WO2022046006A1 - Semisolid pharmaceutical compositions used in treatment of melasma - Google Patents

Semisolid pharmaceutical compositions used in treatment of melasma Download PDF

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Publication number
WO2022046006A1
WO2022046006A1 PCT/TR2021/050625 TR2021050625W WO2022046006A1 WO 2022046006 A1 WO2022046006 A1 WO 2022046006A1 TR 2021050625 W TR2021050625 W TR 2021050625W WO 2022046006 A1 WO2022046006 A1 WO 2022046006A1
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weight
ratio
cream formulation
butyl hydroxyl
formulation according
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PCT/TR2021/050625
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French (fr)
Inventor
Mehtap Saydam
Mustafa Arisoy
Cagri TALAY
Yasemin EKIN DOLAKSIZ
Ozge DEMIRBAS
Muzaffer INOZU
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Drogsan Ilaclari Sanayi Ve Tic. A.S.
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Publication of WO2022046006A1 publication Critical patent/WO2022046006A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the invention is related to a cream containing Fluocinolone acetonide, Hydroquinone and Tretinoine for the treatment of melasma.
  • Melasma is a skin disease known as the sunspot that is observed as black and brown spots on various regions of the skin due to over functioning of the melanin pigment. While the absolute cause of these spots is not known, it is known that genetic factors, hormonal changes, medicine use, light sensitivity and longterm sun exposure are related to melasma.
  • the standard therapy consists of deprivation and bleaching of the affected regions of the skin, use of sunscreens and avoiding sun light.
  • Hydroquinone is the most popular topical depigmentation agent. 5% -10% Hydroquinone concentrations are very affective however can be irritating. As Hydroquinone is easily oxidized the chemical stability of the formulations are important.
  • Tretinoine (Retin-A) is another treatment agent used commonly against melasma.
  • TRI-LUMA cream contains respectively 0.01%/4%/0.05% fluocinolone acetonide, hydroquinone, and tretinoine.
  • Formulation and production method are explained in patent no. EP1562531 Bl (TR2016/03686).
  • the specialty of the production method is the delayed addition of emulsifying agent in the mixture.
  • Fluocinolone acetonide is a synthetic corticosteroid applied topically. Fluocinolone has anti-inflammatory, anti-pruritic and vasoconstrictor effects as other corticosteroids. It can be prepared in forms of cream, pomade, topical solution and shampoo. Hydroquinone is used topically to form depigmentation on the skin. It inhibits one or more steps in the tyrosine-tyrosinase path in the formation of melanin. It decreases the contents of the melanocytes in the skin. It is a strong medicine causing depigmentation by nature. In treatment, generally its creams are utilized. Tretinoine is a natural vitamin-A derivative used orally or topically.
  • Topical tretinoine is used in the treatment of the skin affected by light and damaged. It is affective in reduction of the hyperpigmentation as spots, pebble appearance and looseness of the wrinkles on the skin damaged by the mild effects of light. The positive effects based on topical tretinoine treatment on patients with skins harmed by the effects of light are usually seen within the first month of the treatment.
  • the developed product is a cream formulation containing fluocinolone acetonide, hydroquinone and tretinoine for melasma treatment.
  • the developed cream formulation consists of, as active agent, 0.10% fluocinolone acetonide by weight, 0.05% tretinoine by weight and 4.0% hydroquinone by weight.
  • the solubility of the active agents within the composition of the semisolid product is different from each other. Fluocinolone acetonide is not water-soluble while tretinoine and hydroquinone are water-soluble. It is very critical that active agents tretinoine (%0.05) and fluocinolone acetonide (%0.01), with their small concentrations within the (o/w) finished product that is semisolid and in the form of double phase emulsion, are homogenously dispersed in the industrial production. In that way an efficient and reliable treatment can be achieved. Through the production process developed, it is provided that these three substances are present in the product homogenously.
  • the franz diffusion rates of the active agents used in the formulation affect the efficiency of the finished product. Therefore, it is very important that the franz diffusion rates of three active agents in question should be conforming.
  • Fluocinolone acetonide is an active agent sensitive against acids, bases and oxygen. Hydroquinone is degraded under the effect of light and oxygen. Furthermore, tretinoine is very sensitive against light, heat and humidity. While all of the products in the market that contain one of these active agents can be stored in room temperature, the reference combination product being stored in refrigerator [5] shows that these active agents are incompatible with each other. With the antioxidant substances added in the formulation, this interaction is kept at minimum level and it becomes possible for the finished product to be stored in room temperature.
  • Antioxidants Gallic acid, propyl gallate, alfa tokopherol, tokopherol, sodium sulfite, sodium metabisulfite, phenyl alanine, tryptophan, tioglycerol, cysteine HCI, astaxanthin, butylhydroxylanisole (BHA), butylhidroxytoluene (BHT), ascorbic acid [1] and chelate producing ethylenediamine tetraaceticacid(EDTA).
  • ascorbic acid can be used in the ratio of 0.01-0.35% by weight, EDTA in the ratio of 0.005-0.1% by weight, butylhydroxylanisole (BHA) in the ratio of 0.005-0.02% by weight butylhydroxytoluene (BHT) in the ratio of 0.0075-0.1% by weight.
  • BHA butylhydroxylanisole
  • BHT butylhydroxytoluene
  • a more favorable condition is that ascorbic acid is used in the ratio of 0.05-0.30% by weight, EDTA in the ratio of 0.02-0.03% by weight, butylhydroxylanisole (BHA) in the ratio of 0.03-0.02% by weight, and butylhydroxytoluene (BHT) in the ratio of 0.03-0.02% by weight.
  • ascorbic acid in the ratio of 0.25% by weight, EDTA in the ratio of 0.02% or 0.03% by weight, butylhydroxylanisole (BHA) in the ratio of 0.03% or 0.02% by weight, and butylhydroxytoluene (BHT) in the ratio of 0.03% or 0.02% by weight.
  • benzyl alcohol is preferred. Benzyl alcohol can be used in the ratio of 0.01-10.0% by weight. In a more favorable condition, the amount of benzyl alcohol is 0.3% to 0.5% by weight. In the most favorable condition, the amount of benzyl alcohol is 0.3% orO.5%.
  • Anionic emulsifiers (potassium laurate, triethanolamin stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfate, dioctyl sodium sulfosuccinate), cationic emulsifiers (quaternary ammonium compounds, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride), non-ionic emulsifiers (polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, poloxamers, lanolin alcohols, ethoxylated lanolin alcohols, cetylic alcohol, stearic acid and Glyceryl stearate and PEG 75 stearate), multimolecular monomolecules (gum Arabic, gelatin, lecithin, cholesterol), fine grinded solid particles (bentonit, hectorit, kaolin, magnesium hydroxide and magnesium aluminum silicate) [1], Acacia, Agar,
  • cetyl alcohol in the formulation, as emulsifier, cetyl alcohol, stearic acid, glyseryl stearate and PEG 75 stearate, and magnesium aluminum silicatearepreferred.
  • cetyl alcohol can be used in the ratio of 2.0%- 10.0% by weight, stearic acid in the ratio of 1.0-20.0% by weight, glyseryl stearate and PEG 75 stearate in the ratio of 3.0-12.0% by weight, Magnesium aluminum silicate in the ratio of 2.0-5.0% by weight.
  • cetyl alcohol is in the ratio of 2.0-3.0% by weight, stearicacid in the ratio of 7.0- 10.0% by weight, Glyseryl stearate and PEG 75 stearate in the ratio of 3.0- 4.0% by weight, Magnesium aluminum silicate in the ratio of 2.0% by weight.
  • cetyl alcohol is in the ratio of 2.0% or 3.0% by weight, stearic acid in the ratio of 7.0% or 10.0% by weight, Glyseryl stearate and PEG 75 stearate in the ratio of 3.0% or 4.0% by weight, Magnesium aluminum silicate in the ratio of 2.0% by weight.
  • Castor Oil (Hydrogenated), Cetostearyl Alcohol, Cetyl Alcohol, Cetyl Palmitate, Dextrin,
  • stearyl alcohol is preferred as the stiffening agent.
  • Stearyl alcohol can be used in the ratio of 2.0-10.0% by weight. In a more favorable condition stearylalcohol is used in the ratio of 2.0% by weight.
  • Emollients Alkyl (C12-15) Benzoate, Almond Oil, Aluminum Monostearate, Canola Oil, Castor Oil,
  • glycerin in the formulation, as the emollient glycerin is preferred. Glycerin can be used in the ratio of 1.0- 30.0%by weight. In a more favorable condition Glycerin is used in the ratio of 15.0% by weight.
  • the formulation contains distilled water as the solvent and the carrier.
  • Tank-A In a different production tank (Tank-A), in order, CetylAlcohol,StearicAcid,StearylAlcohol, Glycerin, Glyseryl stearate & PEG 75 stearate (Gelot 64), Benzyl Alcohol, Butyl hydroxyl toluene (BHT), Butyl hydroxyl anisole (BHA),Tretinoineand Fluocinolone Acetonite are added and mixed until fully dissolved.
  • Tank-A CetylAlcohol,StearicAcid,StearylAlcohol, Glycerin, Glyseryl stearate & PEG 75 stearate (Gelot 64), Benzyl Alcohol, Butyl hydroxyl toluene (BHT), Butyl hydroxyl anisole (BHA),Tretinoineand Fluocinolone Acetonite are added and mixed until fully dissolved.
  • Tank-A is added to the Main production tank via utilizing pallet mixer and homogenizator.
  • the emulsification is realized as pallet mixer and homogenizator are together.
  • the main production tank is cooled down with the pallet type mixer until the boiler temperature is down to 35-40°C.
  • the storage condition of the equivalent product is in between 2°-8°C in a refrigerator, it requires a special storage condition both in production and distribution chain, and also during the patient use.
  • the active agents are degraded and the impurities reach levels exceeding limits.
  • the impurities progressed within limits in room conditions for 6 months.
  • the developed product can be stored in room conditions.
  • the stability study at room conditions after 24 months it is shown that the product can be stored without a need for a special condition.

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Abstract

It is a cream formulation for melasma treatment consisting of 0.10% Fluocinolone Acetonite by weight, 0.050% Tretinoine by weight and 4.0% Hydroquinone as active agents, with improved stability and that can be stored at room temperatures and it contains ascorbic acid as antioxidant, EDTA, butyl hydroxyl anisole (BHA), butyl hydroxyl toluene (BHT), Benzyl alcohol as antimicrobial protector, cetyl alcohol, stearic acid, Glyceryl stearate and PEG 75 stearate, and Magnesium aluminum silicate as emulsifier, Stearyl alcohol as stiffening agent, Glycerin as emollient and Distilled water as solvent and carrier.

Description

SEMISOLID PHARMACEUTICAL COMPOSITIONS USED IN TREATMENT OF MELASMA
Field of Invention
The invention is related to a cream containing Fluocinolone acetonide, Hydroquinone and Tretinoine for the treatment of melasma.
State of Art
Melasma is a skin disease known as the sunspot that is observed as black and brown spots on various regions of the skin due to over functioning of the melanin pigment. While the absolute cause of these spots is not known, it is known that genetic factors, hormonal changes, medicine use, light sensitivity and longterm sun exposure are related to melasma.
The standard therapy consists of deprivation and bleaching of the affected regions of the skin, use of sunscreens and avoiding sun light. Hydroquinone is the most popular topical depigmentation agent. 5% -10% Hydroquinone concentrations are very affective however can be irritating. As Hydroquinone is easily oxidized the chemical stability of the formulations are important. Tretinoine (Retin-A) is another treatment agent used commonly against melasma.
Melasma can be successfully treated with products containing Fluocinolone acetonide (0.01%), Hydroquinone (4.0%) and Tretinoine (0.05%) combination [3], TRI-LUMA cream contains respectively 0.01%/4%/0.05% fluocinolone acetonide, hydroquinone, and tretinoine. Formulation and production method are explained in patent no. EP1562531 Bl (TR2016/03686). The specialty of the production method is the delayed addition of emulsifying agent in the mixture.
Figure imgf000003_0001
Fluocinolone acetonide is a synthetic corticosteroid applied topically. Fluocinolone has anti-inflammatory, anti-pruritic and vasoconstrictor effects as other corticosteroids. It can be prepared in forms of cream, pomade, topical solution and shampoo. Hydroquinone is used topically to form depigmentation on the skin. It inhibits one or more steps in the tyrosine-tyrosinase path in the formation of melanin. It decreases the contents of the melanocytes in the skin. It is a strong medicine causing depigmentation by nature. In treatment, generally its creams are utilized. Tretinoine is a natural vitamin-A derivative used orally or topically. Topical tretinoine is used in the treatment of the skin affected by light and damaged. It is affective in reduction of the hyperpigmentation as spots, pebble appearance and looseness of the wrinkles on the skin damaged by the mild effects of light. The positive effects based on topical tretinoine treatment on patients with skins harmed by the effects of light are usually seen within the first month of the treatment.
Background of Invention
The developed product is a cream formulation containing fluocinolone acetonide, hydroquinone and tretinoine for melasma treatment. The developed cream formulation consists of, as active agent, 0.10% fluocinolone acetonide by weight, 0.05% tretinoine by weight and 4.0% hydroquinone by weight.
The solubility of the active agents within the composition of the semisolid product is different from each other. Fluocinolone acetonide is not water-soluble while tretinoine and hydroquinone are water-soluble. It is very critical that active agents tretinoine (%0.05) and fluocinolone acetonide (%0.01), with their small concentrations within the (o/w) finished product that is semisolid and in the form of double phase emulsion, are homogenously dispersed in the industrial production. In that way an efficient and reliable treatment can be achieved. Through the production process developed, it is provided that these three substances are present in the product homogenously.
In addition, the franz diffusion rates of the active agents used in the formulation affect the efficiency of the finished product. Therefore, it is very important that the franz diffusion rates of three active agents in question should be conforming.
Another problem with these active agents is that, as in many active agents, the stability problems observed in interaction with each other and under the environmental conditions. Fluocinolone acetonide is an active agent sensitive against acids, bases and oxygen. Hydroquinone is degraded under the effect of light and oxygen. Furthermore, tretinoine is very sensitive against light, heat and humidity. While all of the products in the market that contain one of these active agents can be stored in room temperature, the reference combination product being stored in refrigerator [5] shows that these active agents are incompatible with each other. With the antioxidant substances added in the formulation, this interaction is kept at minimum level and it becomes possible for the finished product to be stored in room temperature.
As a result, an innovation is needed in the technical field related to the semisolid formulations with improved stability and that can be stored in room temperature, about 15-25°C, that can be used in melasma treatment. The supplementary substances within the formulation of the cream are indicated below:
Antioxidants Gallic acid, propyl gallate, alfa tokopherol, tokopherol, sodium sulfite, sodium metabisulfite, phenyl alanine, tryptophan, tioglycerol, cysteine HCI, astaxanthin, butylhydroxylanisole (BHA), butylhidroxytoluene (BHT), ascorbic acid [1] and chelate producing ethylenediamine tetraaceticacid(EDTA).
In the formulation, ascorbic acid can be used in the ratio of 0.01-0.35% by weight, EDTA in the ratio of 0.005-0.1% by weight, butylhydroxylanisole (BHA) in the ratio of 0.005-0.02% by weight butylhydroxytoluene (BHT) in the ratio of 0.0075-0.1% by weight. A more favorable condition is that ascorbic acid is used in the ratio of 0.05-0.30% by weight, EDTA in the ratio of 0.02-0.03% by weight, butylhydroxylanisole (BHA) in the ratio of 0.03-0.02% by weight, and butylhydroxytoluene (BHT) in the ratio of 0.03-0.02% by weight. In the most favorable conditions ascorbic acid is used in the ratio of 0.25% by weight, EDTA in the ratio of 0.02% or 0.03% by weight, butylhydroxylanisole (BHA) in the ratio of 0.03% or 0.02% by weight, and butylhydroxytoluene (BHT) in the ratio of 0.03% or 0.02% by weight.
In the developed formulation, the effect of ascorbic acid on the stability is clearly apparent and it had shown a synergy with the other antioxidants.
Figure imgf000005_0001
hydroxyl benzoic acid esters, alkyl hydroxyl-benzoates, phenoxy-ethanol, phenyl ethyl alcohol, methyl and propyl hydroxyl-benzoates, benzyl alcohol [1],
In the formulation, benzyl alcohol is preferred. Benzyl alcohol can be used in the ratio of 0.01-10.0% by weight. In a more favorable condition, the amount of benzyl alcohol is 0.3% to 0.5% by weight. In the most favorable condition, the amount of benzyl alcohol is 0.3% orO.5%.
: Anionic emulsifiers (potassium laurate, triethanolamin stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfate, dioctyl sodium sulfosuccinate), cationic emulsifiers (quaternary ammonium compounds, cetyltrimethylammonium bromide, lauryldimethylbenzylammonium chloride), non-ionic emulsifiers (polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, poloxamers, lanolin alcohols, ethoxylated lanolin alcohols, cetylic alcohol, stearic acid and Glyceryl stearate and PEG 75 stearate), multimolecular monomolecules (gum Arabic, gelatin, lecithin, cholesterol), fine grinded solid particles (bentonit, hectorit, kaolin, magnesium hydroxide and magnesium aluminum silicate) [1], Acacia, Agar, Alamic Acid, Alginic Acid, Aluminum Monostearate, Attapulgite (Activated, Colloidal Activated), Bentonite (Purified, Magma), Carbomer (910, 934, 934P, 940, 941, 1342, Copolymer, Homopolymer, Interpolymer, Carboxymethylcellulose (Calcium, Sodium, Enzymatically-Hydrolyzed), Carmellose, Carrageenan, Microcrystalline Cellulose, Microcrystalline Cellulose and Sodium Carboxymethylcellulose, Cetostearyl Alcohol, Chitosan, Corn Syrup (solid), Cyclomethicone, Dextrin, Egg Phospholipids, Ethylcellulose, Gelatin, Gellan Gum, Glyceryl Behenate, Guar Gum, Hydroxylethyl Cellulose, Hydroxylpropyl Cellulose, Hypromellose, Isomalt, Alpha-Lactalbumin, Kaolin, Magnesium Aluminum Silicate, Maltitol Solution, Maltodextrin, Pectin, Polycarbophil, Polydextrose (Hydrogenated), Polyethylene Oxide, Polysorbate (20, 40, 60, 80), Polyvinyl Alcohol, Potassium Alginate, Povidone, Propylene Glycol, Alginate, Pullulan, Silica, Hydrophobic
Colloidal Silicon Dioxide, Colloidal Sodium Alginate, Sorbitan Monolaurate, Sorbitan Monooleate, Sorbitan Monopalmitate, Sorbitan Monostearate, Sorbitan Sesquioleate, Sorbitan Trioleate, Starch, Corn Starch, Hydroxylpropyl Corn Starch, Pregelatinized Hydroxyl propyl Corn Starch, Pea Starch, Hydroxyl propyl Pea Starch, Pregelatinized Hydroxylpropyl Pea Starch, Potato Starch, Hydroxylpropyl Potato Starch, Pregelatinized Hydroxylpropyl Potato Starch, Tapioca Starch, Wheat Sucrose, Sucrose Palmitate, Tragacanth, Vitamin E Polyethylene Glycol Succinate, Xanthan Gum [2],
In the formulation, as emulsifier, cetyl alcohol, stearic acid, glyseryl stearate and PEG 75 stearate, and magnesium aluminum silicatearepreferred. In the formulation cetyl alcohol can be used in the ratio of 2.0%- 10.0% by weight, stearic acid in the ratio of 1.0-20.0% by weight, glyseryl stearate and PEG 75 stearate in the ratio of 3.0-12.0% by weight, Magnesium aluminum silicate in the ratio of 2.0-5.0% by weight. In a more favorable condition cetyl alcohol is in the ratio of 2.0-3.0% by weight, stearicacid in the ratio of 7.0- 10.0% by weight, Glyseryl stearate and PEG 75 stearate in the ratio of 3.0- 4.0% by weight, Magnesium aluminum silicate in the ratio of 2.0% by weight. In the most favorable condition cetyl alcohol is in the ratio of 2.0% or 3.0% by weight, stearic acid in the ratio of 7.0% or 10.0% by weight, Glyseryl stearate and PEG 75 stearate in the ratio of 3.0% or 4.0% by weight, Magnesium aluminum silicate in the ratio of 2.0% by weight.
Castor Oil (Hydrogenated), Cetostearyl Alcohol, Cetyl Alcohol, Cetyl Palmitate, Dextrin,
Hard Fat, Alpha-Lactalbumin, Paraffin (Synthetic), Rapeseed Oil (Fully Hydrogenated,
Superglycerinated Fully Hydrogenated), Sodium Stearate, Stearyl Alcohol, Wax (Cetyl Esters, Emulsifying, Microcrystalline, White, Yellow) [2],
In the formulation, as the stiffening agent, stearyl alcohol is preferred. Stearyl alcohol can be used in the ratio of 2.0-10.0% by weight. In a more favorable condition stearylalcohol is used in the ratio of 2.0% by weight.
Emollients: Alkyl (C12-15) Benzoate, Almond Oil, Aluminum Monostearate, Canola Oil, Castor Oil,
Cetostearyl Alcohol, Cholesterol, Coconut Oil, Cyclomethicone, Dimethicone, Ethylene Glycol Stearates, hexylene glycol, Glyceryl Monooleate, Glyceryl Monostearate, Isopropyl Isostearate,
Isopropyl Myristate, Isopropyl Palmitate, Isostearyl Isostearate, Hydrogenated Lanolin, Lecithin, Mineral Oil (light), Myristyl Alcohol, Octyldodecanol, Oleyl Alcohol, Oleyl Oleate, Petrolatum, Polydecene (Hydrogenated), Propylene Glycol Dilaurate, Propylene Glycol Monolaurate, Safflower Oil, Soybean Oil (Hydrogenated), Sunflower Oil, Wax, Cetyl Esters, Xylitol, Zinc Acetate and Glycerin [2],
In the formulation, as the emollient glycerin is preferred. Glycerin can be used in the ratio of 1.0- 30.0%by weight. In a more favorable condition Glycerin is used in the ratio of 15.0% by weight.
The formulation contains distilled water as the solvent and the carrier.
The production method of the formulation is indicated below: (Figure 1).
• In to the main production tank, distilled water free from dissolved oxygen is taken and heated up to75-80°C.
• In the main production tank, in order MagnesiumAluminumSilicate(Mg-AISilicate),Ascorbicacidand Disodium Ededat (EDTA) are added and dissolved by mixing using pallet mixer (vortex).
• In a different production tank (Tank-A), in order, CetylAlcohol,StearicAcid,StearylAlcohol, Glycerin, Glyseryl stearate & PEG 75 stearate (Gelot 64), Benzyl Alcohol, Butyl hydroxyl toluene (BHT), Butyl hydroxyl anisole (BHA),Tretinoineand Fluocinolone Acetonite are added and mixed until fully dissolved.
• After observing full dissolving, Tank-A is added to the Main production tank via utilizing pallet mixer and homogenizator. The emulsification is realized as pallet mixer and homogenizator are together.
• After emulsification, the main production tank is cooled down with the pallet type mixer until the boiler temperature is down to 35-40°C.
• Then, while slow mixing, Hydroquinone is added slowly.
• After the addition of Hydroquinone, slow mixing is performed by using pallet type mixer.
• The prepared cream is filled to tubes.
Example 1. Formulation Examples (%):
Figure imgf000007_0001
Franz diffusion test (figure 2-4)
In reference product and test products (F48S2-F48S7) the diffusion rate analysis of the active agents tretinoine, hydroquinone and fluocinolone acetonide in the diffusion medium. The ratios of the gradient values of the test products (F48S2-F48S7) to the gradient values of the reference product is calculated and these ratios are given in an ascending order. As the result of the calculations, it is found out that for the test product with the serial number F48S2the 8th smallest value of the ratios obtained is 83% and the 29th smallest value is 109.44%, and for the test product with the serial number F48S7 the 8th smallest value of the ratios obtained is 79% and the 29th smallest value is 96.60%, and it is determined that these values are within the range of 75%-133.33%. It is determined that the diffusion rate of the test products (F48S2-F48S7) is equivalent to the diffusion rate of the reference product. (Source : FDA Guidance for Industry Nonsterile Semisolid Dosage Forms (May 1997)). Stability test
The 6th month stability impurity analysis results for the optimum formulation with antioxidants (Example
2) and formulation without antioxidants (Example-3) are given below.
Figure imgf000008_0001
BDL: Below Disregard Limits
Advantages of the Invention
As the storage condition of the equivalent product is in between 2°-8°C in a refrigerator, it requires a special storage condition both in production and distribution chain, and also during the patient use. When the product is not stored in a refrigerator, the active agents are degraded and the impurities reach levels exceeding limits. As the result of the studies conducted, it is shown that the impurities progressed within limits in room conditions for 6 months. Thus, the developed product can be stored in room conditions. As the result of the stability study at room conditions after 24 months, it is shown that the product can be stored without a need for a special condition.
In addition, through the production method developed, a homogenous finished product is obtained. It is shown that the franz diffusion results of the developed product are statistically similar to that of the reference product.
Explanation of the Figures:
Figure 1. Cream formulation production process
Figure 2. Test (F48S2-F48S7) and Reference Products Tretinoine Diffusion Profiles A=Reference product B=Test productSerial No: F48S2C=TestproductSerial No: F48S7
Figure 3. Test (F48S2-F48S7) and Reference Products Hydroquinone Diffusion Profiles A=Reference product B=Test productSerial No: F48S2C=Test product Serial No: F48S7 Figure 4. Test (F48S2-F48S7) and Reference Products Fluocinolone acetonide Diffusion Profiles A= Reference product B=TestproductSerial No: F48S2C=TestproductSerial No: F48S7 References:
[1] N.Qelebi, Emulsiyonlar, in: Mod. FarmasotikTeknol., 2009: pp.277-299.
[2] NF37, Excipients, in: USP42-NF37, 2020: pp. 1-23 (9305).
[3] P. Grimes, A. P. Kelly, H.Torok, I. Willis, Community-based trial of a triple-combination agent for the treatment of facial melasma, Cutis. 77 (2006) 177-184. [4] USP41, Fluocinolone Acetonide Cream, in: USP, 2018: pp. 1784-1785.
[5] EP9.0, Hydroquinone, in: Eur. Pharmacop., 2018.
[6] X. Li, Q. Yin, W. Chen, J. Wang, Solubility of hydroquinone in different solvents from 276.65 Kto 345.10 K, J. Chem. Eng. Data. 51 (2006) 127-129.

Claims

1. A cream formulation for use in the treatment of melasma comprising 0.10% Fluocinolone Acetonite by weight, 0.050% Tretinoine by weight and 4.0% Hydroquinone as active agents, with improved stability and that can be stored at room temperatures 15-25°C, wherein it comprises ascorbic acid as antioxidant.
2. The cream formulation according to the claim 1, wherein it comprises the combination of ascorbic acid, butyl hydroxyl anisole (BHA) and butyl hydroxyl toluene (BHT) as antioxidant.
3. The cream formulation according to the Claim 1, wherein it comprises a) the combination of ascorbic acid, butyl hydroxyl anisole (BHA) and butyl hydroxyl toluene (BHT) as antioxidant, b) EDTA as chelate agent, c) Benzyl alcohol as antimicrobial protector, d) Cetyl alcohol, stearic acid, Glyceryl stearate, PEG 75 stearate and Magnesium aluminum silicate as emulsifier, e) Stearyl alcohol as stiffening agent, f) Glycerin as emollient, g) Distilled water as solvent and carrier.
4. The cream formulation according to the Claim 1, wherein ascorbic acid is at ratio of 0.01-0.35% by weight, butyl hydroxyl anisole (BHA) is at ratio of 0.005-0.02% by weight, butyl hydroxyl toluene (BHT) is at ratio of 0.0075-0.1% by weight, EDTA is at ratio of 0.005-0.1% by weight.
5. The cream formulation according to the Claim 4, wherein ascorbic acid is at ratio of 0.05-0.25% by weight, butyl hydroxyl anisole (BHA) is at ratio of 0.03-0.02% by weight, butyl hydroxyl toluene (BHT) is at ratio of 0.03-0.02% by weight, EDTA is at ratio of 0.02-0.03% by weight.
6. The cream formulation according to the Claim 5, wherein ascorbic acid is at ratio of 0.25% by weight, butyl hydroxyl anisole (BHA) is at ratio of 0.03% or 0.02% by weight, butyl hydroxyl toluene (BHT) is at ratio of 0.03% or 0.02% by weight, EDTA is at ratio of 0.02% or 0.03% by weight.
7. The cream formulation according to the Claim 1, wherein benzyl alcohol is at ratio of 0.01- 10.0% by weight, in a more favorable condition benzyl alcohol is at ratio of 0.3% to 0.5% by weight, in the most favorable condition benzyl alcohol is at ratio of 0.3% or 0.5% by weight.
8. The cream formulation according to the Claim 1, wherein Cetyl Alcohol is at ratio of 2.0-10.0% by weight, stearic acid is at ratio of 1.0- 20.0% by weight, Glyceryl stearate and PEG 75 stearate is at ratio of 3.0-12.0% by weight, Magnesiumaluminumsilicate is at ratio of 2.0-5.0% by weight.
9. The cream formulation according to the Claim 8, wherein Cetyl Alcohol is at ratio of 2.0-3.0% by weight, stearic acid is at ratio of 7.0- 10.0% by weight, Glyceryl stearate and PEG 75 stearate is at ratio of 3.0-4.0% by weight, Magnesium aluminum silicate is at ratio of 2.0% by weight.
8
10. The cream formulation according to the Claim 1, wherein the stiffening agent Stearyl alcohol is at ratio of 2.0-10.0% by weight, in a more favorable condition it is at ratio of 2.0% by weight.
1 1 . The cream formulation according to the Claim 1, wherein glycerin is at ratio of 1.0-30.0% by weight, in a more favorable condition it is at ratio of 15.0% by weight.
12. The cream formulation according to the Claim 1, wherein ascorbic acid is at ratio of 0.25% by weight, EDTA is at ratio of 0.02% or 0.03% by weight, butyl hydroxyl anisole (BHA) is at ratio of 0.03% or 0.02% by weight, butyl hydroxyl toluene (BHT) is at ratio of 0.03% or 0.02% by weight, benzyl alcohol is at ratio of 0.3% to 0.5% by weight, Cetyl Alcohol is at ratio of 2.0% or 3.0% by weight, stearicacid is at ratio of 7.0% or 10.0% by weight, Glyceryl stearateand PEG75stearateis at ratio of 3.0% or 4.0% by weight, Magnesium aluminum silicate is at ratio of 2.0% by weight, Stearyl alcohol is at ratio of 2.0% by weight, glycerin is at ratio of 15.0% by weight.
13. The cream formulation according to the Claim 12, wherein the production method of the formulation is given below:
• In to the main production tank, distilled water free from dissolved oxygen is taken and heated up to75-80°C,
• In the main production tank, in order MagnesiumAluminumSilicate(Mg-AISilicate),Ascorbicacidand
Disodium Ededat (EDTA) are added and dissolved by mixing using pallet mixer (vortex),
• In a different tank (Tank-A), in order, Cetyl Alcohol, Stearic Acid, Stearyl Alcohol, Glycerin, Glyseryl stearate & PEG 75 stearate (Gelot 64), Benzyl Alcohol, Butyl hydroxyl toluene (BHT), Butyl hydroxyl anisole (BHA), Tretinoineand Fluocinolone Acetonite are added and mixed until fully dissolved,
• After observing full dissolving, Tank-A is added to the Main production tank via utilizing pallet mixer and homogenizator. The emulsification is realized as pallet mixer and homogenizator are together, • After emulsification, the main boiler is cooled down with the pallet type mixer until the boiler temperature is down to 35-40°C,
•Then, while slow mixing, Hydroquinone is added slowly,
• After the addition of Hydroquinone, slow mixing is performed by using pallet type mixer, •The prepared cream is filled to tubes.
9
PCT/TR2021/050625 2020-08-26 2021-06-18 Semisolid pharmaceutical compositions used in treatment of melasma WO2022046006A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060099173A1 (en) * 2003-10-24 2006-05-11 Nancy Puglia Topical skin care composition
WO2007068701A1 (en) * 2005-12-12 2007-06-21 Galderma Research & Development Aqueous-alcoholic depigmenting gel
US20090131381A1 (en) * 2006-05-19 2009-05-21 Galderma S.A. Compositions comprising hydroquinone, fluocinolone acetonide and tretinoin for treating photoaging of the skin
US20130287825A1 (en) * 2010-10-21 2013-10-31 Cadila Healthcare Limited Pharmaceutical compositions comprising nano size droplets of skin whitening agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060099173A1 (en) * 2003-10-24 2006-05-11 Nancy Puglia Topical skin care composition
WO2007068701A1 (en) * 2005-12-12 2007-06-21 Galderma Research & Development Aqueous-alcoholic depigmenting gel
US20090131381A1 (en) * 2006-05-19 2009-05-21 Galderma S.A. Compositions comprising hydroquinone, fluocinolone acetonide and tretinoin for treating photoaging of the skin
US20130287825A1 (en) * 2010-10-21 2013-10-31 Cadila Healthcare Limited Pharmaceutical compositions comprising nano size droplets of skin whitening agents

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