HK1088831B - Topical skin care composition - Google Patents

Description

Topical skin care compositions

Technical Field

The present invention relates generally to a method of producing a pharmaceutical skin treatment composition.

Background

Melasma or chloasma is a common pigmentary disorder that affects women primarily during the childbearing age. Dark, mottled (hyperpigmented) patches can be seen on the face and neck, especially on the cheeks and forehead.

Melasma is usually caused by hormonal activity resulting from pregnancy or contraceptive pills. Thus, the condition is known as "facial spots of pregnancy". This condition occurs when an excess of melanin is deposited in the epidermal and dermal cells. Melasma can persist for long periods of time and often recurs during subsequent pregnancies. The condition is less common in men and accounts for about 10% of all cases.

Standard treatments include depigmentation, or bleaching, of the affected area of the skin, the use of sunscreens and the avoidance of sunlight. Hydroquinone is the most popular topical depigmenting agent. Hydroquinone in concentrations of 5% to 10% is very effective but can cause irritation. Chemical stability of hydroquinone formulations is important because hydroquinone is easily oxidized and deactivated. The most commonly used agents typically require a 16-to 20-week course of treatment, and some therapies may take longer. Tretinoin (Retin-a) is another commonly used therapeutic agent for melasma.

However, there remains a need in the art for a therapeutic method that includes several drugs for the treatment of melasma in a single composition. In addition, it would be highly beneficial to have a therapeutic vehicle such as a cream that would facilitate penetration of the drug into the skin.

U.S. patent No. 5,538,737 discloses a method of preparing a water-in-oil emulsion comprising a pharmaceutically acceptable salt of an H2-antagonist. The method comprises the following steps: dissolving a pharmaceutically acceptable salt in an aqueous medium to form an aqueous portion; mixing the water portion with an oil portion and an emulsifier to form a matrix of the water portion and the oil portion, the oil portion comprising an edible oil comprising an ester or mixed ester of glycerin; the matrix is then emulsified to form a water-in-oil emulsion.

U.S. patent No. 5,656,672 discloses a method for preparing a water-in-oil emulsion using retinal as an active ingredient. The emulsion comprises: an oily phase comprising at least one organic solvent for retinoids (e.g. aliphatic fatty alcohols) and optionally a lipophilic additive; an aqueous phase comprising water and optionally a hydrophilic additive; and an agent for emulsifying the aqueous phase in the oil phase. The oil phase and the aqueous phase are prepared separately and the aqueous phase is added to the oil phase followed by the phase comprising retinol and its solvent.

U.S. patent No. 5,660,837 discloses a process for the preparation of a pharmaceutical formulation in the form of an oil-in-water emulsion. The method comprises the following steps: adding an emulsification-stable surfactant and an optimum conventional surfactant to an oil-water two-phase system at room temperature; equilibrating the emulsion-stabilized surface active drug at the interface; adding an agent that can impart isotonicity to the final formulation; and homogenized by high pressure techniques.

U.S. patent No. 5,976,555 discloses skin care compositions. The oil-in-water emulsion matrix comprises: retinoids (retinoids); mixtures of cetearyl alcohol (ceteary alcohol) and cetearyl glycoside or polyethylene glycol ethers of stearyl alcohol; cetyl alcohol, stearyl alcohol, and mixtures thereof; a light, dry absorbable oil; and a large amount of (substentive) softener oils or waxes.

U.S. patent No. 6,080,393 discloses a skin care composition: comprising an oil-in-water emulsion comprising a therapeutically effective amount of a retinoid; wherein the oil phase comprises one or more oils, and an effective amount of at least one oil-soluble antioxidant; and wherein the composition comprises a corticosteroid.

Nevertheless, there is a need in the art for a method of making a smoother cream base (cream base) that can be used as a therapeutic for treating melasma, which will facilitate penetration of the drug into the skin.

Summary of The Invention

The present invention provides a cream base for topical application of skin care treatments and a method of producing the cream base.

The process for preparing the cream base must consist of (a) mixing the hydrophilic compound with water to form an aqueous phase; (b) mixing hydrophobic compounds to form a hydrophobic (non-aqueous or wax) phase; then (c) mixing the hydrophilic and hydrophobic phases with each other to form a two-phase mixture; and finally (d) adding an emulsifier to the biphasic mixture to form an emulsion. By mixing the aqueous phase and the non-aqueous phase and then mixing with the emulsifier, a cream having a smoother texture and disappearing when applied to the skin is obtained, compared to the prior method of preparing a cream in which an emulsifier is added to the aqueous phase or the non-aqueous phase. Because the last step of adding the emulsifier requires less wax in making the cream, a "thinner" hydrophilic cream that disappears more quickly when applied to the skin is obtained than in earlier methods of making creams where the emulsifier is added to either the aqueous or non-aqueous phase.

The cream base prepared by the method of the invention may be a carrier for any pharmaceutically active agent for dermatological use. For example, anti-acne, anti-cancer, antibiotic, anti-inflammatory, hormonal, antifungal and analgesic actives may be included in the cream base of the present invention.

In a particular embodiment, the cream base of the present invention comprises a steroid.

In a further embodiment, the cream base of the present invention comprises a keratolytic agent.

In yet another embodiment, the cream base of the present invention includes a depigmenting agent.

In further embodiments, the cream base of the present invention comprises two or more of a steroid, a keratolytic agent, and a depigmenting agent.

Examples of steroids are fluocinolone, such as fluocinolone acetonide, of keratolytic agents such as retinoic acid, and of depigmenting agents such as hydroquinone.

In a more specific embodiment, the present invention also provides a cream comprising inactive ingredients butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methyl paraben, PEG-100 stearate, propyl paraben, purified water, sodium metabisulfite, stearic acid and stearyl alcohol.

In a particular embodiment, the cream is a carrier comprising fluocinolone acetonide, hydroquinone, tretinoin and combinations thereof as active ingredients. For example, the cream may be TriCream, the first approved combination of hydroquinone, a standard depigmenting agent, with tretinoin and a steroid with low topical potency, which can be applied as a single preparationAnd (5) producing the product. TriThe recommended course of treatment for the cream is 8 weeks and after the first 4 weeks of treatment, a significant effect can be seen. Another advantage of the process of the present invention is that by controlling the temperature at which the components, including hydroquinone, are added, the cream does not turn brown, resulting in a product with a more desirable color.

Detailed description of the invention:

creams are emulsions of hydrophilic and lipophilic (hydrophobic) components. Emulsifiers or surfactants are typically included to enhance mixing of the agents to form a stable emulsion.

Various compounds including inert carriers are generally known in the art. By "inert" is meant not pharmacologically active. Typical examples of inert compounds comprising a cream base include: cetyl alcohol, lanolin, glycerol, ethanol, EDTA, methyl paraben, zinc oxide, titanium dioxide, benzoic acid, carboxymethylcellulose, dimethyl sulfoxide, polyethylene glycol, petroleum, citric acid, and stearic acid.

The present invention relates to a method of preparing a cream base as an excipient for one or more pharmacologically active agents for dermatological use.

The hydrophilic and lipophilic solutions are then mixed and formulated. One or more pharmaceutically active agents are then added to the blended mixture. One or more emulsifiers are then added to the entire blended mixture to prepare the dermatological cream of the present invention.

The temperature of the heating of the hydrophobic and hydrophilic solutions is sufficient to facilitate the obtaining of a homogeneous solution. Generally, lower elevated temperatures with longer mixing times are preferred. The temperature may also be limited by the nature of any of the individual components therein. Typically, the temperature does not exceed about 100 ℃. Preferably, the temperature does not exceed about 90 ℃ or about 80 ℃ or about 70 ℃ or about 60 ℃. In general, the heating temperature need not be precise, at least within the accuracy of standard temperature measurement methods.

It is not necessary to heat the hydrophobic and hydrophilic solutions to the same temperature. Having the same temperature may facilitate mixing of the two solutions. If the temperatures of the solutions are different, the hotter solution is cooled to the temperature of the colder solution prior to mixing.

The mixed mixture may optionally be cooled prior to mixing in the one or more pharmacologically active agents or agents. The physical properties of the active agent may determine the need for cooling.

After the cooling step and mixing, one or more emulsifiers are added. The mixture was thoroughly mixed to prepare the cream of the present invention. If the temperature is increased, the temperature may be decreased during mixing.

With respect to lipophilic components, as is known in the art, oils can be derived from animals, plants, nuts, petroleum, and the like. Oils derived from animals, plant seeds and nuts are similar to fats and thus may contain many polar acid and/or ester groups. Alternatively, oils derived from petroleum are typically aliphatic or aromatic hydrocarbons that contain substantially no polar substituents.

Oil-based products that can be used include: hydrocarbons or petrolatum obtained by distillation of petroleum (petroleum jelly); vegetable oils and liquid triglycerides; animal fat or solid natural triglycerides; and solid ethers of waxes or fatty acids such as stearic acid and palmitic acid with organic alcohols. Lanolin (Lanolin) or Lanolin (wool fats) prepared from fatty acids and cholesteryl esters; cetyl and stearyl alcohols, which are solid alcohols obtained by hydrogenation of their corresponding acids, may also be used. Depending on whether the lipophilic group is anionic or cationic, amphoteric compounds, such as soaps or fatty acid salts, may be acidic or basic, sulfated alcohols and synthetic surfactants as semisynthetic substances are known in the art, and may also be used. Glycerol is obtained from fats and, due to its hydrophobic nature, has the property of drawing water from the surface of mucous membranes or bare skin. Due to its hydrophilic nature, glycerin does not damage intact skin and is an effective humectant.

Other materials that may be used in the topical formulations of the present invention include: liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives and other similar starting materials. Specific examples include monohydric and polyhydric alcohols, for example, ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexylene glycol, mannitol, cetyl alcohol and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylene; polyethylene glycol having a molecular weight of 200 to 20,000; polyoxyethylene glycerols; polyethylene oxide; sorbitol; and stearoyl diacetin.

Topical carriers often include alcohols and water to accommodate lipophilic and hydrophilic components. Other components include buffers such as sodium hydroxide, sodium citrate or tetrasodium ethylenediaminetetraacetate; an excipient; flavors such as menthol; opacifiers such as zinc oxide, magnesium aluminum silicate and titanium dioxide; preservatives such as dichlorobenzyl alcohol, benzoic acid, methylparaben and benzyl alcohol; an antioxidant; gelling agents such as petrolatum and mineral waxes; thickeners such as carboxymethyl cellulose; a stabilizer; a surfactant; a softening agent; colorants, and the like.

In addition, topical carriers may include penetration enhancers, which may be construed as: various compounds for increasing skin permeability are known in the art, for example, dimethyl sulfoxide (DMSO), Dimethylformamide (DMF) and N, N-Dimethylacetamide (DMA), decylmethyl sulfoxide, polyethylene glycol monolaurate and 1-substituted azepan-2-one.

A wide variety of different emulsifiers or surfactants can be used to prepare the topical formulations of interest. Non-limiting examples of amphoteric surfactants useful in the compositions of the present invention are disclosed in McCutcheon's, "Detergents and Emulsifiers", North American edition (1986) and McCutcheon's, "Functional Materials", North American edition (1992); both of which are incorporated herein by reference in their entirety. Surfactants which may be used are betaines, sulphobetaines and hydroxysulphobetaines. Examples of betaines include higher alkyl betaines, such as coco dimethyl carboxymethyl betaine, lauryl dimethyl alpha-carboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyl dimethyl betaine, lauryl bis (2-hydroxyethyl) carboxymethyl betaine, stearyl (steryl) bis (2-hydroxypropyl) carboxymethyl betaine, oleyl dimethyl gamma-carboxypropyl betaine, lauryl bis (2-hydroxypropyl) alpha-carboxyethyl betaine, coco alkyl (coco) dimethyl sulfopropyl betaine, stearyl dimethyl sulfopropyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl bis (2-hydroxyethyl) sulfopropyl betaine, amido betaines, amido sulfobetaines, oleyl betaine and coconut (cocamido) amidopropyl betaine. Examples of sulfobetaines and hydroxysulfobetaines include cocamidopropyl hydroxysulfobetaine. Examples of other amphoteric surfactants are alkyl imino acetates, imino dialkanoates and aminoalkanoates.

Examples of anionic surfactants are also disclosed in McCutcheon's, "Detergents and emulsifiers", North American edition (1986) and McCutcheon's, "Functional Materials", North American edition (1992). Examples include alkanoyl isothionates (isothionates), alkyl and alkyl ether sulfates, for example, cocoyl (cocoyl) isothionates, cocoyl isothionates, lauroyl isothionates, stearoyl isothionates, and mixtures thereof, sarcosinates, for example, sodium lauroyl sarcosinate, sodium cocoyl sarcosinate and ammonium lauroyl sarcosinate, sodium dodecyl sulfate, ammonium cetyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, ammonium cocoyl isethionate, sodium lauroyl sarcosinate, and mixtures thereof.

Other emulsifiers include tricetareth-4-phosphate, lauryl ether (laureth) -4-phosphate sodium or oleth-3.

Examples of nonionic emulsifiers include sorbitan monostearate, glycerol monostearate, polysorbates, fatty alcohol polyethylene derivatives, fatty alcohol polyoxyethylene ethers, such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene nonylphenyl ether and the like, sorbitan stearates, glycerol stearate, C12-C18 fatty alcohols, esters and ethers thereof, fatty alcohols such as cetyl alcohol or stearyl alcohol or mixtures of both, oxyethylated or polyglycerolated fatty alcohols or α -diols, for example oleyl alcohol polyoxyethylated with 10 moles of ethylene oxide, polyglycerolated (polyglycolated) 1, 2-octadecanediols with 2 or 7 moles of glycidyl, cyclic fatty alcohols, fatty acid glycol esters such as ethylene stearate, glycerol monostearate or distearate, polyethylene glycol esters of fatty acids such as polyethylene glycol stearate, oxyethylenated or non-oxyethylenated sorbitan fatty acid esters sold under the trade name Tweens or Spans, fatty acid esters of sucrose, fatty acid ester derivatives of glucose such as methyl glucoside sesquistearate and methyl glucoside sesquistearate polyoxyethylenated with 20 moles of ethylene oxide, Arlacel 165 and Myrj52, fatty alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide, alkylphenols having 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono-and di-fatty acid esters of ethylene glycol in which the fatty acid moiety contains 10 to 20 carbon atoms, diethylene glycol, polyethylene glycol having a molecular weight of 200 to 6000, propylene glycol having a molecular weight of 200 to 3000, glycerin, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophilic wax esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycol fatty acid esters and polyol fatty acid esters.

Examples of cationic emulsifiers include quaternized ammonium bromide and chloride salts, cetyltrimethylammonium chloride, benzalkonium chloride and cetylpyridinium chloride, aliphatic amines having aliphatic chains, such as oleylamine and dihydroabietylamine; quaternary ammonium compounds, for example, lauryl dimethyl benzyl ammonium chloride, amides derived from amino alcohols, for example N-aminoethyloleamide, N- (stearoyl-cholamino) -formylmethyl) pyridinium chloride, N-soya (soya) -N-ethylmorpholinium ethanesulfonate (ethoxyphase), alkyldimethylbenzyl ammonium chloride, di-isobutylphenoxyethoxyethyldimethylbenzyl ammonium chloride, hexadecylpyridinium chloride, N- (stearoyl-cholamino-formylmethyl) pyridinium chloride, N-soya-N-ethylmorpholinium ethanesulfonate, alkyldimethylbenzyl ammonium chloride, (diisobutylphenoxyethoxy) ethyldimethylbenzyl ammonium chloride, PG-dimonochloridate, stearamidopropyldimonium sulfosuccinate, stearamidopropyldimethyl (tetradecylacetate) ammonium chloride, stearamidopropyldimethylcetylstearylammonium tosylate, stearamidopropyldimethylammonium chloride, stearamidopropyldimethylammonium lactate, ammonium halides, more particularly chlorides and bromides, such as alkyltrimethylammonium chloride, dialkyldimethylammonium chloride and trialkylmethylammonium chlorides, for example stearyltrimethylammonium chloride, distearyldimethylammonium chloride, lauryldimethylammonium chloride, lauryldimethylbenzylammonium chloride and tricetylmethylammonium chloride, commercially available quaternized protein hydrolysates or protein hydrolysates derived with amino groups, for example under the trade name stearamidopropyldimethyl (tetradecylacetate) ammonium chloride, stearamidopropyldimethylcetylammonium tosylate, stearamidopropyldimethylammonium chloride, ammonium chloride, and also ammonium halides, lauryl dimethyl benzyl ammonium chloride and tricetylmethylammonium chloride, and commercially available quaternizedAndstearamidopropyl PG-dimonium chloride phosphate, stearamidopropyl ethyldimonium ethanesulfonate, stearamidopropyl dimethyl (tetradecyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, and stearamidopropyl dimethyl ammonium lactate.

The compositions of the present invention may include various other components. "CTFA Cosmetic Ingredient Handbook", Second edition, 1992, which is incorporated herein by reference in its entirety, describes a variety of Cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the present invention. Examples of functional components are: absorbents, abrasives, anti-acne agents, anti-caking agents, antifoaming agents, antimicrobial agents, antioxidants, binders, biological additives, buffering agents, fillers, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic antimicrobial agents (cosmetic biochides), denaturants, drug astringents, external analgesics, film formers, perfume components, humectants, opacifiers, pH adjusters, plasticizers, preservatives, propellants, reducing agents, skin whitening agents, skin conditioning agents (emollients and humectants), skin protectants, solvents, foam boosters, hydrotropes, solubilizers, suspending agents (non-surfactants), sunscreens, uv absorbers and viscosity increasing agents (aqueous and non-aqueous).

Various starting materials for preparing topical formulations are known in the art, and references can be found in known articles, as well as in U.S. patent nos. 6,013,271; 6,267,985, respectively; 4,992,478; 5,645,854; 5,811,111, respectively; and 5,851,543.

A wide variety of pharmaceutically active agents can be used in dermatological formulations of interest. Thus, any known antibiotic, anti-acne agent, antineoplastic agent, bleaching agent, keratolytic agent, anti-inflammatory agent, antifungal analgesic, and the like may be used.

A variety of cytostatic agents may be used, examples of which include cytostatic agents, alkylating agents, enzyme inhibitors, proliferation inhibitors, DNA synthesis inhibitors, lytic agents, DNA intercalating agents, metabolic antagonists, and the like illustrative agents include steroids, paclitaxel, ionomycin (ionomycin), etoposide, nitrosoureas such as nitrosourea mustard (BCNU), subphenamine, daunorubicin (daunosubicin), actinomycin D, meclorethamine, busulfan, CCNU, Me-CCNU, chlorambucil, actinomycin C (cactinomycin), carcinotropic, dichloroethyl-beta-naphthylamine, 6-chloropurine, azathioprine, fluorouracil, hydroxyurea, thioquinine, camptothecin, mitomycin, cyclohexylurea (CCNU), methylcyclohexylurea (Me-CCnitroso), cantharidine, platinum, toxinones, ricin, interferons, interleukins, tumor necrosis factors, vincristine, mitotane melphalan, methchlorethamine, plicamycin, nitracridine, nitoxantrone, methotrexate, nogomycin, streptonigrin, streptozotocin, tegafur, pyrrolidinomethyltetracycline (tetramin), testosterone decarbonylcolchicine and actinomycin other compounds that may be used include cyctophamide, cyclosporine, amsacrine, bisantrene hydrochloride, camostat mesylate, camptothecin, enocitabine, etoposide, epirubicin hydrochloride, fludarabine phophate, flutamide, fotemustine, noroxydol hydrochloride, ionomycin, onidamine, mitoxantrone hydrochloride, nilutamide, paclitaxel, pirimacin, toremifene citrate, vinorelbine, dimethamicin, quintocin, meclizine, santonine, meclizine, penoxepirubicin, penoxsulin, camptothecin, meclizine, penoxsultrine, tacrine, santonine, meclizine, santonine, penoxsultrine, amonafide, melbaruron, and the like. Other agents that may be used include mitomycin C, cisplatin, mechlorethamine, daunorubicin, nitrosourea mustard, pyrazine diazonium hydroxide, fumagillin analog FF-111142, rhyzoxin, dynemicin A, chlorambucil, methylcyclohexylnitrosourea, and the like.

Suitable keratolytic agents include salicylic acid, derivatives of salicylic acid, such as 5-octanoylsalicylic acid, and resorcinol; retinoids such as vitamin a acid and their derivatives (e.g., cis and trans); sulfur-containing D and L amino acids and derivatives and salts thereof, particularly N-acetyl derivatives, such as N-acetyl-L-cysteine; lipoic acid; antibiotics and antimicrobials such as benzoyl peroxide, actaspirox, tetracycline, trichorbanilide, azelaic acid, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, ethyl acetate, clindamycin and meclocycline; sebostats such as flavonoids; and bile salts such as scymnol sulfate and its derivatives, deoxycholate and cholate.

Examples of anti-wrinkle and anti-skin atrophy actives that may be used in the topical formulations of interest include: retinoic acid and derivatives; retinol; retinyl ester; salicylic acid and derivatives thereof; sulfur-containing D and I amino acids and their derivatives and salts, specifically, N-acetyl derivatives, thiols, such as ethanethiol; α -hydroxy acids, such as glycolic acid, and lactic acid; phytic acid, lipoic acid; lysophosphatidic acid, and skin peeling agents (skin peel agents), for example, phenol.

Examples of non-steroidal anti-inflammatory drugs that may be used in the present invention include propionic acid derivatives; an acetic acid derivative; fenamic acid (fenamic acid) derivatives; a biphenyl carboxylic acid derivative; and oxicams and include acetylsalicylic acid, ibuprofen, naproxen, benoxaprofen, fluhiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pyrrollol, carprofen, oxaprozin, pranoprofen, microprofen, thioprofen, suprofen, alminoprofen, tylophoric acid, fluprofen, and bucloxic acid.

Examples of local anesthetics that can be used in the topical formulations of the present invention include: benzocaine, lidocaine, bupivacaine, chloroprocaine, novocaine, etidocaine, carbocaine, tetracaine, dyclonine, hecaine, procaine, cocaine, ketamine, pramoxine, phenol, and pharmaceutically acceptable salts thereof.

Examples include cortisone, hydrocortisone and derivatives thereof including deoxycrtisone, flucetonide, fludrocortisone acetate, fludroacetonide, medroxyprogesterone; prednisone, prednisolone and its derivatives include amsafari, amcinamide, the benzoate, valerate and dipropionate of betamethasone, clorprenaline acetate, desolone (descalinone) acetonide, desonide, dexamethasone, dichloropine acetate, difluoresinone, fluocinolone acetonide, diflunisal, flunisolide acetate, fluocinolone acetonide, fluocortolone, fluoromethoxyprednisolone, fluperoline acetate, fluprednisolone valerate, methylprednisolone, paramethasone acetate, prednisolomate, acetate, butyl acetate and phosphate sodium salts of prednisone, fluocinolone acetonide, triamcinolone acetonide, diacetate, hydrocortisone butyrate, difluromellone pivalate, halcinonide and triamcinolone acetonide.

Examples of other active ingredients that may be used in the topical formulations of the present invention include acebutolol, acetaminophen, acetylhydroxamic acid, acetophenazine, acyclovir, allopurinol, alprazolam, aluminum hydroxide, amantadine, albuterol, potassium aminobenzoate, amobarbital, amoxicillin, amphetamine, ampicillin, androgen, anesthetic, anticoagulant, anticonvulsant, antithyroid, appetite suppressant, aspirin, atenolol, atropine, azatadine, ampicillin phthalate, baclofen, beclomethasone, belladonna, bendroflumethiazide, benzoyl peroxide, benzylthiazide, benztropine, methionyl choline, ancrod, diacetyloxyphenyl picoline, bromoergoline, diphenhydramine, brompheniramine, chlorpheniramine, clobutazine, butanamide, busulfan, butobarbital, pyrilamine, caffeine, calcium carbonate, captopril, arbamazepine, carbenicillin, carbidopa, levodopa, carbinoxamine inhibitors, carbonic anhydrase, myotonine, acrivaphenazine, cascara, chlorocephalosporin, cefadroxil, cephalomycin IV, cephalomycin VI, chlorodiphenylethamine, chloral hydrate, chlorambucil, chloramphenicol, chlordiazepoxide, chloroquine, chlorothiazide, chlorothianiene, chlorpheniramine, chlorpromazine, chlorpropamide, tylon, chlorthalidone, chlorzoxazone, chlozolone, cholestyramine, cimetidine, cinnoxine, clemastine, clindamine, clindamycin, coronatine, clomiphene, clonidine, cloratronate, chlorazol, colchicine, colesteol, estrogens, contraceptives, androgens, cyclohexacrillin, meclizine, mec, cyclophosphamide, cyclothiazine, cyclizine, cyproheptadine, danazol, dihydroxyanthraquinone, nifedipine, dapsone, dexamphetamine, dexchlorpheniramine, methaphen, diazacycloheptane, dicloxacillin, dicyclomine, diethylstilbestrol, diflunisal, digitapril, quinuclidine, dimenhydrinate, dimetindidine, cotinamine, diphenylpiperidinebutanol, diphenoxylate, diphenoxypyriline, dipyridamole, dosulpine, dithiolin, divalprorex, docusate calcium, docusate potassium, docusate sodium, doxyloamine, cannabinolic ephedrine, epinephrine, goloidmesyles, ergonovine, ergotamine, erythromycin, harestropipute, etynoic acid, chloroethylpentol, prophenamine, ethoximide, 3-ethyl-5-phenylhydantoin, fexofenadine, fenoprofen, ferrous sulfate, flufenapyr, fluorodiazepam, folic acid, furosemide, gemfibrozil, glimepiridine, euglycemic, glycopyrrolate, gold compounds, griseofuwin, guaifenesin, guanabenz, guanaderol, guanethidine, halazepam, haloperidol, hydrastin, cyclohexarbituril, hydralazine, podophyllotoxin (Podofilox) (0classenDermatologics), podophyllum resin (Podophyllin) (Paddock Labs), imiquimod (3M Pharmaceuticals), hydrochlorothiazide, hydroflumethiazide (hydroflumethiazide), hydroxychloroquine, hydroxyzine, hyoscyamine, ibuprofen, indapamide, indomethacin, insulin, iofoquinol, iron-polysaccharides, isopropanoethylnoradrenaline, isoniazid, isoproterenyl, isoproterenol, isotretinoin, isorprenarroneine, isoveronic acid, isosulconazole, kaolin, levosulosin, ketol, levamisole, fluazin, fluazinam, prochlorethamine, prochloraz, propiconazole, fluazin, propiconazole, levamitocin, propiconazole, fluazinam, levamikazinol, propiconazole, propi, magnesium hydroxide, magnesium sulfate, magnesium trisilicate, maprotiline, meclizine, medofenamate, medroxyproylester, melenamic acid, milfoil, mefenton, mefenofibrate, meprobarbital, annine, mercaptopurine, thiamphenicol, dihydroxyphenyl isopropylaminoethanol, metaxalone, methamphetamine, mexofenadine, mequinazone, methabenzydate, urotropin, methicillin, methocarbamol, methotrexate, methsuximine, meththecin, methylcelluose, methyldopa, methylergonovine, ritalin, methylprednisolone, dimethylergometridine, metoclopramide, metoprolol, metronidazole, mitotane, monoamine oxidase inhibitors, hydroxyamphetamine, ethoxynaphthalene, nalidixic acid, naproxen, narcotic analgesics, neomycin, neostigmine, nicotinic acid, nifedipine nitrate, nitrone, nifedipine (nifedipine, benproperine, nystatin, o-tolylhydramine, neopenicillin, nordiazepam, propranolol, oxyphenbutazone, pancrelipase, pantothenic acid, papaverine, para-aminosalicylic acid, tincture of complexed camphor, pemoline, penicillamine, penicillin, pentobarbital, perphenazine, phenacetin, phenazopyridine, antin, phenobarbital, phenolphthalein, coumaryl alcohol, phensuamine, phenylbutazone, phenylephrine, phenylpropanolamine, phenyl tolamine, phenytoin, pilocarpine, propranolol, piperitadine, piroxicam, poloxamer, calcium polycarbophil, polythiazine, potassium supplement, pruzepam, prazosin, mesoline, proparazine, probucol, procainamide, procarbazine, prochlorperazine, promethazine, mepiquin, proparazine, proparacaine, mepiquin, promethazine, pseudoephedrine, pseudopropiram, pseudopicoline-1-methylcamphetamine, pseudopropine, pseudopropidium, pseudoephedrine, pyrodoxine, pyrilamine, phentermine, ethinylestradiol, fluquinidone, quinidine, quinine, ranitidine, rauwoltrine, riboflavin, rifampicin, ritodrine, salicylate, hyoscyamine, secobarbital, senna, sannosides, simethicone, sodium bicarbonate, sodium phosphate, sodium fluoride, spironolactone, sucrolate, sulfacetamide, sulfamethoxazole, sulfasalazine, fensulazolone, sulfisoxazole, sulindac, taberone, tamazepam, terbutaline, terfenadine, terphylate, tetracyclines, thiabendazole, thyroxine, carbothiophene, timolol, tocardine, tolazamide, tolbutamide, tolfenpyrazamide, tolbutamide, thiofenacetrimide, trothiothixene, trimethoprim, thifluazulene, trimethoprim, thifluazulene, triamcinolone, trimethine, thiuram, trimethoprim, thiuracils, trimethoprim, trifluoperazine, triflumomazine, trihexyphenidyl, isobutylazine, trimethobenzamine, trimethoprim, triprenamine, triprolidine, valproic acid, verapamil and xanthine.

The amounts of inert ingredients and active agents(s) in the dermatological preparations of the invention are generally known in the art. One skilled in the art would be able to deduce the specific amounts of the components used to obtain the cream of the present invention.

The particular amount of any one component used is not critical and the precision of the amount used is that of assays or formulation methods known in the art.

In one embodiment of the present invention, wherein the aqueous phase consists essentially of water, magnesium aluminum silicate, glycerol, and butylated hydroxytoluene.

In one embodiment of the invention, about 344.8 kilograms of water, 15.0 kilograms of magnesium aluminum silicate, and 0.2 kilograms of butylated hydroxytoluene are first combined and mixed at 75-80 ℃ to form the aqueous phase. Mixing can be carried out with side-scraping agitation at a fixed rate. The resulting aqueous phase is a suspension.

In the second step, about 20.0kg of cetyl alcohol, 15.0 kg of stearic acid, 20.0kg of stearyl alcohol, 25.0 kg of methylgluceth-10) 0.9 kg of methyl paraben, 0.1 kg of propyl paraben and 20.0kg of glycerin are mixed together at moderate speed at about 75-80 c to form a non-aqueous phase. At one isMix in the mixer at medium speed. The resulting non-aqueous phase is a suspension. The second step may be performed before, after or simultaneously with the first step.

The non-aqueous phase is then added to the aqueous phase and the combined two-phase mixture is cooled to a temperature in the range of 68 ℃ to 72 ℃, or to about 70 ℃, followed by the addition of about 17.5kg165. 0.25kg tretinoin and 0.050kg fluocinolone acetonide, and stirred during cooling. When the mixture reached 60 ℃, 0.25kg of citric acid was added with mixing and cooling.

When the temperature reached 55 deg.C, 20.0kg of hydroquinone were added with mixing and cooling. When the temperature reached about 50 ℃, the mixture was homogenized with a homogenizer with continued cooling. When the mixture reached 45 ℃, 1.0kg of sodium metabisulfite was added with stirring and cooling. Typically, sodium metabisulfite is added about 30 minutes after the addition of hydroquinone. Mixing can be carried out in a side-scraping mixer at a fixed rate. The resulting composition of matter is an emulsion, i.e., a cream.

The addition of sodium metabisulphite as the cream cools advantageously results in a well mixed mixture of substances in which the sodium metabisulphite is uniformly mixed throughout the cream and prevents oxidation of the hydroquinone throughout the cream.

The preparation of the pharmaceutical composition of the present invention is facilitated by the addition of an emulsifier after the non-aqueous and aqueous phases have been mixed. When standard techniques of adding an emulsifier to the non-aqueous phase and then mixing with the aqueous phase are used, an emulsion cannot be formed. However, according to the process of the present invention, an effective emulsion is formed when the emulsifier is added to the cooled mixture of non-aqueous and aqueous phases. Emulsions can be formed even if the relative proportions of the non-aqueous phase and the aqueous phase according to a successful process of the invention are the same as the proportions in which an emulsion cannot be formed using standard techniques for adding a non-aqueous phase containing an emulsifier to an aqueous phase.

The obtained TRIThe cream contains fluocinolone acetonide, hydroquinone and tretinoin in a hydrophilic cream base for topical application. Per gram of TRIThe cream contained fluocinolone 0.01% (0.1mg), hydroquinone 4% (40mg) and tretinoin 0.05% (0.5mg) as active ingredients, and contained butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl glucoside decaethylene oxide (methyl gluceth10), methyl paraben, PEG-100 stearate, propyl paraben, purified water, sodium metabisulfite, stearic acid and stearyl alcohol as inactive ingredients, as shown in table 1.

TABLE 1

Fluocinolone is a synthetic fluorinated corticosteroid used in topical dermatology and is therapeutically classified as an anti-inflammatory agent. It is a white crystalline powder, odorless and stable to light. The chemical name of fluocinolone is (6, 11, 16) -6, 9-difluoro-11, 21-dihydroxy-16, 17- [ (1-methyl)Ethylene) bis (oxy)]-pregna-1, 4-diene-3, 20-dione. The molecular formula is C₂₄H₃₀F₂O₆The molecular weight was 452.50.

Hydroquinone is therapeutically classified as a depigmenting agent. It is prepared by reducing p-benzoquinone with sodium bisulfite. It exists in the form of fine white needles, which darken upon exposure to air. The chemical name of hydroquinone is 1, 4-benzenediol. The molecular formula is C₆H₆O₂The molecular weight was 110.11.

Retinoic acid is all-trans-retinoic acid formed by oxidation of the aldehyde group of retinal to a carboxyl group. It is highly reactive to light and humidity. Retinoic acid is therapeutically classified as a keratolytic. The chemical name of tretinoin is:

(all-E) -3, 7-dimethyl-9- (2, 6, 6-trimethyl-1-cyclohexen-1-yl) -2, 4, 6, 8-nonatetraenoic acid molecular formula is C₂₀H₂₈O₂The molecular weight was 300.44.

TRI-LUMA^TMCreams are typically supplied in 30 gram aluminum tubes, NDC0299-5950-30, and stored at controlled room temperatures of 68 to 77F (20-25℃).

The details of one or more embodiments of the invention are set forth in the description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the methods and materials now described are preferred. 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 "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used 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 the specification are herein incorporated by reference.

The following examples are provided to more fully illustrate preferred embodiments of the invention. These examples should not be construed as limiting the scope of the invention as defined by the appended claims.

Example I

Human pharmacokinetics

1g (group I, n ═ 45) or 6g (group II, n ═ 14) TRI was used daily for 8 weeksCream, unchanged tretinoin, hydroquinone and fluocinolone acetonide were found to be minimally absorbed transdermally into the systemic circulation of two groups of healthy volunteers (total n 59).

Quantifiable plasma concentrations were obtained for tretinoin in 57.78% (26 out of 45) and 57.14% (8 out of 14) subjects in group I. The indicated amounts of tretinoin, reflected by Cmax values, ranged from 2.01 to 5.34ng/mL (group I) and 2.0 to 4.99ng/mL (group II). Thus, TRI is used dailyCreams lead to minimal increase in the intrinsic level of normal tretinoin. Circulating retinoic acid levels represent only a fraction of the retinoids associated with total retinoic acid, which includes metabolites of retinoic acid and is sequestered from surrounding tissues.

For hydroquinone, quantifiable plasma concentrations were obtained in 18% (8 out of 44) subjects in group I. The hydroquinone displayed amount, as reflected by the Cmax value, ranged from 25.55 to 86.52 ng/mL. All group II subjects (6g dose) had undetectable low post-dose plasma concentrations.

For fluocinolone, group I and group II subjects had undetectable low post-dose plasma concentrations.

The following tests may be helpful in evaluating patients: (a) ACTH or corticotropin agonism assays;

(b) a.m. plasma hydrocortisone assay; and (c) the urine free cortisol test.

Example II

Human clinical study

Two efficacy and safety studies were conducted in 641 patients with melasma between the ages of 21 and 75, who had skin phototypes I-IV and moderate to severe facial melasma. Will TRIThe cream was compared with three possible combinations formed by two of the three active ingredients [ (1) hydroquinone 4% (HQ) + tretinoin 0.05% (RA); (2) fluocinolone 0.01% (FA) + tretinoin 0.05% (RA); (3) fluocinolone 0.01% (FA) + Hydroquinone 4% (HQ)]They are contained in and react with TRICream in the same vehicle.

After washing the patient's facial ears with a mild soap-free cleanser, they were asked to use the study medication every night for 8 weeks. Patients were also asked to apply a thin layer of the study drug at the hyperpigmented lesion to ensure coverage of the entire lesion, including the outer margin skin extending to normal pigmented skin. The patient is provided with a mild moisturizer for use as needed and is given daily sunscreen with SPF 30. additionally, the patient is asked to avoid sun exposure to the face and to wear a protective garment.

Patients were assessed for severity of melasma during the initial period and at 1, 2,4 and 8 weeks of treatment. The primary efficacy is based on the proportion of patients assessed by the investigator as successful in treatment, which is defined as the elimination of melasma at the end of the eight week treatment period. The majority of patients enrolled in both studies were caucasian (approximately 66%) and female (approximately 98%). Proved TRIThe cream is significantly more effective than any other combination of active ingredients.

Using TRIPatients with cream experienced improvement in melasma as early as 4 weeks. However, in use TRIOf 7 patients who had black spots cleared after 4 weeks of cream treatment, 4 of them did not maintain remission after 4 additional weeks of treatment.

After 8 weeks of treatment with the study agent, the patient entered an open-standard extension time (openlabel extension time) at which time TRI was administeredCreams are based on the need to treat melasma. In the study, TRI was usedAfter 8 weeks of cream treatment, most patients had at least some improvement. Dark spots in some patients were completely eliminated (38% in one study and 13% in the other).

By TRIIn most patients treated with cream, their melasma returned after treatment. Between the course of the progressive treatment, the period of remission appears to be shortened. In addition, few patients maintain complete clearance of melasma (approximately 1 to 2%).

TABLE 2

Investigator assessment of treatment success at the end of 8 weeks of treatment

Treatment success was defined as: melasma severity score was zero (melasma foci eliminated hyperpigmentation).

# P-was obtained from Cochran-Mantel-Haenszel chi-square statistics, with centralized (spolled) investigators as controls, and TRIThe creams were compared to another treatment group.

On day 56 of treatment, 161 patients were evaluated as improving based on the severity of melasma at the start of the trial. As shown in table 3, 61% (99 patients) experienced an improvement in the condition from "moderate" to "mild" or "clear" and 68% (25 patients) showed an improvement from "severe" to "mild" or "clear" over the 8 week treatment period.

TABLE 3

Investigator's assessment of the change in severity of melasma from start to treatment for 56 days (mixed results from studies 1 and 2)

^aAssessment based on patients with a severity score on day 56. Percentages are based on the total number of populations in the treatment group.

^bPatients who had cleared the patient before day 56 or who missed the assessment on day 56 were excluded. And (4) evaluation scale: eradication (melasma focus approximately corresponds to surrounding normal skin or has little residual pigmentation); mild (slightly darker than surrounding normal skin); moderate (moderately darker than surrounding normal skin);severe (significantly darker than the surrounding normal skin).

Example III

Adverse reaction in humans

In a patch test study to determine the allergic potential in 221 healthy volunteers, three volunteers were paired with TRIThe cream or its component has anaphylaxis.

In a controlled clinical trial, TRI was administered once daily during 8 weeks of treatmentSide effects were monitored in 161 patients on the cream. During these studies, 102 (63%) patients experienced at least one treatment-related side effect. The most commonly reported phenomena are erythema, peeling, burning, dryness, and itching at the site of use. Most of these side effects have mild to moderate severity. Comparison with TRI, according to control clinical studies, reported by at least 1% of patients and judged by the investigatorThe side effects (in descending order of frequency) moderately associated with cream treatment are summarized as follows:

TABLE 4

In at least 1% or more of patients (N161), with TRIThe incidence and frequency of side effects associated with cream treatments

In open-label long-term safety studies, TRI was usedPatients with 6 months of cream accumulation treatment of melasma showed a similar pattern of side effects as in the 8 week study. Topical corticosteroids rarely report the following local side effects. They may occur more often due to the application of occlusive dressings (occlusive dressings), in particular with corticosteroids that have a high potency. These reactions are listed in approximately descending order of occurrence: burns, itching, irritations, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infections, skin atrophy, streaks and miliaria.

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

The foregoing description is provided for the purpose of illustration only and is not intended to limit the invention to the precise form disclosed, but rather is limited only by the scope of the appended claims.

Claims (29)

1. A process for preparing a topical pharmaceutical composition which is an emulsion comprising water and fluocinolone acetonide, hydroquinone and tretinoin as active ingredients, which process comprises:

(a) mixing water and at least one hydrophilic compound selected from the group consisting of magnesium aluminum silicate and butylated hydroxytoluene to form an aqueous phase;

(b) mixing at least two hydrophobic compounds selected from the group consisting of cetyl alcohol, stearic acid, stearyl alcohol, methyl gluceth, methyl paraben, propyl paraben and glycerol to form a non-aqueous phase;

(c) combining the aqueous phase and the non-aqueous phase in the absence of an emulsifier to form a biphasic mixture;

(d) mixing fluocinolone acetonide and tretinoin into the mixture of step (c);

(e) mixing at least one emulsifier selected from the group consisting of glyceryl stearate, polyethylene glycol (PEG) stearate, and combinations thereof into the mixture of step (d); and

(f) the mixture is homogenized to form an emulsion,

wherein hydroquinone is added in step (d) or after addition of at least one emulsifier in step (e).

2. The method of claim 1, wherein the non-aqueous phase comprises cetyl alcohol, stearic acid, stearyl alcohol, methylparaben, and propylparaben.

3. The method of claim 1, wherein step (a), step (b), or both are performed at a temperature above room temperature to provide a heated phase.

4. The process of claim 3, wherein said heated phase is cooled prior to said mixing step (c).

5. The process of claim 3, wherein said heated biphasic mixture is cooled prior to step (d).

6. The method of claim 1 wherein the emulsifier is165。

7. The process of claim 1, wherein the aqueous phase consists of: water, magnesium aluminum silicate and butylated hydroxytoluene.

8. The process of claim 1, wherein the non-aqueous phase consists of: cetyl alcohol, stearic acid, stearyl alcohol, methyl g1uceth, methylparaben, propylparaben and glycerol.

9. The process of claim 1, wherein the hydroquinone is added after the at least one emulsifier is added in step (e).

10. The process of claim 1, further comprising adding sodium metabisulfite to said mixture of step (e) after adding said at least one emulsifier.

11. The process of claim 1, wherein the water and the at least one hydrophilic compound are mixed at an elevated temperature sufficient to facilitate the obtainment of a homogeneous solution, the elevated temperature being from 75 ℃ to 80 ℃.

12. The method of claim 1, wherein the at least two hydrophobic compounds are mixed at an elevated temperature sufficient to facilitate the obtaining of a homogeneous solution, the elevated temperature being 75 ℃ to 80 ℃.

13. The method of claim 1, wherein the water and the at least one hydrophilic compound are mixed at 75 ℃ to 80 ℃, and the at least two hydrophobic compounds are mixed at 75 ℃ to 80 ℃.

14. The process of claim 13, wherein the mixture of step (c) is cooled prior to adding the fluocinolone acetonide and the tretinoin of step (d).

15. The method of claim 14, wherein the cooling temperature is 68 ℃ to 72 ℃.

16. The process of claim 13, wherein the mixture of step (d) is cooled while adding the at least one emulsifier in step (e).

17. The process of claim 14, wherein the hydroquinone is added to step (d) after cooling the mixture of step (c).

18. The process of claim 17, wherein the mixture is cooled to 55 ℃ prior to the addition of the hydroquinone.

19. The process of claim 13, wherein said homogenizing step (f) is conducted at a temperature of 50 ℃.

20. The process of claim 16, wherein the hydroquinone is added to step (e) after the at least one emulsifier is added.

21. The process of claim 18, wherein the mixture is cooled to 45 ℃ and then sodium metabisulfite is added to the cooled mixture.

22. A topical pharmaceutical composition made by the method of any one of claims 1-21.

23. The topical pharmaceutical composition of claim 22, comprising 0.01 wt% fluocinolone acetonide; 4 wt% hydroquinone and 0.05 wt% tretinoin.

24. A pharmaceutical composition for topical application, the composition being an emulsion comprising fluocinolone acetonide, hydroquinone and tretinoin as active ingredients, the composition being prepared by a process comprising the steps of:

(a) mixing water and at least one hydrophilic compound selected from the group consisting of magnesium aluminum silicate and butylated hydroxytoluene while heating at a temperature of not more than 80 ℃ to form an aqueous phase;

(b) mixing at least two hydrophobic compounds selected from the group consisting of cetyl alcohol, stearic acid, stearyl alcohol, methyl gluceth, methyl paraben, propyl paraben and glycerol, while heating at a temperature not higher than 80 ℃ to form a non-aqueous phase;

(c) combining the aqueous phase and the non-aqueous phase in the absence of an emulsifier to form a biphasic mixture;

(d) stirring and cooling the biphasic mixture to a temperature of 70 ℃ and then adding the fluocinolone acetonide and tretinoin;

(e) while stirring and cooling the mixture to a temperature of 70 ℃, adding at least one emulsifier selected from the group consisting of glyceryl stearate, polyethylene glycol (PEG) stearate, and combinations thereof; and

(f) the mixture is homogenized to form an emulsion,

wherein hydroquinone is added in step (d) or after addition of at least one emulsifier in step (e).

25. The pharmaceutical composition of claim 24, comprising 0.01% by weight fluocinolone acetonide, 4% by weight hydroquinone and 0.05% by weight tretinoin.

26. The pharmaceutical composition of claim 24 wherein the emulsifying agent is165。

27. The pharmaceutical composition of claim 24, wherein hydroquinone is added after step (e).

28. The pharmaceutical composition of claim 27, further comprising adding sodium metabisulfite to the mixture of step (e) after the addition of at least one emulsifier.

29. A pharmaceutical composition consisting essentially of: 0.01% by weight fluocinolone acetonide; 4% by weight of hydroquinone; 0.05 wt% tretinoin; 0.04 wt% butylated hydroxytoluene; 4% by weight cetyl alcohol; 0.05 wt% citric acid; 4% by weight of glycerol; 3% by weight of magnesium aluminum silicate; 5% by weight methyl gluceth; 0.18% by weight of methylparaben; 3.5% by weight glyceryl stearate, polyethylene glycol (PEG) stearate, or a combination thereof, 0.02% by weight propyl paraben, 0.2% by weight sodium metabisulfite, 3% by weight stearic acid, and 4% by weight stearyl alcohol.