ZA200503906B - Topical skin care composition - Google Patents

Description

MNO 2004703720 PCT/US2003/033876

TOPICAL SKIN CARE COMPOSITION

FIELD OF THE INVENTION

The invention relates generally to a method of making a medicated skin (Fealng composition. s BACKGROUND OF THE INVENTION

Melasma or chloasma is a common pigmentary condition that affects primarily women in their reproductive years. Dark, mottled (hyperpigmented) pitches appear on the face and neck, especially on the cheeks and forehead.

Meclasma 1s usually triggered by hormonal activity that is the result of pregnancy 1) or birth control pifls. Thus, the condition 1s known as the “mask of pregnancy.”

The condition occurs when excess melanin is deposited in the cells of the epidermis and dermis. Melasma can persist for long periods of time and often recurs with subsequent pregnancies. The condition is less common among men, who account for about 10% of all cases.

Standard therapy involves depigmenting, or bleaching, the affected areas of the skin, the use of sunscreens, and avoidance of sunlight. Hydroquinone is the most popular topical depigmenting agent. Concentrations of 5%-10% hydroquinone are very cifective, but can be writating. The chemical stability of hvdroquimone formulations is important because hydroquinone is easily oxidized and loses potency. The most commonly used agent usually involves a 16-week to 20-week course of therapy, and some therapies can take longer. Tretinoin (Retin-A) is another widely used therapy for melasma. : Nevertheless, there remains a need in the art for a therapeutic approach that would contain scveral medicines for the treatment of melasma in a single composition. Moreover, it would be useful to have a therapeutic carrier, such as a cream. that would facilitate the penetration of the medicaments into the skin. i

£2200 90c

WO Zind03720 et VA 5906 138 Pat. No. 3.538.737 discloses a method of making a water-in-oil emulsion containing a pharmaceutically accepiable salt of an Hy-antagonist. The weps mehude dissolving the pharmaceutically acceptable salt in an aqueous medium to orm a water portion; combining the waiter portion with an oil portion, .

So compnsing an edible oil comprising an ester or mixed ester of glycerol and an emulsifying agent to form a water portion and oil portion matrix; then emulsifying . the matrix 10 form the water-in-oil emulsion.

Lis. Pat. No. 3.656,672 discloses a process for preparing a water-in-oil emulsion wiih retinal as the active ingredient. The emulsion contains an oil phase mcluding at lcast one organic solvent for retinal (such as aliphatic fatty alcohols) snd optional lipophilic additives; an aqueous phase containing water and optional hydrophilic additives; and an agent for emulsifying the aqueous phasc in the oil phase. The oil phase and the aqueous phase arc mmdependently prepared, and the aqueous phase 1s incorporated into the oil phase, with subsequent addition of a {5 phase-containing retinol and its solvent. 1J.S. Pat. No. 5,660,837 discloses a process for the preparation of a pharmaceutical formulation in the form of an oil-in-water emulsion. The steps of ihc process mclude of adding the cmulsion-stabilizing surface active drug and an optimal conventional surfactant to a two-phase, oil-water system at room temperature; allowing the emulsion-stabilizing surface active drug to equilibrate at an interface; adding an agent giving isotonicity to the final formulation, and homogenizing by high pressure technique.

US. Pat. No. 5,976,555 discloses skin care compositions. An oil-in-water emulsion base contains retinoids; cetearyl alcohol and cetearyl glucoside or a mixture of a polyethylene glycol ethers of stearyl alcohol; cetyl alcohol, stearyl alcohol and mixtures thereof; a light, dry absorbable oil; and substantive, cmollient oils or waxes.

L.S. Pat. No. 6,080,393 discloses a skin care composition comprising an , oil-in-water emulsion with a therapeutically effective amount of a retinoid; wherein the oil phase comprising one or more oils, and an effective amount of at .

3720 PCT/UN2003/033876 east one onl-sotuble annoxidant; and wherein the composition comprises a corneosierond

Nevertheless, there remains a need in the art for a method of making a smoother cream base for the application of therapeutic agents for the treatment of .

So melasma. which will facilnate the peneration of the medicaments into the skin.

SUMMARY OF THE INVENTION

‘I'he invention provides a cream basc for the topical application of skin care therapeutics and a process for making the cream base.

The process for making the cream base entails (a) mixing the hydrophilic compounds with water to form an aqueous phase; (b) mixing the hydrophobic compounds to form a hydrophobic (non-aqueous or wax) phase; then (c) mixing the hydrophilic and hydrophobic phases with one another to form a biphasic mixture; and finally (d) adding an emulsifier to the biphasic mixture to form the emulsion. By mixing the emulsifier after the aqueous and non-aqueous phases

IS have been mixed, the result is a smoother-textured cream that disappears on application to skin, as compared to creams made by processes where the emulsifier is added to the aqueous or non-aqueous phases earlier in the process.

Because the emulsifier is added as the final step, less wax 1s needed in making the cream, resulting in a “thinner” hydrophilic cream that disappears faster when applied to the skin, as compared to creams made by processes where the cmulsifier is added to the aqueous or non-aqueous phases earlier in the process.

The cream base made by the method of interest can be a carrier for any of a variety of pharmaceutically active agents for dermatologic use. For example, anti-acne, anti-cancer, antibiotic, anti-inflammatory, hormone, anti-fungal and analgesic active agents can be incorporated into a cream base of interest. [nn a specific embodiment, a cream base of interest comprises a steroid. in another embodiment, a cream base of interest comprises a keratolytic agent.

HER TB PCT/US2003/033876

In wet another specific embodiment, a cream base of interest comprises a

Aepiemienung seent.

In another embodiment. a cream base of interest comprises {wo or more of 1 sterend. keraiolyiic agent and depigmenting agent. : An exampic of a steroid is fluocinolone, such as fluocinolone acetonide, of : a kernolviic agent is uetinoin and of a depigmenting agent is hydroquinone. in a more specific embodiment, the invention also provides a cream, which “includes the inactive ingredients butylated hydroxytoluene, cetyl alcohol, citne acid, plyeenn, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid and stearyl alcohol.

In a particular embodiment, the cream is a carrier that contains as an active ingredient. fluocinolone acetonide, hydroquinone, tretinoin and combinations thereol. Tfor example, the crcam can be Tri-Iuma® Cream, which is the first 1% approved product to combine the standard depigmenting agent, hydroquinone, with tretinoin and a topical low-potency steroid that can be applied as a single preparation. The recommended course of therapy for Tri-Luma® Cream is 8 weeks, and significant results have been seen after the first 4 weeks of treatment.

Another advantage of the process of the invention is that by controlling the temperature at which the components, including hydroquinone, are added, the cream does not turn as brown, resulting in a more pleasing-colored product.

DETAILED DESCRIPTION OF THE INVENTION

Creams are enulsions of hydrophilic and lipophilic (hydrophobic) components. Generally, an emulsifier or surface active agent is included to enhance the mixing of the reagents resulting in a stable emulsion.

The various compounds that comprise an inert carrier are generally known inn the art. By “inert” is meant not having a pharmacologic activity. Typical examples of inert compounds comprising a cream base include cetyl alcohol,

: MO 200403720 PCT/1iS2003/033876 anon, glveenn, ethanol. EDTA, methyl paraben, zinc oxide, titanium dioxide. benzoic acid, carboxyvinethyleellulose, dimethvisulfoxide, polvethyleneglycol, petroleum. cic acid and stearic acid.

Fhe instant invention relates to a method of making a cream base as a

N vehicle for one or more pharmacologically active agents for dermatologic applications. The method of icrest comprises a particular order of adding and mixing of the ingredients of a cream. The hydrophilic ingredients, including water, ae mixed. Heating may be used to facilitate dissolving and solubility to produce a solution. The lipophilic or hydrophobic ingredients are mixed 10 separately. Heatmg may be used to facilitate mixing and homogenization.

The hydrophilic solution and the lipophilic solution then are mixed and blended. One or more pharmacentically active agents then are added to the blended mixture. Then, one or more emulsifiers are added and the entire mixture blended to produce a dermatologic cream of interest. 15 ‘the temperatures for heating the hydrophobic and hydrophilic solutions is that sufficient to facilitate the obtention of a homogeneous solution. Generally, a lower elevated temperaturc with longer mixing time is preferred. The temperature also may be hmited by the propertics of any one of the individual ingredients therein. Generally, the lemperature does not exceed about 100°C. Preferably, the 20 temperature does not exceed ahout 90°C or about 80°C or about 70°C or about 00°C. Generally, the temperature of heating need not be exact, at least within the accuracy of standard temperature measurement means.

The hydrophobic and hydrophilic solutions need not be heated to the same temperature. Having the same temperature facilitates the mixing of the two 25 solutions. If the solutions are at different temperatures, the warmer solution is cooled to the temperature of the cooler solution prior to mixing, ‘The blended mixture optionally may be cooled prior to mixing in the one or morc pharmacologically active agent or agents. The physical properties of the active agents may dictale a need for cooling.

Following that step and blending, one or more emulsifiers are added. The mizture 1s blended thoroughly to produce a cream of interest. If elevated, the emperaiure can be reduced during the blending.

As to the lipophilic ingredients, as known in the art, oils may be derived > from animals, plants, nuts, petroleum etc. Those derived from animals, plant seeds and nuts are similar to fats and consequently, may contain a significant number of polar acid and/or ester aroups. Alternatively, oils derived from petroleum are nsnally aliphatic or aromatic hydrocarbons that are essentially {rec of polar substation. 1 Oil-based products which can be used include hydrocarbons or mineral fats obtained by the distillation of petroleum (petroleum jelly); vegetable oils and liquid triglycerides; animal fats or solid, natural triglycerides; and waxes or solid ethers of fatty acids, such as stearic acid and palmitic acid, and organic alcohols.

Lanolin or wool fats made of fatty acids and cholesterol esters; and cetyl and stearyl alcohols, which are solid alcohols obtained by hydrogenation of their respective acids are also useable. Amphoteric compounds such as soaps or salts of fatty acids that may be acidic or basic depending on whether the lipophilic group is anionic or cationic, sulfated alcohols which are semi-synthetic substances and synthetic surface active agents are known in the art and also can be used.

Glycerin is obtained from fats and, due to the hydrophobicity thereof, has the property of extracting water from the surface of mucosa or denuded skin.

Gilycerin does not damage tact skin because of having hydrophilic properties, and 15 a useful humectant. : Other matenals that may be used in a topical preparation of interest 23 include liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, quid amides, liquid protein hydrosylates, liquid alkylated protein hydrosylates, liquid lanolin and lanolin derivatives and other like materials. Particular examples include monohydric and polyhydric alcohols, e. g -, ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexylene glycol, mannitol, cetyl alcohol and propylene glycol; ethers such as diethyl or dipropyl

NWO 2004/0370 PCT/US2003/033876 ether: polyethylene glveols and methoxypolyoxyethylenes; carhowaxes having molecular weights ranging from 200 10 20,000: polyoxyethylene glycerol; polyoxverhvlene: sorhitols; and stearoy! diacetin.

The topical carriers often include both an alcohol and water 50 as to > accommodate lipophilic and hydrophilic components. Other ingredients include buffers. such as sodium hydroxide, sodium citrate or tetrasodium EDTA: excipients: fragrances such as menthol: opacifiers such as zinc oxide, magnesium ahiminum silicate and titanium dioxide: preservatives such as dichlorobenzyl alcohol. benzoic acid, methylparaben and phenyl! carbinol; antioxidants; gelling agents such as petrolatum and mineral wax; thickening agents such as carboxymnethyleellulose: stabilizers; surfactants; emollients; coloring agents and the hike.

In addition, the topical carrier may include a penetration enhancer defined as a matenal that mereases the permeability of the skin to one or more active

IS agents so as to allow for cutaneous delivery of a pharmacologically active agent.

Various compounds for enhancing the permeability of skin are known in the art. lor example, dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and

N.N-dimethylacctamide (DMA), decylmethylsulfoxide, polyethylene glycol : monolaurate and the 1-substituted azacycloheptan-2-ones.

A number of different emulsifiers or surfactants can be used to prepare a topical preparation of interest. Nonlimiting examples of amphoteric surfactants usctul in the compositions of the present invention are disclosed in McCutcheon's, “Detergems and Emulsifiers™, North American edition (1986) and McCutcheon's, “Functional Materials”, North American edition (1992); both of which are mcorporated by reference herein in their entirety. Surfactants that can used are the betaines, suhaines and hydroxysultaines. Examples of betaines include the higher alkyl betanes, such as coco dimethyl carboxymethyl betaine, lauryl dimethyl carboxymethyl betaine, laury] dimethyl alphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyl dimethyl betaine, lauryl bis-(2-hydroxyethyl) carboxymethyl betaine, steryl bis-(2-hydroxypropyl) carboxymethyl betaine, oleyl dimethyl sinnnia-carboxypropyl betaine, lauryl bis-(2-hydroxypropyl)alpha carboxvethvi betaine, coco dimethyl sulfopropyl betaine, stcaryl dimethyl <ulfopropyl betaine, siearyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl bs (2-hydroxyvethyl) sulfopropyl betaine, amidobetaines, amidosulfobetaines, olevl betaine und cocamidopropyl betame. Examples of sultaines and hvdroxvsuliaines include cocamidopropyl hydroxysultaine. Examples of other amphoteric surfactants are alkyliminoacetates. iminodialkanoates and amoalkanoates. } _ Examples of anionic surfactants also are disclosed in McCutcheon’s,

IO “Tocterpenis and Bmulsifiers”, North American edition (1986) and McCuicheon’s, “Functional Materials”, North American edition (1992). Examples include the alkovl isothionates. the alkyl and alkyl ether sulfates, such as, ammonium cocoyl isothionate, sodium cocovl isothionate, sodium lauroyl isothionate, sodium stearoy] isothionate and mixturcs thereof, the sarcosinates, such as sodium lauroyl }5 sarcosinate, sodium cocoyl sarcosinate and ammonium lauroyl sarcosinate, sodium lauryl sulfate, ammonium lauryl sulfate, ammonium cetyl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, ammonium cocoyl isethionate, sodium

Lanrovl iseihionate, sodium lauroyl sarcosinate and mixtures thereof.

Omer emulsifiers includes tricetareth-4-phosphate, sodium laureth-4-phosphate or oleth-3. tixamples of non-ionic emulsifiers include sorbitan monostearate, glyceryl monostearate, polysorbates, polyethylene derivatives of fatty alcohols, polyoxyethylene ethers of fatty alcohols, such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene nonylphenyl ether and the like, sorbitan stearate, glyceryl stearate, Cj,-Cyg fatty alcohols, esters and ethers thereof, aliphatic fatty alcohols such as cetyl alcohol or stearyl alcohol or a mixture of the (wo, fatty alcohols or a-diols oxyethylenated or polyglycerolated such as oley! alcohel polyoxyethylenated with 10 moles of ethylene oxide, } .2-octadecanediol polyglycerolated with 2 or 7 moles of glycidol, cyclic fatty alcohols, glycol esters of tatty acids such as ethylene glycol stearate, the monostcarates or distearates of glycerol, the polyethylene glycol esters of fatty

WO) 2004i037 201 PCT/US2003/033876 aids auch as nolvethylene zlveol stearates, the fatty esters of sorbitan nxvethvlenated or not and sold under the trade name of Tweens or Spans, the fatty caters of sucrose, the fatty esters of glucose denvatives such as methylglucoside sesquistearate and methylglocoside sesquisiearate polyoxyethylenated with 20 moles of ethylene oxide, Arlacel 165 and Myr) 52, fatty alcohols having 10 to 20 carbon aioms, fatty alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles ol ethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon moms mn the allyl chain condensed with 2 to 20 moles of ethylene oxide, mono-Talty acid and di-fatry acid esters of ethylene oxides, mono-fatty acid and (0 "di-Matty acid esters of ethylene glycol wherein the fatty acid moiety contains from to 20 carbon atoms, diethylene glycol, polyethylene glycols of molecular weight 200 to 6000. propylene glycols of molecular weight 200 to 3000, glycerol, sorbitol. sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophilic wax esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polvoxyethylene glycol fatty acid esters and polyol fatty acid esters.

Zxamples of cationic emulsifiers include quatemnized ammonium bronude and chloride salts, cetyltimethylammonium chloride, benzalkonium chloride and cetyl pyridinium chloride, aliphatic amines having fatty chains, e.g. oleylamine and dihydroabietylamine; quaternary ammonium compounds, e.g., lauryl dimethylbenzyl ammonium chloride, amides denved from amino alcohols, e.g.,

N-aminoethyl oleylamide, n-(stearoyl-colamino-formylmethyl) pyridinium chloride, N-soya-N-ethyl morpholinium ethosulphate, alkyl dimethyl benzyl ammonium chloride, di-isobutylphenoxyethoxyethyl dimethyl benzyl ammonium chloride, cetyl pyridinium chloride, N-(stearoyl-colamino- formylmethyl) pyridinium chloride, N-soya-N-ethyl morpholinium ethosulfate, alkyl dimethyl benzyl ammonium chloride, (diisobutyl-phenoxy-ethoxy) ethyl dimethyl benzyl ammonium chloride, PG-dimonium chloride phosphate, stearamidopropyl ethyldimonium ethosulfate, stcaramidopropyl dimethyl (myristyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stcaramidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, ammonium halides, more especially chlorides and bromides,

anch as alkyl irimethylammonium chlorides, dialkyl dunethylammonium chlorides amd malkyl methvlammonium chlorides, for example. stearyl trimethylanumonium chloride. disteary! dimethylammonium chloride, lauryl dimethylammonium chloride. Tauryt dimethyl benzylammonium chloride and mceryl p methylamimonium chloride, quaternized protein hydrolyzates or protein hvdrolyzates derivatized with amino groups which are marketed, for example, under the names Lamequat™ and Mackpro®, stearamidopropyl PG-dimonium chlonde phosphate, siearamidopropyl ethyldimonium ethosulfate, stearanudopropyl dimethyl (myristyl acetate) ammonium chloride,

LO stearanmidopropyl dimethyl cetearyl ammonium tosylate, stcaramidopropyl dimethyl ammonium chloride, and stearamidopropyl dimethyl ammonium lactate.

The compositions of the instant invention can comprise a wide range of additional components. The “CTFA Cosmetic Ingredient Handbook”, Second edition, 1992, which 1s incorporated by reference herein in its entirety, describes a 15 wide vancty of cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the instant vention. Examples of functional classes of ingredients are absorbents, abrasives, anti-acnc agents, anticaking agents, antifoarming agents, antimicrobial agents, antioxidants, binders, biological additives, buffering agents, bulking : 20 apents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers, [raprance components, humectants, opacifying agents, pH adjusters, platicizers, preservatives, propellants, reducing agents, skin bleaching agents, skin conditioning agents (emollients and humectants), skin protectants, solvents, foam 25 boosters, hydrotropes, solubilizing agents, suspending agents (nonsurfactant), sunscreen agents, ultraviolet light absorbers and viscosity increasing agents {aqueous and nonaqueous).

The various starting materials for making a topical preparation are known in the art and reference can be made to known treatises, as well as U.S. Patent 30 Nos. 6,013,271; 6,267,985; 4,992,478; 5,645,854; 5,811,111; and 5,851,543.

& YT b

MNO 2004/0370 PCT/US2003/0033876

A number of pharmaceuucally active agents can be used in the dermatologic preparations of interest. Thus, anv of the known antibiotics,

Anu-acne agents, antineoplasnte agents, bleaching agents, keratolvtic agents, anu-imtlammatories, antifungal analgesics and so on, can be used. > A wide variety of cytostatic agents may be used. Examples include cytostatic agents, alkylating agents, enzyme inhibitors, proliferation inhibitors,

INA synthesis inhibitors, lytic agents, DNA intercalators, antimetabolites and the ike. Husirauve agents include steroids, paclitaxel, ionomycin, etoposide, nrosoureas such as carmustine (BCNU), doxorubicin, daunoxubicin, actinomycin yl 12. mectorethamine, busuifin, CCNU, Me-CCNU, chlorambucil, cactinomyein, carzinophilin, chlomaphazine, 6-chloropurine, azathioprine, fluorouracil, hvdroxyurea, thioquamne, campothecin, mitomycin, lomustine (CCNU), semustine (Me-CCNU), canthandmn, camptothecin, carboplatin, ricin, pscudontonas exotoxin, interferons, mterleukins, tumor necrosis factors, {5 vincristine. mitotane melphalan, methchlorethanine, plicamycin, nitracine, niioxantrone, methotrexate, nogalamycin, streptonigrin, streptozocin, tegafur, 1erramin. testolactone demecolcine and dactinomycin. Other compounds that can he used mclude cyctophamide, cyclosporin, amsacrine, biantrene hydrochloride, camostat mesylate, campothecin, enociiabine, etoposide, epirubicin hydrochloride, {ludarabine phosophate, flutamide, fotemustine, 1idarubicin hydrochloride, ionomycin, omdamine, mitoxanirone hydrochloride, nilutamide, paclitaxel, pirarubicin, toremifene, vinorelbine, didemnin, bactracychn, mitoquidone, penclomedine, phenazinomycin, U-73975, saintopin, 9-aminocamptothecin, amonafide. merbarone and the like. Additional agents that can be used include mitomycin C, cisplatin, mechlorethamine, daunorubicin, carmustine, pyrazine diazohydroxide, fumagillin analog FF- 11 1142, rhyzoxin, dynemicin A, chlorambucil, semustine and the hke.

Suitable keratolytics include salicylic acid, derivatives of salicylic acid such as 3-octanoy] salicylic acid, and resorcinol; retinoids such as retinoic acid and dernvarives thereof (e.g., cis and trans); sulfur-containing D and L amino acids and dentvatives and salts thereof, particularly N-acetyl derivatives, such as

N-acervl-l-cvstemne: lipoic acid; antibiotics and antimicrobials such as benzoyl peroxide. actopirox. weiracyeline, trichlorobanihde. azelaic acid, phenoxyethanol, phenoxypropanol. phenoxyisopropanol, eihyl acetate, clindamycin and mecloeyeime: schostats such as flavonoids; and bile salts such as scymnol sulfate > and denvauves thereof. deoxycholate and cholate. xamples of antiwrinkde and anti-skin atrophy actives that can be used in the topical preparations of interest include retinoic acid and derivatives; retinol, retmyl esters: salicylic acid and denvatives thereof; sulfur-containing D and 1, : amino acids and their derivatives and salts, particularly the N-acetyl derivatives, 0 thiols. co. ethane thiol; alpha-hydroxy acids, e.g. glycolic acid, and lactic acid; phytic acid. lipoic acid; lvsophosphatidic acid, and skin peel agents, e.g., phenol.

Fixamples of non-steroidal anti-inflammatories that can be used in the instant invenuon include propionic acid derivatives; acetic acid derivatives; fenamic acid denvauves; biphenylcarboxylic acid derivatives; and oxicams, and include acetyl salicylic acid, ibuprofen, naproxen, benoxaprofen, fluhiprofen, [enoprofen, [enbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen. mmcroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen and bucloxis acid. txamples of topical anesthetic drugs that can be used in the topical preparation of interest include benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaime, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine, phenol, and pharmaceutically acceptable salts thereof.

Corticosteroids including halogenated corticosteroids that can be used in the topical preparations of interest generally arc known and are commercially available. Examples include cortisone, hydrocortisone and derivatives thereof cluding cortodoxone, flucetonide, fludrocortisone acetate, flurandrenolone acetonide, medrysone; prednisone, prednisolone and derivatives thereof including . amcinafal, amcinafide, betamethasone benzoate, valerate and dipropionate, chloroprednisone acetate. descinalone acetonide, desonide, dexamethasone,

dichlorisone aceraie, difluprednate, flucloronide, flumethasonce, flunisolide - acetate, fluocinelone acetonide, fluocinonide, fluocortolone, fluorometholone,

Jiperoline acetate, fluprednisolone valerate, meprednisone, methyl prednisolone, naramethasone acclate, prednisolomate. prednisolone acetate, butylacetate and © phosphate sodium. rriamcinolone acetomde, hexacetonide, diacetate, hvdrocorusone butyrate, flumeihasone pivalate, halcimnide and clobetasol

NIOPIONULE. :

Examples of other active ingredients that can be used mn a topical _ Preparation of mierest clude acebutolol, acetaminophen, acetohydoxamic acid, 10 acetophenazine, acyclovir, allopunnol. alprazolam, aluminum hydroxide, amantadine, ambenonium, amiloride, aminobenzoate potassium, amobarbital, amoxicilin, amphetamine, ampicillin, androgens, anesthetics, anticoagulants, anticonvulsants, antithyroids, appetite suppressants, aspirin, atenolol, atropine, avatadine, bacampicillin, baclofen, beclomethasone, belladonna, hendroflumethiazide, benzoyl peroxide, benzthiazide, benztropine, bethanechol, . hiperiden, bisacodyl, bromocriptine, bromodiphenhydramine, brompheniramine, buclizine, bumetanide, busulfan, butabarbital, butaperazine, caffeine, calcium carbonate. captopril, arbamazepine, carbenicillin, carbidopa, levodopa, carbinoxamine inhibitors, carbonic anhydrase, carisoprodol, carphenazine, cascara, cctaclor, cefadroxil, cephalexin, cephradine, chlophedianol, chloral hydrate, chlorambucil, chloramphenicol, chlordiazepoxide, chloroquine, chlorothhazide, chlorotianisene, chiorphenivamine, chlorpromazine, chlorpropamide, chlorprothixene, chlorthalidone, chlorzoxazone, cholestyramine, cimetidine, cinoxacin, clemastine, clidinium, clindamycin, clofibrate, clomiphere, clomdine, clorazepate, cloxacillin, colchicine, coloestipol, estrogens, contraceptives, androgens, cromolyn, cyclacillin, cyclandelate, cyclizine, cyclobenzaprine, cyclophosphamide, cyclothiazide, cycrimine, cyproheptadine, danazol, danthron, dantrolene, dapsone, dextroampheiamine, dexchlorpheniramine, dextromethorphan, diazepan, dicloxacillin, dicyclomine, diethylsalbestrol, diflunisal, digitalis, diltiazen, dimenhydrinate, dimethindene, diphenhydramme, diphenidol, diphenoxylate, diphenylopyraline, dipyradamole,

disopvramide. disulfiram. divalporex, docusatc calcium, docusate potassium, docusate sodium. doxyloamine. dronabinol ephedrine, epinephrine, erzolordmesylates, ergonovine, ergotamine, crythromycins, estropipute, etharynic acid, ethehlorvynol, cthopropazine, cthosaximide, ethotoin, fenoprofen, ferrous : marae. rerrons gluconate, ferrous sulfate, flavoxate, flecainide, fluphenazine,

Hupredmsolone, flurazepam, folic acid, furosemide, gemfibrozil, glipizide, clvburide. glycopyrrolate, gold compounds, griseofuwm, guaifenesin, guanabenz, guanadrel, guanethidine, halazepamn, haloperidol, hetacillin, hexobarbital, hydralazine, podofilox (Oclassen Dermatologics), podophyllin (Paddock Labs),

I imaquimod (3M Pharmaceuticals), hydrochlorothiazide, hydroflunethiazide, hvdroxychloroquine, hydroxyzine, hyoscyamine, ibuprofen, mdapamide, mdomethacin, insulin, 10foquinol, iron-polysaccharide, isoethanne, 1somazid, isopropanmde, isoproterenol, isotretinoin, 1soxsuprine, kaolin, pectin, ketoconazole, Jacilose, levodopa, lincomycin, hothyronine, liotrix, lithium, loperamide. lorazepam, magnesium hydroxide, magnesium sulfate, magnesium trisilicate, maprotiline, meclizine, medofenamate, medroxyproyesterone, melenamic acid, melphalan, mephenytoin, mephobarbital, meprobamate, mercaptopurine, mesoridazine, metaproterenol, metaxalone, methamphetamine, mecthaqualone, metharbital, methenamine, methicillin, methocarbamol, methotrexate, methsuximide, methyclothinzide, methylcellulose, methyldopa, methylergonovine, methylphenidate, methylprednisolone, methysergidc, metoclopramide, metolazone, metoprolol, metronidazole, minoxidil, mitotane, monamine oxidase inhibitors, nadolol, nafcillin, nalidixic acid, naproxen, narcotic analgesics, neomycin, neostigmine, niacin, nicotine, nifedipine, nitrates, nitrofurantorn, nomifensine, nylidrn, nystatin, orphenadrine, oxacillin, oxazepam, oxprenolol, oxymetazoline, oxyphenbutazone, pancrelipase, pantothenic acid, papaverine, paraaminosalicylic acid, paregoric, pemoline, penicillamine, penicillins, pentobarbital, perphenazine, phenacetin, phenazopyridine, pheniramine, phenobarbital, phenolphthalein, phenprocoumon, phensuximide, phenylbutazone, phenylephrine, phenylpropanolamine, phenyl toloxamine, phenytoin, pilocarpine, pindolol, piperacetatine, piroxicam, poloxamer, polycarbophil calcium, polythiazide, potassium supplements, pruzepam, prazosin,

primidone. probenceid, probucol, procainamide, procarbazine, prochlorperazine, procveligine. prormazine, promethazine, propantheline, propranolol, pscudoephiedrine, psoralens, psyllium, pyndostigmine, pyrodoxine, pyrilamine, pyTvinium, quinestrol, quincihazone, quinidine, quinine, ranitidine, rauwolfia “alkaloids, ribofiavin, rifampin, ritodrine, salicylates, scopolamine, secobarbital, senna, sannosides. simethicone, sodium bicarbonate, sodium phosphate, sodium iluoride. spironolactone, sucralfate, sulfacytine. sulfamethoxazole, sulfasalazine, sulfinpyrazone, sullisoxazole, sulindac, talbutal, tamazepam, terbutabne., wericnadine, terphinhydrate, teracyclines, thiabendazole, thiamine, thioridazine, thiothixene. thyroglobulin, thyroid, thyroxine, ticarcillin, timolol, tocainide, iolizamide. tolbutamide. tolmetin, trozodone, tretinoin, triamcinolone, tnianterene, trinzolam, trichlormethiazide, tricyclic antidepressants, trifluoperazine, ri flupromazine, trihexyphenidyl, trimeprazine, trimethobenzamine, trimethoprim, lripclennamine, triprolidine, valproic acid, verapamil and xanthine.

EN The amounts of the inert ingredients and active agent(s) in the dermatologic preparation of interest generally are known in the art. It is within the ambit of the artisan to derive particular amounts of the ingredients to obtain a cream of interest.

The particular amount of any onc ingredient used is not substantially 20 critical and the amounts used are at the accuracy of the measuring or dispensing nicans known in the art.

In one embodiment of the invention, approximately 344.8 kg of water, 15.0 kg magnesium ahmninum silicate, and 0.2 kg butylated hydroxytoluene are first combined and mixed at 75-80°C to form the aqueous phase. The mixing can 25 he by side scrape agitation at a fixed speed. The resultmg aqueous phase is a

SUSPENSION.

Second, approximately 20.0 kg of cetyl alcohol, 15.0 kg of stearic acid, 20.0 kg of stearyl alcohol, 25.0 kg of methyl gluceth-10, 0.9 kg of methylparaben, 0.1 ke of propylparaben, and 20.0 kg of glycerin are mixed together at medium 30 speed at about 75-80°C to form the non-aqueous phase. The mixing can be at

WO m3 PCT/US2003/033876 medium speed in a Lichinin® mixer. The resulting non-aqueous phase 1s a snepension. The second step can be performed before, after or concurrently with the first siep.

I'hen, the non-aqueous phase is added to the aqueous phase and the it combined biphasic mixture is cooled to a temperature in the range of 68°C to

TOC, or about 70°C, after which about 17.5 kg of Arlacel® 165, 0.25 keg tretinoin and 0.030 ky fluocinolone acetonide are added and stirred with cooling. When the mixture teaches 60°C, 0.25 kg citric acid is added with mixing and cooling.

When the temperature reaches 55°C, 20.0 kg hydroquinone 1s added with mixing and cooling. When the temperature reaches about 50°C, the nuxture is homogemzed with a homogenizer, with continued cooling. When the mixture reaches 45°C. 1.0 kg of sodium metabisulfite is added with stirring and cooling.

Typically, the sodium metabisulfite is added about 30 minutes after the addition of the hydroquinone. The mixing can be at fixed speed ina side scrape agitator. The resulting composition of matter is an emulsion, i.e., a cream.

The presence of sodium metabisuitite in the cream prevents the oxidation of hydroquinone. The addition of sodium metabisulfitc as the cream is cooling advanmagecously results in a well-mixed composition of matter, with the sodium metabisulfite evenly mixed throughout the cream and preventing the oxidation of the hydroguinone throughout the cream. Another advantage of the process of the invention is that by controlling the temperature at which the components, including hydroquinone, are added, the cream docs not turn as brown, resulting in a more pleasing-colored product.

The addition of the emulsifier following the mixing of the non-aqueous and aqueous phases is advantageous for the making of the pharmaceutical composition of the invention. When a standard technique of adding the emulsifier 10 the non-aqueous phase and then mixing with the aqueous phase was used, no emulsion formed. However, when the emulsifier was added to the mixture of the non-aqueous and aqueous phases with cooling, according to the method of the invention, a useful emulsion did form. This emulsion formed even though the relative proportion of he non-aqueous and aqueous phases according to the successful meibod of the vention was the same as when an emulsion did not form using the standard technique of adding a non-aqueous phase containing an cinulsifier io an aqueous phase. = The resulting TRI-LUMA® Cream contains {luocinolone acetonide, hydroquinone and treimoin in a hydrophilic cream base for topical application. [ach gram of TRI-LUMA® Cream contains as active ingredients, fluocinolone acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5

Jim), and as inactive ingredients, butylated hydroxytoluene, cetyl alcohol, citric

I acid. glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, punfied water, sodium metabisulfite, stearic acid, and stearyl alcohol, sec TABLE 1.

TABLE 1 500 kg Batch ~~ 800 ko Batch .

Ineredient Quantity Quantity Formula magnesium alunimum silicate NT 15 ke 24 kg 3.00% butviated invdroxvioluene NIY 200g 204g 0.04% } coetvlaleohol NI 20 ke 32kg 4.00% sieane aad NF 15 kg 24 kg 3.00% steary) alcohol NF 20kg 32kg 4.00% methylparaben NF 900g 1,440 g 0.18% propylparaben Ni- 100 g 160 g 0.02%

Arlacel® 165 [glycerol stearate and 17.5kg 28 kg 3.50% © PEG-100 stearate glycerol monostearate methyl gluceth-10 25kg 40 kg 5.00% olycerin USP 20 kg 32kg 4.00% ’ tretinoin GSP 250g 400 g 0.05% tinocinolone acetonide USP 50g 80g 0.01% citric acid USP 250 ¢ 400 g 0.05% hydroquinone USP 20 kg 32kg 4.00% sodium mewabisulfite NF 1 kg 1.6 kg 0.20% puntfied water USP 3448 kg 551.6 ke 68.95%

TOTAL 100.00% 3 [fluocinolone acetonide is a synthetic fluorinated corticosteroid for topical dermatological use and is classified therapeutically as an anti-inflammatory. It is a white crystallime powder that 1s odorless and stable in light. The chemical name for fluecinolone acetonide 1s (6,11,16)-6,9-difluoro-11,21-dihydroxy-16,1 7-[(1-methylethylidene)bis(oxy)]- pregna-1.-4-diene-3,20-dione. The molecular formula is Co4H30F,Og and molecular weight is 452.50.

Hyvdroquinonc is classified therapeutically as a depigmenting agent. It is prepared from the reduction of p-benzoquinone with sodium bisulfite. 1t occurs as tine white needles that darken on exposure to air. The chemical name for 3 hydroquinone is 1,4-benzenediol. The molecular formula is CsHgQ, and molecular weights 110.11.

NWO 2004/0537 201 PCT/US2003/033876

Freimoin is all-rrans-retinoie acid formed from the oxidation of the aldehyde group of retinene to a carboxyl group. It is highly reactive to light and moisture. Tretmoin is classified therapeutically as a keratolvtic. The chemical name for netinoin is:

So all I-37 dimethyl-9-(2.6,6-trimethyl-1-cvclohexen-1-y1)-2,4,6,S-nonatetracnoic acid. The molecular formula is CypHagOr and molecular weight is 300.44.

TIRED UMA ™ Cream 1s typically supplied in 30 g aluminum tubes,

NDC 0299-2950-30, ands stored at controlled room temperature 68 to 77°F (20-25°C). [I The details of one or more embodiments of the invention are set forth in the accompanying description above. Although any methods and materials similar ur equivalent to those described herein can be used in the practice or sting of the present mvention, the preferred methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all techmical and scientific terms uscd herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated by reference.

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 clams.

EXAMPLE]

HUMAN PHARMACOKINETICS

Percutancous absorption of unchanged tretinoin, hydroquinone and

Nuocimolone acetonide into the systemic circulation of two groups of healthy

MO 2004037201 PCT/US2003/033876 volunicers (Towa n=39) was found to be minimal following 8 weeks of daily application of 1 g (Group I. n=45) or 6 ¢ (Group 11, n=14) of TRI-LUMA® Cream.

For reunoin quanafiable plasma concentrations were obtained in 57.78% (20 out of 43) of Group I and 57.14% (8 out of 14) of Group II subjects. The : axposure to iretinoin as reflected by the Cp, values ranged from 2.01 to 5.34 nam (Group 1) and 2.0 10 4.99 ng/mL (Group I). Thus, daily application of

TRI-LUMAY Cream resulted in a minimal increase of normal endogenous levels of metinom. The circulating tretinoin levels represent only a portion of total _iretinoin-associated retinoids, which would include metabolites of tretinoin and that sequestered into peripheral tissucs. ‘ For hydroquinone quantifiable plasma concentrations were obtained in 18% (8 out of 44) Group I subjects. The exposure to hydroquinone as reflected by the Cony values ranged from 25.55 to 86.52 ng/mL. All Group II subjects (6g dose) had undetectably low post-dose plasma concentrations. or fluocinolone acetonide, Groups I and II subjects had undetectably low posi-dose plasma concentrations.

The following tests may be helpful in evaluating patients: (a) ACTH or cosyntropin stimulation tests; (b) the A.M. plasma cortisol test; and (c) the urinary free cortisol test. 200 EXAMPLETY

HUMAN CLINICAL STUDIES

Twa efficacy and safety studies were conducted in 641 melasma patients between the ages of 21 to 75 years, having skin phototypes I-IV and moderate to severe melasma of the face. TRI-LUMA® Cream was compared with three 25 possible combinations of two of the three active ingredients {(1) hydroquinone 4% (IQ) + tretinoin 0.05% (RA); (2) fluocinolonc acetomde 0.01% (FA) + tretinoin 0.05% (RA); (3) fluocinolone acetonide 0.01% (FA) ‘+ hydroquinone 4% (HQ), . contained in the same vehicle as TRI-LUMA® Cream.

NO 20047037201 PCT/US2003/033876

The patients were structed to apply their study medication each might, after washing their face with a mild soapless cleanser, for 8 weeks. The patients were also instructed to apply a thin layer of study medication 0 the hvperpigmented lesion, making surc to cover the entire lesion including the 3 owside borders extending to the normal pigmented skin. The patients were provided a miid moisturizer for use as needed and a sunscreen with SPF 30 for daily use. Moreover. the patients were instructed to avoid sunlight exposure to the lace. wear protective clothing Protective clothing and avoidance of sunlight exposure 10 the face was recommended.

Ho The patients were evaluated for melasma severity at bascline and al wecks 1,2. 4. and § of treatment. Primary efficacy was based on the proportion of patients who had an investigators’ assessment of treatment success, defined as the clearing of melasma at the cnd of the eight-week treatment period. The majority of patients enrolled m the two studies were white (approximately 66%) and female 1S (approximately 98%). TRI-LUMA® Crcam was demonstrated to be significantly more effective than any of the other combinations of the active mgredients.

Patients experienced improvement of their melasma with the use of

TRI-LUMAY Cream as carly as 4 weeks. However, among 7 patients who had clearing at the end of 4 weeks of treatment with TRI-LUMA® Cream, 4 of them . 50 did not maintain the remission after an additional 4 weeks of treatment.

Afier § weeks of treatment with the study drug, patients entered into an open-label extension period in which TRI-LUMA® Cream was given on an as- needed basis for the treatment of melasma. In studies, after 8 weeks of treatrnent with TRI-LUMA® Cream, most patients had at least some improvement. Some 75 had their dark spots clear up completely (38% in one study and 13% in another).

In most patients trcated with T RI-LUMA® Cream, their mclasma came back after treatment. The remission periods appeared to shorten between progressive courses of treatment. Additionally, few patients maintained complete cleaning of melasma (approximately 1 to 2%).

J I0AMSTI00 PCT/US2003/033876 ’ TABLE 2 tnvesticaiors’ Assessment of Treatment Success® ) At the End of 8 Weeks of Treatment

TRI-LUMA® HO+RA FA+RA FA+HQ

Cream study No 1 Number of 83 83 85 85

Panents

Number of 32 12 0 3

Successes

Proporuon of 38% 15% 0% 4%

Successes

P-value <0.001 <0.001 0.001

Swdv No. 2 Number of 76 75 76 78

Patents

Number of 10 3 3 1

Successes

Proportion of 13% 4% 4% 1%

Successes

P.vahueir 0.045 0.042 0.005 #Ireatment success was defined as melasma severity score of zero (mclasma lesions cleared of hyperpigmentation). ) #P-value is from Cochran-Mantel-Haenszel chi-square statistics controlling for pooled investigator and comparing TRI-LUMA® Cream to the other treatment

LIOUPS.

Based on melasma severity at the beginning of the trial, 161 patients were assessed for improvement at day 56 of treatment. 61% (99 patients) expenienced symptom improvement from “moderate” to “mild” or “cleared,” and 68% (25) showed improvement from “severe” to “mild” or “cleared” over the 8-week treatment period as shown in TABLE 3.

NO 2004037200 PCT/US2003/033876

TABLE 3 levestiemors’ Assessment of Change in Melasma Severity ] trom Baseline to Dav 56 of Treatment : (combined results from studies 1 and 2)

Number(%) of Patients at Day 56°

Baseline Cleared” Mild" Moderate” Severe’ Missin

Severity N N(%) N(%) N{%a) N(%) N(%

Rating

Tr-Luma' Moderate 24 36 (29) 63 (51) 18 (16) 0 (0) 7 (6% {ream Severe 37 6 (16) 19 (51) 9 (24) 2(5) 1 (3%

N16] "Assessment based on patients with severity scores at day 56. Percentages are hased on the otal number in the treatment group population. "Does not include patients who cleared before day 56 or were missing from the day 56 assessment. Assessment scale: Cleared (melasma lesions approximately equivalent to suroundimg normal skin or with nunimal residual hyperpigmentation): Mild (slightly darker than the surrounding normal skin);

Moderate (moderately darker than the surrounding normal skin); Severe 1S (markedly darker than the surrounding normal skin).

ENAMPLE III

ADVERSE REACTIONS IN HUMANS in a patch test study to detenmine sensitization potential in 221 healthy volunteers. three volunteers developed sensitivity reactions to TRI-LUMA®

Cream or 1ts components.

In the controlled clinical trials, adverse events were monitored in the 161 patients who used TRI-LUMA® Cream once daily during an 8-week treatment period. There were 102 (63%) patients who experienced at least one treatment-retated adverse event during these studies. The most frequently reported events were erythema, desquamation, burning, dryness, and pruritus at the site ol application. The majority of these events were mild to moderate in 30) severity. Adverse events reported by at least 1% of patients and judged by the investigators to be reasonably related to treatment with TRI-LUMA® Cream from

W022 7 : } 2004/0037 2001 PCT/US2003/033876 ihe conrolled clinical studies are summarized (in decreasing order of frequency) ax follows:

TABLE 4

Incidence and Frequency of Treatment-Related Adverse Events with TRI-LUMA® . 2 Cream In

At Least 1% or More of Patients (N=161) vdverse Kvent Number (%0) of Patients

Pruihema 66 (41%) esquamanon 61 (38%)

Burmny 29 (18%)

Dryness 23 (14%)

Praritus 18 (11%)

Acne S (5%)

Paresthesia 5 (3%)

Telangiectasia 5 (3%)

Hyperesthesia 3 (2%)

Pigmentary changes 3 (2%)

Irritation 3 (2%)

Papules 2 (1%)

Acne-like rash 1 (1%)

Rosacea 1 (1%)

Dry mouth 1 (1%)

Rash : 1 (1%)

Vesicles 1 (1%)

In an open-label long-term safety study, patients who have had cumulative treatment of melasma with TRI-LUMA® Cream for 6 months showed a similar pattern of adverse events as in the 8-week studies. The following local adverse reactions have been reported infrequently with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher . potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform cruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria.

All references cited herein are herein incorporated by reference in entirety.

The foregoing description has been presented only for the purposes of illustration and is not intended to limit the invention to the precise form disclosed, hut by the claims appended hereto.

Claims (1)

1. LS W02004/037201 PCT/US2003/033876 What is Claimed Claim 1: A method of making a topical pharmaceutical composition comprising water, hydrophilic compounds and hydrophobic compounds, and consisting of fluocinolone acetonide, hydroquinone and tretinoin as active ingredients, comprising: (a) mixing water and at least one hydrophilic compound to form an aqueous composition; (b) mixing at least two hydrophobic compounds to form a non- aqueous composition; (c) mixing said aqueous composition and said non-aqueous composition to form a mixture; (d) combining said fluocinolone acetonide and said tretinoin with said mixture of step (¢); (e) mixing at least one emulsifier into said mixture of step (d); and 63) homogenizing the mixture of step (e); wherein said hydroquinone is added in step (d) or after adding said at least one emulsifier in step

   (e). Claim 2: The method of claim 1, wherein said aqueous composition comprises water, magnesium aluminium silicate and butylated hydroxytoluene. Claim 3: The method of claim 1, wherein said non-aqueous composition comprises at least two hydrophobic compounds selected from the group consisting of cetyl alcohol, stearic acid, stearyl alcohol methyl gluceth, methylparaben, propylparaben and glycerin. Claim 4: The method of claim 3, wherein said non-aqueous composition comprises cetyl alcohol, stearic acid, stearyl alcohol, methyl gluccth, methylparaben, propylparaben and glycerin. Claim 5: The method of claim 1, wherein said at least one emulsifier is glyceryl stearate, polyethylene glycol (PEG) stearate or a combination thereof. Claim 6: The method of claim 5, wherein said at least one emulsifier is a combination of glyceryl stearate and polyethylene glycol stearate. AMENDED SHEET

   W02004/037201 PCT/US2003/033876

   Claim 7: The method of claim 1, wherein said hydroquinone is added after adding said at least one emulsifier in step (e).

   Claim 8: The method of claim 1, further comprising adding sodium metabisulfite to said mixture of step (e) after adding said at least one emulsifier.

   Claim 9: The method of claim. 1, wherein said water and said at least one hydrophilic compound are mixed at an elevated temperature.

   Claim 10: The method of claim 9, wherein said elevated temperature is from about 75°C to about 80°C.

   Claim 11: The method of claim 1, wherein said at least two hydrophobic compounds are mixed at an elevated temperature.

   Claim 12: The method of claim 11, wherein said elevated temperature is from 75°C to 80°C.

   Claim 13: The method of claim 1, wherein said water and said at least one hydrophilic compound are mixed at a temperature of from about 75°C to 80°C, and said at least two hydrophobic compounds are mixed at a temperature of from 75°C to 80°C.

   Claim 14: The method of claim 13, wherein said mixture of step (c) is cooled before adding said fluocinolone acetonide and said tretinoin in step (d).

   Claim 15: The method of claim 14, wherein said cooled temperature is from 68°C to

   72°C.

   Claim 16: The method of claim 14, wherein said mixture of step (d) is cooled while said at least one emulsifier is mixed into said mixture of step (e). Claim 17: The method of claim 16, wherein said hydroquinone is added in step (d) following cooling of said mixture. 26 AMENDED SHEET

   © W02004/037201 PCT/US2003/033876 Claim 18: The method of claim 17, wherein said mixture is cooled to about 55° before adding said hydroquinone.

   Claim 19: The method of claim 13, wherein said homogenizing step (f) occurs at a temperature of about 50°C.

   Claim 20: The method of claim 19, wherein said hydroquinone is added in step (€) after said at least one emulsifier is mixed into said mixture.

   Claim 21: The method of claim 13, wherein said mixture of step (f) is cooled to about 45°C and then adding sodium metabisulfite to said cooled mixture.

   Claim 22: A pharmaceutical preparation made by the process of anyone of claims 1-21. Claim 23: A dermatological composition containing fluocinolone acetonide, hydroquinone and tretinoin as active agents, said composition made by the process comprising: (a) mixing water and at least one hydrophilic compound to form an aqueous composition; (b) mixing at least two hydrophobic compounds to form a non-aqueous composition; (©) mixing said aqueous composition and said non-aqueous composition to form a mixture; (d) combining said fluodnolone acetonide and said tretinoin with said mixture of step (c); (e) mixing at least one emulsifier into said mixture of step (d); and (f) homogenizing the mixture of step (e); wherein said hydroquinone is added in step (d) or after adding said at least one emulsifier in step (e). Claim 24: The dermatological composition of claim 23, wherein said aqueous composition comprises water, magnesium aluminium silicate and butylated hydroxytoluene. 27 AMENDED SHEET

   W02004/037201 PCT/US2003/033876

   Claim 25: The dermatological composition of claim 23, wherein said non-aqueous composition comprises at least two hydrophobic compounds selected from the group consisting of cetyl alcohol, stearic acid, stearyl alcohol, methyl gluceth, methylparaben, propylparaben and glycerin,

   Claim 26: The dermatological composition of claim 25, wherein said non-aqueous composition comprises cetyl alcohol, stearic acid, stearyl alcohol, methyl gluceth, methylparaben, propylparaben and glycerin.

   Claim 27: The dermatological composition of claim 23, wherein said at least one emulsifier is glyceryl! stearate, polyethylene glycol (PEG) stearate or a combination thereof.

   Claim 28: The dermatological composition of claim 27, wherein said at least one emulsifier is a combination of glyceryl stearate and polyethylene glycol stearate.

   Claim 29: The dermatological composition of claim 23, wherein said hydroquinone is added after adding said at least one emulsifier in step (e).

   Claim 30: The dermatological composition of claim 23, further comprising adding sodium metabisulfite to said mixture of step (e) after adding said at least one emulsifier.

   Claim 31: The dermatological composition of claim 23, wherein said water and said at least one hydrophilic compound are mixed at an elevated temperature.

   Claim 32: The dermatological composition of claim 31, wherein said elevated temperature is from 75°C to 80°C.

   Claim 33: The dermatological composition of claim 23, wherein said at least two hydrophobic compounds are mixed at an elevated temperature.

   Claim 34: The dermatological composition of claim 33, wherein said elevated temperature is from 75°C to 80°C. 28 AMENDED SHEET

   W02004/037201 PCT/US2003/033876 Claim 35: The dermatological composition of claim 23, wherein said water and said at least one hydrophilic compound are mixed at a temperature of from 75°C to 80°C, and said at least two hydrophobic compounds are mixed at a temperature of from 75°C to 80°C.

   Claim 36: The dermatological composition of claim 35, wherein said mixture of step (c) 1s cooled before adding said fluocinolone acetonide and said tretinoin in step (d). Claim 37: The dermatological composition of claim 36, wherein said cooled temperature is from 68°C to 72°C.

   Claim 38: The dermatological composition of claim 36, wherein said mixture of step (d) is cooled while said at least one emulsifier is mixed into said mixture of step (e). Claim 39: The dermatological composition of claim 38, wherein said hydroquinone is added in step (d) following cooling of said mixture.

   Claim 40: The dermatological composition of claim 39, wherein said mixture 1s cooled to 55°C before adding said hydroquinone.

   Claim 41: The dermatological composition of claim 35, wherein said homogenizing step (f) occurs at a temperature of 50°C.

   Claim 42: The dermatological composition of claim 41, wherein said hydroquinone is added in step (e) after said at least one emulsifier is mixed into said mixture.

   Claim 43: The dermatological composition of claim 35, wherein said mixture of step (f) is cooled to about 45°C and then adding sodium metabisulfite to said cooled mixture.

   Claim 44: The dermatological composition of claim 23 having 0.01% by weight fluocinolone acetonide, 4% by weight hydroquinone and 0.05% by weight tretinoin.

   Claim 45: A dermatological composition comprising a cream base, and 0,01% by weight fluocinolone acetonide, 4% by weight hydroquinone and 0.05% by weight tretinoin. 29 AMENDED SHEET

   W02004/037201 PCT/US2003/033876 Claim 46: The dermatological composition of claim 45, further comprising a fatty alcohol, a fatty acid, a buffer, glycerin and an emulsifier.

   Claim 47: The dermatological composition of claim 46, wherein said fatty alcohol is cetyl alcohol.

   Claim 48: The dermatological composition of claim 46, wherein said fatty acid 1s stearic acid.

   Claim 49: The dermatological composition of claim 46, wherein said buffer is citric acid.

   Claim 50: The dermatological composition of claim 46, wherein said emulsifier comprises glyceryl stearate.

   Claim 51: The dermatological composition of claim 50, further comprising polyethylene glyceryl stearate.

   Claim 52: The dermatological composition of claim 46, further comprising an opacifier.

   Claim 53: The dermatological composition of claim 52, wherein said opacifier is magnesium aluminium silicate.

   Claim 54: The dermatological composition of claim 46, further comprising a preservative.

   Claim 55: The dermatological composition of claim 54, wherein said preservative is a paraben.

   Claim 56: The dermatological composition of claim 46, further comprising butylated hydroxytoluene.

   AMENDED SHEET

   - +,” W02004/037201 PCT/US2003/033876 Lf Claim 57; The dermatological composition of claim 56, further comprising magnesium aluminium silicate, butylated hydroxytoluene, cetyl alcohol, stearic acid, stearyl alcohol, methyl paraben, propyl paraben, a mixture of glyceryl stearate and polyethylene glycol stearate, methyl gluceth, glycerin and citric acid.

   Claim 58: A cream having as the active ingredients fluocinolone acetonide hydroquinone and tretinoin, wherein said cream is absorbed rapidly by the skin. 31 AMENDED SHEET