WO2017109761A1 - Composition topique pour le traitement de l'acné - Google Patents

Composition topique pour le traitement de l'acné Download PDF

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Publication number
WO2017109761A1
WO2017109761A1 PCT/IB2016/057966 IB2016057966W WO2017109761A1 WO 2017109761 A1 WO2017109761 A1 WO 2017109761A1 IB 2016057966 W IB2016057966 W IB 2016057966W WO 2017109761 A1 WO2017109761 A1 WO 2017109761A1
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Prior art keywords
composition
acid
benzoyl peroxide
present application
silicone
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Application number
PCT/IB2016/057966
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English (en)
Inventor
Sushil Kumar PATIL
Rajeev Soni
Kaushalesh Kumar VAISHNAV
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Dr. Reddy's Laboratories Ltd
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Application filed by Dr. Reddy's Laboratories Ltd filed Critical Dr. Reddy's Laboratories Ltd
Priority to RU2018126808A priority Critical patent/RU2018126808A/ru
Publication of WO2017109761A1 publication Critical patent/WO2017109761A1/fr

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    • 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
    • A61K31/327—Peroxy compounds, e.g. hydroperoxides, peroxides, peroxyacids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present application relates to a topical composition comprising benzoyl peroxide in combination with one or more silicone compounds and a zinc compound.
  • the present application further relates to the use of the topical composition as well as a process for making such topical composition.
  • Acne vulgaris (or simply acne) is a common human skin disease, characterized by areas of skin with seborrhea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), nodules (large papules), pimples, and possibly causing scars.
  • Acne affects integumentary system mostly skin with the densest population of sebaceous follicles; these areas include the face, the upper part of the chest, and the back.
  • Severe acne is inflammatory in nature, but acne can also manifest in non-inflammatory forms. The lesions are caused by changes in pilosebaceous units, skin structures consisting of a hair follicle and its associated sebaceous gland, changes that require androgen stimulation.
  • Ice pick scars Deep pits that are the most common and a classic sign of acne scarring.
  • Box car scars Angular scars that usually occur on the temple and cheeks, and can be either superficial or deep, these are similar to chickenpox scars.
  • Rolling scars Scars that give to skin a wave-like appearance.
  • Hypertrophic scars Thickened or keloid scars.
  • Benzoyl peroxide is a first-line treatment for mild and moderate acne due to its effectiveness and mild side-effects (mainly irritant dermatitis). It works against the "P. acnes" bacterium, helps prevent formation of comedones, and has anti-inflammatory properties. Benzoyl peroxide normally causes dryness of the skin, slight redness, and occasional peeling. Benzoyl peroxide has been found to be nearly as effective as antibiotics with all concentrations being equally effective. Unlike antibiotics, benzoyl peroxide does not appear to generate bacterial resistance. Benzoyl peroxide is often combined with antibiotics.
  • Silicone-based products represent one of the most common and effective solutions in preventing and treating hypertrophic acne scars.
  • the silicone gel was introduced in the treatment of hypertrophic acne scars to overcome the difficulties in the management of silicone sheets. Indeed, the silicone gel has several advantages: it is transparent, quick drying, non- irritating and does not induce skin maceration; it can be used to treat extensive scars and uneven areas of skin. Silicone gels are popularly used for prevention of scar and keloid formation. However, prolonged exposure to silicone may cause dryness and skin irritation.
  • compositions comprising benzoyl peroxide wherein silicone copolymers, silicone oils and/or zinc compounds are employed as solubilizing agents, vehicle components and anti-irritating agents respectively.
  • silicones are useful for prevention and treatment of scars, these compounds on prolonged exposure may also cause skin problems such as dryness, irritation and itching.
  • benzoyl peroxide also causes dryness of the skin, the concentration of silicones in benzoyl peroxide compositions may be critical.
  • a pH-balanced composition is desired wherein pH of the composition matches with the slightly acidic skin pH which is about 3 to about 6.
  • the available literature does not disclose a single topical composition comprising a combination of benzoyl peroxide, silicone compounds and zinc compounds, which is useful for the treatment of acne with simultaneous prevention and/or treatment of acne scars and other scars. It is also desired to have a composition that prevents skin problems such as dryness and irritation resulting from benzoyl peroxide application, and also has an enhanced stability.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients.
  • compositions comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients.
  • compositions comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition comprises silicone to water in a weight ratio of from about 1:0.4 to about 1: 1.5.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; (d) a stabilizer selected from organic acids; and (e) one or more pharmaceutically acceptable excipients.
  • the topical composition is silicone-in-water emulsion.
  • the topical composition is an emulgel.
  • the topical composition comprises silicone-in-water emulsion and is in the form of an emulgel.
  • the hydrophobic phase is substantially free of non-silicone water- immiscible substances.
  • An aspect of the present application relates to a method of treating and/or preventing an inflammatory skin disorder and/or related conditions thereof; the method comprising topically administering a composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; and (c) a zinc compound; wherein said inflammatory skin disorder and/or related condition is selected from acne, psoriasis, rosacea, dermatitis, erythema, actinic keratosis, and scars formed by the skin disorders.
  • the said method prevents the formation of acne scars and other scars along with the treatment of acne, and/or treats existing acne scars and other scars along with the treatment of acne.
  • An aspect of the present application relates to a method of treating and/or preventing an inflammatory skin disorder and/or related conditions thereof; the method comprising topically administering a composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; and (c) a zinc compound; wherein said composition is administered at least once daily to a subject in need thereof.
  • Another aspect of the present application relates to a method of treating and/or preventing an inflammatory skin disorder and/or related conditions thereof; the method comprising topically administering a composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; and (c) a zinc compound; wherein said composition is administered two to three times daily to a subject in need thereof.
  • An aspect of the present application relates to a method of administering a topical composition comprising combination of benzoyl peroxide, one or more silicone compounds and a zinc compound, to a subject in need thereof, the method comprises: (a) identifying a subject having an inflammatory skin disorder; and (b) topically administering said composition at least once daily for a period of from about one day to about 12 weeks, or until complete clearance of acne and/or acne scars and other scars, or as directed by physician; wherein said method provides therapeutically effective concentration of benzoyl peroxide in skin layers for at least about 5 hours from the application time.
  • Another aspect of the present application relates to a method of administering a topical composition comprising combination of benzoyl peroxide, one or more silicone compounds and a zinc compound, to a subject in need thereof, the method comprises: (a) identifying a subject having an inflammatory skin disorder; and (b) topically administering said composition two to three times daily for a period of from about one day to about 12 weeks, or until complete clearance of acne and/or acne scars and other scars, or as directed by physician; wherein said method provides therapeutically effective concentration of benzoyl peroxide in skin layers for at least about 5 hours from the application time.
  • An aspect of the present application relates to a process of preparing a topical composition comprising a combination of benzoyl peroxide, one or more silicone compounds, and a zinc compound, comprising steps of: (a) preparing a hydrophilic phase comprising benzoyl peroxide; (b) preparing a hydrophobic phase comprising one or more silicone compounds and a zinc compound; (c) emulsification of step (a) and step (b); wherein said process comprises temperature-controlled intermittent homogenization which prevents the degradation of benzoyl peroxide.
  • FIGURE 1 Mean concentrations (in ⁇ g/gram of skin tissue) of benzoyl peroxide and benzoic acid after 8 hours of administration in rat skin samples.
  • This figure shows that the compositions of present application (example 1 and example 2) provide benzoyl peroxide and benzoic acid concentrations similar to those of BENZAC AC®, and that the presence of silicones in the compositions of present application does not affect the concentration of benzoyl peroxide in the skin.
  • FIGURE 2 Comparative IVRT data of compositions of present application (example 3 and example 4) with BENZAC AC®. This figure shows that the in-vitro release of benzoyl peroxide from example 3 and example 4 composition is similar to that of BENZAC AC® in spite of presence of one or more silicone compounds.
  • FIGURE 3 Trans-epidermal water loss data of compositions of present applications (example 3 and example 4) in comparison with the blank skin. This figure shows that the compositions of present application minimize the moisture loss from the skin as compared to blank skin.
  • an effective amount or “therapeutically effective amount” or “therapeutically effective concentration” as used herein refer to a non-toxic, but sufficient amount of the drug in the skin tissue, required for part or complete clearances of skin disorders in a subject.
  • the term "about,” when referring to a value, or to an amount of mass, weight, time, volume, concentration or percentage, is meant to encompass variations of, in some aspects, +10%, in some aspects, +5%, in some aspects, +1%, in some aspects +0.5%, and in some aspects, +0.1% of the specified amount, as such variations are appropriate to perform the disclosed method.
  • pH-balanced refers to a composition having pH from about 3 to about 7. In some aspects, the pH of the topical composition of present application is from about 4 to about 6.
  • applying refers to topical application of composition to affected and adjoining areas of skin by spreading or gentle rubbing or massaging.
  • topical composition refers to a topically administrable composition of present application. In some aspects, it refers to a topically administrable composition comprising a combination of benzoyl peroxide and one or more silicone compound. In some aspects, it refers to a topically administrable composition comprising a combination of benzoyl peroxide, one or more silicone compounds, and a zinc compound.
  • the topical composition is in the form of semi-solid dosage form or liquid dosage form, selected from, but not limited to, solution, emulsion, gel, cream, emulgel, ointment, lotion, spray or any suitable topical dosage form.
  • emulgel refers to a topical composition in the form of biphasic emulsion containing gelling agent, and in the form of thickened cream or gel, or in other words it is called as a cream gel.
  • active refers to benzoyl peroxide or pharmaceutically acceptable forms of benzoyl peroxide.
  • active substance refers to a combination of benzoyl peroxide, one or more silicone compounds and a zinc compound in therapeutically effective concentrations.
  • related substance refers to one or more degradation substances of benzoyl peroxide during shelf life of the composition; or intermediates or by-products occurring in the manufacturing process of benzoyl peroxide.
  • the impurity comprises one or more related substances selected from benzaldehyde, benzoic acid, ethyl benzoate and one or more unknown impurities.
  • skin disorder refers to a disease condition of the skin.
  • the skin disorder refers to inflammatory skin disorders.
  • the skin disorder refers to acne or acne scars in a subject.
  • stabilizer refers to a chemical substance of organic or inorganic nature that provides chemical, physical and/or polymorphic stability to the active substance (i.e.) benzoyl peroxide and/or to the composition comprising the active substances.
  • acne or "acne and related conditions” as used herein refer broadly to inflammatory skin conditions such as acne vulgaris, acne conglobate, acne varioliformis, acne tropica, infantile acne, acne excoriee, unspecified acne or inflammation of acne or acne rosacea.
  • acne scars refers to the scars formed due to the formation of acne on the skin and include post-acne scars, any existing or previously present scars, and scars formed during the treatment period therein.
  • other scars include keloid scars, hypertrophic scars, scars of rosacea, and scars formed by any other inflammatory skin conditions.
  • the term "subject” as used herein refers to any mammal such as human, rat, mouse, monkey and the like. In an aspect, the subject is human. The term “subject” can be interchangeably used with the term “patient”. In an aspect, the term “subject” is used to denote a human patient suffering from inflammatory skin disorder such as acne or scars of inflammatory skin disorders.
  • excipient or “topically acceptable excipient” or “pharmaceutically acceptable excipient” or “dermatologically acceptable excipient” are used interchangeably to mention any excipient which is acceptable for using in topical compositions and does not provide any therapeutic effect, and may contribute to aesthetic properties or any relevant nontherapeutic function of the topical composition.
  • the terms compound, excipient, ingredient and agent encompass both the singular and plural forms to indicate one or more such compounds, excipients, ingredients or agents.
  • the term “simultaneous prevention” as used herein means not allowing the scars to be formed during the period of treatment of acne. This term differs from the term “treatment” which refers to the treatment of already existing scars and the scars, if any, which are formed during or after the period of treatment of acne.
  • substantially amount indicates the amount of a compound present in the composition ranging from at least about 25%w/w to about 60%w/w based on the total weight of the composition. In an aspect, this term refers to the amount of the total silicone compounds of at least about 35%w/w based on the total weight of the composition.
  • substantially free indicates that the specified substance referred to is present in amounts not more than 10% by weight of the total composition or in amounts not more than about 9% by weight of the total composition, or in amounts not more than about 8% by weight of the total composition, or in amounts not more than about 7% by weight of the total composition, or in amounts not more than about 6% by weight of the total composition, or in amounts not more than about 5% by weight of the total composition, or in amounts not more than about 4% by weight of the total composition, or in amounts not more than about 3% by weight of the total composition, or in amounts not more than about 2% by weight of the total composition or in amounts not more than about 1% by weight of the total composition or in an amount about 0% by weight of the total composition or completely free of specified substance (i.e.) 0%.
  • the term "reference product” refers to an approved topical composition comprising benzoyl peroxide or its salts, solvates, enantiomers or mixtures thereof, at strengths of 5% and/or 2.5%. In an aspect, this term refers to a topical gel product marketed under the brand name BENZAC AC® at 5% and 2.5% strengths by Galderma, or any of its later approved pharmaceutical equivalents or its therapeutic equivalents or its bioequivalents.
  • propellant-free or “free of propellant(s)” as used herein indicates that the compositions are not delivered and/or not prepared using any of the commonly used aerosol propellants, such as fluorochloro hydrocarbons, hydrocarbons, compressed gases, and the like.
  • the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients.
  • the topical composition comprises zinc compound in combination with a stabilizer, wherein the stabilizer provides chemical and/or physical stability to benzoyl peroxide.
  • the stabilizer is selected from organic acids, amino acids, fatty acids, inorganic acids and mixtures thereof.
  • the zinc compound in combination with the stabilizer provides enhanced stability to benzoyl peroxide.
  • the zinc compound in combination with the stabilizer provides enhanced stability to composition comprising benzoyl peroxide.
  • the stabilizer of the present application is selected from, but not limited to, straight or branched or saturated or unsaturated C2 to C20 acid, such as short chain carboxylic acid such as formic acid (HCOOH) to long chain fatty acid such as oleic acid.
  • C2 to C20 acid such as short chain carboxylic acid such as formic acid (HCOOH) to long chain fatty acid such as oleic acid.
  • the stabilizer according to present application is selected from the group comprising, but not limited to, formic acid, lactic acid, acetic acid, dehydroacetic acid, maleic acid, fumaric acid, citric acid, anhydrous citric acid, citric acid monohydrate, ascorbic acid, isoascorbic acid, aspartic acid, benzenesulfonic acid, edetic acid, cyclamic acid, dihydroxybenzoic acid, glutamic acid, hydrochloric acid, oleic acid, linoleic acid, capric acid, lauric acid, palmitic acid, palmitoleic acid, stearic acid and mixtures thereof.
  • the organic acid comprises suitable salt forms of acid and are selected from, but not limited to, sodium citrate, zinc lactate, and the like.
  • the stabilizer is selected from lactic acid and/or optimal isomers, salts thereof, citric acid and/or salts thereof.
  • the stabilizer is S-lactic acid.
  • the benzoyl peroxide is hydrous benzoyl peroxide.
  • the percentage or concentration of benzoyl peroxide is expressed to denote anhydrous benzoyl peroxide.
  • the benzoyl peroxide is present in the topical composition from about 0.5% w/w to about 15% w/w. In another aspect, the benzoyl peroxide is present from about 1% w/w to about 12%w/w.
  • the benzoyl peroxide is present in the concentration selected from, but not limited to, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%
  • the anhydrous benzoyl peroxide is present in the concentration of about 2.5% w/w and about 5% w/w based on the total weight of the composition; and the concentration of hydrous benzoyl peroxide is present in the concentration of about 3.36% w/w and about 6.66% w/w based on total weight of the composition.
  • the zinc compound is selected from zinc oxide, zinc sulfate, zinc lactate, silicone coated zinc salts, and the like.
  • the zinc compound is zinc oxide or zinc sulfate or mixtures thereof.
  • the silicone compound is one or more of the compounds including, but not limited to, polysiloxane compounds selected from cyclic siloxane such as cyclotetrasiloxane (octamethylcyclotetrasiloxane) also known as cyclomethicone, cyclopentasiloxane (decamethylcyclopentasiloxane), cyclohexasiloxane (dodecamethylcyclohexasiloxane), and mixtures thereof; or linear silicones such as dimethicone; or silicone elastomer such as polysilicone-11, cetearyl dimethicone/vinyl dimethicone crosspolymer, dimethicone/phenyl vinyl dimethicone crosspolymer, dimethicone/vinyl dimethicone crosspolymer or cyclopentasiloxane, and dimethicone crosspolymer; or silicone oils such as cyclic siloxane such as
  • the silicone compound is combination of two or more silicone compounds.
  • the silicone compound is elastomer 10.
  • the silicone compound is DC7040 (caprylyl methicone and polyethylene glycol-12 dimethicone/polypropylene glycol-20 crosspolymer).
  • the silicone compound is a linear chain silicone compound such as dimethicone.
  • the silicone compound is cyclomethicone.
  • the silicone compound is dimethiconol.
  • the silicone compound is present in an amount ranging from about 5%w/w to about 70%w/w based on the total weight of the composition. In some aspects, the silicone compound is present in an amount of at least about 10% w/w based on total weight of the composition.
  • the topical composition of the present application comprises substantial amount of total silicone compounds ranging from at least about 25%w/w to about 60%w/w based on the total weight of the composition.
  • the topical composition of the present application comprises substantial amount of total silicone compounds of at least about 35%w/w based on the total weight of the composition.
  • the topical composition of the present application is a monophasic composition.
  • the topical composition of the present application is in the form of a homogenous composition comprising one or more ingredients in suspended form.
  • the topical composition comprises benzoyl peroxide in suspended form.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; (d) a stabilizer; and (e) one or more pharmaceutically acceptable excipients.
  • Topical composition of the present application comprises at least two immiscible phases.
  • the hydrophilic phase comprises water, and one or more water- miscible substances, and the hydrophobic phase comprises one or more water- immiscible substances.
  • the topical composition of the present application is in the form of an emulsion selected from oil-in-water or water-in-oil.
  • the hydrophilic phase comprises benzoyl peroxide and water.
  • the hydrophilic phase comprises benzoyl peroxide, a gelling agent, and water.
  • the hydrophobic phase comprises one or more silicone compounds.
  • the hydrophobic phase comprises one or more silicone compounds, and one or more water-immiscible substances.
  • the water-immiscible substance is selected from, but not limited to, vegetable oil, saturated paraffin oil, fatty acid, fatty alcohol, mineral oil, white wax, medium chain triglyceride and the like.
  • examples of the water-immiscible substance also include, but not limited to, oils of natural origin such as almond oil, coconut oil, olive oil, palm oil, peanut oil, fatty acids such as lauric acid, myristic acid, palmitic acid, and stearic acid, monohydric alcohol esters of the fatty acids such as ethyl laurate, isopropyl laurate, ethyl myristate, n-propyl myristate, isopropyl myristate, ethyl palmitate, isopropyl palmitate, methyl palmitate, methyl stearate, ethyl stearate, isopropyl stearate, butyl stearate, isobutyl stearate,
  • emollients include, but not limited to, caprylic/capric triglyerides, castor oil, ceteareth-20, ceteareth-30, cetearyl alcohol, ceteth 20, cetostearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, cocoa butter, diisopropyl adipate, glycerin, allantoin, glyceryl monooleate, glyceryl monostearate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffins, linoleic acid, mineral oil, oleic acid, white petrolatum, polyoxyethylene glycol fatty alcohol ethers, and mixtures thereof.
  • the hydrophobic phase comprises one or more silicone compounds and is substantially free of non-silicone water-immiscible substances.
  • the topical composition is a silicone-in- water emulsion.
  • the topical composition is an emulgel.
  • the topical composition comprises silicone-in-water emulsion and is in the form of an emulgel.
  • the topical composition comprises an emulsifying agent.
  • the emulsifying agent is selected from, but not limited to, anionic surfactants, cationic surfactants, or non-ionic surfactants.
  • Anionic surfactants used in pharmaceutical preparations include, but not limited to, alkali-metal soaps (monovalent alkyl carboxylates) which are the sodium and potassium salts of the higher fatty acids. They are often produced from vegetable oils or from specific fatty acids such as stearic acid, lauric acid, or oleic acid; animal fats such as tallow may also be used.
  • Metallic soaps polyvalent alkyl carboxylates), the calcium, zinc, magnesium, and aluminum salts of the higher fatty acids.
  • Amine soaps which are the amine salts of fatty acids and include trolamine (triethanolamine) stearate and diolamine (diethanolamine) stearate.
  • Ester carboxylates which are salts of fatty acids esterified with hydroxyacids or dicarboxylic acids; they include sodium stearoyl-lactylate and sodium stearyl fumarate.
  • Alkyl sulfates sulfated fatty alcohols; alkyl ester sulfates
  • sodium lauryl sulfate which are the salts of sulfuric acid esters of fatty alcohols.
  • Alkyl ether sulfates ethoxylated alkyl sulfates
  • Alkyl ether sulfates are similar compounds but the fatty alcohols are ethoxylated; examples include sodium laureth sulfate.
  • Sulfated oils which are vegetable and animal oils and fats that have been treated with sulfuric acid and then neutralized.
  • Sulfated castor oil neutralized with sodium hydroxide
  • Sulfonated compounds include alkyl sulfonates such as sodium caprylyl sulfonate and sodium cocoyl isetionate, and alkyl aryl sulfonates such as sodium dodecylbenzenesulfonate.
  • Salts of sulfonated carboxylic acids such as sodium lauryl sulfoacetate disodium lauryl sulfosuccinate and docusate sodium (sodium dioctyl sulfosuccinate).
  • Alkyl phosphates including alkyl ester phosphates such as sodium lauryl phosphate and alkyl ether phosphates such as sodium laureth phosphate.
  • Alkyl sarcosidesor sarcosinates are fatty acid amides produced from acylation of the synthetic amino acid sarcosine (N-methylglycine) with fatty acids. Salts such as sodium cocoyl sarcosinate and sodium lauroyl sarcosinate.
  • anionic surfactants selected from, but not limited to, aluminium monostearate, calcium stearoyl-lactylate, sodium cetostearyl sulfate, sodium cocoyl isetionate, sodium cocoyl sarcosinate, sodium lauryl sulfate, sodium lauroyl isetionate, sodium lauroyl sarcosinate, sodium oleate, sodium stearate, sodium stearoyl-lactylate, sulfated castor oil.
  • Cationic surfactants are used alone or in combination with other emulsifying agents.
  • cationic surfactants include, but not limited to, tonzonium bromide.
  • Non-ionic surfactants are selected from, but not limited to, glycol and glycerol (glyceryl) esters: Simple esters of fatty alcohols and fatty acids have some surfactant properties but this can be improved by further hydroxyl or ester groups. Glycol and glycerol esters (monoesters of ethylene glycol, diethylene glycol, and propylene glycol, and mono- or diesters of glycerol) contain both ester and hydroxyl groups and are widely used as non-ionic surfactants.
  • Macrogol esters Polyethoxylation of glycols provides additional hydrophilicity, which increases with the degree of ethoxylation, and fatty acid esters with a wide range of macrogols (polyethylene glycols) are used.
  • Glycol ethers Ethers of glycols with fatty alcohols are generally included in the same class as macrogol ethers and are used similarly.
  • Macrogol ethers Ethers of macrogols with fatty alcohols (macrogol alkyl ethers) or alkylphenols (macrogol aryl ethers) have similar properties to macrogol esters but the ether linkage is more stable to hydrolysis making macrogol ethers more resistant to acids and alkalis.
  • Polyalcohol esters Fatty acid esters of polyalcohols such as glycerol polymers (polyglycerols), sorbitol, and sucrose also have nonionic surfactant properties.
  • Sorbitan esters esters of the cyclic mono- or di-anhydrides of sorbitol with fatty acids
  • Polysorbates polyethoxylated sorbitan esters
  • Poloxamers are copolymers of polyoxyethylene and polyoxypropylene.
  • non-ionic surfactants are selected from, but not limited to, acetoglycerides, diethylene glycol esters, diethylene glycol ethers, ethylene glycol esters, glyceryl behenate, glyceryl mono- and di-esters, glyceryl monocaprylocaprate, glyceryl monolinoleate, glyceryl mono-oleate, glyceryl stearates, macrogol cetostearyl ethers, macrogol/glycerol esters, macrogol 6 glyceryl caprylocaprate, macrogol 20 glyceryl monostearate, macrogol 15 hydroxystearate, macrogol laurates, macrogol lauryl ethers, macrogol monomethyl ethers, macrogol oleates, macrogol oleyl ethers, macrogol 40 sorbitol heptaoleate, macrogol stearates, macrogolglycerol cocoates, nonoxinols, oc
  • Glycol and glycerol esters are selected from glyceryl behenate, glyceryl mono- and di-esters, glyceryl monocaprylocaprate, glyceryl monolinoleate, glyceryl mono-oleate, glyceryl distearate, glyceryl monostearate, glyceryl palmitostearate, diethylene glycol esters such as diethylene glycol monolaurate, diethylene glycol mono-oleate, diethylene glycol monostearate, diethylene glycol palmitostearate, ethylene glycol esters such as ethylene glycol distearate, ethylene glycol monopalmitostearate, propylene glycol esters such as propylene glycol dicaprylocaprate, propylene glycol monocaprylate, propylene glycol diacetate, propylene glycol dilaurate, propylene glycol monolaurate, propylene glycol monopalmitostearate, glycol ethers di
  • the emulsifying agent is a non-ionic emulsifying agent.
  • the emulsifying agent is selected from poloxamer, polyoxyl 40 hydrogenated castor oil, and/or sodium lauryl sulfate.
  • the emulsifying agent is polyoxyl 40 hydrogenated castor oil.
  • the topical composition comprises one or more gelling agents.
  • the gelling agents are selected from, but not limited to, carbomers, polyethylene glycols acrylate polymers, methacrylate polymers, polyvinylpyrrolidones, copolymers based on butyl methacrylate and methyl methacrylate povidone, vinyl acetates, polyvinyl acetates, celluloses, gums, alginates, cellulose acetate phthalates, cellulose acetate butyrates, hydroxypropyl methyl cellulose phthalates, and the like.
  • Examples include commercially available products, such as, but not limited to, CARBOPOL® products, PEG 400, EUDRAGIT® 100, EUDRAGIT® RSPO, EUDRAGIT® RLPO, EUDRAGIT® ND40, PLASDONE®, Dry-FLO (aluminium starch octenyl succinate), Sepineo -P600 (a mixture of acrylamide acryloyldimethyl taurate copolymer, isohexadecane and polysorbate 80), copolymers based on butyl methacrylate and methyl methacrylate (PLASTOID® B), alkyl celluloses such as ethyl celluloses and methyl celluloses, hydroxyalkyl celluloses such as hydroxyethyl cellulose and hydroxypropyl cellulose, hydroxyalkyl alkyl celluloses such as hydroxypropyl methylcelluloses and hydroxy butyl methylcelluloses, gums such as xanthan gum, tragacan
  • the gelling agent is a mixture of acrylamide acryloyldimethyl taurate copolymer, isohexadecane and polysorbate 80, commercially known as SEPINEO-P600®.
  • the topical composition comprises one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from, but not limited to, moisturizers, humectants, solvents, co-solvents, emulsifying agents, solubilizing agents, amphiphilic substances, preservatives, buffers, skin penetration enhancers, gelling agents, antioxidants, film forming agents and the like.
  • the topical composition comprises a humectant selected from glycerine, sorbitol, xylitol, maltitol, polydextroses, urea, and the like.
  • the topical composition comprises glycerine as the humectant.
  • topical composition of the present application is substantially free of (C1-C4) alcohols and/or propylene glycol, such that any amounts present do not cause significant skin irritation or impart any undesired attributes to the composition.
  • the composition of the present application is substantially free of glycols.
  • the glycols according to the present application are alkylene or polyalkylene glycols. Examples include (CI to C6) alkylene and polyalkylene glycols, such as ethylene glycol, polyethylene glycol (2 to 20 monomers), propylene glycol, dipropylene glycol,29 butylene glycol, pentylene glycol and hexylene glycol. They may or may not be oxyethylenated (2 to 50 EO).
  • glycol ethers such as ethoxydiglycol or diethylene glycol monoethyl ether, marketed under the trademark Transcutol HP by Gattefosse, propylene glycol laurate marketed under the trademark Lauroglycol by Gattefosse, propylene glycol dicaprate dicaprylate marketed under the trademark Estol 1526 by Uniqema,and propylene glycol dipelargonate.
  • topical composition of the present application is propellant-free or substantially free of propellants.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; (d) a stabilizer; and (e) one or more pharmaceutically acceptable excipients; wherein said composition is a stable composition.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound (d) a stabilizer; and (e) one or more pharmaceutically acceptable excipients; wherein said composition is a stable composition.
  • the topical composition of the present application is stable for at least about 3 months.
  • the topical composition is stable for at least about 6 months or for at least about 12 months.
  • the topical composition is physically and chemically stable for a period of at least about 12 months when stored at 25 ° C/60%RH or at 30 ° C/65%RH.
  • the topical composition of the present application is pH-balanced composition having a pH ranging from about 3 to about 7.
  • the topical composition of the present application is pH-balanced composition having a pH from ranging about 4 to about 6.
  • the topical composition of the present application has a viscosity of about 4 poise to about 12 poise.
  • the topical composition of the present application is physically and chemically stable for at least about 12 months, wherein the composition comprises not more than about 10% of benzoic acid, and not more than about 1% of the total unknown impurities, and wherein the composition is pH-balanced and has a viscosity of about 4 poise to 12 poise, when tested for stability in about 12 months, under the conditions of 25 ° C/60%RH or at 30 ° C/65%RH.
  • the viscosity was measured using Brookfield viscometer of CAP 2000+ model with spindle number 01 and spindle speed of and 50 rpm, at a temperature of 30°C, with run time of 100 seconds and hold time of 20Sec.
  • a topical composition comprises: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; (d) a stabilizer; and (e) one or more pharmaceutically acceptable excipients; wherein said zinc compound and stabilizer is in the weight ratio of from about 1: 1 to about 1:5.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound (d) a stabilizer; and (e) one or more pharmaceutically acceptable excipients; wherein said zinc compound and stabilizer is in the weight ratio of from about 1: 1 to about 1:5.
  • the weight ratio between the zinc compound and the stabilizer is selected from about 1: 1 or 1: 1.1 or 1: 1.2 or 1: 1.3 or 1: 1.4 or 1: 1.5 or 1: 1.6 or 1: 1.7 or 1: 1.8 or 1: 1.9 or 1:2 or 1:2.1 or 1:2.2 or 1:2.3 or 1:2.4 or 1:2.5 or 1:2.6 or 1:2.7 or 1:2.8 or 1:2.9 or 1:3.0 or 1:3.1 or 1:3.2 or 1:3.3 or 1:3.4 or 1:3.5 or 1:3.6 or 1:3.7 or 1:3.8 or 1:3.9 or 1:4.0.
  • the zinc compound and the stabilizer are present in the weight ratio of about 1:2 or about 1:2.5 or about 1:3 or about 1:3.5 or about 1:4.
  • the zinc compound is zinc oxide
  • the stabilizer is S-lactic acid having the weight ratio of about 1: 1, or about 1:2.5, or about 1:3.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition provides therapeutically effective concentration of benzoyl peroxide for a period of at least about 5 hours in the skin layers of a subject.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition provides therapeutically effective concentration of benzoyl peroxide for a period of at least about 5 hours in the skin layers of a subject.
  • the topical composition of the present application provides therapeutically effective concentration of benzoyl peroxide for a period of at least about 6 hours, or for a period of at least about 7 hours or for period of at least about 8 hours in the skin layers of a subject.
  • the therapeutically effective concentration of benzoyl peroxide provided by the topical composition of the present application is similar to that of BENZAC AC®.
  • the topical composition of the present application shows statistically similar concentration of benzoyl peroxide to that of BENZAC AC®.
  • the topical composition of the present application provides therapeutically effective concentration of benzoyl peroxide for a period of at least about 5 hours or up to about 12 hours in the skin layers of a subject.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition provides the mean cumulative percentage release of benzoyl peroxide of at least about 10% of applied dose in 6 hours.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition provides the mean cumulative percentage release of benzoyl peroxide of at least about 10% of applied dose in 6 hours.
  • the topical composition provides the mean cumulative percentage release of benzoyl peroxide of at least about 0.5% of applied dose at half-an-hour, or at least about 2% of applied dose at 1 hour, or at least about 5% of applied dose at 2 hours, or at least about 7% of applied dose at 3 hours, or at least about 9% of applied dose at 4 hours, or at least about 10% of applied dose at 6 hours.
  • the mean cumulative percentage release of benzoyl peroxide from the topical composition of the present application is similar to that of BENZAC AC®.
  • the topical composition comprises: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein the mean cumulative percentage release of benzoyl peroxide from the topical composition of the present application is similar to that of BENZAC AC®; and said silicone compound is present in an amount of at least about 10% w/w based on the total weight of the composition.
  • a topical composition comprises: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein the mean cumulative percentage release of benzoyl peroxide from the topical composition of the present application is similar to that of BENZAC AC®; and said silicone compound is present in an amount of at least about 10% w/w based on the total weight of the composition.
  • the topical composition provides similar mean cumulative percentage release of benzoyl peroxide as compared to non- silicone topical composition of benzoyl peroxide (i.e.) BENZAC AC®.
  • the topical composition comprises: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition provides the mean cumulative percentage release of benzoyl peroxide at least about 10% of applied dose at 6 hours, when subjected to in-vitro release study using a synthetic cellulose nitrate membrane with 0.22 micron thickness, and the receptor fluid is Phosphate-buffered saline (PBS buffer) and ethanol (50:50) v/v of polyethylene glycol 400, and applied composition weight is about 50 mg.
  • PBS buffer Phosphate-buffered saline
  • ethanol 50:50
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition provides the mean cumulative percentage release of benzoyl peroxide at least 10% of applied dose at 6 hours, when subjected to in-vitro release study using a synthetic cellulose nitrate membrane with 0.22 micron thickness, and the receptor fluid is Phosphate -buffered saline (PBS buffer) and ethanol (50:50) v/v of polyethylene glycol 400, and applied composition weight is about 50 mg.
  • PBS buffer Phosphate -buffered saline
  • ethanol 50:50
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition is occlusive to the skin.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition is occlusive to the skin.
  • the topical composition is occlusive, wherein said composition provides average moisture loss of not more than about 5 g/m 2 h after about 6 hours from the application time in trans-epidermal water loss study.
  • the topical composition is occlusive, wherein said composition reduces trans-epidermal water loss by at least about 20% after about 6 hours as compared to that of the unapplied skin, otherwise called as blank skin.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compound; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein the weight ratio of benzoyl peroxide to silicone compound is from about 1:4 to about 1: 10.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein the weight ratio of benzoyl peroxide to silicone compound is from about 1:4 to about 1: 10.
  • the weight ratio between benzoyl peroxide to silicone compound is about 1:4, or about 1:5, or about 1:6, or about 1:7, or about 1:8, or about 1:9, or about 1: 10.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein the weight ratio of zinc compound to benzoyl peroxide is from about 1:2 to about 1: 17.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein the weight ratio of zinc compound to benzoyl peroxide is from about 1:2 to about 1: 17.
  • the weight ratio between zinc compound to benzoyl peroxide is about 1:3, or about 1:4, or about 1:5, or about 1:6, or about 1:7.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein the weight ratio between benzoyl peroxide to silicone compounds to zinc compound is selected from 3:30: 1, 3:35: 1, 3:40: 1, 3:45: 1, 4:30: 1, 4:35: 1, 4:40: 1, 4:45: 1, 5:30: 1, 5:35: 1, 5:40: 1, 5:45: 1, 3:1: 1, 6:35: 1, 6:40: 1, 6:45: 1, 7:30: 1, 7:35: 1, 7:40: 1, and 7:45: 1.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein the weight ratio between benzoyl peroxide to silicone compound to zinc compound is selected from 3:30: 1, 3:35: 1, 3:40: 1, 3:45: 1, 4:30: 1, 4:35: 1, 4:40: 1, 4:45: 1, 5:30: 1, 5:35: 1, 5:40: 1, 5:45: 1, 3:1: 1, 6:35: 1, 6:40: 1, 6:45: 1, 7:30: 1, 7:35: 1, 7:40: 1, and 7:45: 1.
  • the weight ratio between benzoyl peroxide to silicon compounds to zinc compound is selected from about 3:35: 1, about 4:35: 1, about 5:45: 1, about 6:45: 1, about 7:45: 1, about 5:35: 1, about 6:35: 1, and about 7:35: 1.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compound; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition comprises at least about 10% w/w of a silicone compound based on total weight of the composition.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition comprises at least about 10% w/w of a silicone compound based on total weight of the composition.
  • the topical composition comprises one or more silicone compounds in an amount of at least about 15% w/w, or at least about 20%w/w, or at least about 25% w/w, or at least about 30% w/w, or at least about 35% w/w, or at least about 40% w/w, or at least about 45% w/w, or at least about 50% w/w or at least about 55% w/w, or at least about 60% w/w based on total weight of the composition.
  • the topical composition comprises substantial amounts of one or more silicone compounds, wherein said composition is occlusive and provides the retention of moisture content and prevents irritation/dryness to the subject's skin.
  • the topical composition is easily water- washable and non-greasy.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition comprises water in an amount of at least about 10% w/w.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition comprises water in an amount of at least about 10% w/w.
  • the topical composition comprises water in an amount of at least about 15% w/w, or at least about 20% w/w, or at least about 25% w/w, or at least about 30% w/w, or at least about 35% w/w, or at least about 40% w/w, or at least about 45% w/w, or at least about 50% w/w based on total weight of the composition.
  • the composition comprises one or more silicone compounds in an amount of at least about 10% w/w, or at least about 15% w/w, or at least about 20%w/w, or at least about 25% w/w, or at least about 30% w/w, or at least about 35% w/w, or at least about 40% w/w, or at least about 45% w/w, or at least about 50% w/w or at least about 55% w/w, or at least about 60% w/w based on total weight of the composition.
  • the topical composition has a weight ratio of silicone to water from about 1:0.4 to about 1: 1.5.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide and water; (b) a hydrophobic phase comprising one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition is silicone-in-water emulsion and has a silicone-to-water weight ratio from about 1:0.4 to about 1: 1.5.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide; (b) one or more silicone compounds; (c) a zinc compound; and (d) one or more pharmaceutically acceptable excipients; wherein said composition has a silicone-to- water weight ratio from about 1:0.4 to about 1: 1.5.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) benzoyl peroxide in an amount of from about 1% w/w to about 12% w/w; (b) one or more silicone compounds in an amount of from about 10%w/w to about 60%w/w; (c) a zinc compound in an amount of from about 0.5% w/w to about 5%w/w; (d) a stabilizer; and one or more pharmaceutically acceptable excipients; wherein the stabilizer is lactic acid.
  • An aspect of the present application relates to a topical composition
  • a topical composition comprising: (a) a hydrophilic phase comprising benzoyl peroxide in an amount of from about 1% w/w to about 12% w/w and water; (b) a hydrophobic phase comprising one or more silicone compounds in an amount of from about lOw/w to about 60%w/w; (c) a zinc compound in an amount of from about 0.5% w/w to about 5%w/w; (d) a stabilizer; and one or more pharmaceutically acceptable excipients; wherein the stabilizer is lactic acid.
  • one or more silicone compounds are selected from elastomer- 10, dimethicone, cyclomethicone, dimethicone crosspolymers and mixtures thereof.
  • the zinc compound is selected from zinc oxide, zinc sulfate, zinc lactate and mixtures thereof.
  • An aspect of the present application relates to a process of preparing a topical composition comprising a combination of benzoyl peroxide, and one or more silicone compound, comprising: (a) preparing an active substance phase comprising benzoyl peroxide with one or more gelling agents; (b) preparing a dispersion containing one or more silicone compounds; (c) blending of step (a) and step (b) to prepare homogenous monophasic dispersion; and (d) filling the composition of step (c) into a suitable dispensing device.
  • An aspect of the present application relates to a process of preparing a topical composition comprising a combination of benzoyl peroxide, and one or more silicone compound, comprising: (a) preparing a hydrophilic phase comprising benzoyl peroxide; (b) preparing a hydrophobic phase comprising one or more silicone compound; (c) adding the dispersion of step (b) to step (a); and (d) filling the composition of step (c) into a suitable dispensing device.
  • the intermittent homogenization process is the process of homogenization followed in the steps of hydrophilic phase preparation and emulsification, wherein the homogenization is carried out below 20°C throughout the process, and the homogenization is stopped in between whenever the temperature of the process goes above 20°C.
  • the temperature of the process is controlled using a device such as chilled water circulating -jacketed manufacturing vessel, or any suitable other methods of controlling temperature.
  • the intermittent homogenization process is essential for preparing composition comprising temperature sensitive drugs such as benzoyl peroxide, and this intermittent homogenization process along with temperature controlled device are important to carry out the process of preparing topical composition comprising benzoyl peroxide and silicone compounds.
  • the temperature is continuously monitored during the process.
  • the process of preparing a topical composition of the present application is temperature-controlled and involves intermittent homogenization, wherein the temperature is maintained below about 20°C in order to prevent the degradation of benzoyl peroxide.
  • the intermittent homogenization is a temperature-controlled process carried out below about 20°C to about 10°C with the homogenization speed of about 2500 rpm to about 10000 rpm.
  • the intermittent homogenization involves homogenization at 2500 rpm to 10000 rpm with a temperature below about 20°C.
  • the step of preparing hydrophilic phase is carried out at a low temperature below about 20°C to about 10°C.
  • An aspect of the present application relates to a process of preparing a topical composition comprising a combination of benzoyl peroxide, one or more silicone compound, and a zinc compound, wherein said process comprises steps of: (a) preparing a hydrophilic phase comprising benzoyl peroxide, an emulsifying agent, and water with intermittent homogenization at temperatures below about 20°C; (b) preparing a hydrophobic phase comprising one or more silicone compound and a zinc compound; (c) emulsification of dispersion from step (a) and step (b) with intermittent homogenization at a temperature below about 20°C; and (d) dispensing the composition of step (c) in a suitable device; wherein the intermittent homogenization is carried out to keep the temperature below about 20°C.
  • An aspect of the present application relates to a method of treating and/or preventing an inflammatory skin disorder, comprising a step of administration of a topical composition comprising: benzoyl peroxide, one or more silicone compound, and a zinc compound.
  • An aspect of the present application relates to a method of treating and/or preventing an inflammatory skin disorder and/or related conditions thereof, comprising a step of administration of a topical composition comprising: benzoyl peroxide, one or more silicone compounds, and a zinc compound.
  • the inflammatory skin disorder is selected from, but not limited to, acne, psoriasis, rosacea, dermatitis, erythema, actinic keratosis, and the like.
  • the inflammatory skin disorder and/or related conditions thereof is selected from acne, psoriasis, rosacea, dermatitis, erythema, actinic keratosis, and scars formed by the skin disorders.
  • the inflammatory skin disorder is acne vulgaris.
  • the inflammatory skin disorder and/or related conditions thereof include acne vulgaris and acne scars.
  • An aspect of the present application relates to a method of treating and/or preventing an inflammatory skin disorder, comprising topical administration of a composition comprising benzoyl peroxide, one or more silicone compounds, and a zinc compound, wherein said method provides therapeutically effective concentration of benzoyl peroxide similar to that of BENZAC AC® in the skin layers of a subject.
  • An aspect of the present application relates to a method of treating and/or preventing an inflammatory skin disorder and/or related conditions thereof, comprising topical administration of the composition comprising benzoyl peroxide, one or more silicone compounds, and a zinc compound, wherein said method provides therapeutically effective concentration of benzoyl peroxide similar to that of BENZAC AC® in the skin layers of a subject.
  • the method relates to simultaneous treatment and/or prevention of inflammatory skin disorder and related conditions thereof.
  • the method relates to simultaneous treatment and/or prevention of acne and acne scars and other scars in a subject.
  • the present application relates to a method of treatment and/or prevention of acne and other skin inflammation associated with acne with simultaneous prevention and/or treatment of acne scars and other scars, comprising topically administering a composition comprising benzoyl peroxide, one or more silicone compounds, and a zinc compound from about one day to about 12 weeks, or up to the clearance of the skin disorder, wherein said method provides therapeutically effective concentration of benzoyl peroxide for at least about 5 hours in the skin layers of a subject.
  • the method comprises administration of the topical composition from about one day to about 12 weeks, or up to the clearance of the skin disorder.
  • the method prevents the formation of acne scars and other scares along with the treatment of acne, and treats the existing acne scars along with the treatment of acne.
  • An aspect of the present application relates to a method of administering a topical composition comprising combination of benzoyl peroxide, one or more silicone compound and a zinc compound, to a subject in need thereof, the method comprising: (a) identifying a subject having an inflammatory skin disorder; and (b) topically administering said composition at least once daily for a period of from about one day to about 12 weeks, or until complete clearance of acne and/or acne scars and other scars, or as directed by physician.
  • An aspect of the present application relates to a method of administering a topical composition comprising combination of benzoyl peroxide, one or more silicone compound and a zinc compound, to a subject in need thereof, the method comprising: (a) identifying a subject having an inflammatory skin disorder; and (b) topically administering said composition two to three times daily for a period of from about one day to about 12 weeks, or until complete clearance of acne and/or acne scars and other scars, or as directed by physician.
  • the method comprises administration of the topical composition once daily to the subject.
  • the method comprises administration of the topical composition twice daily to the subject.
  • the method provides a therapeutically effective concentration of benzoyl peroxide similar to that of BENZAC AC®.
  • the method provides a therapeutically effective concentration of benzoyl peroxide at least for a period of about 5 hours or up to about 12 hours in the skin layers of a subject.
  • the topical composition is physically and chemically stable for at least about 12 months, wherein the composition comprises not more than about 10% of the benzoic acid, and not more than about 1% of the total unknown impurities, when tested for stability in 12 months, under the conditions of 25 ° C/60%RH or at 30 ° C/65%RH.
  • Topical compositions comprising benzoyl peroxide, one or more silicone compounds and a zinc compound were manufactured, and are illustrated as Examples 1-5 in Table 1.
  • Table 1 Topical compositions comprising benzoyl peroxide, silicone compound and zinc compound
  • hydrous benzoyl peroxide 6.66% is equivalent to 5% of anhydrous benzoyl peroxide, and 3.36% is equivalent to 2.5% of anhydrous benzoyl peroxide;
  • Elastomer 10 is a mixture of high molecular weight silicon elastomer (contained up to 12%) and remaining portion is decamethylcyclopentasiloxane;
  • Sepineo-P600 is a mixture of acrylamide acryloyldimethyl taurate copolymer, isohexadecane and polysorbate 80;
  • DC7040 is caprylyl methicone and polyethylene glycol-12 dimethicone/polypropylene glycol-20 crosspolymer.
  • Preparing hydrophilic phase A stainless steel vessel was charged with purified water and homogenization was carried out at 2500-3000 rpm, further poloxamer 188 was dissolved under homogenization for 15 minutes under controlled temperature 10°C - 20°C in the stainless steel vessel to form a dispersion and glycerine was added to the dispersion followed by hydrous benzoyl peroxide under continuous homogenization maintaining temperature 10°C - 20°C, and finally polyoxyl 40 hydrogenated castor oil was added to the benzoyl peroxide dispersion of step 3 under homogenization maintaining temperature 10°C - 20°C. Homogenization was continued for 30 minutes.
  • hydrophobic phase was prepared separately in main manufacturing vessel.
  • the vessel was charged with silicone compounds (elastomer- 10, DC7040, cyclomethicone, and/or dimethicone 350 cSt), S-lactic acid and mixed to form homogenous dispersion and the zinc compound was dispersed in above the dispersion containing silicones and mixed to form a uniform dispersion of hydrophobic silicone phase.
  • silicone compounds elastomer- 10, DC7040, cyclomethicone, and/or dimethicone 350 cSt
  • Emulsification The hydrophobic phase was transferred to hydrophilic phase under homogenization maintaining temperature 10°C - 20°C and continued homogenization for 1 hour. Finally Sepineo-P 600 was added to the above dispersion and further homogenized for 1 hour and the emulsion was homogenized at 500 rpm for 30 minutes.
  • Example 6 Comparative Pharmacokinetics of composition of the Example 1 and Example 2 and the reference product (BENZAC AC® 5%) in Male Sprague Dawley Rats
  • Pharmacokinetic study protocol The protocol was to estimate the concentrations of benzoyl peroxide (BPO) and benzoic acid in rat skin after single topical application of compositions of example 1 and example 2 at specified time period (8 hours), in comparison to the reference product BENZAC AC® 5%, in male Sprague Dawley rats.
  • BPO benzoyl peroxide
  • Table 2 Summary of mean concentrations of benzoyl peroxide and benzoic acid g/g) in rat skin samples
  • Example 1 and 2 compositions of the present application showed comparable benzoyl peroxide and benzoic acid exposures to the reference product in at 8hrs after dosing. It was observed that the release of benzoyl peroxide was not affected by the presence of silicones in the compositions of example 1 and 2, as against the reference product which does not contain any silicone compound.
  • Example 7 The in- vitro release studies (IVRT) of compositions of example 3 and example 4 [0208] This in- vitro active substance release from composition was studied in comparison with BENZAC AC®. The release rate of benzoyl peroxide from reference product (BENZAC AC®) was compared with release rates of compositions (Examples 3 and 4) of the present application, across a synthetic membrane.
  • IVRT study parameters The receptor fluid was phosphate buffer with ethanol (50:50) in polyethylene glycol 400 medium, the membrane was cellulose nitrate (0.22 ⁇ ), temperature: 32° C + 1°C. The samples were tested using HPLC method.
  • Table 3 Comparative IVRT data of example 3 and example 4, and BENZAC AC®
  • - benzoic acid is a related substance, and often called as impurity B of benzoyl peroxide; ND- not detected
  • Example 3 and 4 were found to be stable with respect to benzoic acid and other unknown impurities which were maintained well within the limits, and the both compositions were lactic acid (stabilizer)- containing compositions. It was observed that the Example 5 (devoid of stabilizer) composition was relatively unstable with the increased benzoic acid and total unknown impurities, imbalanced pH, and increased viscosity found within the time period of 2 months. The presence or increase in lactic acid concentration has improved the stability with reduced impurities, balance in the pH and viscosity.
  • Example 9 Trans-epidermal water loss (TEWL) study
  • TEWL Trans-epidermal water loss study was conducted with the aim to investigate the influence of compositions of Example 3 (5% benzoyl peroxide) and Example 4 (2.5% benzoyl peroxide) on the TEWL of the skin. All the compositions were applied to the surface of dermatomed human skin. This experimental study helped in understanding the TEWL of skin after application of compositions of the present application on human skin.
  • compositions of example 3 and example 4 were found to be reduced by 26.32% and 33.33% respectively after 6 hours of topical application, as compared to that of the blank skin as a control which was found to be increased by 3.7%. This suggests that compositions of example 3 and example 4 of the present application minimize the TEWL and thus retain the skin moisture and prevent the skin dryness. It was concluded that the compositions of the present application were occlusive in nature.

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Abstract

La présente invention concerne une composition topique stable comprenant du peroxyde de benzoyle en combinaison avec un ou plusieurs composés de silicone et un composé de zinc. La présente invention concerne en outre l'utilisation de la composition topique, ainsi qu'un procédé de préparation d'une telle composition topique.
PCT/IB2016/057966 2015-12-23 2016-12-23 Composition topique pour le traitement de l'acné WO2017109761A1 (fr)

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RU2018126808A RU2018126808A (ru) 2015-12-23 2016-12-23 Композиция для местного применения для лечения акне

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113631141A (zh) * 2019-03-01 2021-11-09 瓦塞尔曼梅迪奇公司 新组合物及其用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996012498A2 (fr) * 1994-10-20 1996-05-02 The Procter & Gamble Company Compositions dermatologiques contenant du peroxyde de benzoyle et compose reduisant l'irritation de la peau
EP2319510A1 (fr) * 2009-10-02 2011-05-11 Johnson and Johnson Consumer Companies, Inc. Composition au peroxyde de benzoyle pour le traitement de la peau

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996012498A2 (fr) * 1994-10-20 1996-05-02 The Procter & Gamble Company Compositions dermatologiques contenant du peroxyde de benzoyle et compose reduisant l'irritation de la peau
EP2319510A1 (fr) * 2009-10-02 2011-05-11 Johnson and Johnson Consumer Companies, Inc. Composition au peroxyde de benzoyle pour le traitement de la peau

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113631141A (zh) * 2019-03-01 2021-11-09 瓦塞尔曼梅迪奇公司 新组合物及其用途

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