraffin maintained at 60°C using a water bath. Homogenize the contents using a homogenizer.
h) While mixing, add Step d) to Step c). Mix vigorously at room temperature until a uniform dispersion is achieved.
d) Homogenize the dispersion under vacuum at 0.4-0.6 bar at 10rpm.
e) Transfer to a storage vessel and fill.

Example 4
Component % w/w
Ap01 0.5
Oleyl Alcohol 10
White soft Paraffin 84.7
Hard Paraffin 0.3
Microcrystalline wax 3.5
DMSO 1

Manufacturing Process:
a) Add white soft paraffin and microcrystalline wax into a melting vessel and heat to 70°C to melt. Transfer to Becomix, and maintain at 40°C – 45°C.
b) While mixing, add oleyl alcohol to the base obtained in Step a) and maintain at 40°C – 45°C.
c) Dissolve the drug in DMSO and add to the melt obtained in Step b). Homogenize for 5 minutes.
d) Allow to cool to 30°C and transfer to storage vessel and fill.

Example 5
Component % w/w
Ap01 0.5
Methyl Paraben 0.025
Propyl Paraben 0.015
Sodium Lauryl Sulphate 1
DMSO 1
Propylene Glycol 12
Stearyl alcohol 25
White Petrolatum 25
Water 36
Manufacturing Process:
a) Add stearyl alcohol and white petrolatum on a steam bath into a melting vessel and warm to about 75°C.
b) Dissolve Ap01 in DMSO and dissolve other ingredients in purified water. Warm to about 75°C.
c) Mix all ingredients together and stir until the mixture congeals.
d) Transfer to a storage vessel and fill.

Example 6
Component % w/w
Ap01 0.5
White wax 12
Cetyl esters wax 12
Mineral Oil 40
DMSO 15
Sodium Borate 0.5
Water 20

Manufacturing Process:
a) Add white wax and cetyl ester wax into a melting vessel and melt the components at 70°C.
b) Add mineral oil to the mix obtained in Step a) and mix until uniform.
c) Dissolve Ap01 in DMSO and add to the mix obtained in Step b).
d) Transfer water and sodium borate to the mix of Step c).
e) While mixing, slowly add water phase to the oil phase.
f) Transfer to a storage vessel and fill.

Example 7
Component % w/w
Ap01 0.5
Propylene Glycol 48.025
Glyceryl Monostearate 5
Cetostearyl alcohol 4
White wax 0.6
Chlorocresol 0.075
Water 40
DMSO 1

Manufacturing Process:
a) Add white wax, cetostearyl alcohol, and Glyceryl monostearate into a melting vessel and mix continuously while heating to 75°C. Add DMSO and mix until uniform.
b) Add Ap01 to the mix obtained in Step a) and maintain the temperature at 75°C.
c) Add water and propylene glycol into a melting vessel and heat the contents to 61-65°C.
d) Add chloro cresol to the water phase and mix until uniform.
e) Slowly add water phase to the oil phase with continuous stirring.
f) Transfer to a storage vessel and fill.