WO2001060337A1

WO2001060337A1 - Compositions for topical delivery of a pharmaceutically active agent having reduced oxidation

Info

Publication number: WO2001060337A1
Application number: PCT/US2001/004697
Authority: WO
Inventors: Jeffrey Warren Clymer
Original assignee: The Procter & Gamble Company
Priority date: 2000-02-14
Filing date: 2001-02-13
Publication date: 2001-08-23
Also published as: PE20011099A1; AU2001236997A1; CO5261580A1

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, from about 0.01% to about 10% of at least one pharmaceutically active agent, from about 0.01% to about 0.5% by weight of at least one chelating agent, and at least one suitable carrier material selected from components used in compositions for topical application. The at least one chelating agent prevents or reduces the oxidation of the topical compositions of the present invention.

Description

COMPOSITIONS FOR TOPICAL DELIVERY OF A PHARMACEUTICALLY ACTIVE AGENT HAVING REDUCED OXIDATION

The present invention relates to compositions comprising a high level of at least one phospholipid, at least one pharmaceutically active agent, and at least one chelating agent.

The present invention further relates to a method of preventing or reducing the oxidation of compositions containing high levels of at least one phospholipid and at least one pharmaceutically active agent. The method comprises adding a safe and effective amount of a chelating agent to compositions containing high levels of phospholipids and at least one pharmaceutically active agent.

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).

Liposomes are typically comprised of phospholipids from natural sources, e.g., soy phosphatidylcholine. Natural lipid sources are unsaturated, and so may be susceptible to oxidation. Medicaments added to liposomes, in particular non-steroidal anti-inflammatory drugs (NSAID), e.g., ketoprofen, ibuprofen, and the like, are also susceptible to oxidation under certain conditions. For example, US Patent 5,185,373 (Motola et al.) discloses a method for stabilizing ibuprofen subjected to thermal degradation. It has been determined that the combination of a phospholipid and an NSAID are more susceptible to oxidation than either component alone, and that this oxidation may proceed readily even at ambient temperatures.

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 0.01% to about 10% of at least one pharmaceutically active agent, from about 0.01% to about 0.5% by weight of at least one chelating 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 the oxidation of compositions containing greater than about 1% by weight, of at least one phospholipid and at least one pharmaceutically active agent. The method of the present invention comprises adding a safe and effective amount, preferably from about 0.01% to about 0.5%) by weight, of a chelating agent to compositions containing greater than about 1% by weight, of at least one phospholipid and at least one pharmaceutically active agent.

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 oxidation of compositions having greater than about 1% by weight of a phospholipid compound, especially unsaturated or partially saturated phospholipids, and at least one pharmaceutically active agent can be reduced or prevented by the addition of a safe and effective amount of at least one chelating agent to these compositions Such compositions are typically used for dermal or transdermal delivery of pharmaceutically active agent or agents.

The present invention relates to compositions which contain from about 1% to about 50%) by weight of at least one phospholipid, from about 0.01% to about 10% of at least one pharmaceutically active agent, from about 0.01% to about 0.5%) by weight of at least one chelating 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 the oxidation of compositions having greater than about 1% by weight of at least one phospholipid and at least one pharmaceutically active agent. The method comprises adding a safe and effective amount, preferably from about 0.01% to about 0.5% by weight, of at least one chelating agent, preferably selected from the group consisting of edetic acid (EDTA) and its salts including, edetate sodium, edetate disodium, and edetate trisodium, and the like, and mixtures thereof, to compositions containing greater than about 1% by weight, of at least one phospholipid and at least one pharmaceutically active agent.

The at least one chelating agent prevents or reduces the oxidation of compositions comprising high levels of phospholipids and pharmaceutically active agents. 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, emulsifϊers, 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. 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.

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.

Chelating Agents

The compositions of the present invention comprise at least one chelating agent. Chelating agents useful in the compositions of the present invention may be selected according to the kind and amount(s) of the phospholipids and pharmaceutically active agent used in the compositions of the present invention. Chelating agents of particular usefulness in the compositions of the present invention include, but are not limited to, edetic acid (EDTA) and its 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. Typically, the amount of chelating agents used in the compositions of the present invention is 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. The preferred chelating agent includes edetic acid (EDTA), edetate sodium, edetate disodium, and edetate trisodium. The more preferred chelating agent is edetate disodium.

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%o 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; skin conditioning agents such as 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 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,l-dimethylethyl)-4- hydroxyphenyl)-l-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; 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; skin conditioning agents typically comprise 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; 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; 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 0.01% to 10%> of at least one pharmaceutically active agent; c) from 0.01%) to 0.5%> by weight of at least one chelating agent selected from the group consisting of edetic acid, edetate sodium, edetate disodium, edetate trisodium, sodium hexametaphosphate, gentisic acid ethanolamide, oxyquinoline sulfate, citric acid, sodium citrate, thioglycolic acid, thiolactic acid, thioglycerol, and mixtures thereof; 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 chelating agent is selected from the group consisting of edetic acid, edetate sodium, edetate disodium, and edetate trisodium.

6. A composition according to any preceding claim wherein said chelating agent is edetate disodium.

7. A composition according to any preceding claim wherein said phospholipid comprises from 1.5% to 40%> by weight of said composition.

8. A composition according to any preceding claim wherein said phospholipid comprises from 2% to 30%) by weight of said composition.

9. A composition according to any preceding claim wherein said phospholipid comprises from 2.5%> to 20%> by weight of said composition.

10. A composition according to any preceding claim wherein said chelating agent comprises from 0.02% to 0.2% by weight of said composition.

11. A composition according to any preceding claim wherein said chelating agent comprises from 0.05% to 0.15% by weight of said composition.

12. A composition according to any preceding claim wherein said composition further comprises an antioxidant selected from the group consisting of benzenesulfonic acid 4- [(3 -(3 ,5-bis( 1 , 1 -dimethylethyl)-4-hydroxyphenyl)- 1 -oxopropyl) amino] monosodium salt (Tinogard⁷ AO-6), 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 mixtures thereof.

3. A composition according to any preceding claim containing gi'eater than 1% by weight, of at least one phospholipid and at least one pharmaceutically active agent, wherein from 0.01%> to 0.5%> by weight, of at least one chelating agent is added to said composition to prevent or reduce the oxidation of said composition.