WO2001060336A1 - Compositions for topical delivery of a pharmaceutically active agent having reduced skin irritation - Google Patents

Compositions for topical delivery of a pharmaceutically active agent having reduced skin irritation Download PDF

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Publication number
WO2001060336A1
WO2001060336A1 PCT/US2001/004696 US0104696W WO0160336A1 WO 2001060336 A1 WO2001060336 A1 WO 2001060336A1 US 0104696 W US0104696 W US 0104696W WO 0160336 A1 WO0160336 A1 WO 0160336A1
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WIPO (PCT)
Prior art keywords
weight
composition
composition according
compositions
skin
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Application number
PCT/US2001/004696
Other languages
French (fr)
Inventor
Paul Robert Tanner
Thomas Edward Huetter
Original Assignee
The Procter & Gamble Company
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Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to AU2001236996A priority Critical patent/AU2001236996A1/en
Publication of WO2001060336A1 publication Critical patent/WO2001060336A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A61K8/553—Phospholipids, e.g. lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/925—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of animal origin
    • 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
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/75—Anti-irritant

Definitions

  • the present invention relates to compositions comprising high levels of at least one phospholipid and at least one skin conditioning agent for the topical delivery of at least one pharmaceutically active agent.
  • the present invention further relates to a method of preventing or reducing drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive application of topical compositions which contain high levels of phospholipids to the skin of animals and/or humans.
  • the method comprises adding a safe and effective amount of at least one skin conditioning agent to compositions containing high levels of phospholipids.
  • phospholipids offer the potential of improved transdermal drug delivery. It is known, for example, that liposomes made from phospholipids are able to facilitate the uptake of certain compounds across the skin barrier. Phospholipids are used in a wide variety of pharmaceutical compositions, as well as cosmetics and food products. Phospholipids are used in pharmaceutical compositions as dispersing, emulsifying, and stabilizing agents and are included in intramuscular, intravenous, parenteral, and topical compositions. Examples of topical compositions comprising phospholipids include U.S.
  • Patent 5,064,655 (Uster, et al.), which discloses a topical liposome gel composition having a high viscosity for application and delivery of a drug active at a wound site or mucosal tissue site;
  • U.S. Patent 5,945,409 (Crandall), which discloses topical compositions comprising phospholipids for moisturizing keratinous tissue of a human or animal;
  • U.S. Patent 5,814,343 Jones, et al.
  • Patent 5,654,337 (Roentsch, et al.), which discloses a topical composition comprising phospholipids useful in delivering pharmaceutically active agents through the skin; and U.S. Patent 5,869,090 (Rosenbaum), which discloses a topical composition comprising phospholipids as vehicles for the transdermal delivery of dehydroepiandrosterone (DHEA).
  • DHEA dehydroepiandrosterone
  • phospholipids are used at low concentrations, e. g., at or below about 1% by weight of the topical composition, and are generally regarded as non-irritating and non-sensitizing. However, when phospholipids are used at concentrations greater than about 1% by weight of the topical composition, they may cause drying, irritation, or itching of the skin when the topical composition is continuously or repetitively applied to the skin of animals and/or humans.
  • compositions for the topical delivery of at least one pharmaceutically active agent comprising from about 1% to about 50% by weight of at least one phospholipid, from about 0.1% to about 50% by weight of at least one skin conditioning agent, from about 0.01% to about 10% of at least one pharmaceutically active agent, and at least one suitable carrier material selected from components used in compositions for topical application.
  • the present invention further relates to a method of preventing or reducing conditions of the skin, such as drying, irritation, and itching in animals or humans, caused by the continuous or repetitive application of topical compositions comprising greater than about 1% by weight, of at least one phospholipid, to the skin of an animal or human.
  • the method comprises adding a safe and effective amount, preferably from about 0.1% to about 50% by weight, of at least one skin conditioning agent to the topical composition.
  • the at least one skin conditioning agent prevents or reduces the drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive application of topical compositions comprising greater than about 1% by weight, of at least one phospholipid to the skin of animals and/or humans.
  • Compositions of the present invention may be in the form of emulsions, creams, lotions, ointments, gels, pastes, solutions, or any other suitable topical skin formulation.
  • compositions having greater than about 1% by weight of a phospholipid compound, especially unsaturated or partially saturated phospholipid compounds, are continuously or repetitively applied to the skin of animals and/or humans, can be reduced or prevented by the addition of a safe and effective amount of at least one skin conditioning agent to these topical compositions.
  • Such compositions are typically used for dermal or transdermal delivery of pharmaceutically active agent or agents.
  • compositions for the topical delivery of at least one pharmaceutically active agent comprising from about 1% to about 50% by weight of at least one phospholipid, from about 0.1% to about 50%> by weight of at least one skin conditioning agent, from about 0.01% to about 10% of at least one pharmaceutically active agent, and at least one suitable carrier material selected from components used in compositions for topical application.
  • the present invention further relates to a method of preventing or reducing drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive topical application of emulsions, creams, lotions, ointments, gels, pastes, solutions, and the like to the skin of animals and/or humans, which contain greater than about 1% by weight, of at least one phospholipid.
  • the method of the present invention comprises adding a safe and effective amount, preferably from about 0.1 % to about 50% by weight, of at least one skin conditioning agent preferably selected from the group consisting of glycerin, lanolin, petrolatum, panfhenol, and mixtures thereof, to topical compositions containing greater than about 1% by weight, of at least one phospholipid.
  • a skin conditioning agent preferably selected from the group consisting of glycerin, lanolin, petrolatum, panfhenol, and mixtures thereof, to topical compositions containing greater than about 1% by weight, of at least one phospholipid.
  • compositions of the present invention may be in the form of emulsions, creams, lotions, ointments, gels, pastes, solutions, or any other suitable topical skin formulation. Depending upon the intended use of the skin preparation, other components may be incorporated into the compositions. Such formulations may comprise topically acceptable carrier materials as are helpful.
  • Topical application means directly spreading, spraying or laying of a compound or composition onto epidermal tissue. Topical application can be achieved by rubbing, applicator pads, containers with applicator filaments, sprays, or any other convenient means.
  • safe and effective amount means an amount of a substance, compound, or composition high enough to provide a significant positive modification of the condition to be treated, e. g., drying, irritation, and/or itching of the skin of an animal or human, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • a "safe and effective amount” of the substance, compound, or composition may vary with the kind and amount(s) of other ingredients used in combination with the particular substance, compound, or composition, the condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors.
  • compositions of the present invention can contain other ingredients which are compatible with the compositions and which preferably do not substantially modify the compositions of the present invention.
  • the term encompasses the terms “consisting of and “consisting essentially of.
  • pastes are liquids for topical application, preferably to the skin of an animal or human, whose viscosity is enhanced to the point that flow is largely inhibited by the presence of undissolved, as well as dissolved, solids.
  • gels are semisolid systems of suspended inorganic particles or organic macromolecules interpenetrated by a liquid for topical application, preferably to the skin of an animal or human.
  • emulsions are multiphase liquids for topical application, preferably to the skin of an animal or human, containing special components such as surfactants and/or thickeners that inhibit or delay the separation of the phases.
  • solutions are single phase liquids substantially free of solids, but small amounts of haze or cloudiness may be tolerated, for topical application, preferably to the skin of an animal or human.
  • suitable carrier materials may include components typically used in compositions for topical application, preferably to the skin of an animal or human, but are not limited to, solvents, emollients, emulsifiers, humectants, thickeners, antioxidants, chelating agents, dispersing agents, preservatives, buffers, fragrances, colorants, substances which are used for the microbial and chemical stabilization of the composition, and the like.
  • carrier materials are well known to and easily selected by the skilled artisan.
  • compositions of the present invention The following provides a detailed description of the essential and non-essential components of the compositions of the present invention. All percentages and ratios used herein are by weight, and all measurements made at 25 °C, unless otherwise specified.
  • compositions of the present invention comprise at least one phospholipid compound.
  • Phospholipids useful in the compositions of the present invention may be selected by the skilled artisan according to the kind and amount(s) of other ingredients used in the compositions of the present invention, the condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors.
  • the preferred phospholipids useful in the compositions of the present invention include all lipoidal constituents, natural and/or synthetic, saturated, partially saturated, or unsaturated, that contain phosphorus in their molecules.
  • the more preferred phospholipids for use in the compositions of the present invention include, but are not limited to, lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, sphingomyelins, and mixtures thereof. While there are no particular limitations to the quality, purity, and/or saturation level of the phospholipids used, the phospholipids are preferably unsaturated or partially saturated, of high quality, pharmaceutical grade. A most preferred phospholipid for use in the compositions of the present invention is phosphatidylcholine.
  • Phosphatidylcholine may be obtained as commercially available soya or egg phosphatidylcholine. More preferably the phosphatidylcholine for use in the compositions of the present invention is soya phosphatidylcholine.
  • the amount of phospholipid used in the compositions of the present invention is typically from about 1%» to about 50%>, preferably from about 1.5% to about 40%), more preferably from about 2% to about 30%>, most preferably from about 2.5% to about 20%) by weight of the compositions of the present invention.
  • compositions of the present invention comprise at least one skin conditioning agent.
  • Skin conditioning agents useful in the compositions of the present invention may be selected according to the kind and amount(s) of phospholipids and other ingredients used in the compositions of the present invention, the condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors.
  • the preferred skin conditioning agents useful in the compositions of the present invention are those compounds that are safe and effective in preventing or reducing drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive application of topical compositions to the skin of animals and/or humans, which contain high levels of phospholipids.
  • the skin conditioning agents for use in the compositions of the present invention include, but are not limited to, petrolatum, liquid paraffin, paraffin wax, beeswax, spermaceti, microcrystalline wax, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, oleyl alcohol, isopropyl myristate, isopropyl palmitate, vegetable oil, squalene, squalane, palmitic acid, stearic acid, cetyl palmitate, lanolin, tocopherol, tocopherol acetate, glycerin, hexylene glycol, propylene glycol, sorbitol, panthenol, polyalcohols having 3-5 carbon atoms, and mixtures thereof; more preferably the skin conditioning agents for use in the compositions of the present invention include glycerin, petrolatum, lanolin, panthenol, and mixtures thereof; most preferably the skin conditioning agent for use in the compositions of
  • the skin conditioning agents are preferably of high quality, pharmaceutical grade.
  • the amount of skin conditioning agents used in the compositions of the present invention may vary according to the amount of phospholipids present in the compositions of the present invention, but is typically in the range of from about 0.1 %> to about 50%), preferably from about 1%> to about 40%>, more preferably from about 2% to about 30%), most preferably from about 3%> to about 20% by weight of the compositions of the present invention.
  • compositions of the present invention comprise at least one pharmaceutically active agent.
  • Pharmaceutically active agents to be delivered topically and found useful in the compositions of the present invention include, but are not limited to, analgesic/anti- inflammatory agents such as aspirin, ibuprofen, ketoprofen, diclofenac, naproxen, indomethacin, piroxicam, flurbiprofen, meclofenamate, ketorolac, tenidap, tebufelone, and their derivatives, isomers, and salts; anti-infective agents such as penicillin, erythromycin, tetracycline, clotrimazole and their derivatives, isomers, and salts; anti- diabetics such as chlorpropamide, glymidine, insulin, and their derivatives, isomers, and salts; anti-arrhythmics such as moricizine, propanolol, amiodarone, and their derivatives, isomers, and salts
  • the particular pharmaceutically active agent(s) and amount of pharmaceutically active agent(s) used in the compositions of the present invention are selected to be safe and effective and may vary with the kind and amount(s) of other ingredients used in combination with the particular pharmaceutically active agent(s), the condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors.
  • the amount of pharmaceutically active agent(s) used in the compositions of the present invention is from about 0.01% to about 10%, preferably from about 0.025%) to about 8%, more preferably from about 0.05% to about 6%, most preferably from about 0.1 % to about 4% by weight of the compositions of the present invention.
  • the preferred pharmaceutically active agent(s) used in the compositions of the present invention comprises analgesic/anti-inflammatory agents selected from the group consisting of aspirin, ibuprofen, naproxen, indomethacin, piroxicam, flurbiprofen, meclofenamate, ketoprofen, ketorolac, diclofenac, tenidap, tebufelone, their derivatives, isomers, and salts, and mixtures thereof.
  • analgesic/anti-inflammatory agents selected from the group consisting of aspirin, ibuprofen, naproxen, indomethacin, piroxicam, flurbiprofen, meclofenamate, ketoprofen, ketorolac, diclofenac, tenidap, tebufelone, their derivatives, isomers, and salts, and mixtures thereof.
  • the more preferred pharmaceutically active agent(s) used in the compositions of the present invention analgesic/anti-inflammatory agents selected from the group consisting of ibuprofen, naproxen, indomethacin, piroxicam, flurbiprofen, ketoprofen, ketorolac, diclofenac, their derivatives, isomers, and salts, and mixtures thereof.
  • the most preferred pharmaceutically active agent(s) used in the compositions of the present invention analgesic/anti-inflammatory agents selected from the group consisting of ketoprofen, ibuprofen, diclofenac, naproxen, their derivatives, isomers, and salts, and mixtures thereof.
  • Water employed in the compositions of the present invention should preferably be of low ion content and free of organic impurities. Typically, water comprises from about 2% to about 99%o, preferably from about 20% to about 95%>, more preferably from about 40%) to about 90%, most preferably from about 60%> to about 85% by weight of the compositions of the present invention.
  • Carrier materials may or may not be used in the compositions of the present invention. If used, they may be selected from components typically used in compositions for topical application, preferably to the skin of an animal or human, i. e., emulsions, creams, lotions, ointments, gels, pastes, solutions, and the like.
  • the carrier materials may be selected from polar and/or non-polar solvents such as glycerin, polyglycerin, glycerin esters, propylene glycol, polypropylene glycol, ethylene glycol, triethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, 1,3-butylene glycol, maltitol, benzyl alcohol, ethanol, ethyl acetate, heptane, canola oil, olive oil, mineral oil, water, and the like; emulsifiers/surfactants such as sodium, potassium, and triethanolamine salts of oleic and stearic acids, dioctyl sodium sulfosuccinate, sodium dodecyl sulfate, glycerol monooleate, glycerol monostearate, ethoxylated sorbitan esters such as Polysorbate 20, Polysorbate 65, and Polysorbate 80, polymers such as acrylate,
  • thickeners such as agar, carrageenan, food starch, modified starch, gelatin, gum arabic, guar gum, cellulose gel, carbomer (Carbopol ® ), hydroxyethylcellulose, hydroxypropyl methylcellulose, pectin, sodium carboxymethylcellulose, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, and the like; antioxidants such as benzenesulfonic acid 4-[(3-(3 ,5-bis(l , 1 -dimethylethyl)-4-hydroxyphenyl)- 1 -oxopropyl) amino] monosodium salt (Tinogard TM AO-6, Ciba Specialty Chemical Co., High Point, NC), ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium formaldehyde
  • these carrier materials may be present in the compositions of the present invention in amounts which provide their intended purpose.
  • solvents typically comprise from about 2% to about 99%>, preferably from about 20%) to about 95%, more preferably from about 40% to about 90% by weight of the compositions of the present invention
  • emulsifiers typically comprise from about 0.05% to about 20%, preferably from about 0.1 % to about 15%, more preferably from about 0.3% to about 10% by weight of the compositions of the present invention
  • thickeners typically comprise from about 0.05% to about 10%, preferably from about 0.1% to about 7.5%, more preferably from about 0.2% to about 5% by weight of the compositions of the present invention
  • antioxidants typically comprise from about 0.01% to about 0.5%, preferably from about 0.02%> to about 0.2%, more preferably from about 0.05% to about 0.15% by weight of the compositions of the present invention
  • chelating agents typically comprise from about 0.01%> to about 0.5%>, preferably from about 0.02%> to about 0.2%, more
  • the pharmaceutically active agent is added to most of the water and enough sodium hydroxide is added to the mixture to raise the pH to allow complete dissolution of the pharmaceutically active agent.
  • the sodium phosphate salts, EDTA disodium, and benzyl alcohol are added to the solution containing the pharmaceutically active agent and the mixture is stirred until all the components are dissolved.
  • the phosphatidylcholine is added to the solution which is then stirred for at least 4 hours to insure liposomes are formed.
  • the liposome solution is then filtered to achieve a selected size distribution of the liposomes.
  • the petrolatum, lanolin, fragrance, and acrylates/C 10-30 acrylate crosspolymer are added to the remaining amount of the water in a separate container which is agitated vigorously to form an emulsion. This emulsion is then added to the liposomes and blended. Carbomer is added slowly to the mix along with the glycerin and the remainder of the sodium hydroxide. The liposome preparation is then agitated for at least 30 minutes until a smooth mixture of the proper viscosity is obtained.

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Abstract

The present invention relates to compositions for the topical delivery of at least one pharmaceutically active agent comprising from about 1 % to about 50 % by weight of at least one phospholipid and from about 0.1 % to about 50 % by weight of at least one skin conditioning agent. The at least one skin conditioning agent prevents or reduces the drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive application of topical compositions to the skin of animals and/or humans, which contain high levels of phospholipids.

Description

COMPOSITIONS FOR TOPICAL DELIVERY OF A PHARMACEUTICALLY ACTIVE AGENT HAVING REDUCED SKIN IRRITATION
The present invention relates to compositions comprising high levels of at least one phospholipid and at least one skin conditioning agent for the topical delivery of at least one pharmaceutically active agent.
The present invention further relates to a method of preventing or reducing drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive application of topical compositions which contain high levels of phospholipids to the skin of animals and/or humans. The method comprises adding a safe and effective amount of at least one skin conditioning agent to compositions containing high levels of phospholipids.
BACKGROUND
There has been much interest in recent years in devising ways to achieve efficient transdermal delivery of pharmaceutically active agents. It has been found that phospholipids offer the potential of improved transdermal drug delivery. It is known, for example, that liposomes made from phospholipids are able to facilitate the uptake of certain compounds across the skin barrier. Phospholipids are used in a wide variety of pharmaceutical compositions, as well as cosmetics and food products. Phospholipids are used in pharmaceutical compositions as dispersing, emulsifying, and stabilizing agents and are included in intramuscular, intravenous, parenteral, and topical compositions. Examples of topical compositions comprising phospholipids include U.S. Patent 5,064,655 (Uster, et al.), which discloses a topical liposome gel composition having a high viscosity for application and delivery of a drug active at a wound site or mucosal tissue site; U.S. Patent 5,945,409 (Crandall), which discloses topical compositions comprising phospholipids for moisturizing keratinous tissue of a human or animal; U.S. Patent 5,814,343 (Jones, et al.), which discloses a cosmetic composition comprising phospholipids for delivering a cosmetically-effective benefit agent to a target site on the skin and/or hair; U.S. Patent 5,654,337 (Roentsch, et al.), which discloses a topical composition comprising phospholipids useful in delivering pharmaceutically active agents through the skin; and U.S. Patent 5,869,090 (Rosenbaum), which discloses a topical composition comprising phospholipids as vehicles for the transdermal delivery of dehydroepiandrosterone (DHEA).
Typically phospholipids are used at low concentrations, e. g., at or below about 1% by weight of the topical composition, and are generally regarded as non-irritating and non-sensitizing. However, when phospholipids are used at concentrations greater than about 1% by weight of the topical composition, they may cause drying, irritation, or itching of the skin when the topical composition is continuously or repetitively applied to the skin of animals and/or humans.
SUMMARY OF THE INVENTION
The present invention relates to compositions for the topical delivery of at least one pharmaceutically active agent comprising from about 1% to about 50% by weight of at least one phospholipid, from about 0.1% to about 50% by weight of at least one skin conditioning agent, from about 0.01% to about 10% of at least one pharmaceutically active agent, and at least one suitable carrier material selected from components used in compositions for topical application.
The present invention further relates to a method of preventing or reducing conditions of the skin, such as drying, irritation, and itching in animals or humans, caused by the continuous or repetitive application of topical compositions comprising greater than about 1% by weight, of at least one phospholipid, to the skin of an animal or human. The method comprises adding a safe and effective amount, preferably from about 0.1% to about 50% by weight, of at least one skin conditioning agent to the topical composition.
The at least one skin conditioning agent prevents or reduces the drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive application of topical compositions comprising greater than about 1% by weight, of at least one phospholipid to the skin of animals and/or humans. Compositions of the present invention may be in the form of emulsions, creams, lotions, ointments, gels, pastes, solutions, or any other suitable topical skin formulation.
DETAILED DESCRIPTION OF THE INVENTION The present inventors have discovered that the drying, irritation, and/or itching of the skin, caused when topical compositions, having greater than about 1% by weight of a phospholipid compound, especially unsaturated or partially saturated phospholipid compounds, are continuously or repetitively applied to the skin of animals and/or humans, can be reduced or prevented by the addition of a safe and effective amount of at least one skin conditioning agent to these topical compositions. Such compositions are typically used for dermal or transdermal delivery of pharmaceutically active agent or agents.
The present invention relates to compositions for the topical delivery of at least one pharmaceutically active agent comprising from about 1% to about 50% by weight of at least one phospholipid, from about 0.1% to about 50%> by weight of at least one skin conditioning agent, from about 0.01% to about 10% of at least one pharmaceutically active agent, and at least one suitable carrier material selected from components used in compositions for topical application.
The present invention further relates to a method of preventing or reducing drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive topical application of emulsions, creams, lotions, ointments, gels, pastes, solutions, and the like to the skin of animals and/or humans, which contain greater than about 1% by weight, of at least one phospholipid.
The method of the present invention comprises adding a safe and effective amount, preferably from about 0.1 % to about 50% by weight, of at least one skin conditioning agent preferably selected from the group consisting of glycerin, lanolin, petrolatum, panfhenol, and mixtures thereof, to topical compositions containing greater than about 1% by weight, of at least one phospholipid.
Compositions of the present invention may be in the form of emulsions, creams, lotions, ointments, gels, pastes, solutions, or any other suitable topical skin formulation. Depending upon the intended use of the skin preparation, other components may be incorporated into the compositions. Such formulations may comprise topically acceptable carrier materials as are helpful.
As used herein, "topical application" means directly spreading, spraying or laying of a compound or composition onto epidermal tissue. Topical application can be achieved by rubbing, applicator pads, containers with applicator filaments, sprays, or any other convenient means.
As used herein, "safe and effective amount" means an amount of a substance, compound, or composition high enough to provide a significant positive modification of the condition to be treated, e. g., drying, irritation, and/or itching of the skin of an animal or human, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A "safe and effective amount" of the substance, compound, or composition may vary with the kind and amount(s) of other ingredients used in combination with the particular substance, compound, or composition, the condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors.
As used herein, "effective" means successful treatment resulting in slowing, halting, or reversing, e. g., healing, the adverse condition being addressed.
As used herein "comprising" means that the compositions of the present invention can contain other ingredients which are compatible with the compositions and which preferably do not substantially modify the compositions of the present invention. The term encompasses the terms "consisting of and "consisting essentially of.
As used herein, "pastes" are liquids for topical application, preferably to the skin of an animal or human, whose viscosity is enhanced to the point that flow is largely inhibited by the presence of undissolved, as well as dissolved, solids.
As used herein, "gels" are semisolid systems of suspended inorganic particles or organic macromolecules interpenetrated by a liquid for topical application, preferably to the skin of an animal or human.
As used herein, "emulsions", "creams", and "lotions" are multiphase liquids for topical application, preferably to the skin of an animal or human, containing special components such as surfactants and/or thickeners that inhibit or delay the separation of the phases.
As used herein, "solutions" are single phase liquids substantially free of solids, but small amounts of haze or cloudiness may be tolerated, for topical application, preferably to the skin of an animal or human. As used herein, "suitable carrier materials" may include components typically used in compositions for topical application, preferably to the skin of an animal or human, but are not limited to, solvents, emollients, emulsifiers, humectants, thickeners, antioxidants, chelating agents, dispersing agents, preservatives, buffers, fragrances, colorants, substances which are used for the microbial and chemical stabilization of the composition, and the like. Such carrier materials are well known to and easily selected by the skilled artisan.
The following provides a detailed description of the essential and non-essential components of the compositions of the present invention. All percentages and ratios used herein are by weight, and all measurements made at 25 °C, unless otherwise specified.
Phospholipids
The compositions of the present invention comprise at least one phospholipid compound. Phospholipids useful in the compositions of the present invention may be selected by the skilled artisan according to the kind and amount(s) of other ingredients used in the compositions of the present invention, the condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors. However, the preferred phospholipids useful in the compositions of the present invention include all lipoidal constituents, natural and/or synthetic, saturated, partially saturated, or unsaturated, that contain phosphorus in their molecules. The more preferred phospholipids for use in the compositions of the present invention include, but are not limited to, lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, sphingomyelins, and mixtures thereof. While there are no particular limitations to the quality, purity, and/or saturation level of the phospholipids used, the phospholipids are preferably unsaturated or partially saturated, of high quality, pharmaceutical grade. A most preferred phospholipid for use in the compositions of the present invention is phosphatidylcholine. Phosphatidylcholine may be obtained as commercially available soya or egg phosphatidylcholine. More preferably the phosphatidylcholine for use in the compositions of the present invention is soya phosphatidylcholine. The amount of phospholipid used in the compositions of the present invention is typically from about 1%» to about 50%>, preferably from about 1.5% to about 40%), more preferably from about 2% to about 30%>, most preferably from about 2.5% to about 20%) by weight of the compositions of the present invention.
Skin Conditioning Agents
The compositions of the present invention comprise at least one skin conditioning agent. Skin conditioning agents useful in the compositions of the present invention may be selected according to the kind and amount(s) of phospholipids and other ingredients used in the compositions of the present invention, the condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors. However, the preferred skin conditioning agents useful in the compositions of the present invention are those compounds that are safe and effective in preventing or reducing drying, irritation, and/or itching of the skin of animals and/or humans caused by the continuous or repetitive application of topical compositions to the skin of animals and/or humans, which contain high levels of phospholipids. Preferably the skin conditioning agents for use in the compositions of the present invention include, but are not limited to, petrolatum, liquid paraffin, paraffin wax, beeswax, spermaceti, microcrystalline wax, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, oleyl alcohol, isopropyl myristate, isopropyl palmitate, vegetable oil, squalene, squalane, palmitic acid, stearic acid, cetyl palmitate, lanolin, tocopherol, tocopherol acetate, glycerin, hexylene glycol, propylene glycol, sorbitol, panthenol, polyalcohols having 3-5 carbon atoms, and mixtures thereof; more preferably the skin conditioning agents for use in the compositions of the present invention include glycerin, petrolatum, lanolin, panthenol, and mixtures thereof; most preferably the skin conditioning agent for use in the compositions of the present invention is glycerin.
While there are no particular limitations to the quality and/or purity of the skin conditioning agents used, the skin conditioning agents are preferably of high quality, pharmaceutical grade. The amount of skin conditioning agents used in the compositions of the present invention may vary according to the amount of phospholipids present in the compositions of the present invention, but is typically in the range of from about 0.1 %> to about 50%), preferably from about 1%> to about 40%>, more preferably from about 2% to about 30%), most preferably from about 3%> to about 20% by weight of the compositions of the present invention.
Pharmaceutically Active Agents
The compositions of the present invention comprise at least one pharmaceutically active agent. Pharmaceutically active agents to be delivered topically and found useful in the compositions of the present invention include, but are not limited to, analgesic/anti- inflammatory agents such as aspirin, ibuprofen, ketoprofen, diclofenac, naproxen, indomethacin, piroxicam, flurbiprofen, meclofenamate, ketorolac, tenidap, tebufelone, and their derivatives, isomers, and salts; anti-infective agents such as penicillin, erythromycin, tetracycline, clotrimazole and their derivatives, isomers, and salts; anti- diabetics such as chlorpropamide, glymidine, insulin, and their derivatives, isomers, and salts; anti-arrhythmics such as moricizine, propanolol, amiodarone, and their derivatives, isomers, and salts; anti-coagulants such as heparin, warfarin, and their derivatives, isomers, and salts; poison antidotes such as amiphenazol, obidoxim chloride, D- penicillamin, tiopromin, and their derivatives, isomers, and salts; androgens or antiandrogens such as testosterone, yohimbe, and their derivatives, isomers, and salts; vitamins or nutrients such as folic acid and niacin; corticosteroids such as beclomethasone, fluticasone, dexamethasone, and their derivatives, isomers, and salts; anticholinergics such as atropine, ipratropium, and their derivatives, isomers, and salts; antihistamines such as brompheniramine, doxylamine, diphenhydramine, and their derivatives, isomers, and salts; ganglionic stimulants such as nicotine and its derivatives, isomers, and salts; vasoconstrictors such as pseudoephedrine, phenylpropanolamine, and their derivatives, isomers, and salts; methylxanthines such as caffeine, theophylline, and their derivatives, isomers, and salts; and mixtures thereof.
The particular pharmaceutically active agent(s) and amount of pharmaceutically active agent(s) used in the compositions of the present invention are selected to be safe and effective and may vary with the kind and amount(s) of other ingredients used in combination with the particular pharmaceutically active agent(s), the condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors. Typically, the amount of pharmaceutically active agent(s) used in the compositions of the present invention is from about 0.01% to about 10%, preferably from about 0.025%) to about 8%, more preferably from about 0.05% to about 6%, most preferably from about 0.1 % to about 4% by weight of the compositions of the present invention. The preferred pharmaceutically active agent(s) used in the compositions of the present invention comprises analgesic/anti-inflammatory agents selected from the group consisting of aspirin, ibuprofen, naproxen, indomethacin, piroxicam, flurbiprofen, meclofenamate, ketoprofen, ketorolac, diclofenac, tenidap, tebufelone, their derivatives, isomers, and salts, and mixtures thereof. The more preferred pharmaceutically active agent(s) used in the compositions of the present invention analgesic/anti-inflammatory agents selected from the group consisting of ibuprofen, naproxen, indomethacin, piroxicam, flurbiprofen, ketoprofen, ketorolac, diclofenac, their derivatives, isomers, and salts, and mixtures thereof. The most preferred pharmaceutically active agent(s) used in the compositions of the present invention analgesic/anti-inflammatory agents selected from the group consisting of ketoprofen, ibuprofen, diclofenac, naproxen, their derivatives, isomers, and salts, and mixtures thereof.
Water
Water employed in the compositions of the present invention should preferably be of low ion content and free of organic impurities. Typically, water comprises from about 2% to about 99%o, preferably from about 20% to about 95%>, more preferably from about 40%) to about 90%, most preferably from about 60%> to about 85% by weight of the compositions of the present invention.
Carrier Materials
Carrier materials may or may not be used in the compositions of the present invention. If used, they may be selected from components typically used in compositions for topical application, preferably to the skin of an animal or human, i. e., emulsions, creams, lotions, ointments, gels, pastes, solutions, and the like. Typically, the carrier materials may be selected from polar and/or non-polar solvents such as glycerin, polyglycerin, glycerin esters, propylene glycol, polypropylene glycol, ethylene glycol, triethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, 1,3-butylene glycol, maltitol, benzyl alcohol, ethanol, ethyl acetate, heptane, canola oil, olive oil, mineral oil, water, and the like; emulsifiers/surfactants such as sodium, potassium, and triethanolamine salts of oleic and stearic acids, dioctyl sodium sulfosuccinate, sodium dodecyl sulfate, glycerol monooleate, glycerol monostearate, ethoxylated sorbitan esters such as Polysorbate 20, Polysorbate 65, and Polysorbate 80, polymers such as acrylates/C 10-30 alkyl acrylate crosspolymers (Pemulen® TR.-1, B.F. Goodrich), and the like; thickeners such as agar, carrageenan, food starch, modified starch, gelatin, gum arabic, guar gum, cellulose gel, carbomer (Carbopol®), hydroxyethylcellulose, hydroxypropyl methylcellulose, pectin, sodium carboxymethylcellulose, polyacrylic acid, polyvinyl alcohol, polyethylene glycol, and the like; antioxidants such as benzenesulfonic acid 4-[(3-(3 ,5-bis(l , 1 -dimethylethyl)-4-hydroxyphenyl)- 1 -oxopropyl) amino] monosodium salt (Tinogard™ AO-6, Ciba Specialty Chemical Co., High Point, NC), ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sodium pyrosulfite, acetone sodium bisulfite, sulfur dioxide, t-butylhydroquinone, tocopherol, tocopherol polyethylene glycol succinate, octadecyl hydroxycinnamate, pentaerythrityl-tetrakis, di-t- amylhydroquinone, pyrocatechol, pyrogallal, nordihydroguaiarectic acid, benzalkonium chloride, di-coco-dimethylammonium chloride, dilauryl thiodipropionate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and the like; chelating agents such as edetic acid (EDTA) and it salts including, edetate sodium, edetate disodium, and edetate trisodium, sodium hexametaphosphate, gentisic acid ethanolamide, oxyquinoline sulfate, citric acid, sodium citrate, thioglycolic acid, thiolactic acid, thioglycerol, and the like; dispersing agents, preservatives, buffers, fragrances, colorants, and the like.
Typically, these carrier materials may be present in the compositions of the present invention in amounts which provide their intended purpose. For example, solvents typically comprise from about 2% to about 99%>, preferably from about 20%) to about 95%, more preferably from about 40% to about 90% by weight of the compositions of the present invention; emulsifiers typically comprise from about 0.05% to about 20%, preferably from about 0.1 % to about 15%, more preferably from about 0.3% to about 10% by weight of the compositions of the present invention; thickeners typically comprise from about 0.05% to about 10%, preferably from about 0.1% to about 7.5%, more preferably from about 0.2% to about 5% by weight of the compositions of the present invention; antioxidants typically comprise from about 0.01% to about 0.5%, preferably from about 0.02%> to about 0.2%, more preferably from about 0.05% to about 0.15% by weight of the compositions of the present invention; chelating agents typically comprise from about 0.01%> to about 0.5%>, preferably from about 0.02%> to about 0.2%, more preferably from about 0.05% to about 0.15% by weight of the compositions of the present invention; preservatives typically comprise from about 0.01%> to about 5%, preferably from about 0.05%> to about 3%>, more preferably from about 0.1 %> to about 2% by weight of the compositions of the present invention; buffers typically comprise from about 0.01%) to about 10%), preferably from about 0.1%> to about 5%>, more preferably from about 0.5%) to about 2%> by weight of the compositions of the present invention; fragrances typically comprise from about 0.01%> to about 1%>, preferably from about 0.05%) to about 0.5%>, more preferably from about 0.1%> to about 0.3%> by weight of the compositions of the present invention.
Examples
The following examples are provided as illustrations of the composition and methods of the present invention, but are not limitations of the scope of the present invention.
Example 1
Ingredient Wt. %
Ketoprofen 2.00
Phosphatidylcholine 8.00
Glycerin 10.00
Sodium hydroxide (50%) 1.48
Sodium phosphate, dibasic 0.10
Sodium phosphate, monobasic 0.02
Benzyl alcohol 0.53
EDTA Disodium 0.10
Carbomer 0.90 Fragrance 0.20
Acrylates/C 10-30 alkyl acrylate crosspolymer 0.10 Water 76.57
Example 2
Ingredient Wt. %
Naproxen 1.00
Phosphatidylcholine 8.00
Petrolatum 5.00
Sodium hydroxide (50%>) 1.54
Sodium phosphate, dibasic 0.10
Sodium phosphate, monobasic 0.02
Benzyl alcohol 0.53
EDTA Disodium 0.05
Carbomer 0.50
Acrylates/C 10-30 alkyl acrylate crosspolymer 0.45
Water 82.81
Example 3
Ingredient Wt. %
Diclofenac 1.00
Phosphatidylcholine 6.00
Lanolin 5.00
Glycerin 5.00
Sodium hydroxide (50%>) 1.54
Sodium phosphate, dibasic 0.10
Sodium phosphate, monobasic 0.02
Benzyl alcohol 0.53
EDTA Disodium 0.05
Carbomer 0.45 Fragrance 0.20
Acrylates/C 10-30 alkyl acrylate crosspolymer 0.50
Water 79.61
In each of the above examples, the pharmaceutically active agent is added to most of the water and enough sodium hydroxide is added to the mixture to raise the pH to allow complete dissolution of the pharmaceutically active agent. The sodium phosphate salts, EDTA disodium, and benzyl alcohol are added to the solution containing the pharmaceutically active agent and the mixture is stirred until all the components are dissolved. The phosphatidylcholine is added to the solution which is then stirred for at least 4 hours to insure liposomes are formed. The liposome solution is then filtered to achieve a selected size distribution of the liposomes. The petrolatum, lanolin, fragrance, and acrylates/C 10-30 acrylate crosspolymer are added to the remaining amount of the water in a separate container which is agitated vigorously to form an emulsion. This emulsion is then added to the liposomes and blended. Carbomer is added slowly to the mix along with the glycerin and the remainder of the sodium hydroxide. The liposome preparation is then agitated for at least 30 minutes until a smooth mixture of the proper viscosity is obtained.
While particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications to the present invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

Claims

WHAT IS CLAIMED IS:
1. A composition for the topical delivery of at least one pharmaceutically active agent comprising: a) from 1%> to 50%> by weight of at least one phospholipid selected from the group consisting of unsaturated phospholipids, partially saturated phospholipids, and mixtures thereof; b) from 0.1%) to 50%o by weight of at least one skin conditioning agent selected from the group consisting of petrolatum, liquid paraffin, paraffin wax, beeswax, spermaceti, microcrystalline wax, cetyl alcohol, hexadecyl alcohol, stearyl alcohol, oleyl alcohol, isopropyl myristate, isopropyl palmitate, vegetable oil, squalene, squalane, palmitic acid, stearic acid, cetyl palmitate, lanolin, tocopherol, tocopherol acetate, glycerin, hexylene glycol, propylene glycol, sorbitol, panthenol, polyalcohols having 3-5 carbon atonfs, and mixtures thereof; c) from 0.01% to 10% of at least one pharmaceutically active agent; and d) at least one suitable carrier material selected from components used in compositions for topical application.
2. A composition according to Claim 1 wherein said phospholipid is selected from the group consisting of lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, sphingomyelins, and mixtures thereof.
3. A composition according to any preceding claim wherein said phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and mixtures thereof.
4. A composition according to any preceding claim wherein said phospholipid is phosphatidylcholine.
5. A composition according to any preceding claim wherein said skin conditioning agent is selected from the group consisting of glycerin, petrolatum, panthenol, lanolin, and mixtures thereof.
6. A composition according to any preceding claim wherein said skin conditioning agent is selected from the group consisting of glycerin, petrolatum, and mixtures thereof.
7. A composition according to any preceding claim wherein said skin conditioning agent is glycerin.
8. A composition according to any preceding claim wherein said phospholipid comprises from 1.5% to 40% by weight of said composition.
9. A composition according to any preceding claim wherein said phospholipid comprises from 2% to 30%> by weight of said composition.
10. A composition according to any preceding claim wherein said phospholipid comprises from 2.5% to 20% by weight of said composition.
11. A composition according to any preceding claim wherein said skin conditioning agent comprises from 1%> to 40%> by weight of said composition.
12. A composition according to any preceding claim wherein said skin conditioning agent comprises from 2% to 30% by weight of said composition.
13. A composition according to any preceding claim wherein said skin conditioning agent comprises from 3%> to 20%> by weight of said composition.
14. A composition according to any preceding claim comprising greater than 1% by weight of at least one phospholipid, wherein from 0.1%> to 50%> by weight, of at least one skin conditioning agent is added to said composition to prevent or reduce conditions of the skin, such as drying, irritation, and itching, caused by the continuous or repetitive application of said composition, to said skin of an animal or human.
PCT/US2001/004696 2000-02-14 2001-02-13 Compositions for topical delivery of a pharmaceutically active agent having reduced skin irritation WO2001060336A1 (en)

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