Title of Invention

ANTI-MICROBIAL COMPOSITIONS

Abstract

1. An anti-microbial composition comprising: (i) a C1 to C4 monohydric alcohol carrier fluid, present at a level of at least 25% by weight of the total composition (excluding any volatile propellant present); (ii) an iron (III) chelator having an iron (III) binding constant of 1023 or greater; (iii) a solubility promoter selected from the group consisting of; (a) water; (b) an organic amine; (c) a polyhydric alcohol or derivate thereof; (d) a volatile propellant having fluorine-carbon or oxygen-carbon bonds; (e) any combination of (a) to (d)

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) COMPLETE SPECIFICATION (See Section 10 ; rule 13) 1. TITLE OF INVENTION ANTI-MICROBIAL COMPOSITIONS 2. HINDUSTAN LEVER LIMITED, of Hindustan Lever House, 165/166, Backbay Reclamation, Mumbai - 400 020, Maharashtra, India, a company incorporated under the Indian Companies Act, 1913. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. Field of Invention This invention relates to the field of anti-microbial compositions and to methods of reducing microbial numbers. In particular, this invention is concerned with reducing microbial numbers upon the surface of the human body or upon articles worn in close proximity thereto, thereby reducing malodour. The compositions and methods involved utilise particular iron (III) chelators as anti-microbial agents in compositions also comprising a short chain alcohol and a solubility promoter. When used, on the human body, the compositions and methods of the invention are of greatest benefit when used on the most malodorous areas of the human body, for example the underarm areas or feet. Background Anti-microbial agents may function by a variety of means. When used upon the human body, such agents may significantly reduce microbial numbers either by reducing perspiration or by directly effecting the micro-organisms on the surface of the body as represented herein by skin. It is with this latter class of agents, often called deodorant agents, that this invention is largely concerned. Most deodorant agents reduce the number of viable micro¬organisms on the surface of the skin. It is well known that sweat is usually odourless until it has been degraded by the skin microflora. Typical deodorants include ethanol and triclosan (2',4,4' -trichloro,2-hydroxy-diphenyl ether) which is a well known anti-microbial agent. However, the deodorising effect obtained with such deodorants wears off with the passage of time and the microflora progressively recover their numbers. There is, therefore, a continuing requirement for effective, long lasting deodorant compositions for the market. The problem to be solved is not simply reducing microbial numbers on the body surface,- equally important is maintaining low microbial numbers (particularly low bacterial numbers) on the body surface (particularly in the rcost malodorous- areas, eg. the axillae). Certain iron (III) chelators have previously been incorporated into deodorant compositions. US 4,356,190 (Personal Products Co.) discloses the use of selected aminopolycarboxylic acid compounds for inhibiting the formation of short chain fatty acids by Corynebacterium on the skin surface. For topical application, alkanolamine salts are stated to be preferred. Especially preferred salts are stated to be di- and trialkanolamine salts such as triethanolamine, diethanolamine, and triisopropanolamine salts. It is also stated that a solvent compatible with the system in which the chelator is incorporated may be employed; however, products comprising mixed solvent systems are not disclosed. TO 97/02010 (Procter and Gamble Co.) discloses the use of chelators selected from the succinic acid, glutaric acid, and phosphonic acid classes as bactericidal compounds. NO 97/44006 (Ciba Speciality Chemicals Holding, Inc.) claims :he use of particular nitrogen-containing complexing agents for the anti-microbial treatment of the skin and of textile fibre materials. Complexing agents mentioned include those formed from neutralising N,N-ethylenediaminedisuccinic acid (EDDS) with ethanolamine or laurylamine. Deodorant compositions comprising EDDS, ethanol, and water are also disclosed. EDDS has an iron (III) binding constant of 1022 ("Critical Stability Constants, Volume 1: Amino Acids", p92, Martell and Smith, Plenum Press, 1974.) WO 97/01360 (Concat Ltd.) claims a method of inhibiting bacterial growth using particular substituted polyaza compounds that show affinity for first transition series elements. It is stated that compatible salts may be formed by neutralisation with inorganic or organic bases, including primary, secondary and tertiary amines, notably ethanolamine, diethanolamine, morpholine, glucamine, N,N-dimethylglucamine, and N-methylglucamine Other patents indicate that iron (III) chelators can improve the efficacy of particular known anti-microbials. WO 89/12399 (Public Health Research Institute of the City of New York) discloses improved performance of lanthionine-containing bacteriocins. in compositions also comprising a iron (III) chelator. WO 97/09974 (Laboratoire Medix) discloses compositions comprising chlorhexidine and a chelator. EP 0019670 Bl (Glyco Chemicals, Inc.) discloses anti-microbial compositions comprising a condensation product of 5,5-dimethyl hydantoin and formaldehyde in combination with a water-soluble chelating agent selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) or the alkali metal salts thereof. US 4,199,602 (Economics Laboratory, :nc.) discloses the potentiation of anti-microbial litroalkanes by aminocarboxylic-type chelating agents. JS 5,688,516 (University of Texas System et al) discloses compositions comprising non-glycopeptide anti-microbials (other than vancomycin) in combination with a selection of components, including a chelating agent. WO 99/10017 (University of Texas System et al) discloses a method for controlling the growth of micro-organisms using a chelating agent and an anti-microbial agent. GB 1,420,946 (Beecham Group Ltd.) discloses that the activity of selected phenolic anti-microbials can be vastly increased by certain chelating agents, in particular the disodium salt of EDTA. Summary of the Invention This invention is concerned with the formulation of stable, prolonged activity, anti-microbial compositions. The compositions of the invention comprise an alcohol carrier fluid, an iron (III) chelator having an iron (III) binding constant 1023 or greater, and a solubility promoter selected from a specific group of materials. The particular iron (III) chelators of the invention lead to prolonged anti¬microbial activity upon application. The alcohol carrier fluid and solubility promoter enable the chelator to be formulated into a stable, preferably homogeneous, anti¬microbial composition. The prolonged anti-microbial activity often manifests itself as a long-lasting deodorancy benefit, for example lasting a day. Furthermore, in compositions comprising fragrance material, the anti-microbial activity may manifest itself as enhanced fragrance intensity. The stability of the compositions of the invention is a result of good compatibility between the components - this can also lead to benefits in terms of performance and aesthetics. Preferred compositions of the invention are homogeneous solutions. Such solution compositions have advantages with respect to many of the problems associated with alternative suspension compositions; for example, valve blocking, settling and caking of the suspended solids, and uneven application can all be reduced. Thus, according to a first aspect of the present invention, there is provided an anti-microbial aerosol composition comprising: (i) a C1 to C4 monohydric alcohol carrier fluid, present at a level of at least 25% by weight of the total composition (excluding any volatile propellant present); (ii) an iron (III) chelator having an iron (III) binding constant of 10" or greater; (iii) a solubility promoter selected from the group consisting of: (a) water; (b) an organic amine; (c) a polyhydric alcohol or derivative thereof; (d) a volatile propellant having fluorine-carbon or oxygen-carbon bonds; (e) any combination of (a) to (d) . According to a second aspect of the present invention, there is provided a method of controlling microbial numbers, said method comprising the application to a substrate of an anti¬microbial aerosol composition as provided in accordance with the first aspect of the invention. An application of this aspect of the invention is the control of microbial numbers upon the surface of the human body or upon articles worn in close proximity thereto. According to a third aspect of the present invention, there is provided a method of inhibiting the generation of malodour comprising the topical application to the human body or to apparel worn in close proximity thereto of a composition as provided in accordance with first aspect of the invention. This method may also be used to deliver enhanced fragrance intensity from a fragrance-containing composition according to the invention. According to a fourth aspect of the present invention, there is provided a method for the manufacture of an anti¬microbial composition, said method comprising the formation of a solution of an iron (III) chelator having an iron (III) binding constant of 1023 or greater in a C1 to C4 monohydric alcohol carrier fluid, present at a level of at least 25% by weight of the total composition (excluding any volatile propellant present), and also comprising a solubility promoter selected from- the group consisting of: (a) water; (b) an organic amine; (c) a polyhydric alcohol or derivative thereof; (d) a volatile propellant having fluorine-carbon bonds or oxygen-carbon bonds; any combination of (a) to (d). Detailed Description The novel anti-microbial compositions of the present invention perform unexpectedly well in terms of anti- microbial efficacy and maintenance of low malodour, particularly when applied to the human body. Without wishing to be bound by theory, it is hypothesised that after reduction of microbial numbers by other co-applied agents and/or by some external treatment like washing, the chelator effectively inhibits the up-take of essential transition metal ion nutrients, in particular iron (III), by the remaining microbes, thereby minimising their re-growth. The above anti-microbial and deodorancy benefits are particularly significant when the composition is applied to a particularly malodorous area of the human body or to apparel worn in close proximity thereto. Thus, it is particularly advantageous to apply the compositions of the present invention to the underarm areas, the feet, and to socks and shoes. Benefits for fragrance--containing compositions of the present invention have been observed to include enhanced fragrance intensity, particularly when many hours have passed following application. This benefit is believed to be an aspect of the deodorancy benefit,, both benefits deriving from the excellent anti-microbial properties of compositions of the invention. The stability benefit of the compositions of the invention results from making the iron (III) chelator compatible with the alcoholic carrier fluid in the composition. This is done using particular solubility promoters (vide infra). This aspect of the invention also enables formulation of the preferred homogeneous compositions. It is particularly preferred that aerosol compositions are homogeneous solutions, since valve blockage can be a severe problem in such products. When compositions according to the invention are applied to surfaces, any volatile propellant present evaporates, leaving the chelator, generally dissolved in the carrier fluid and solubility promoter, upon the surface being treated. This solution aspect can lead to significant benefits, both in terms of performance and aesthetics, for example lack of powdery deposits. Preferred compositions comprise a solution of the chelator in the carrier fluid and solubility promoter. Preferably, such solutions have an absorbance, relative to the carrier fluid, of less than 0.2, especially less than 0.1 (for a 1 cm pathlength at 600 nm) measured using a Pharmacia Biotech Ultrospec 200 Spectrophotometer or similar instrument. Preferred compositions are homogeneous solutions. It is preferred that such composition solutions also meet the absorbance criteria set out above: less than 0.2, especially less than 0.1, measured at 600 nm. The compositions of the invention may be applied to the surface requiring treatment by any means. Whilst direct application is likely to be the most common method for most product uses, pre-application onto a carrier matrix like paper, fabric, or sponge and application by contacting said carrier matrix with the surface, is also a possibility. Carrier Fluid The compositions of the present invention comprise greater than 25%, preferably greater than 50%, and more preferably greater than 65%, of C1 to C4 monohydric alcohol carrier fluid, by weight of the total composition (excluding any volatile propellant present). The exclusion of volatile propellant during the calculation of the above values is equivalent to saying that the levels quoted relate the 'base' composition when the composition concerned comprises a volatile propellant. Within the base composition of aerosol compositions, it is further preferred that the alcohol carrier fluid is present at a level in the base composition of greater than 90% by weight, more preferably greater than 95% by weight. The compositions of the invention preferably have a weight ratio of C1-C4 monohydric alcohol carrier fluid to water of greater than 65:35, more preferably greater than 90:10. In certain particularly preferred compositions, notably aerosol compositions, the weight ratio of C1-C4 monohydric alcohol carrier fluid to water is between 95:5 and 99:1. In other particularly preferred compositions, notably aerosol compositions, the weight ratio of C1-C4 monohydric alcohol carrier fluid to water is greater than 99:1. The monohydric alcohol carrier fluid is preferably a C2 or C3 alcohol or mixture thereof. Particularly preferred alcohols are ethanol and isopropanol, with ethanol being most preferred. Iron (III) Chelators The chelators of the invention have an iron (III) binding constant of 1023 or greater. Chelators having lower iron (III) binding constants are, in general, less effective in anti-microbial compositions. Chelators having an iron (III) binding constant of 1026 or greater are preferred, with chelators having an iron (III) binding constant of 1028 or greater being particularly preferred. The 'iron (III) binding constant' is the absolute stability constant for the chelator-iron (III) complex. Such values are independent of pH and consider only the most anionic, fully deprotonated form of the chelator. Measurements can be made potentiometrically, and in a number of other ways. Full details of suitable methods can be found in "Determination and Use of Stability Constants", A. E. Martell and R. J. Motekaitis (VCH, New York, 1989). Tables of such values may be found in numerous sources, for example "Critical Stability Constants", R. M. Smith and A. E. Martell {Plenum Pub. Corp., 1977). Iron (III) chelators are, in general, acids. They may be used as such in the compositions of the invention, although they are preferably used as their salts or acid salts. In certain preferred compositions of the invention, notably compositions (particularly aerosol compositions) having a ratio of C1-C4 monohydric alcohol to water of greater than 90:10, it is preferred to have the' chelator in the form of a salt, or acid salt, with an organic cation. Protonated or quaternised amines are typical of such cations. More information is given relating to the amines used to form such salts in the part of the specification discussing amine solubility promoters. Chelators salts or acid salts having a mixture of associated cations, including mixtures of both organic and inorganic cations, may also be employed. The iron (III) chelators used in the present invention preferably have acid forms with at least two, preferably at least four, and most preferably at least five, ionisable acid groups. The acid.groups are preferably carboxylic and/or phosphonic, but may be sulphonic or phosphinic, or any mixture of these groups. Particularly suitable chelators with acid forms having carboxylic acid groups are polycarboxylate compounds, in particular aminopolycarboxylate compounds. The acid forms of the aminopolycarboxylate compounds include ethylenediaminetetraacetic acid (EDTA) and trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA). More preferred aminopolycarboxylate chelators have the acid forms N,N'-ethylenebis[2-(2-hydroxyphenyl) glycine] (EDDHA), triethylenetetraaminehexaacetic acid (TTHA), and diethylenetriaminepentaacetic acid (DTPA). The chelators preferably have, only moderate molecular weight, by which it is meant that the chelators, in their . acid forms, have "a molecular weight of less than 1000, more preferably 200 to 800, and most preferably 290 to 580, and in their salt form have a molecular weight of less than 2000, more preferably 300 to 1400, and most preferably 500 to 1000. The chelator is preferably incorporated into the composition at a level of 0.01% to 10%, more preferably at a level of 0.05% to 5%, and most preferably at a level 0.3% to 3% by weight of the composition, excluding any volatile propellant present. Mixtures of chelators may also be used. Solubility Promoter A solubility promoter selected from the aforementioned alternatives is an essential component of the invention. The choice of solubility promoter is influenced by the nature of the composition and the other components therein. Guidance as to the selection of the solubility promoter is given below. Water Water is a preferred solubility promoter in compositions comprising a chelator that is in the form of a salt or acid salt having an.inorganic cation or a organic cation formed from a water-soluble amine. The water serves as a solubility promoter by increasing the polarity of the total solvent system. In compositions for use in roll-en, squeeze spray, or pump spray dispensers, the water is preferably present at a level of from 5 to 50% and more preferably at a level of from 15 to 40% by weight. In aerosol compositions, the water is preferably present at less than 25%, preferably less than 10%, by weight of the base composition and is preferably used in combination with an organic amine solubility promoter. In aerosol compositions, it is preferred that the weight ratio of C1-C4 monohydric alcohol carrier fluid to water is greater than 65:35, more preferably greater than 90:10. Certain preferred aerosol compositions comprising water have a weight ratio of C1-C4 monohydric alcohol carrier fluid to water of 95:1 to 99:1 and an organic amine solubility promoter. Other preferred aerosol compositions have a weight ratio of C1-C4 monohydric alcohol carrier fluid to water of greater than 99:1 and particular organic amine and/or other solubility promoter(s) present {vide, infra). Compositions with relatively- low levels of water can be of particular value in products applied to the human body. When such compositions contain relatively high levels of water, they can sometimes cause an undesirable wet sensation on application. Relatively low Water level compositions can also be of benefit with regard to container choice: such compositions enable metal containers to be used with less risk of corrosion. A further benefit of compositions having relatively low water levels is their compatibility with additional hydrophobic components, for example fragrance components (see "Perfumery: practice and principles", R.R.Calkin and S.Jellinek, [Wiley, 1994, pl71]). Organic Amines An organic amine is a preferred sol,ubility promoter in compositions comprising a weight ratio of C1-C4 monohydric alcohol carrier fluid to water of greater than 75:25 by weight, particularly in aerosol compositions. The organic amine may serve as a solubility promoter by neutralising or partially neutralising acid groups on the chelator, thereby increasing the chelator's solubility in the C2-C4 monohydric alcohol carrier fluid. Quaternised amines may also be employed for this purpose, these amines being conveniently added as their hydroxide salts. The amine is preferably used at a level sufficient to neutralise at least 40%, more preferably at least 60%, of such acid groups. Thus, the preferred amount of amine to be added is dependent upon the amount of chelator present, the relative molecular, weights of the amine and the chelator, and the stoichiometry of the neutralisation reaction. For example, it is preferred that at least 2 molar equivalents of a monobasic amine, or at least 3 molar equivalents of a monobasic amine, are added to a chelator possessing 5 acid groups in order to achieve at least 40%, or at least 60%, neutralisation of the acid groups. Preferably, when an organic amine.is employed, the amount added is that which would lead to an aqueous solution of the chelator salt having a pH of between 6 and 8 (at a .molar concentration of chelator salt equal to that present in the composition). Preferred amines are liquids at 20°C and atmospheric pressure. This can be of advantage with regard to formulation and processing. Preferred amines are of relatively low odour. This is of potential benefit during manufacture and during selection and use of compositions comprising amine solubility promoters. Related to this point is the preference for amines having relatively low volatility: a boiling point of 130PC or greater at atmospheric pressure being preferred. Typical amine solubility promoters of the invention comprise at least one C1-C10 terminal hydrocarbyl group; such a group containing solely carbon and hydrogen atoms. Preferred amines of such type are isopropanolamine, 2-amino-2-ethyl-1,3-propanediol, 2-(N,N-dimethylamino)-2-methyl-l-propanol (DMAMP) and N,N-dimethylaminoethanol. Particularly preferred amines, are 2-amino-2-methyl-l-propanol (AMP), diisopropanolamine, 2-aminobutan-l-ol, cyclohexylamine, and mixtures thereof. Such relatively hydrophobic amines are of particular benefit in aerosol compositions having a weight ratio of C1-C4 monohydric alcohol carrier fluid to water of greater than 90:10, in particular between 95:5 and 99:1. The benefit is of particular value in aerosol compositions comprising greater than 4 0% by weight of volatile propellant and of even greater value in aerosol compositions comprising greater than 50% by weight volatile propellant. When the ratio of C1-c4 monohydric alcohol carrier fluid to water is greater than 99:1, it is preferred that the amine is free of any N-H bonds and/or is free of any O-H bonds (thereby promoting the chelator's solubility in such a hydrophobic system). Such amines can alternatively be described as tertiary amines and/or non-hydroxylated amines. Particularly preferred amines for such compositions are DMAMP, cyclohexylamine, diisopropylamine, tert-butylamine, N,N-diethylhexylamin.e, ' and mixtures • thereof . This preference is particularly valuable in aerosol compositions, especially those comprising greater than 40% by weight of volatile propellant and of even more, especially those comprising greater than 50% by weight volatile propellant. Polyhvdric Alcohol or Derivative Thereof Solubility promoters that are polyhydric alcohols or derivatives thereof are particularly useful in compositions having a weight ratio of C1-C4 monohydric alcohol carrier fluid to water of greater than 90:10, particularly in aerosol compositions. The polyhydric alcohol or derivative thereof generally serves as a solubility promoter by increasing the polarity of the total solvent system. The amount of polyhydric alcohol or derivative thereof employed is preferably between 1% and 20% by weight, more preferably between 5% and 15% by weight, of the composition, excluding any volatile propellant present. This form of solubility promoter is preferably used in combination with an organic amine solubility promoter. Particularly great benefits are found in aerosol compositions, especially those having a weight ratio of C1-C4 monohydric alcohol carrier fluid to water of greater than 95:5, more particularly when said ratio is greater than 99:1. Benefits for polyhydric alcohols or derivatives thereof are also of great worth in aerosol compositions comprising greater than 40% by weight. o.f. volatile, propellant and of even greater value in aerosol compositions comprising greater than 50% by weight of volatile propellant. The polyhydric alcohols of the invention are materials having at least two hydroxyl groups on a carbon backbone (optionally interrupted by hetero-atoms). The derivatives are esters, ethers, and carbonates, including partial esters and ethers. Preferred polyhydric alcohols are alkane-diols, such as 1,2-diols of C2 to C12 alkanes. Preferred derivatives are esters, such as C2 to C12 di-esters of 1,2-

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