Claims:We claim:
1. A topical pharmaceutical composition, comprising at least two active ingredients selected from the group consisting of methotrexate, acitretin and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient.
2. The topical pharmaceutical composition, according to claim 1, wherein it comprises methotrexate and acitretin or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient.
3. The topical pharmaceutical composition, according to claim 1, wherein it comprises methotrexate and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient.
4. The topical pharmaceutical composition, according to claim 1, wherein it comprises acitretin and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient.
5. The topical pharmaceutical composition, according to claim 1, wherein it comprises methotrexate, acitretin and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient.
6. The topical pharmaceutical composition, according to claim 1, wherein it is in the pharmaceutical form of a solution, gel, hydrogel, cream, cream-gel lotion, suspension, emulsion, ointment, spray, foam, paste, patch, liposome, ethosome, niosome, solid lipid nanoparticles or any combination thereof.
7. The topical pharmaceutical composition, according to claim 1, wherein it is in the pharmaceutical form of a liposome.
8. The topical pharmaceutical composition, according to claim 1, wherein it comprising a penetration enhancer.
9. The topical pharmaceutical composition, according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of acidifying agents, alkalinizing agents, antioxidant agents, chelating agents, preservative agents, wetting agents, emulsifying agents, surfactant agents, aqueous vehicles and oily vehicles.
10. The topical pharmaceutical composition, according to claim 1, wherein
(i) methotrexate is at a concentration from 0 to 50% by total weight of the composition;
(ii) acitretin is at a concentration from 0 to 50% by total weight of the composition;
(iii) cyclosporine is at a concentration from 0 to 50% by total weight of the composition.
11. A method of preparation of a topical pharmaceutical composition, comprising at least two active ingredients selected from the group consisting of methotrexate, acitretin and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient.
12. The topical pharmaceutical composition, according to claim 1, wherein it is used in the treatment of psoriasis, atopic dermatitis or chronic eczemas, optionally either alone or in combination with other systemic or topic treatments.
13. The topical pharmaceutical composition, according to claim 1, wherein it is used in the treatment of psoriasis, optionally either alone or in combination with other systemic or topic treatments.
, Description:TOPICAL PHARMACEUTICAL COMPOSITIONS

FIELD OF THE INVENTION
The present invention relates to a topical pharmaceutical composition comprising a combination of two or more orally or systemically administered active ingredients e.g. methotrexate, acitretin and cyclosporine; a process for producing the same and the use of the composition in the treatment of psoriasis (e.g. psoriasis vulgaris), atopic dermatitis and chronic eczema. The composition of this invention can be used alone or in combination with other topical or systemic therapies. The present invention further discloses a process for producing the topical pharmaceutical composition.

BACKGROUND OF THE INVENTION
Psoriasis is a quite common chronic, non-contagious skin disorder, autoimmune dermatitis, characterized by hyperproliferation of skin cells. It appears in many different forms and can affect any part of the body. The etiology of psoriasis is unknown, and emotional phenomena are often related to its emergence or aggravation, probably acting as triggering factors of a genetic predisposition to the disease.

Over the years a wide variety of topical and systemic treatment methods that inhibit the inflammation, cell proliferation, or cell differentiation have been developed. Treatment of psoriasis remains a challenge because of its chronic recurrent nature. Various types of temporary reliefs are available and their effectiveness varies among patients. Topical and systemic treatments, or a combination thereof, are currently used for treating plaque psoriasis. Among the systemic treatments, there can be cited the use of biological products administered parenterally (e.g. Humira®, Remicade®, Enbrel®) and the use of active ingredients, such as methotrexate, cyclosporine and acitretin administered orally.

These treatments are not effective for a definitive cure, only an improvement during treatment being observed. Biological products currently available on the market are very expensive and invasive, whose application can only be made in an ambulatory environment, leading to a scarcely accessible and low adherence treatment.

Oral treatments are mostly toxic to the patient and only show improvements during the treatment period. Oral or systemic administration of active ingredients used for treatment of psoriasis is indented to deliver the medicament to an affected, local area of a living subject, particularly skin, using a systemic route is problematic because of many severe, sometimes life threatening, side effects associated with systemic delivery.

Even though local treatment is the most ideal option for treating psoriasis, very few options are available for topical use. Further the existing topical formulations have own disadvantages.

The mostly used topical treatments are products containing highly potent corticosteroids or calcipotriol (synthetic derivative of vitamin D) such treatments being, however, only palliative. Calcipotriol is very weak and only presents improvements in mild cases. Also, the prolonged or continuous use of topic corticosteroids on the same area causes thinning of the epidermis and alterations in the dermis. In most cases, the process is reversible with discontinuation of use, but the skin may take months to return to its normal state. These treatment methods have proven to be of limited value due to disadvantages such as cosmetic liabilities, severe side effects, high cost, and minimal or short-term efficacy.

There is a need to develop a formulation which will overcome the drawbacks of the existing therapy.

Acitretin, a metabolite of etretinate, is available as an oral capsule dosage form and is indicated for the treatment of severe psoriasis. It is all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid. It is related to both retinoic acid and retinol (vitamin A). It is a yellow to greenish-yellow powder with a molecular weight of 326.44. The structural formula is:

Acitretin is an oral retinoid used in the treatment of severe resistant psoriasis. Because of the potential for problems and severe side effects it is generally used in only very severe cases of psoriasis that have been unresponsive to other treatments.

Acitretin is readily absorbed and widely distributed after oral administration but the therapeutic effect occurs after 2 to 4 weeks or longer. It induces keratinocyte differentiation and reduces epidermal hyperplasia, leading to the slowing of cell reproduction. It binds to nuclear receptors that regulate gene transcription. Because of significant adverse effects associated with its use, acitretin should be prescribed only by those knowledgeable in the systemic use of retinoids. Further the combination of methotrexate with acitretin is also contraindicated due to chance of an increased risk of hepatitis.

Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea. Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic-(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-a -amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl). It is approved in form of capsule, injection, oral solution, injection and ophthalmic emulsion. Injection is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants whereas oral dosage is indicated for the prophylaxis of organ rejection and for the treatment of rheumatoid and psoriasis. The ophthalmic emulsion is used for the treatment of dry eyes and as a treatment for persistent nummular keratitis following adenoviral keratoconjunctivitis.

Following oral administration, absorption of cyclosporine is incomplete. The extent of absorption of cyclosporine is dependent on the individual patient, the patient population, and the formulation. Further, cyclosporine can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine, and therefore, renal function must be monitored during therapy.

Methotrexate is an antimetabolite and an analogue of folic acid, used in the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. It is usually administered orally, but it can also be administered intramuscularly, intravenously and intrathecally. Chemically, methotrexate is N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid.

The structural formula is:

Methotrexate acts on the S-phase of the cell cycle in tissues with a high cellular proliferation rate such as neoplastic tissue, bone marrow, epithelial cells or foetal cells seem to be the most susceptible. Methotrexate is used for this reason in the treatment of psoriasis, where the rate of production of epithelial cells of the skin is much higher than that of normal cells.

Methotrexate may be of value in the symptomatic control of severe, recalcitrant, disabling psoriasis, which is not adequately responsive to other forms of treatment. However, due to the high risk associated with its use, Methotrexate should be used after the diagnosis has been definitely established, as by biopsy and/or after dermatologic consultation. In the treatment of psoriasis, Methotrexate is contraindicated in pregnant women and in patients with poor nutritional status, severe hepatic disorders or in those with pre-existing blood dyscrasias (such as bone marrow hypoplasia, leucopenia, thrombocytopenia or anaemia).

Use of a combination treatment incorporating two or more different pharmacologically active compounds to treat psoriasis is the most effective way of treatment. Use of combination of corticosteroids and calcipotriol as topical formulation is known. Also there are documents that describe the use of orally or systemically administered active ingredients in topical compositions for treating psoriasis is known. But use of combination of two or more orally or systemically administered active ingredients in topical dosage form to treat psoriasis is not know in the prior art. Using a combination of two or more active ingredients in topical form reduces the adverse effects of orally or systemic administered active ingredients and shows good therapeutic efficacy due to local delivery of the active ingredients.

Regarding the treatment of psoriasis, atopic dermatitis or chronic eczema, and diseases that affect the skin, it is of utmost importance that active principles, when applied topically, have greater concentration in the epidermis and, in some cases, such as in the use of active principles which have toxic adverse effects (methotrexate), it is very important that permeation is effective only at the epidermis level, and does not reach deeper layers of the dermis. Therefore, in accordance with this invention, the researchers developed a topical pharmaceutical composition containing the combination of two or more orally or systemically administered active ingredients e.g. methotrexate, acitretin and cyclosporine, in which active ingredients are able to permeate through the skin and reach the epidermis showing effectiveness, but virtually without systemic absorption, eliminating nearly all observed adverse effects of its systemic use.

In face of the above scenario, available psoriasis treatments on the market, including topical ones, are not effective for a definitive cure, and prolonged use of some active principles has remarkable undesirable side effects. Thus, searching for new effective treatments for psoriasis, atopic dermatitis or chronic eczemas, the inventors developed a stable topical formulation, which presents a suitable profile of security and ease of administration, containing a combination of two or more orally or systemically administered active ingredients used for the treatment of psoriasis atopic dermatitis or chronic eczemas.

SUMMARY OF THE INVENTION
The present invention aims at providing a topical pharmaceutical composition comprising a combination of two or more orally or systemically administered active ingredients e.g. methotrexate, acitretin and cyclosporine; and its use for treating inflammatory skin processes, more specifically for treating psoriasis (e.g. psoriasis vulgaris), atopic dermatitis and chronic eczemas.

An object of the invention is to provide a topical pharmaceutical composition for dermal use, where the composition comprises a combination of two or more orally or systemically administered active ingredients used for the treatment of psoriasis. The provision of the composition will result in a substantial improvement in quality of life for a large population of psoriasis patients.

Another object of the invention is a topical pharmaceutical composition, comprising at least two active ingredients selected from the group consisting of methotrexate, acitretin and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient. The topical pharmaceutical composition comprises either (a) a combination of methotrexate and acitretin or their pharmaceutically acceptable salts thereof, (b) a combination of methotrexate and cyclosporine or their pharmaceutically acceptable salts thereof, (c) a combination of acitretin and cyclosporine or their pharmaceutically acceptable salts thereof or (d) a combination of methotrexate, acitretin and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient.

Another object of the invention is a topical pharmaceutical composition comprising a combination of two or more orally or systemically administered active ingredients used for the treatment of psoriasis, wherein the pharmaceutical composition is in form of a solution, gel, hydrogel, cream, cream-gel lotion, suspension, emulsion, ointment, spray, foam, paste, patch, liposome, ethosome, niosome, solid lipid nanoparticles or any combination thereof.

Another object of the invention is a topical pharmaceutical composition, comprising at least two active ingredients selected from the group consisting of methotrexate, acitretin and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in form of a solution, gel, hydrogel, cream, cream-gel lotion, suspension, emulsion, ointment, spray, foam, paste, patch, liposome, ethosome, niosome, solid lipid nanoparticles or any combination thereof.

Another object of the invention is the pharmaceutically acceptable excipient used in the topical dosage form of the invention is selected from the group consisting of acidifying agents, alkalinizing agents, antioxidant agents, chelating agents, preservative agents, wetting agents, emulsifying agents, surfactant agents, aqueous vehicles and oily vehicles.

Another object of the invention is the topical composition of the invention comprising one or more of (a) an aqueous phase consisting of 0.01 to 0.5% of an antioxidant agent; 0.01 to 1.0% of a chelating agent; 1 to 20% of a wetting agent; and 55 to 90% of aqueous vehicle; by total weight of the composition, and may optionally contain 0.5 to 3.0% of acidifying agent; 0.1 to 2.0% of alkalinizing agent; and 0.1 to 1.5% of preservative agent; by total weight of the composition, and (b) an oily phase consisting of 5 to 20% of an emulsifying agent; 0.5 to 5% of a surfactant agent; and 1.0 to 10.0% of an oily vehicle; by total weight of the composition.

Another object of the invention is a topical pharmaceutical composition of the invention also a penetration enhancer. The penetration enhancer is selected from the group from consisting of sulfoxides such as dimethylsulfoxide (DMSO) and the like; cyclic amides such as 1-dodecylazacycloheptane-2-one (Azone™, a registered trademark of Nelson Research, Inc.) and the like; amides such as N,N-dimethyl acetamide (DMA) N,N-diethyl toluamide, N,N-dimethyl formamide, N,N-dimethyl octamide, N,N-dimethyl decamide, and the like; pyrrolidone derivatives such as N-methyl-2-pyrrolidone, 2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, N-(2-hydroxyethyl)-2-pyrrolidone or fatty acid esters thereof, 1-lauryl-4-methoxycarbonyl-2-pyrrolidone, N-tallowalkylpyrrolidones, and the like; polyols such as propylene glycol, ethylene glycol, polyethylene glycol, dipropylene glycol, glycerol, hexanetriol, and the like; linear and branched fatty acids such as oleic, linoleic, lauric, valeric, heptanoic, caproic, myristic, isovaleric, neopentanoic, trimethyl hexanoic, isostearic, and the like; alcohols such as ethanol, propanol, butanol, octanol, oleyl, stearyl, linoleyl, and the like; anionic surfactants such as sodium laurate, sodium lauryl sulfate, and the like; cationic surfactants such as benzalkonium chloride, dodecyltrimethylammonium chloride, cetyl trimethylammonium bromide, and the like; non-ionic surfactants such as the propoxylated polyoxyethylene ethers, e.g., Poloxamer 231, Poloxamer 182, Poloxamer 184, and the like, the ethoxylated fatty acids, e.g., Tween 20, Myrj 45, and the like, the sorbitan derivatives, e.g., Tween 40, Tween 60, Tween 80, Span 60, and the like, the ethoxylated alcohols, e.g., polyoxyethylene (4) lauryl ether (Brij 30), polyoxyethylene (2) oleyl ether (Brij 93), and the like, lecithin and lecithin derivatives, and the like; the terpenes such as D-limonene, a-pinene, ß-carene, a-terpineol, carvol, carvone, menthone, limonene oxide, a-pinene oxide, eucalyptus oil, and the like.

Another object of the invention is a topical pharmaceutical composition comprises
a) methotrexate is at a concentration from 0 to 50% by total weight of the composition;
b) acitretin is at a concentration from 0 to 50% by total weight of the composition;
c) cyclosporine is at a concentration from 0 to 50% by total weight of the composition.

Another object of the present invention is a method of preparation of a topical pharmaceutical composition, comprising at least two active ingredients selected from the group consisting of methotrexate, acitretin and cyclosporine or their pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable excipient.

Another object of the present invention is use of topical pharmaceutical composition of the invention in the treatment of psoriasis, atopic dermatitis or chronic eczemas, optionally either alone or in combination with other systemic or topic treatments. The topical pharmaceutical composition is used in the treatment of psoriasis, optionally either alone or in combination with other systemic or topic treatments.

DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a topical pharmaceutical composition comprising a combination of two or more orally or systemically administered active ingredients e.g. methotrexate, acitretin and cyclosporine and a pharmaceutically acceptable excipient. The topical composition is used for treating inflammatory skin processes, more specifically for treating psoriasis (e.g. psoriasis vulgaris), atopic dermatitis and chronic eczemas.

The cyclosporine comprised in the composition of the present invention can be used in a range from 0.1% to 50% of the total weight of the composition, being preferably present at 1% of the total weight of the composition.

The acitretin comprised in the composition of the present invention can be used in a range from 0.1% to 50% of the total weight of the composition, being preferably present at 2% of the total weight of the composition.

According to the present invention, the methotrexate comprised in the composition can be in the form of free base or pharmaceutically acceptable salts or hydrates thereof, the mono-hydrated form of methotrexate being preferentially used.

The methotrexate comprised in the composition may be used in a range from 0.05% to 50% of the total weight of the composition, being preferably present at about 0.1% to 5% of the total weight of the composition.

The pharmaceutically acceptable excipients comprised in the composition of the present invention include, but are not limited to, an acidifier agent, an alkalinizing agent, an antioxidant agent, a chelating agent, a preservative agent, a wetting agent, an emulsifying agent, a surfactant agent, an aqueous vehicle and an oily vehicle.

Examples of acidifying agents include, but are not limited to, lactic acid, citric acid, hydrochloric acid, phosphoric acid, citric acid, tartaric acid, propionic acid and glycolic acid. The acidifying agent may be present from about 0.05% to about 3.0% of the total weight of the composition. Preferably, the acidifying agent is lactic acid and is present from 0.1% to 2% of the total weight of the composition.

Examples of alkalinizing agents include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium phosphate, ammonia solution, sodium borate, sodium carbonate, diethanolamine, triethanolamine and monoethanolamine. The alkalinizing agent may be present from 0.1% to 2.0% of the total weight of the composition. Preferably, the alkalinizing agent is sodium hydroxide and is present from 0.1% to 1% of the total weight of the composition.

Examples of antioxidant agents include, but are not limited to, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), ascorbyl palmitate, alpha-tocopherol (vitamin E), and mixtures thereof. The antioxidant agent may be present from 0.01% to 0.5% of the total weight of the composition. Preferably, the oxidizing agent is butyl hydroxyanisole (BHA) and is present from 0.01% to 0.03% of the total weight of the composition.

Examples of Chelating agents include, but are not limited to, edetate disodium dihydrate (disodium EDTA dihydrate), disodium edetate (disodium EDTA), edetic acid (EDTA), calcium disodium edetate dihydrate, potassium edetate, sodium edetate, trisodium edetate and mixtures thereof. The chelant agent may be present from 0.01 to 1.0% of the total weight of the composition. Preferably, the chelant agent is edetate disodium dihydrate (disodium EDTA dihydrate) and is present from 0.08% to 0.16% of the total weight of the composition.

Examples of preservative agents include, but are not limited to, phenylpropanol, bronopol, butylparaben, ethylparaben, imidazolidinyl urea, methylparaben, benzyl alcohol, benzoic acid, chlorphenesin, sorbic acid, phenoxyethanol and mixtures thereof. The preservative agent may be present from 0.001% to 2.0% of the total weight of the composition. Preferably, the preservative agent is phenylpropanol and is present in the range from 0.2% to 0.5% of the total weight of the composition.

Examples of wetting agent include, but are not limited to, glycerol (glycerin), propylene glycol, sorbitol, trehalose, triacetin, cyclomethicone and mixtures thereof. The wetting agent may be present in the composition from 1% to 20% of the total weight of the composition. Preferably, the wetting agent is glycerin and is present from 8% to 12% of the total weight of the composition.

Examples of emulsifying agents include, without limitation, cetostearyl alcohol, stearyl alcohol, cetyl alcohol, carbomer (acrylic acid polymer), poloxalene (poloxamer), self-emulsifying wax, polyethylene glycol stearate, ethylene glycol distearate, polyethylene glycol distearate, diethylene glycol monostearate, ethylene glycol monostearate, glyceryl monostearate, self-emulsifying glyceryl monostearate and mixtures thereof. The emulsifying agent may be present from about 5% to about 40% of the total weight of the composition. Preferably, the emulsifying agent is the mixture of cetostearyl alcohol and polyethylene glycol stearate and is preferably present in a range from 10 to 20% of the total weight of the composition.

Examples of surfactant agents include, but are not limited to, sorbitan monostearate, sorbitan tristearate, sorbitan stearate, sorbitan diisostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate, sodium lauryl sulfate, polysorbate, sodium docusate and mixtures thereof. The surfactant agent may be present in the range from 0.5% to 5% of the total weight of the composition. Preferably, the surfactant agent is the mixture of sorbitan monostearate and polysorbate, and is present in the range from 0.5% to 3% of the total weight of the composition.

Examples of oily vehicles include, but are not limited to, liquid petrolatum (liquid paraffin or mineral oil), olive oil, castor oil, corn oil, cottonseed oil, peanut oil, sesame oil, soybean oil, canola oil, polyethylene glycol, ethyl oleate, isopropyl myristate, isopropyl palmitate, medium chain triglycerides or mixtures thereof. The oily vehicle may be present in the range from 1% to 10% of the total weight of the composition. Preferably, the oily vehicle is liquid petrolatum and is present in the range from 1.5% to 3% of the total weight of the composition.

Suitable gelling agents, that may be employed, in the topical pharmaceutical composition include, but are not limited to, xanthan gum, sodium alginate (Manugel DMB), Carbopol.RTM. ETD 2020, polycarbophil, polysaccharides, natural gums, acacia, tragacanth, starch, cellulose derivatives such as carboxy methyl cellulose, hydroxyl propyl methyl cellulose, hydroxypropyl methylcellulose (Methocel K4 M), methacrylate polymers, polyvinyl pyrrolidone, bentonite, alginic acid, carbomer, ethyl cellulose, gelatin, guar gum, hydroxyl ethyl cellulose, hydroxyl propyl cellulose, hydroxyethyl methylcellulose, glyceryl behenate, algae extracts, gums, polysaccharides, polyethylene oxide, poloxamer, pectins, hydrolysed proteins, polymers comprising pendant carboxylic acid groups, or esters thereof, polymers comprising pendant anhydrides of dicarboxylic acid groups and block co-polymers based on ethylene oxide and/or propylene oxide and the like or mixtures thereof. Preferably, the one or more gelling agent may be present in an amount ranging from about 0.05% to about 10% by weight of the total composition.

Bioadhesives or polymers that may be used in the topical pharmaceutical composition, include, but are not limited to hydroxyethyl cellulose, gelatin, carbopol, polycarbophil, cross-linked polymethacrylic acid, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene glycol, polysaccharide hyaluronic, polyvinylpyrrolidone, sodium alginate, sodium carboxymethylcellulose, methyl cellulose, starch and the like or combinations thereof. Suitable humectants and/or emollients provide smoothness and lubricity which in turn facilitate the filling and dispensing of the topical pharmaceutical composition.

Emollients that may be used in the topical pharmaceutical composition, include, but are not limited to, polyhydric alcohols such as glycols, and polysaccharides, such as glycerin, ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, dipropylene glycol, diglycerin, sorbitol, malvitol, trehalose, raffmose, xylitol, mannitol, polyethylene glycol, propylene glycol, polyglycerin, cholesterol, squaline, fatty acids, octyldodecanol, myristyl alcohol, urea, lanolin, lactic acid, esters such as isopropyl stearate, isopropyl myristate, isopropyl palmitate and isopropyl laurate and the like or combinations thereof. Preferably, the emollients may be present in an amount ranging from about 2% to about 20% by weight of the total composition.

Viscosity modifiers or regulators improve the formation of a gel. Suitable viscosity modifiers or regulators that may be used in the topical pharmaceutical composition, include, but are not limited to, polyolefins, polyethylenes, polypropylenes, polyalphaolefins, ethylene-propylene copolymers, maleneated derivatives of the materials herein, polyisobutylenes, maleic anhydride and their diene derivatives, polymethacrylates, maleic anhydride-styrene copolymers and esters and their diene derivatives, hydrogenated copolymers of styrene-butadiene, ethylene-propylene copolymers, polyisobutenes, hydrogenated styrene-isoprene polymers, hydrogenated isoprene polymers, polymethacrylates, polyacrylates, polyalkyl styrenes, alkenyl aryl conjugated diene copolymers, polyolefins, esters of maleic anhydride-styrene copolymers, ethylene-propylene copolymers functionalized with the reaction product of maleic anhydride and an amine, polymethacrylate functionalized with an amine, styrene-maleic anhydride copolymers reacted with an amine, polymethacrylate polymers, esterified polymers, esterified polymers of a vinyl aromatic monomer and an unsaturated carboxylic acid or derivative thereof, olefin copolymers, ethylene-propylene copolymer, polyisobutylene and the like or combinations thereof.
Suitable tonicity modifiers or osmolar agents to match the osmolality (mosm) of the physiological fluids include, but are not limited to, glycerine, sodium chloride, potassium chloride, mannitol, sucrose, lactose, fructose, maltose, dextrose, dextrose anhydrous, propylene glycol, glycerol and the like or combinations thereof.

According to the present invention, the aqueous vehicle is water and may be present in the composition in the range from 45% to 90% or more specifically in an amount sufficient to 100% (q.s.) of the total weight of the composition.

Suitable solvents/co-solvents, solubilizers or vehicles, that may be employed, in the topical pharmaceutical composition include, but are not limited to, water, glycerine, coconut fatty acid diethanolamide, medium and/or long chain fatty acids or glycerides, monoglycerides, diglycerides, triglycerides, structured triglycerides, soyabean oil, peanut oil, corn oil, corn oil mono glycerides, corn oil di glycerides, corn oil triglycerides, polyethylene glycol, caprylocaproyl macroglycerides, caproyl 90, propylene glycol, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, castor oil, cottonseed oil, olive oil, safflower oil, peppermint oil, coconut oil, palm seed oil, beeswax, oleic acid, methanol, ethanol, isopropyl alcohol, butanol, acetone, methylisobutyl ketone, methylethyl ketone or mixtures thereof. Preferably, the one or more solvent may be present in an amount ranging from about 0.05% to about 20% by weight of the total composition.

In another aspect of the present invention the topical pharmaceutical composition may also be in the form of a nanoemulsion. Nanoemulsions are emulsions with mean droplet diameters ranging from 50 to 1000 nm and the droplet size between 100 and 500 nm. The particles can exist as water-in-oil and oil-in-water forms. Nanoemulsions can be obtained by any of the processes such as, but not limited, to high pressure homogenization, phase inversion temperature technique and microfluidization. The nanoemulsions may comprise suitable excipients that may be used for formulating the nanoemulsions, such as, but not limited to oils, emulsifiers, antioxidants, tonicity modifiers, pH adjusting agents and preservatives.

In another aspect of this invention, the topical formulation is an oil/water emulsion, in a ratio of 10/90 to 45/55 by weight. Preferably, the composition of this invention is an oil/water emulsion at a ratio of 15/85 to 35/65, comprising 0.05% to 50% of methotrexate, 0.1 to 50% of acitretin, from 0.1 to 50% of cyclosporine and pharmaceutically acceptable excipients.

According to the present invention, the topical composition in the form of oil/water emulsion consists of an oily phase and an aqueous phase. The oily phase of the composition can be comprised by, but is not limited to, the following excipients: emulsifying agent, surfactant agent and oily vehicle. The formulation can also be an emulgel in which aqueous phase is a gel.

The aqueous phase composition can be composed by, but is not limited to, the following excipients: antioxidant agent, chelant agent, wetting agent and aqueous vehicle, and it can further contain an acidifying agent, alkalizing agents and a preservative agent.

In a more preferred aspect, the aqueous phase of the composition consists of 0.01 to 0.5% of an antioxidant agent; 0.01 to 1.0% of a chelating agent; 1 to 20% of wetting agent; and 45 to 90% of aqueous vehicle, by total weight of the composition. Additionally, 0.5 to 3.0% of acidifying agent; 0.1 to 2.0% of alkalinizing agent; and 0.1 to 1.5% of preservative agent, by total weight of the composition, may be added to the aqueous phase.

In a more preferable aspect, the oily phase of the composition consists of 5 to 20% of emulsifying agent; 0.5 to 5% of surfactant agent; and 1.0 to 10.0% of oily vehicle; by total weight of the composition.

According to this invention, the topical pharmaceutical composition comprising a combination of at least two active ingredients selected from the group consisting of methotrexate, acitretin and cyclosporine is used for treating inflammatory skin processes, more specifically for treating psoriasis (e.g. psoriasis vulgaris), atopic dermatitis and chronic eczemas. And this composition can be used alone or in combination with other topical or systemic therapies.

Another important feature of the present invention relates to the fact that the methotrexate present in the topical composition has quick skin permeation and, after 24 hours, methotrexate residues are not detected anymore on the skin in the depths of interest.

Another important aspect of the present invention refers to the process for producing a topical composition in the form of an oil/water emulsion, which comprises the steps of:
(a) Preparation of the oily phase, which comprises: (i) mixing the oily phase compounds; and (ii) heating the mixture to 60-75ºC under constant stirring, until complete fusion of the compounds; (b) Preparation of the aqueous phase, which comprises: (i) mixing the aqueous phase compounds; and (ii) heating the mixture to 60-75ºC, under constant stirring; (c) Incorporation of acitretin and cyclosporine to the oily phase; (d) Cream formation, which comprises: (i) incorporating step "b" in step "a", and (ii) cooling the mass to 35-45ºC, under constant stirring; and (e) Incorporation of methotrexate under constant stirring.

In another aspect of the present invention the topical pharmaceutical composition may also be in the form of a nanosuspension. Nanosuspensions are very finely colloidal, biphasic dispersed solid drug particles in an aqueous vehicle, size below 1 µm.

In another aspect of the present invention, the topical pharmaceutical composition may also be in the form of solid lipid nanoparticles.

In another aspect of the present invention, the topical pharmaceutical composition may also comprise micelles. A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. When surfactants are present above the CMC (Critical micelle concentration), they can act as emulsifiers that will allow a compound that is normally insoluble (in the solvent being used) to dissolve.

In another aspect of the invention the topical pharmaceutical composition may also be in the form liposomes. Liposomes are microscopic vesicles in which a variety of drugs can be incorporated to form a non-toxic and biodegradable formulation because of the similarity of the primary components of liposomes with natural membranes. It allows high cellular penetration, efficient targeting of macrophage-rich tissues and a marked improvement in drug pharmacokinetics.

Liposomes are small vesicles comprising amphipathic lipids arranged in spherical bilayer. Liposomes may contain many concentric lipid bilayers separated by aqueous channels (multilamellar vesicles or MLVs), or alternatively, they may contain a single membrane bilayer (unilamellar vesicles), which may be small unilamellar vesicles (SUVs) or large unilamellar vesicles (LUVs). The lipid bilayer is composed of two lipid monolayers having a hydrophobic "tail" region and a hydrophilic "head" region. In the membrane bilayer, the hydrophobic "tails" of the lipid monolayers orient towards the center of the bilayer, whereas the hydrophilic "heads" orient toward the aqueous phase.

In another aspect of the invention, it is provided topical compositions containing lamellar bilayer vesicles comprised of glycerophospholipids, stratum corneum type lipids and a combination of two or more orally or systemically administered active ingredients e.g. methotrexate, acitretin and cyclosporine or their pharmaceutically acceptable salts thereof.

Preferably the bilayer vesicles are unilamellar, oligolamellar or multilamellar, more preferably multilamellar vesicles. Preferably the vesicles are comprised of glycerophospholipids from natural or synthetic sources. Preferably the natural glycerophospholipids are chosen from egg or soy lecithin, and more preferably from soy lecithin. Preferably the glycerophospholipids are chosen from one or more of phosphatidylcholine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidic acid, phosphatidylethanolamine. More preferably the glycerophospholipid is chosen from phosphatidylcholine, and more preferably a phosphatidylcholine with side chains comprised of 10 to 18 carbon atoms and even more preferably with saturated side chains. Preferably the glycerophospholipids are present in the final topical composition at a concentration of about 1% to about 4%, and more preferably between 1.5 and 2.5%.

Preferably the stratum corneum type lipids are present in the final topical composition at a concentration of about 0.001 % to about 0.10%. Preferably, the stratum corneum lipids are chosen from cholesterol and its derivatives, ceramides, sphingomyelin, long chain fatty acids such as stearic, palmitic and myristic acid.

Preferably the active ingredients are present in the composition at a concentration of about 0.1 % to about 50%, more preferably 0.5 to 10% (all weights given herein are by percentages unless otherwise specified).

The final compositions of the invention may further include from about 0.5 to 3% ethyl alcohol; from about 1 % to about 10% of a humectant; from about 1 % to about 5% of an emollient; from about 1 % to about 5% of a viscosity promoting agent; from about 0.1 % to about 2% of an alkalizing agent; from about 0.05 to about 0.25% of an antioxidant; from about 0.1 % to about 2% of a preservative.

According to another aspect of the invention there is provided processes for preparing liposome concentrate compositions that are easily dispersed into conventional topical hydrophilic base compositions. Although any method and material similar to those described herein can be used in the practice for testing of the present invention, the preferred methods and materials are described.

According to a preferred aspect of the invention the entire processing operation is conducted under nitrogen blanketing.

The batch sizes for the liposome concentrate phase of the operation are preferably in the range of about 5 to 40% of the final topical composition, more preferably in the range of about 15 to about 25% percent.

Alcohol, glycerophospholipid, other stratum corneum type lipids and one or more phenolic anti-inflammatory agents are stirred until dissolved in a suitable container. In a separate container purified water is added in small portions to the alcohol phase with continuous stirring. When transition temperatures (TC) of the glycerophospholipids exceed room temperatures, both alcohol and aqueous phases are preheated to temperatures several degrees above TC. The water phase is initially added slowly and immediately following a thickening and then thinning phase of the stirred dispersion, the water phase can be added at a more rapid rate. In the event of excessive precipitation problems occurring during the concentrate preparation, a suitable portion of the contributing bioactive agent(s) must be removed from the batch and incorporated in the base cream phase with special attention to its oil/water solubility characteristics and inclusion if necessary of appropriate oil-solubilizing ingredients. The end result for the liposome concentrate composition is a homogeneous milky emulsion which is stored under nitrogen blanketing in well-sealed containers until required.

According to one embodiment of the present invention the topical pharmaceutical composition may comprise actives in a nanosize range.
Nanosizing leads to increase in the exposure of surface area of particles leading to an increase in the rate of dissolution. The nanoparticles of the present invention can be obtained by any process such as, but not limited to milling, precipitation, homogenization, spray-freeze drying, supercritical fluid technology, PRINT (Particle replication in non-wetting templates), capillary aerosol generator, ultrasonication and spray drying.

The following examples are presented to more fully illustrate the preferred embodiments of the invention. These examples should in no way be construed as limiting the scope of the invention, as defined by the appended claims.

EXAMPLES:
1. Topical Solution: 1gm methotrexate, 1 gm acitretin, 1 gm cyclosporine is dissolved in 50 ml of ethanol while stirring on a magnetic stirrer. This solution is added to 50 ml distilled water while stirring. After the dispersion is achieved, the solution is stored in amber color vials to obtain the final formulation.

2. Topical ointment: A mixture of 450 gm of white beeswax and 50 gm of lanolin is melted in a stainless steel container containing Teflon coated magnetic bead on a magnetic stirrer/heater to 60° C while stirring. 5 gm of methotrexate, 5 gm of acitretin and 5 gm of cyclosporine is added to this molten ointment base and mixed well to dissolve the drugs thoroughly in the base. After dissolution, slowly the ointment is cooled while stirring. The ointment is obtained at the end of cooling.

3. Topical Cream
White bees wax 7.3 gm
Stearic acid 13.6 gm
Wool fat 9.0 gm
Liquid paraffin 15.0 gm
Terpineol 1.5 gm
Triethanolamine 1.9 gm
Propylene glycol 7.3 gm
Water 43.2 gm
Perfume Sufficient quantity (Q.s.)

Stearic acid, white bees wax, wool fat is melted on water bath and then terpinol is added. Separately water is heated at the same temperature in another beaker and trietanolamine is added with warmed water. The warm aqueous liquid is incorporated into the melted oils and stir consistently to get creamy emulsion. Stirring thoroughly until the smooth cream is found and then cool it down to room temperature. This results in the formation of placebo cream. Topical cream containing the drugs, methotrexate, acitretin and cyclosporine 1 gm of each (either a combination of two e.g. methotrexate and acitretin, methotrexate and cyclosporine, acitretin and cyclosporine or all the three drugs) is taken and dissolved in the melted oils and the procedure is same as that obtained with placebo cream.

4. Niosomal Gel: The niosomes is prepared using lipid hydration method of its modification. The drugs methotrexate, acitretin and cyclosporine 1 gm of each (either a combination of two e.g. methotrexate and acitretin, methotrexate and cyclosporine, acitretin and cyclosporine or all the three drugs) is incorporated to the phospholid layer while preparing niosomes. Soylecithin is used as the phospolipid. Once the niosomes are formed, the niosomes are dispersed in carbapol gel to form a 100 gm of final gel to be used. Carbapol gel is prepared by dispersing Carbopol 934 (1g) in demineralised water (88ml) by stirring at 800 rpm for 60 minutes, then, adding propylene glycol (10ml) and neutralize the mixture by dropwise addition of 10% NaOH, continue to mix until a transparent gel appear, while the amount of the base is adjusted to achieve a gel with pH 6.5.

5. Liposomal Gel: The liposomes (multilamellar vesicle i.e. MLVs) are prepared by using lipid hydration method of its modification. The drugs methotrexate, acitretin and cyclosporine 1 gm of each (either a combination of two e.g. methotrexate and acitretin, methotrexate and cyclosporine, acitretin and cyclosporine or all the three drugs) is added to the phospholid layer while preparing liposomes. Soylecithin is used as the phospolipid. The formed MLVs is sonicated to obtain small unilamellar vesicles (SUVs) using a probe sonicator. The free drug present in the liposomal formulation is removed by using a dialyser. Once the SUV liposomes are formed, the SUVs is dispersed in carbapol gel to form a 100 gm of final topical gel to be used. Carbapol gel is prepared by dispersing Carbopol 934 (1g) in demineralised water (88ml) by stirring at 800 rpm for 60 minutes, then, adding propylene glycol (10ml) and neutralize the mixture by dropwise addition of 10% NaOH, continue to mix until a transparent gel appear, while the amount of the base is adjusted to achieve a gel with pH 6.5.

6. Ethosomal Gel: The ethosomes (multilamellar vesicle i.e. MLVs) are prepared using lipid hydration method of its modification. The drugs methotrexate, acitretin and cyclosporine 1 gm of each (either a combination of two e.g. methotrexate and acitretin, methotrexate and cyclosporine, acitretin and cyclosporine or all the three drugs) is added to the phospholid layer while preparing ethosomes. Soylecithin is used as the phospolipid. The formed MLVs are sonicated to obtain small unilamellar vesicles SUVs using a probe sonicator. The free drug present in the liposomal formulation is removed using a dialyser. Once the SUV liposomes are formed, disperse the SUVs in carbapol gel to form a 100 gm of final topical gel to be used. Carbapol gel is prepared by dispersing Carbopol 934 (1g) in demineralised water (88ml) by stirring at 800 rpm for 60 minutes, then, adding propylene glycol (10ml) and neutralize the mixture by dropwise addition of 10% NaOH, continue to mix until a transparent gel appear, while the amount of the base is adjusted to achieve a gel with pH 6.5.