GB2413077A

GB2413077A - Anti-microbial composition comprising 8-hydroxyquinoline, or derivative thereof, a polyethoxylated wetting agent and a water miscible vehicle

Info

Publication number: GB2413077A
Application number: GB0408112A
Authority: GB
Inventors: Alan Edwin Jemmett
Original assignee: Individual
Current assignee: Individual
Priority date: 2004-04-13
Filing date: 2004-04-13
Publication date: 2005-10-19
Also published as: GB0408112D0

Abstract

A metal-chelating composition comprises an 8-hydroxyquinoline compound (or derivatised form thereof which retains metal-chelating properties), a wetting agent selected from an alcohol ethoxylate, a polyoxyethylene ether and a polyoxyethylene sorbate, together with a water miscible vehicle, with the proviso that the wetting agent is not an alkylphenol ethoxylate. The wetting agent is preferably Synprol (RTM) 91, Tween (RTM) 20 or particularly Atlas (RTM) G4829 Pharma ("Laureth-9"). The water miscible vehicle is preferably a polyol solvent, such as ethylene glycol or propylene glycol. It is thus possible to achieve stable cold solutions (ie dissolution without the application of heat) which offer inhibiting effects upon susceptible micro-organisms, such as bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). By chelating metals other than sodium and potassium, the compositions chelate the various metals required by micro-organisms for metabolism. The micro-organisms are thus eliminated by starvation rather than by direct attack and no mutation is found.

Description

241 3077 Lrnproved formulation This invention relates to improved

fonnulation in the form of a stalely solutiu containing quinoxin. or optionally including one or more of its closely related compounds.

Such compounds are known per:e, nn1 non. Alert gn.nP.nIIy referred to a; quinoli:n S related group is tefrred to as isuquinclines. (originally extracted from coal tar, such compounds have been the subject of extensive investigation for over a century. They are generally considered as heterocylic NoillatiC ens, Yin a double dug structure exhibiting properties similar to those observed in a benzene dog, and being derived fiom napthalene wit} trivalent nitrogen atom substituted for a carrots atom on one of the rings.

Quinoline can be exkacted Mom coal tar) and by a process involving caustic extraction and distillation of the oily extrar.r one may obtain a methylnapthalene fraction. This can be wn,stl Fitly lil'6tt iLIlplILIIiL 'dLi] [U pl U4UC 'llph.4c salt&. The mlxlllrc of compounds attained can then be farther separated by chromatography.

Substitution of a hydroxyl Coup on position 8 of the aromatic nucleus of quinoline converts it to oxyquinoline(also called 8-quinolinol) and confers phenolic properties tLipnich, I., 2001, FDA, Division of OIC Drug Products, Office of Drug Evaluation V, Center for Drug Evaluation and Research.). The salt hrdroxyquinoline sulphate has been proposed for use as a topical antiseptic, disinfectant, antiperspirant, deodorant, and fungicide (NIP).

Hydroxyquinoline sulphate is listed by the INS Phannocopeia as a "pharmaccutic aid (complexing agent)" rather Can as an anti-microbial agent (USP 2000). The term antibiotic is generally considered to include a wide number of diverse classes of chemical structures, and can be described as "chemical substances produced by microorganisms and other living systems that are capable in low concentrations of inhibiting the growth of bacteria or other microorganism" (Ki-Othmer, 4' ed. 1996. Encyclopedia of Chemical Technology. Vol. 2, Antibiotics (surrey) pp 893-905. New York, lolm Wiley), Quinolines do not fall into the generally described classes of antibiotics. lIowever, another medical text defines antibiotics as "any of a variety of natural or synthetic substances that inhibit grown of or destroy microorganisms," and further defines a bactenostatic as an "antibiotic that inhibits growth of microorganisms" (Taber, 1981).

Another and possibly more widely useful property of the compound 3hydroxyquinoline is m eta l-.helting cap ability. 8.Hydro>::rquinolin. is considered to be strong oholatir ' agent that precipitates heavy metals. The chelating property may explain the effect against pathogens, The postulated mode of action would be by chelating venous metals required S by microorganisms for metabolism, but alternatively, it may act as a transport mechanism to introduce a metal toxin to the microorganism, e.g. a chelate of copper derived from host tissues may readily pass into the cell of an invading pathogen, and accumulation of released copper may then kill the pathogen (Lipnicki 2001).

Many metal-chelating resins are known which incorporate 8hydroxyquinoline, or derivatives thereof by inmobilisation.

However, best exploitation of the chelating property of 8hydroxyquinoline is hindered by the problem in obtaining adequate solubility thereof in water and oil with retention of its faroured properties. The problem of solubility of ^hydroxyquinoline without impairment of its chelating properties, in water and on has existed for some twenty years.

The use of 8-hydroxyquinoline in aqueous media to provide a chelating enact on metal surfaces has been investigated and described (J. Schofield of Liverpool University). This work involved the use of a wetting agent (Triton 100) which is obta.inable commercially from Sigmas Aldrich. Tutor 100 is a non-ionic surfactant, identified as an alkylaxyl polyether alcohol or polyoxyethylated octyl phenol.

The formulations produced by J Schofield produced excellent lubricity and it was observed that the formulation attacked and destroyed various bacteria found in cutting fluids. Later unpublished work by the present inventor showed that another non-ionic surfactant, a fatty alcohol ethexylate based on octyl phenol (SynperoniOP10), would solubilise 8bydroxyquinoline into water/glycol fluids and retain the desirable chelating ability on all metals except sodium and potassium. This fonnulation would not only provide good lubricity but would also destroy bacteria and fungi which depend on trace metals for their existence. Thus the Composition deprived the organisms of vital nutrient arid this would lead to a reduction in proliferation, and then death.

Unfortunately, the fatty alcohol ethoxylate which proved successful has been subject to limitations on use by environmental protective legislation because both Synperonic OP10 and Triton 100 are residual materials which are not biodegradable by natural processes.

It is now discovered by the current inventor that various grades of fatty alcohol ethoxylates, polysorbates and polyoxyethylated alcohols offer the same properties as the materials now precluded [torn use by legislation. Namely, the said fatty alcohol ethoxylates, polysorbates and polyoxyethylated alcohols act as wetting agents with regard to 8hydroxyquinoline without inhibiting its chelating properties on metals.

A:ccordingly, this invention provides a stable liquid formulation containing 8-hydroxyquiroline or a derivatisod form thereof which retains metal- chelating properties, and offers inhibiting effects upon susceptible micro-orgamsms which is charactertsed by the presence of an environmentally-tolerable wetting agent selected From the Coup consisting of fatty alcohol ethoxylaes, polysorbates and polyoxyethylated alcohols, in a solvent, with the proviso that the wetting agent is not an alkylphenol ethoxylate, particularly excluding nonylphenol ethexylate. 9 By virtue of this invention, it is possible to achieve stable cold solutions, i.e. dissolution without applying heat. Thus a stable solution exists at ambient temperatures for routine use, the presence of glycol solvent permits the activity to be observed in a stable liquid solution way below temperatures tolerable to humans without protection. ; Preferred fatty alcohol ethoxylates include the non-ionic surfactant "Synprol 91" wherein the alcohols include C, and Cat aliphatic alcohols.

Preferred polysorbates include the non-ionic surfactant 'tweed 20" which is a saturated polyoxyethylene sorbitan fifty acid ester.

Preferred polyoxyethylaed alcohols include the non-ionic surfaetant "Atlas G-4829 9 Pharma" which may be descnbed as macrogol luryl ether 9 ("Laureth-9"). 9 The compositions described herein may be formulated for coating surfaces to inhibit effects susceptible micro-organisms that may contaminate such surfaces, especially those of metal or containing metals useful to the micro-organisms. Optionally the formulation may include cosolvents, extenders or fillers.

The invention will be Farther described bar way of the currently best ksovn mode of performance which utilises the product available under the proprietary nanny Atlas G-4829 Phann (Laureth-9). Using this wetting agent, stable liquid formulations of 8-hydroxyquinoline were obtainable.

Example 1

A stable liquid solution Divas prepared coneaining: 8-hydroxyquinoline a; 1-4%, polyethoxylated alcohol at7-11 /, and ethylene glycol at 9285%.

Example 2

stable liquid solution was prepared containing: 8-hydoxyquinoline at 140/o, polyethoxylated alcohol at 7-11%, and lO propylene glycol at 92-85%.

Example 3

A particularly preferred formulation contained, 8-hydroxyquinoline at 2%, polyethexylated alcohol at 8% and a glycol at 90%.

This formulation was tested with a variety of metals and found to exhibit chelating properties, except with regard to sodium and potassium, and the formulation provided a rapid and complete removal of al] bacterial and fungal contaminations of the tested substrate.

This formulation was found to be effective Fairest methicillin-resistant Staphylococcus aureus (MRSA) even at 1 part in 200,00Q.

Test Examples:

Assessment of activity on Ciram-gative and Ciram.nositive bacteria and Yeast spp Two formulations according to the teachings of this invention were prepared incorporating respectively, 0.05% and 2% 8-hydroxyquinoline. These formulations were stable with no SigD of any solubility problems with 8-hydroxyquinoline in the diluent used.

Agar plates were prepared for the preliminary assessment of these formulations, using appropriate agar media (nutrient agar, diagnostic sensitivity test (DST) lysed agar, and IsoSensitest agar) providing nomally favourable cultivation media for the test organism.

Wells were cut into the ages, and filled with 15) of test fonnu!'tion. The organisms tested were all wild types from clinical specimens. and one strain of each was tested. The organis7.ns were inoculated onto the agar (lawn plated) to give semicon1uent growth. The plates were incubated for 24h at 37 C under appropriate atmospheric conditions.

Inhibition zone sizes were read, but not measured, for both formulations and no controls were included in this preliminary assessment. In this Table the following abbreviations are used: "(-ve)" negative, "(-eve)" positive; "meth-s" methicillin-sensitive; "meth-r" methicillin-resistant; advancer" vancomycin-resistant; ''pen-r" penicillin resistant, "ins-pen r" intermediate penicillin resistant; "M-L'' medium to large; "g cliff." good diffusion.

Or anism Strains | Observations Assessment Bacillus subtilis.-- M L zoneg.diff. Pass Bacillus careus --- M-L Pass Corynebacterium sp. -- . M L zore-g.diff. Pass Staphylococcus aureus "Oxford" meth-r M-L zone-g.dff. I Pass Staphylococcus Duress MRSA:E I 5,E HE 6/7S M-L zone-g.diff. I Pass I Coagulate (-ve) staphylococcus methyls meth-r M L zone g.diff._ Pass _ j St7 eptococcus pyoge7'es _Group A Strep. M-L zone g.diff. Pass streptococcus agalactae Group B Strep. M-L zonc-g.diff. 1 Pass Streptococcus equisimil.s I Group C Strewed, M-Lzone-g.dff. I Pass Er, rerococcusfaecalts I incl. Wincer strains 1 M-Lzoneg.df I Pass I Enterococcusfaecum incl. vanc-r strains I M-L zone-g.dff. Pass in 1. intpen-r stsair M-L zone-g.dff. Pass Neisseria gonorrhoeae. L zone g.dff. Pass Maroxella(Branhametla)catarrhals - M-L zoned Pass I En'robctcrla: scherichia colt - . _. Pass " Shigella sonnet I M-L zone-g.df Pass " Salmonella sp. M-L zone-g.dff. Pass ebsiella pnesmoniae. I M-L zone-g. diff. Pass " Proteus mrabilis. . M L zone-g.diff_ Pass ' Proteus vulgaris j M--L zone-g.dif Pass ' nterobacter cloacae. M-L zone-g.dff. Pass " Pees dome n as a eruginosa Rae small zone- g.diff. Acce " Vibrioparahaemolyticus L --- M-L zone g.dlff. Pass " Haemophilus influenzas. . M.L zone-g.dff. Pass Candida albiáns M L zoneg.dif Piasa Candida glabrata(torulopsisJ... M-L zoneg.diff. Pass Candida krusei i... M-L zone g.diff. Pass Candirta tropicalis _ | M L zone-g.diff. Pass

Claims

1. A metal-chelating composition comprising an S-hydroxyquinoline

compound, or a derivatised form thereof which retains metal-chelating properties, a wetting agent selected from the group consisting of an alcohol thoxylate, polyoxyethylene ether, and a polyoxyethylene sorbate, together with a wer-miscible Vehicle, with the proviso that the wetting agent is not an alkylpheno, ethoxylate.

2. A metal chelating composition according to Claim 1, wherein the vehicle is a polyol solvent.

3 A netal-chelating composition according to Claim 1 or Claim 2, wherein the wetting agent is a polyoxyethylene ether and the vehicle is an ethylene glycol or propylene glycol.

4. .A coating formulation for coating of surfaces. comprising a composition according to any one of the preceding claims, optionally containing additional co-solvents, extenders or fillers, which offers inhibiting effects upon susceptible micro-organisms that may seek to contaminate the surfaces.