WO2012150890A1 - Antibacterial composition - Google Patents

Antibacterial composition Download PDF

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Publication number
WO2012150890A1
WO2012150890A1 PCT/SE2012/000056 SE2012000056W WO2012150890A1 WO 2012150890 A1 WO2012150890 A1 WO 2012150890A1 SE 2012000056 W SE2012000056 W SE 2012000056W WO 2012150890 A1 WO2012150890 A1 WO 2012150890A1
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WIPO (PCT)
Prior art keywords
composition
silver
lipid
silicone oil
aliphatic alcohol
Prior art date
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PCT/SE2012/000056
Other languages
French (fr)
Inventor
Anders Carlsson
Bengt Herslöf
Jan HOLMBÄCK
Original Assignee
Lipidor Ab
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Publication of WO2012150890A1 publication Critical patent/WO2012150890A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005Antimicrobial preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/38Silver; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08Peptides having 5 to 11 amino acids
    • A61K38/085Angiotensins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1729Cationic antimicrobial peptides, e.g. defensins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/29Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34Alcohols
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55Phosphorus compounds
    • A61K8/553Phospholipids, e.g. lecithin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/89Polysiloxanes
    • A61K8/891Polysiloxanes saturated, e.g. dimethicone, phenyl trimethicone, C24-C28 methicone or stearyl dimethicone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02Local antiseptics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41Particular ingredients further characterized by their size
    • A61K2800/413Nanosized, i.e. having sizes below 100 nm
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/70Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007Drug-containing films, membranes or sheets

Definitions

  • the present invention relates to an antibacterial composition capable of forming a layer comprising a pharmacologically effective amount of an antibacterial agent, to a method of manufacture of the composition and to a method of applying it on a wound.
  • Antibacterial compositions for topical administration are known in the art. Their administration to the skin or to a wound, in particular to skin of which the integrity has been jeopardized by, for instance, inflammation or irritation, is however still problematic.
  • the physical form of silver incorporation ranges from elemental metallic silver nanoparticles to salts of varying sparing solubility in water. In all instances, however, it is the silver ion species, produced by oxidation or dissolution that is believed to be the antimicrobially active agent (Texter J et al., Bactericidal silver ion delivery into hydrophobic coatings with surfactants. J Ind Microbiol Biotechnol [2007) 34: 571-575].
  • composition is easily applicable to the skin or the wound so as to form a coherent layer on it.
  • Still another object of the invention is to provide such a composition that does not cause swelling when applied to the skin.
  • a further object of the invention is to provide such a composition that does not give a burning feeling when applied to the skin.
  • compositions of the aforementioned kind comprising or substantially consisting of an oily lipid, in particular a polar oily lipid, a volatile silicone oil, a silver source, and optionally a lower aliphatic alcohol.
  • the silver source is present in dissolved and/or suspended form in the composition.
  • the silver source comprises silver in elemental and/or ionic form capable of exerting an antimicrobial effect. It is preferably selected from the group consisting of silver salt, in particular salt of monovalent silver (Ag + X ), silver complex, in particular organic silver complex, colloidal silver, silver particles, in particular silver
  • nanoparticles and their mixtures.
  • the silver source is an inorganic silver salt such as silver nitrate or an organic silver salt such as silver dihydrogen citrate.
  • the silver source is monovalent silver ion stabilized by ⁇ -complex formation with a ⁇ -bond of cis- configuration comprised by an unsaturated chain of an oily lipid, such as a mono- or polyunsaturated aliphatic chain, in particular a mono- or polyunsaturated aliphatic chain of a polar oily lipid such as dioleoylphosphatidylcholine (DOPC) and
  • DOPC dioleoylphosphatidylcholine
  • dioleoylphosphatidylethanolamine DOPE
  • examples of other polar lipids useful in the invention include monooleoylglycerol and soy bean lecithin.
  • the silver source is a complex between silver ion and a thiol group-containing compound.
  • Complexes of this kind are disclosed in EP 727 427 Al, which is incorporated herein by reference.
  • the silver source is a complex between silver ion and a N-heterocyclic carbene.
  • Complexes of this kind are disclosed in US 2008/0267867 Al, which is incorporated herein by reference.
  • the silver source is a monovalent silver salt of an anionic surfactant or detergent such as l,4-bis(2- ethylhexyl) sulphosuccinate (dioctyl sulfosuccinate or docusate ⁇ .
  • an anionic surfactant or detergent such as l,4-bis(2- ethylhexyl) sulphosuccinate (dioctyl sulfosuccinate or docusate ⁇ .
  • the silver source is finely dispersed elemental silver, such as of an average particle size of less than 20 ⁇ , in particular of less than 5 ⁇ , and silver nanoparticles, such as of a size of 100 nanometers or less.
  • the composition of the invention consists of a single phase.
  • the low viscosity of the composition allows administration of the composition to the skin or a wound by spraying.
  • the composition forms a coherent layer from which the solvent evaporates or, in respect of the alcohol, if present, may be partially absorbed by the skin or tissue. Evaporation of the volatile components transforms the initially formed layer into a residual layer of oily lipid, in particular of oily polar lipid, and silver source.
  • the composition can comprise other antimicrobial agents, such as antimicrobial peptides or peptides promoting wound healing.
  • Preferred wound healing promoting peptides of the invention include angiotensin II, a wound healing fragment, analog or derivative of angiotensin II, human parathyroid hormone, a wound healing fragment, analog or derivative of human parathyroid hormone, cathelicidin polypeptide LL37, a wound healing fragment, analog or derivative of cathelicidin polypeptide LL37.
  • a wound of which the healing can be promoted by the composition of the invention may, for instance, be a shallow or deep wound formed by incision or other damage of the skin such as by abrasion or a wound caused by burning, such as skin damaged by burning, but also a bone fracture.
  • the present invention is based on the finding that a particular class of solvents, volatile silicone oils, optionally in combination with a lower aliphatic alcohol, are particularly useful in formulating a composition comprising a polar lipid, suitable for incorporation of the antimicrobial agent of the invention.
  • a particular class of solvents, volatile silicone oils, optionally in combination with a lower aliphatic alcohol are particularly useful in formulating a composition comprising a polar lipid, suitable for incorporation of the antimicrobial agent of the invention.
  • the composition of the invention forms an instable polar lipid layer from which the volatile silicone oil and, if present, the lower aliphatic alcohol, evaporate readily, leaving a stable oily polar lipid layer substantially consisting of polar lipid comprising the silver source of the invention.
  • the low viscosity of the composition of the invention seems, i.a., to be due to the inability of polar lipids to form lyotropic liquid crystals, such as lamellar hexagonal and various cubic phases of high viscosity.
  • the composition of the invention is clear and of low viscosity even at concentrations of polar lipid as high as 20 % by weight.
  • polar lipid compositions corresponding to those of the invention but in which the silicone oil component is substituted by a corresponding weighed amount of water are slightly viscous dispersions at low membrane lipid concentrations or thick gels at 20 % by weight of membrane lipid in respect of the composition, the highest membrane lipid concentration tested;
  • the high viscosity of the composition comprising 20 % by weight of membrane lipid does not allow it to be administered by spraying.
  • Silicone oils of pharmaceutical grade useful in the invention are known in the art.
  • useful silicone oils include dekamethylcyclopentasiloxane [Dow Corning ® 345 Fluid and cyclomethicone 5-NF) and dodekamethylcyclohexasiloxane [Dow Corning ® 246 Fluid). While pentasiloxanes and hexasiloxanes are preferred, terra-, hepta-, and octasiloxanes are also potentially useful.
  • the silicone oils of the invention can be used in pure form or in admixture.
  • one or more methyl groups of a siloxane can be substituted by lower alkyl, in particular by ethyl, propyl or isopropyl.
  • Siloxanes partially or fully substituted by lower trifluoroalkyl, in particular trifluoromethyl and pentafluoroethyl, are also useful in the invention.
  • silicone oil in the invention is determined by its volatility.
  • a silicone oil of the invention evaporates easily. This is due to the low heat of vaporization of this class of compounds.
  • a silicone oil having a heat of vaporization (kj/kg) at 25 °C of from about 100 kj/kg to about 300 kj/kg, more preferred of from about 120 kj/kg to about 200 kj/kg are particularly useful. Even more preferred is a silicone oil having a heat of vaporization of from 140 kj/kg to about 180 kj/kg at 25 °C.
  • the silicone oil of the invention provides the composition of the invention with at least the following advantageous features: i] the ability to incorporate high contents of polar lipid material; / ' ) the formation of thermodynamically stable solutions; Hi] the low viscosity of the solutions formed making them suitable for, e.g., spraying, dropping, painting or instilling.
  • the lower aliphatic alcohol of the invention is a C 2 to C 4 alcohol or a mixture of such alcohols, in particular an alcohol selected from C 2 to C3 alcohol and tert- butanol. Particularly preferred is ethanol. Also useful in the invention is a partially or fully fluorinated Ci to C 4 alcohol, a mixture of such alcohols, and a mixture of Ci to C 4 alcohol and a partially or fully fluorinated Ci to C 4 alcohol.
  • the C 2 to C 4 alcohol may comprise 1,2-propanediol, and/or glycerol, in an amount of up to 20 % or 50 % by weight of the C 2 to C 4 alcohol.
  • the oily polar lipid of the invention can be described as a lipid capable of interaction with water (as defined in D. Small, The Physical Chemistry of Lipids. Plenum Press 1986, section 4.3), for example formed of membrane lipid, that is, lipid
  • Membrane lipids contain a polar, hydrophilic head group and one or more lipophilic hydrocarbon chains. This combination makes the membrane lipid molecules amphipathic and enables their association with water and with oil. Membrane lipids can be classified according to their chemical structure, which is a function of how the polar head group is linked to the lipophilic chains. Sphingolipids (linked by sphingosine) and glycerolipids [linked by glycerol) are the two main groups. Depending on the characteristics of the polar head group sphingolipids and glycerolipids can be further classified as phospholipids comprising a phosphate ester head group and glycolipids comprising a carbohydrate head group.
  • membrane lipids are sometimes called, for instance, galactolipids, which are glycerolipids with galactose in the polar head group.
  • galactolipids which are glycerolipids with galactose in the polar head group.
  • Examples of common membrane lipids are phosphatidylcholine (PC),
  • Membrane lipids of interest can be extracted from, for example, egg yolk (egg lecithin), milk and dairy products, soybeans (soy lecithin), other oil crops, oat kernels, and other cereal and grains. These extracts can be further treated to obtain, for instance, PC from soy beans and galactolipids from oats.
  • Preferred polar lipids are galactolipids, in particular galactolipids from oat kernels, or phospholipids from soybeans (soy lecithin or soy-PC).
  • Synthetic or semi-synthetic polar lipids and membrane lipid analogues based on a carbohydrate or phosphate ester moiety are also comprised by membrane lipids of the invention.
  • Examples of synthetic polar lipids comprise dioleoylphosphatidylcholine and dioleoylphosphatidylethanolamine.
  • Other lipids capable of interaction with water are monoglycerides, for example monooleylglycerol.
  • the oily lipid of the invention can be a polar or non-polar lipid, comprising a side chain with a ⁇ -bond of cis-configuration.
  • the oily lipid of the invention comprises an unsaturated mono-, di-, or triglyceride, in particular one comprising one or more mono-unsaturated acyl residues of cis-configuration, most particularly oleic acid.
  • the oily lipid of the invention can be obtained from natural sources or be of synthetic or semi-synthetic origin.
  • the use of a lower aliphatic alcohol such as ethanol for the dissolution of the oily polar lipid of the invention is particularly useful with a lipid with a low chain- melting temperature.
  • the chain-melting temperature is the temperature at which the acyl chains of the membrane lipid undergo a phase transition in an excess of water, from a solid-like state to a melted or liquid-like state.
  • Lipoid S75, Lipoid S45, Phospholipon 50, Lipoid SlOO, and DOPC all have chain-melting temperatures below 0°C and can thus be readily dissolved in absolute ethanol at concentrations up to 50 % by weight and even higher.
  • the polar lipid in particular a membrane lipid mixture such as lecithin or fractionated oat oil, may alternatively be dissolved in a lower aliphatic alcohol and then diluted with a volatile silicone oil, resulting in a low-viscous, sprayable, homogenous liquid.
  • Fractionated oat oil is obtained from crude oat oil and is enriched in polar lipids.
  • non-polar lipids such as triacylglycerols and diacylglycerols
  • polar lipids such as phospholipids and glycolipids.
  • the content of digalactosyldiacylglycerol in fractionated oat oil is about 20 % by weight.
  • Suitable fractionated oat oils are disclosed, for instance, in WO 99/44585 Al.
  • Lipids like phosphatidylethanolamine and dioleylphosphatidylethanol- amine can also be used as the polar lipid component of the invention as such or in admixture with other polar lipids.
  • DOPE has a chain-melting temperature of -16°C in water and can be dissolved in absolute ethanol at 50 % by weight or higher at elevated temperatures (>60°C). Such solution can be diluted with volatile silicone oil such as DC 345, resulting in a clear, low-viscous liquid.
  • the antimicrobial composition of the invention is preferably substantially water-free, in particular has a water content of less than 5 % by weight, preferably of less than 2 % or 1 % by weight and even less than 0.5 % by weight or 0.2 % by weight.
  • the antimicrobial composition of the invention comprises from 10 % by weight to 30 % by weight of membrane lipid, from 10 % by weight to 30 % by weight of ethanol, from 0.01 % by weight to 5 % by weight of antimicrobial agent, the remainder being volatile silicone oil, with the proviso that the content of volatile silicone oil is 40 % by weight or more.
  • Silver l,4-bis(2-ethylhexyl) sulphosuccinate was prepared according to the following procedure which is a modification of the method used by Petit et al., J Phys Chem 1993, 97, 12974-12983.
  • a slurry of 6.7 g of Dowex Monosphere M-31 strongly acidic cation exchange resin in ca 20 ml of deionized water is applied to a 25 x 150 mm glass column. The resin is regenerated by elution with 10 ml of 1.0 M HCl and washed with 10 ml of deionized water followed by 10 ml of methanol/water 1:2 (v/v).
  • 1,4-bis (2 -ethylhexyl) sulphosuccinate [222 mg) is dissolved in 3.0 ml of methanol/water 1:2 (v/v) and applied to the column. 1,4-Bis(2- ethylhexyl) sulphosuccinic acid is eluted by 7 ml of methanol/water 1:2 (v/v).
  • a slurry of 13,5 g of Lewatit CNP 105 weakly acidic cation exchange resin in about 20 ml of deionized water is applied to a second 25 x 150 mm glass column and washed with 10 ml of deionized water, followed by 10 ml of methanol/water 1:2 (v/v).
  • Silver nitrate (164 mg) is dissolved in 5 ml of methanol/water 1:2 (v/v) and applied to the second column.
  • the resin is washed by 5 ml of deionized water followed by 10 ml of methanol/water 1:2 (v/v).
  • the solution of l,4-bis(2-ethylhexyl) sulphosuccinic acid was applied to the second column, and silver 1,4-bis (2 -ethylhexyl) sulphosuccinate is eluted by 23 ml of methanol/water 1:2 (v/v).
  • the eluate is evaporated, resulting in 83.3 mg of a white semisolid residue.
  • compositions according to the invention comprising silver 1,4-bis (2 -ethylhexyl) sulphosuccinate were prepared by mixing a alcoholic solution of docusate silver with volatile silicone oil (DC 245, DC 246 or DC 345) and polar oily lipid by ultrasonication.
  • DC 245, DC 246 or DC 3405 volatile silicone oil
  • polar oily lipid by ultrasonication.
  • composition of the invention comprising Ag + / olefin complex.
  • Silver nitrate (13.7 mg) was dissolved in 4.73 g of ethanol.
  • the silver nitrate solution (1.50 g) was then mixed with DC 345, resulting in a clear homogenous solution.
  • DOPE (48.8 mg) was dissolved in the mixture by ultrasonication.
  • the thus obtained mixture contains 0.07 % by weight of silver nitrate, 2.4 % by weight of DOPE, 24.3 % by weight of ethanol and 73.2 % by weight of DC 345.
  • the concentration of silver nitrate in the non-volatile part of the composition is 2.8 % by weight.
  • the presence of Ag + /olefin complex was demonstrated by 13 C NMR spectroscopy (Table 2).
  • a solution suitable for NMR analysis was prepared in the following manner. Silver nitrate (1.08 mg) and 15.7 mg of DOPE was dissolved in 90.0 mg of methanol-d 4 in a vial by ultrasonic agitation to form a first mixture. In another vial 131.8 mg of chloroform-di was mixed with 516.1 mg of DC 345 to form a second mixture. The first and second mixtures were combined and ultrasonicated. The resulting clear colourless solution was transferred to a 0.5 mm ID NMR tube.
  • composition A Composition B
  • a pre-weighed amount of silver nitrate was dissolved in ethanol.
  • To the solution was added 50 % (w/w) of phospholipid.
  • Complete dissolution of the phospholipid in the ethanolic solution was accomplished by short ultrasonication in a bath-type sonicator at about 40 °C.
  • the resulting clear yellow solutions were diluted with silicone oil and stored in air-tight glass vials at room temperature.
  • Silver nanoparticles prepared by the method of R Das et al., Preparation of Silver Nanoparticles and Their Characterization. AZojon, Journal of Nanotechnology Online, DOI: 10.2240/azojono0129
  • a pre-weighed amount of silver oleate was dissolved in ethanol, then phospholipid was added to the ethanolic solution. After treatment in a bath-type sonicator at about 35°C, a clear solution was obtained. The solution was diluted with the volatile silicone oil and the resulting clear, colourless solution was stored in an airtight glass vial at room temperature.
  • Table 3 Presented in Table 3 are data on miscibility of ethanolic phospholipid solutions with either volatile silicone oil or water. The mixtures with a low content of
  • PL/ethanol in the silicone oil had a clear appearance immediately after preparation, but separated within a month at room temperature.
  • the formulation with a concentration of PL/ethanol of 20 % was miscible with the volatile silicone oil, did not change in appearance during this time period and can thus be considered to be physically stable.
  • the phospholipid of Table 3 is Lipoid S75 manufactured by Lipoid GmbH,
  • This phospholipid material from soybean contains about 68 -
  • PC phosphatidylcholine
  • suitable phospholipid materials are, for example, Lipoid S45, Phospholipon 50, and Lipoid S100, all made from soybean and manufactured by Lipoid GmbH, covering a range of PC content of about 50 % up to 100 %.
  • Further useful phospholipids are synthetic dimyristoylphosphatidylcholine (DMPC), dioleylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC).

Abstract

A lipid layer forming antibacterial composition that comprises volatile silicon oil, oily lipid, a silver source, and optionally C2-C4 aliphatic alcohol, The silver source is selected from the group consisting of silver salt (Ag+X-), colloidal silver, silver complex, silver particles, silver nanoparticles, and their mixtures. Also disclosed is a method of forming the lipid layer on the skin or a wound, and a method of manufacturing the composition. Preferred ingredients include siloxanes, in particular decamethylcyclopentasiloxane and dodecamethylchclohexasiloxane, with a defined boiling point, and a polar oily lipid, e.g. a membrane lipid such as a phospholipid, glycolipid or sphingolipid.

Description

ANTIBACTERIAL COMPOSITION
FIELD OF THE INVENTION The present invention relates to an antibacterial composition capable of forming a layer comprising a pharmacologically effective amount of an antibacterial agent, to a method of manufacture of the composition and to a method of applying it on a wound. BACKGROUND OF THE INVENTION
Antibacterial compositions for topical administration are known in the art. Their administration to the skin or to a wound, in particular to skin of which the integrity has been jeopardized by, for instance, inflammation or irritation, is however still problematic.
The efficacy and importance of silver ion as an antimicrobial agent has been known for many years, and the use of silver salts to combat infection dates to ancient time. It is known that silver ion binds to thiols in enzymes and other proteins often leading to deactivation. It is also known that silver ion interferes with ion transport and respiration across the cytoplasmic membrane; organisms with higher turnover rates with extracellular ions appear more susceptible to silver ion poisoning. Recently, silver in various forms has been incorporated into clothing articles and coatings of diverse materials and products, as the efficacy of silver ion in combating body odour and general bacterial infestation has become more broadly appreciated. The physical form of silver incorporation ranges from elemental metallic silver nanoparticles to salts of varying sparing solubility in water. In all instances, however, it is the silver ion species, produced by oxidation or dissolution that is believed to be the antimicrobially active agent (Texter J et al., Bactericidal silver ion delivery into hydrophobic coatings with surfactants. J Ind Microbiol Biotechnol [2007) 34: 571-575].
l OBJECTS OF THE INVENTION
It is an object of the invention to provide a composition for administration of an antibacterial silver source to the skin or a wound of a mammal including man, in which the source is present in dissolved or finely dispersed form and which
composition is easily applicable to the skin or the wound so as to form a coherent layer on it.
It is another object of the invention to provide such a composition that does not irritate the skin.
Still another object of the invention is to provide such a composition that does not cause swelling when applied to the skin.
A further object of the invention is to provide such a composition that does not give a burning feeling when applied to the skin.
Additional objects of the invention will be evident from the following summary of the invention, preferred embodiments thereof described in form of examples, and from the appended claims.
SUMMARY OF THE INVENTION
According to the present invention is disclosed a composition of the aforementioned kind, comprising or substantially consisting of an oily lipid, in particular a polar oily lipid, a volatile silicone oil, a silver source, and optionally a lower aliphatic alcohol. The silver source is present in dissolved and/or suspended form in the composition.
The silver source comprises silver in elemental and/or ionic form capable of exerting an antimicrobial effect. It is preferably selected from the group consisting of silver salt, in particular salt of monovalent silver (Ag+X ), silver complex, in particular organic silver complex, colloidal silver, silver particles, in particular silver
nanoparticles, and their mixtures.
According to a first preferred aspect of the invention the silver source is an inorganic silver salt such as silver nitrate or an organic silver salt such as silver dihydrogen citrate. According to a second preferred aspect of the invention the silver source is monovalent silver ion stabilized by π-complex formation with a π-bond of cis- configuration comprised by an unsaturated chain of an oily lipid, such as a mono- or polyunsaturated aliphatic chain, in particular a mono- or polyunsaturated aliphatic chain of a polar oily lipid such as dioleoylphosphatidylcholine (DOPC) and
dioleoylphosphatidylethanolamine (DOPE). Examples of other polar lipids useful in the invention include monooleoylglycerol and soy bean lecithin.
According to a third preferred aspect of the invention the silver source is a complex between silver ion and a thiol group-containing compound. Complexes of this kind are disclosed in EP 727 427 Al, which is incorporated herein by reference.
According to a fourth preferred aspect of the invention the silver source is a complex between silver ion and a N-heterocyclic carbene. Complexes of this kind are disclosed in US 2008/0267867 Al, which is incorporated herein by reference.
According to a fifth preferred aspect of the invention the silver source is a monovalent silver salt of an anionic surfactant or detergent such as l,4-bis(2- ethylhexyl) sulphosuccinate (dioctyl sulfosuccinate or docusate}.
According to a sixth preferred aspect of the invention the silver source is finely dispersed elemental silver, such as of an average particle size of less than 20 μιη, in particular of less than 5 μηι, and silver nanoparticles, such as of a size of 100 nanometers or less.
Apart from the optionally dispersed silver source the composition of the invention consists of a single phase. The low viscosity of the composition allows administration of the composition to the skin or a wound by spraying. When sprayed onto the skin or a wound the composition forms a coherent layer from which the solvent evaporates or, in respect of the alcohol, if present, may be partially absorbed by the skin or tissue. Evaporation of the volatile components transforms the initially formed layer into a residual layer of oily lipid, in particular of oily polar lipid, and silver source.
In addition to the silver source of the invention the composition can comprise other antimicrobial agents, such as antimicrobial peptides or peptides promoting wound healing. Preferred wound healing promoting peptides of the invention include angiotensin II, a wound healing fragment, analog or derivative of angiotensin II, human parathyroid hormone, a wound healing fragment, analog or derivative of human parathyroid hormone, cathelicidin polypeptide LL37, a wound healing fragment, analog or derivative of cathelicidin polypeptide LL37.
A wound of which the healing can be promoted by the composition of the invention may, for instance, be a shallow or deep wound formed by incision or other damage of the skin such as by abrasion or a wound caused by burning, such as skin damaged by burning, but also a bone fracture.
The present invention is based on the finding that a particular class of solvents, volatile silicone oils, optionally in combination with a lower aliphatic alcohol, are particularly useful in formulating a composition comprising a polar lipid, suitable for incorporation of the antimicrobial agent of the invention. After application on the skin or a wound surface the composition of the invention forms an instable polar lipid layer from which the volatile silicone oil and, if present, the lower aliphatic alcohol, evaporate readily, leaving a stable oily polar lipid layer substantially consisting of polar lipid comprising the silver source of the invention. The low viscosity of the composition of the invention seems, i.a., to be due to the inability of polar lipids to form lyotropic liquid crystals, such as lamellar hexagonal and various cubic phases of high viscosity. The composition of the invention is clear and of low viscosity even at concentrations of polar lipid as high as 20 % by weight.
In contrast, polar lipid compositions corresponding to those of the invention but in which the silicone oil component is substituted by a corresponding weighed amount of water are slightly viscous dispersions at low membrane lipid concentrations or thick gels at 20 % by weight of membrane lipid in respect of the composition, the highest membrane lipid concentration tested; The high viscosity of the composition comprising 20 % by weight of membrane lipid does not allow it to be administered by spraying. By using the volatile silicone oil of the invention as diluent instead of water, it is possible to incorporate a surprisingly high amount of polar lipid while only insignificantly affecting viscosity.
Silicone oils of pharmaceutical grade useful in the invention are known in the art. Examples of useful silicone oils include dekamethylcyclopentasiloxane [Dow Corning® 345 Fluid and cyclomethicone 5-NF) and dodekamethylcyclohexasiloxane [Dow Corning® 246 Fluid). While pentasiloxanes and hexasiloxanes are preferred, terra-, hepta-, and octasiloxanes are also potentially useful. The silicone oils of the invention can be used in pure form or in admixture. While permethyl substitution is preferred, one or more methyl groups of a siloxane can be substituted by lower alkyl, in particular by ethyl, propyl or isopropyl. Siloxanes partially or fully substituted by lower trifluoroalkyl, in particular trifluoromethyl and pentafluoroethyl, are also useful in the invention.
In addition to chemical inertness the usefulness of silicone oil in the invention is determined by its volatility. In spite of its high boiling point above 180 °C, in particular above 200 °C, a silicone oil of the invention evaporates easily. This is due to the low heat of vaporization of this class of compounds. In the invention a silicone oil having a heat of vaporization (kj/kg) at 25 °C of from about 100 kj/kg to about 300 kj/kg, more preferred of from about 120 kj/kg to about 200 kj/kg are particularly useful. Even more preferred is a silicone oil having a heat of vaporization of from 140 kj/kg to about 180 kj/kg at 25 °C.
The silicone oil of the invention provides the composition of the invention with at least the following advantageous features: i] the ability to incorporate high contents of polar lipid material; /') the formation of thermodynamically stable solutions; Hi] the low viscosity of the solutions formed making them suitable for, e.g., spraying, dropping, painting or instilling.
The lower aliphatic alcohol of the invention is a C2 to C4 alcohol or a mixture of such alcohols, in particular an alcohol selected from C2 to C3 alcohol and tert- butanol. Particularly preferred is ethanol. Also useful in the invention is a partially or fully fluorinated Ci to C4 alcohol, a mixture of such alcohols, and a mixture of Ci to C4 alcohol and a partially or fully fluorinated Ci to C4 alcohol.
According to a preferred aspect of the invention, the C2 to C4 alcohol may comprise 1,2-propanediol, and/or glycerol, in an amount of up to 20 % or 50 % by weight of the C2 to C4 alcohol.
The oily polar lipid of the invention can be described as a lipid capable of interaction with water (as defined in D. Small, The Physical Chemistry of Lipids. Plenum Press 1986, section 4.3), for example formed of membrane lipid, that is, lipid
constituents of biological membranes. Membrane lipids contain a polar, hydrophilic head group and one or more lipophilic hydrocarbon chains. This combination makes the membrane lipid molecules amphipathic and enables their association with water and with oil. Membrane lipids can be classified according to their chemical structure, which is a function of how the polar head group is linked to the lipophilic chains. Sphingolipids (linked by sphingosine) and glycerolipids [linked by glycerol) are the two main groups. Depending on the characteristics of the polar head group sphingolipids and glycerolipids can be further classified as phospholipids comprising a phosphate ester head group and glycolipids comprising a carbohydrate head group. Depending on the specific nature of the carbohydrate group, membrane lipids are sometimes called, for instance, galactolipids, which are glycerolipids with galactose in the polar head group. Examples of common membrane lipids are phosphatidylcholine (PC),
phosphatidylethanolamine (PE), and digalactosyldiacylglycerol (DGDG). Membrane lipids of interest can be extracted from, for example, egg yolk (egg lecithin), milk and dairy products, soybeans (soy lecithin), other oil crops, oat kernels, and other cereal and grains. These extracts can be further treated to obtain, for instance, PC from soy beans and galactolipids from oats. Preferred polar lipids are galactolipids, in particular galactolipids from oat kernels, or phospholipids from soybeans (soy lecithin or soy-PC). Synthetic or semi-synthetic polar lipids and membrane lipid analogues based on a carbohydrate or phosphate ester moiety are also comprised by membrane lipids of the invention. Examples of synthetic polar lipids comprise dioleoylphosphatidylcholine and dioleoylphosphatidylethanolamine. Other lipids capable of interaction with water are monoglycerides, for example monooleylglycerol.
The oily lipid of the invention can be a polar or non-polar lipid, comprising a side chain with a π-bond of cis-configuration.
In one embodiment the oily lipid of the invention comprises an unsaturated mono-, di-, or triglyceride, in particular one comprising one or more mono-unsaturated acyl residues of cis-configuration, most particularly oleic acid.
The oily lipid of the invention can be obtained from natural sources or be of synthetic or semi-synthetic origin.
The use of a lower aliphatic alcohol such as ethanol for the dissolution of the oily polar lipid of the invention is particularly useful with a lipid with a low chain- melting temperature. The chain-melting temperature is the temperature at which the acyl chains of the membrane lipid undergo a phase transition in an excess of water, from a solid-like state to a melted or liquid-like state. Membrane lipid materials like
Lipoid S75, Lipoid S45, Phospholipon 50, Lipoid SlOO, and DOPC all have chain-melting temperatures below 0°C and can thus be readily dissolved in absolute ethanol at concentrations up to 50 % by weight and even higher. To produce the composition of the invention the polar lipid, in particular a membrane lipid mixture such as lecithin or fractionated oat oil, may alternatively be dissolved in a lower aliphatic alcohol and then diluted with a volatile silicone oil, resulting in a low-viscous, sprayable, homogenous liquid. Fractionated oat oil is obtained from crude oat oil and is enriched in polar lipids. It typically contains about 50 % by weight of non-polar lipids, such as triacylglycerols and diacylglycerols, and about 50 % by weight of polar lipids such as phospholipids and glycolipids. Typically, the content of digalactosyldiacylglycerol in fractionated oat oil is about 20 % by weight. Suitable fractionated oat oils are disclosed, for instance, in WO 99/44585 Al.
Lipids like phosphatidylethanolamine and dioleylphosphatidylethanol- amine (DOPE) can also be used as the polar lipid component of the invention as such or in admixture with other polar lipids. DOPE has a chain-melting temperature of -16°C in water and can be dissolved in absolute ethanol at 50 % by weight or higher at elevated temperatures (>60°C). Such solution can be diluted with volatile silicone oil such as DC 345, resulting in a clear, low-viscous liquid.
Although small amounts of water, such as 1 % or 2 % and even up to about 5 % by weight can be tolerated, the antimicrobial composition of the invention is preferably substantially water-free, in particular has a water content of less than 5 % by weight, preferably of less than 2 % or 1 % by weight and even less than 0.5 % by weight or 0.2 % by weight.
According to a preferred aspect, the antimicrobial composition of the invention comprises from 10 % by weight to 30 % by weight of membrane lipid, from 10 % by weight to 30 % by weight of ethanol, from 0.01 % by weight to 5 % by weight of antimicrobial agent, the remainder being volatile silicone oil, with the proviso that the content of volatile silicone oil is 40 % by weight or more.
The invention will now be described in greater detail by reference to a number of preferred but not limiting examples. DESCRIPTION OF PREFERRED EMBODIMENTS Materials Table 1. Silicone oils and lipids
Figure imgf000009_0001
EXAMPLE 1
Preparation of docusate silver. Silver l,4-bis(2-ethylhexyl) sulphosuccinate was prepared according to the following procedure which is a modification of the method used by Petit et al., J Phys Chem 1993, 97, 12974-12983. A slurry of 6.7 g of Dowex Monosphere M-31 strongly acidic cation exchange resin in ca 20 ml of deionized water is applied to a 25 x 150 mm glass column. The resin is regenerated by elution with 10 ml of 1.0 M HCl and washed with 10 ml of deionized water followed by 10 ml of methanol/water 1:2 (v/v). Sodium 1,4-bis (2 -ethylhexyl) sulphosuccinate [222 mg) is dissolved in 3.0 ml of methanol/water 1:2 (v/v) and applied to the column. 1,4-Bis(2- ethylhexyl) sulphosuccinic acid is eluted by 7 ml of methanol/water 1:2 (v/v). A slurry of 13,5 g of Lewatit CNP 105 weakly acidic cation exchange resin in about 20 ml of deionized water is applied to a second 25 x 150 mm glass column and washed with 10 ml of deionized water, followed by 10 ml of methanol/water 1:2 (v/v). Silver nitrate (164 mg) is dissolved in 5 ml of methanol/water 1:2 (v/v) and applied to the second column. The resin is washed by 5 ml of deionized water followed by 10 ml of methanol/water 1:2 (v/v). The solution of l,4-bis(2-ethylhexyl) sulphosuccinic acid was applied to the second column, and silver 1,4-bis (2 -ethylhexyl) sulphosuccinate is eluted by 23 ml of methanol/water 1:2 (v/v). The eluate is evaporated, resulting in 83.3 mg of a white semisolid residue. The residue is dissolved in 10 ml of ethanol 99.9 % and the solution decanted off the remaining precipitate and evaporated, resulting in 69.4 mg of silver l,4-bis(2-ethylhexyl) sulphosuccinate mg as a white solid.
EXAMPLE 2 Preparation of the composition of the invention comprising docusate silver.
Compositions according to the invention comprising silver 1,4-bis (2 -ethylhexyl) sulphosuccinate were prepared by mixing a alcoholic solution of docusate silver with volatile silicone oil (DC 245, DC 246 or DC 345) and polar oily lipid by ultrasonication. EXAMPLE 3
Preparation of the composition of the invention comprising Ag+/ olefin complex. Silver nitrate (13.7 mg) was dissolved in 4.73 g of ethanol. The silver nitrate solution (1.50 g) was then mixed with DC 345, resulting in a clear homogenous solution. DOPE (48.8 mg) was dissolved in the mixture by ultrasonication. The thus obtained mixture contains 0.07 % by weight of silver nitrate, 2.4 % by weight of DOPE, 24.3 % by weight of ethanol and 73.2 % by weight of DC 345. The concentration of silver nitrate in the non-volatile part of the composition is 2.8 % by weight. The presence of Ag+/olefin complex was demonstrated by 13C NMR spectroscopy (Table 2).
Table 2. Selected 13C NMR signals from compositions with and without silver nitrate in DOPE/silicone oil/CD3OD/CDCh
Origin of signal Sample without AgN03 Sample with AgN(>3
Chemical shift, ppm Chemical shift, ppm
DOPE, acyl
C18 13.73 13.79
C17 22.54 22.58
C16 31.83 31.88
C, allylic 27.03 27.11
C, olefinic 129.70 129.39 129.46
C, olefinic 129.41 129.14 129.21
C3 24.72 24.77 24.77 24.83
C2 33.77 33.92 33.82 33.97
CI 172.93 173.19 172.98 173.21
DOPE, glyceryl
sn-1 62.42 62.50
sn-2 70.33 70.39
sn-3 63.65 63.83
DOPE, aminoethyl
Figure imgf000011_0001
DC 345 0.42 0.53 0.47 0.58
A solution suitable for NMR analysis was prepared in the following manner. Silver nitrate (1.08 mg) and 15.7 mg of DOPE was dissolved in 90.0 mg of methanol-d4 in a vial by ultrasonic agitation to form a first mixture. In another vial 131.8 mg of chloroform-di was mixed with 516.1 mg of DC 345 to form a second mixture. The first and second mixtures were combined and ultrasonicated. The resulting clear colourless solution was transferred to a 0.5 mm ID NMR tube.
An equivalent solution, lacking silver nitrate, was prepared in a second NMR tube. The 13C NMR spectra of the two samples show identical signal patterns with the exception for the olefinic region. In the spectrum of the sample containing silver ions, two extra signals arise next to the two signals from position 9 and 10 in the oleyl moieties of DOPE (Table 2), indicating a specific interaction between the silver ions and a portion of the double bonds between these two carbons.
EXAMPLE 4. Antimicrobial compositions I
Composition A Composition B
Component % (w/w) % fw/wl
Silver nitrate 0.005 0.005
Phospholipid (Lipoid S75) 14.0 21.1
Absolute ethanol 14.0 21.1
Volatile silicone oil (DC 345) 72.0 57.7
A pre-weighed amount of silver nitrate was dissolved in ethanol. To the solution was added 50 % (w/w) of phospholipid. Complete dissolution of the phospholipid in the ethanolic solution was accomplished by short ultrasonication in a bath-type sonicator at about 40 °C. The resulting clear yellow solutions were diluted with silicone oil and stored in air-tight glass vials at room temperature.
EXAMPLE 5. Antimicrobial composition II
Component % iw/wj
Silver docusate 0.003
Lipoid DMPC 15.0
Absolute ethanol 20.0
Volatile silicone oil (DC 345) 65.0
A pre-weighed amount of silver docusate was dissolved in ethanol, then phospholipid was added to the ethanolic solution as described in EXAMPLE 3, so as to make it 1:1 by weight in respect of ethanol and phospholipid. After treatment in a bath-type sonicator at about 35°C, a clear solution was obtained. The solution was diluted with the volatile silicone oil and the resulting clear, colourless solution was stored in an air-tight glass vial at room temperature. EXAMPLE 6. Antimicrobial composition III
Component % (w/w)
Silver nanoparticles 0.005
Triolein 30.0
Volatile silicone oil (DC 345) 70.0
Silver nanoparticles prepared by the method of R Das et al., Preparation of Silver Nanoparticles and Their Characterization. AZojon, Journal of Nanotechnology Online, DOI: 10.2240/azojono0129
(http://wwww.azonano.com/article.aspx? ArticleID=2318) were dispersed by stirring in a mixture of triolein and volatile silicone oil. EXAMPLE 7. Antimicrobial composition IV
Component % (w/w)
Silver oleate 0.004
Lipoid DOPC 20.0
Absolute ethanol 20.0
Volatile silicone oil (DC 345) 60.0
A pre-weighed amount of silver oleate was dissolved in ethanol, then phospholipid was added to the ethanolic solution. After treatment in a bath-type sonicator at about 35°C, a clear solution was obtained. The solution was diluted with the volatile silicone oil and the resulting clear, colourless solution was stored in an airtight glass vial at room temperature.
EXAMPLE 8. Miscibility test
Presented in Table 3 are data on miscibility of ethanolic phospholipid solutions with either volatile silicone oil or water. The mixtures with a low content of
PL/ethanol in the silicone oil had a clear appearance immediately after preparation, but separated within a month at room temperature. On the other hand, the formulation with a concentration of PL/ethanol of 20 % was miscible with the volatile silicone oil, did not change in appearance during this time period and can thus be considered to be physically stable.
Table 3. Dilution ofethanolic phospholipid (PL; Lipoid S75) solutions with volatile silicone oil (DC 345) and water, respectively. All percentages are by weight
Figure imgf000014_0001
The phospholipid of Table 3 is Lipoid S75 manufactured by Lipoid GmbH,
Ludwigshafen, Germany. This phospholipid material from soybean contains about 68 -
73 % of phosphatidylcholine (PC). Other suitable phospholipid materials are, for example, Lipoid S45, Phospholipon 50, and Lipoid S100, all made from soybean and manufactured by Lipoid GmbH, covering a range of PC content of about 50 % up to 100 %. Further useful phospholipids are synthetic dimyristoylphosphatidylcholine (DMPC), dioleylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC).

Claims

C l a i m s
1. Lipid layer forming antibacterial composition comprising volatile silicone oil, oily lipid, in particular polar oily lipid, a silver source, optionally C2 - C4 aliphatic alcohol .
2. The composition of claim 1, wherein the silver source is selected from the group consisting of silver salt (Ag+X"), silver complex, colloidal silver, silver particles, in particular silver nanoparticles, and their mixtures.
3. The composition of claim 1 or 2, substantially consisting of volatile silicone oil, oily lipid, silver source, optionally C2 - C4 aliphatic alcohol.
4. The composition of any of claims 1 to 3, wherein the lipid is a polar oily lipid, in particular a membrane lipid.
5. The composition of claim 4, wherein the membrane lipid is selected from
phospholipid, glycolipid, sphingolipid, and their mixtures.
6. The composition of claim 1 to 5, wherein the lower aliphatic alcohol is ethanol.
7. The composition of claim 1 to 5, wherein the lower aliphatic alcohol is or
comprises propane-l,2-diol and glycerol in an amount of up to 20 % by weight and even up to 50 % by weight or more of the alcohol.
8. The composition of any of claims 1 to 5, comprising less than 5 % by weight of water, in particular less than 1 % by weight of water.
9. The composition of any of claims 1 to 8, wherein the silicone oil is a siloxane, in particular dekamethylcyclopentasiloxane, dodekamethylcyclohexasiloxane or a mixture thereof.
10. The composition of any of claims 1 to 7, wherein the silicone oil has a boiling point above 180 °C, in particular above 200 °C, and a heat of vaporization (kj/kg) at 25 °C of from about 100 kj/kg to about 300 kj/kg, in particular of from 120 kj/kg to 200 kj/kg, most particularly of from 140 kj/kg to 180 kj/kg.
11. The composition of any of claims 1 to 10, wherein X" is NO3' or docusate.
12. The composition of claim 11, further comprising a wound healing promoting agent, in particular a wound healing promoting peptide.
13. The composition of claim 12, wherein the peptide is selected from angiotensin II, a wound healing fragment, analog or derivative of angiotensin II, human parathyroid hormone, a wound healing fragment, analog or derivative of human parathyroid hormone, cathelicidin polypeptide LL37, a wound healing fragment, analog or derivative of cathelicidin polypeptide LL37.
14. The composition of any of claim 1 to 13, wherein the oily lipid comprises one or more π-bonds of cis-configuration in an aliphatic chain thereof.
15. A method of forming a stable lipid layer comprising an antibacterial agent in form of a silver source on the skin or on a wound, the method comprising:
providing the composition of any of claims 1 to 14;
applying a desired amount of the composition to the skin or wound so as to form a lipid layer thereon containing silicone oil and, optionally, C2 - C4 aliphatic alcohol; allowing the silicone oil and, if present, the C2 - C4 aliphatic alcohol, to evaporate at the temperature of the wound surface to form a stable lipid layer on the skin or wound.
16. The method of claim 15, wherein application is by spraying.
17. The method of claim 15 or 16, wherein the applied amount of composition is selected so as to obtain a stable lipid layer of from 1 μηι to 500 μηι thickness.
18. A method of preparing the antibacterial composition of any of claims 1 to 14, comprising:
providing a pharmacologically effective amount of an antibacterial agent selected from the group consisting of silver salt (Ag+X ), colloidal silver, silver complex, silver particles, in particular silver nanoparticles, and their mixtures;
dissolving the antibacterial agent in a C2 to C4 aliphatic alcohol or a mixture of C2 to C4 aliphatic alcohol and oily lipid to form an alcoholic solution;
mixing the alcoholic solution with oily lipid and/or silicone oil to form said antibacterial composition.
19. The method of claim 18, wherein the mixing is promoted by ultrasonication at a temperature of from 20 °C to 50 °C.
20. The method of claim 18 or 19, wherein the silicone oil is one having a boiling point above 180 °C, in particular above 200 °C, and a heat of vaporization
(kj/kg) at 25 °C of from about 100 kj/kg to about 300 kj/kg, in particular of from 120 kj/kg to 200 kj/kg, most particularly of from 140 kj/kg to 180 kj/kg.
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