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    • 专利摘要:
    The present invention relates to a water-in-oil-in-water (W1/O/W2) double emulsion comprising: (a) an internal water phase (W1) comprising: (a1) one or more non-volatile biocide active ingredient; (a2) one or more lipophilic surfactants; and (a3) water; (b) an intermediate oily phase (O) between the internal water phase and the external water phase comprising one or more oil compounds; and (c) an external water phase (W2) comprising: (c1) one or more volatile biocide active ingredient; (c2) one or more hydrophilic surfactants; and (c3) water.
    公开号:ES2642671A2
    申请号:ES201790025
    申请日:2015-12-04
    公开日:2017-11-17
    发明作者:Gérard MARTORELL LOUBIÈRE；Daniel Maspoch Comamala；Antonia María Cano Sarabia；Vicente AUSINA RUIZ；Águeda HERNÁNDEZ RODRÍGUEZ
    申请人:Desinfeccion Profesional S L；Desinfeccion Profesional SL；Institucio Catalana de Recerca i Estudis Avancats ICREA；Institut Catala de Nanociencia i Nanotecnologia ICN2；Fundacio Institut dInvestigació en Ciencies de la Salut Germans Trias I Pujol IGTP；
    IPC主号:
    专利说明:

    DESCRIPTION
    Biocidal composition with immediate and remaining dual activity
    The present invention relates to the field of biocidal compounds. 5 Particularly in the field of antiseptics and disinfectants. More particularly, to compositions with immediate and remaining dual biocidal activity; to a procedure for its preparation; to compositions containing them; and its use as a biocidal agent for living tissues and / or inanimate surfaces. 10
    PREVIOUS TECHNIQUE
    Biocidal agents have been used as antiseptics and disinfectants to destroy or restrict the growth of microorganisms when applied to living tissue such as skin or inanimate objects such as hard surfaces. Biocidal agents are widely used in hospitals and other healthcare settings for a variety of topical and hard surface applications. In particular, they are an essential part of infection control practices and help in the prevention of nosocomial infections. These 20 have a huge impact on costs for healthcare and human beings in general.
    Therefore, healthcare professionals continually demand new developments of effective, safe and rapid disinfection systems that provide protection against re-infections.
    The efficacy of a biocidal composition can be defined as the potency to produce the antiseptic or disinfecting effect, and is related to the intrinsic efficacy of the active substance / component contained therein. However, this efficacy can be influenced by physical and chemical factors such as, for example, temperature, pH, relative humidity and water hardness, but also by the presence of other substances such as body fluids, additives or other active agents.
    35
    Most of the biocidal active ingredients widely used in the healthcare field have shown a broad spectrum of biocidal activity.
    Examples of broad spectrum biocidal active ingredients are hypochlorite salts such as sodium hypochlorite and oxygen releasing compounds such as hydrogen peroxide. However, other types of biocidal active ingredients also used such as phenols, quaternary ammonium compounds and biguanides (including chlorhexidine) are relatively ineffective against bacterial spores, and many of them have limited the ability to destroy non-enveloped viruses and mycobacteria.
    Therefore, new compositions have been developed that combine two or more cleaning agents, antiseptics and / or disinfectants. Typically, each of the agents included in those compositions has a different biocidal active spectrum that together can increase or amplify the disinfecting efficacy of the composition. Unfortunately, it has been reported that some microorganisms can develop resistance to exposure to some of that combination of biocidal active ingredients. 15 Additionally, the existence of incompatibilities between some biocides that produce dangerous or ineffective compounds has also been reported. Different approaches have been described to avoid these biocidal incompatibilities in the state of matter. One of these approaches involves encapsulating at least one of the biocides. In particular, disinfectant compositions comprising two or more incompatible biocides containing at least one in encapsulated form have been described.
    Some of the commonly used biocidal actives are volatile biocides, for example sodium hypochlorite and oxygen releasing compounds. It has been reported that when a volatile biocidal active ingredient is contacted with a fluid (eg, water), the fluid causes vaporization of the biocidal agent. Therefore, the volatile biocidal actives are commonly used in a closed (encapsulated) system so that the antimicrobial vapor does not vanish. In particular, the US patent application number US20100158851 and the scientific article Langmuir (2009; Joseph KC Kwan et al. "A multilevel antimicrobial coating based on polymer-encapsulated ClO2", Langmuir, 2009, vol. 25 ( 23), pp. 13472-13480) describe a double water-in-oil-in-water emulsion (W1 / O / W2) containing a volatile biocidal active ingredient and a non-volatile biocidal active ingredient, in which the active ingredient Volatile biocide is encapsulated to provide sustained release of the volatile biocide. The
    application of these emulsions on an inert object allows to form an antimicrobial surface coating with the effects of destruction of release, destruction of contact and anti-adhesion. These emulsions preferably comprise a mixture of chlorine dioxide, a chlorite salt and chlorine as encapsulated volatile biocide, and the non-volatile biocidal active ingredient is limited to biocidal active ingredients containing a metal, triclosan, carboxylic acids, sugar acids or their combinations.
    However, those compositions comprising at least one encapsulated volatile biocidal active ingredient in combination with a non-encapsulated non-volatile biocide have limited biocidal efficacy. This limited efficacy results from the limited biocidal activity of the immediate activity of the non-volatile biocidal active ingredient, and the ineffectiveness of the encapsulated volatile biocidal active ingredient when applied to a dry inert surface. Finally, the use of these compositions does not avoid possible incompatibilities between both biocidal active principles, even due to destabilization of the double water-in-oil-in-water emulsion (W1 / O / W2); or by the release of the encapsulated volatile biocidal active ingredient when the non-volatile biocidal active ingredient is still on the inert surface. twenty
    Therefore, it follows from what is known in the art that there is still a need to provide safer and more effective antiseptic and disinfectant compositions that have both immediate and carryover broad spectrum biocidal activity. 25
    SUMMARY OF THE INVENTION
    The inventors have found that the specific composition of the double water-in-oil-in-water emulsion comprising a non-volatile encapsulated biocidal active ingredient and a volatile non-encapsulated biocidal active ingredient of the present invention have the disinfecting efficacy required for the treatment of living tissue and inanimate objects in healthcare facilities. Those emulsions are stable under normal conditions of use and storage allowing a long half-life. Unlike the ineffectiveness of state-of-the-art disinfectant compositions, the double emulsion of the invention shows both high biocidal activity of broad
    immediate spectrum combined with extended remaining broad spectrum biocidal activity even in case of re-contamination. The prolonged high disinfecting efficacy of the dual emulsion of the present invention allows for the reduction of cleaning procedures without compromising hygiene. It is advantageous because it can be associated with a reduction in the economic cost of hygiene procedures.
    Thus, a first aspect of the present invention refers to a double water-in-oil-in-water emulsion (W1 / O / W2) comprising: (a) an internal aqueous phase (W1) comprising: (a1) one or more active ingredients 10 non-volatile biocides; (a2) one or more lipophilic surfactants; and (a3) water; (b) an oil phase intermediate (O) between the internal aqueous phase (W1) and the external aqueous phase (W2) comprising one or more oil compounds; and (c) an external aqueous phase (W2) comprising: (c1) one or more volatile biocidal active ingredients; (c2) one or more hydrophilic surfactants; and (c3) water; In which: the amount of non-volatile biocidal active principle is comprised from 0.4 to 3% by weight of the total weight of the double emulsion; the amount of volatile biocidal active principle is comprised from 0.3 to 40% by weight of the total weight of the double emulsion; the amount of intermediate oil phase (O) (b) is comprised from 2.5 to 30% by weight of the total weight of the double emulsion; and the mean particle size of the emulsion (W1 / O) ranges from 50 nm to 300 nm.
    A second aspect of the present invention refers to a process for the preparation of the double water-in-oil-in-water emulsion according to the first aspect of the invention which comprises: (a) Mixing one or more oily compounds (O) and one or more non-volatile biocidal active ingredients to obtain a mixture; (b) Add a solution of one or more lipophilic surfactants in water to the mixture obtained in step (a) to obtain a water-in-oil emulsion (W1 / O) with an average particle size ranging from 5 µm to 20 µm; (c) Reducing the particle size of the water-in-oil emulsion obtained in step (b) to obtain a water-in-oil emulsion having a particle size comprised from 50 nm to 300 nm; and (d) Disperse the water-in-oil emulsion (W1 / O) obtained in step (c) in a mixture of the volatile biocidal active ingredient and one or more of the hydrophilic surfactant in water (W2) to obtain an emulsion of water-in-oil-in water (W1 / O / W2).
    A third aspect of the present invention relates to a composition comprising the water-in-oil-in-water double emulsion according to the first aspect of the invention together with one or more suitable excipients or vehicles. 5
    Finally, the fourth aspect of the invention refers to the use of the double water-in-oil-in-water emulsion of the first aspect of the invention as a biocidal compound.
    10
    BRIEF DESCRIPTION OF THE DRAWINGS
    Figure 1. is a schematic showing one embodiment of the water-in-oil-in-water emulsion of the present invention. The symbols in figure 1 represent the following: W1 represents the internal aqueous phase comprising the non-volatile biocidal active ingredient, O represents the oil phase comprising the oily compounds, W2 represents the external aqueous phase comprising the non-volatile biocidal active ingredient. volatile, ▲ represents hydrophilic surfactant and ∆ represents lipophilic surfactant.
    twenty
    DETAILED DESCRIPTION OF THE INVENTION
    All terms used herein in the present application, unless stated otherwise, are to be understood in their usual meaning as is known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims, unless an expressly stated definition otherwise provides a broader definition. 30
    In the context of the invention, the terms "water-in-oil-in-water", "water-in-oil-in-water", "W / O / W", "W1 / O / W2" and double emulsion of "Water-in-oil-in water" have the same meaning and are used interchangeably. They refer to an emulsion that includes an internal emulsion (also called discontinuous phase of the internal emulsion), which is the "water-in-oil emulsion" (W1 / O) comprising a multiplicity of discrete oil phase
    dispersed within the outer "water" phase (W2) (also called continuous phase), wherein the oil phase comprises an inner "water" phase (W1) (see Figure 1).
    The terms "water-in-oil", "water-in-oil" and "W1 / O" emulsion have the same meaning and are used interchangeably. They refer to an emulsion that includes a discontinuous phase, which is the "water" phase (W1) or predominantly aqueous phase, and a continuous phase, which is an "oil" phase, or predominantly organic liquid phase, such as a liquid phase. predominantly polymer solvent. The oil phase is at least partially immiscible with the aqueous phase. This "water-in-oil emulsion" (W1 / O) is forming "particles" in a discontinuous aqueous phase. The terms "particles" or "drops" have the same meaning and are used interchangeably.
    The term "particle size" refers to the particle diameter of the internal emulsion (W1 / O), that is, to the discontinuous phase of the internal emulsion based on an approximate spherical shape of the particle based on a volumetric measurement of the particle. In addition to spherical particles, the oil-in-water emulsions of the present invention may also comprise, without limitation, ellipsoid and / or cylindrical particles. twenty
    In the context of the invention, the term "nanoparticle" or "nano-scale droplets" have the same meaning and are used interchangeably. They refer to a particle with at least two dimensions on the nanoscale, particularly with the three dimensions on the nanoscale, where the nanoscale is in the range from 20 nm to 500 nm.
    The term "size" refers to a characteristic physical dimension. For example, in the case of a nanoparticle that is substantially spherical, the size of the nanoparticle corresponds to the diameter of the nanoparticle. In the case of a nanoparticle that is substantially rod-shaped with a substantially circular cross-section, such as a nanowire or a nanotube, the size of the nanoparticle corresponds to the diameter of the cross-section of the nanoparticle. In the case of a nanoparticle that is substantially box-shaped, such as a nanocube, a nanocage, or a nanocage, the size of the
    nanoparticle corresponds to the maximum length of the edge. When referring to a set of nanoparticles as having a particular size, it is contemplated that the set of nanoparticles may have a size distribution around the specified size. Thus, as used herein, a size of an array of nanoparticles can refer to a mode of a size distribution, such as a peak size of the size distribution.
    The method for determining the particle size of the compositions of the present invention may be the dynamic light scattering (DLS) technique.
    The particle size of the nanoparticles (nano-scale droplets) of the double emulsion of the present invention can be measured by any method described in the state of the art to measure the particle size of the nanoparticles. In particular, the method used in the present invention to measure particle size is the dynamic light scattering (DLS) technique. Particle size distributions were measured using a Malvern Zetasizer instrument in undiluted samples. twenty
    The term "surfactant" refers to a material that reduces the surface tension of a liquid and the interfacial tension between two liquids, allowing easier mixing and diffusion. Surfactants have a hydrophilic head that is attracted to water molecules and a hydrophobic tail that repels water and simultaneously binds itself to oil and grease in dirt. These opposing forces loosen dirt and suspend it in water, which has the ability to remove it from surfaces such as human skin, fabrics, and other solids, when surfactants are dissolved in water.
    30
    The term "hydrophilic surfactant" refers to a surfactant having a "hydrophilic-lipophilic balance value" (HLB) value equal to or greater than 10.
    The term "lipophilic surfactant" refers to a surfactant having a "hydrophilic-lipophilic balance value" (HLB) value of less than 10. The terms "lipophilic" and "hydrophobic" have the same meaning and are used interchangeably.
    As used herein, the term "hydrophilic-lipophilic balance value" or "HLB" have the same meaning and are used interchangeably. They refer to an empirical parameter used to characterize the relative hydrophilicity or lipophilicity of an amphiphilic compound, such as a surfactant. The determination of HLB is well defined within the ability of one of ordinary skill in the art. However, it should be appreciated that the HLB value of a surfactant is merely an approximate orientation generally used to allow the formulation of various products. For many important surfactants, including various polyethoxylated surfactants, it has been reported that the HLB values can differ by no less than about 8 HLB units, depending on the empirical procedure chosen to determine the HLB value (Schott et al., "Comments on hydrophile – lipophile balance systems ”J. Pharm. Sciences, 1990, vol. 79 (1), pp. 87-88).
    fifteen
    The term "polyglycol" refers to a dihydroxyether formed by dehydration of two or more glycol molecules.
    The term "biocidal active ingredient" refers to a chemical active ingredient that can destroy a harmful organism; or counteract, neutralize or prevent the action of a harmful organism; or exercise any control over a harmful organism, by chemical or biological means. Examples of biocidal actives include, but are not limited to, sodium hypochlorite, hydrogen peroxide, amines, quaternary ammonium compounds, and chlorine dioxide.
    25
    The term "volatile biocidal active ingredient" includes any biocidal active ingredient that is easily vaporizable at a relatively low temperature, such as room temperature or human body temperature. The term "room temperature" refers to the temperature ranging from 20 ° C to 25 ° C, and the term "human body temperature" is the temperature ranging from 34 ° C to 41 ° C.
    The term "oxygen releasing compound" refers to any compound that contains a dioxygen (O-O) bond, particularly bivalent O-O bonds. Non-limiting examples of oxygen releasing compounds include peracids, peracid salts, and peroxides such as hydrogen peroxide.
    The term "alkyl" refers to a straight or branched saturated hydrocarbon chain containing the number of carbon atoms specified in the description or claims. If no number of carbon atoms is specified, then the alkyl group has from 1 to 12 carbon atoms. Examples include the group methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.
    The known term "aryl" refers to a ring system with 1-3 rings containing the number of carbon atoms specified in the description or claims, the rings being saturated, partially unsaturated, or being aromatic; and being condensed, bridged, or may contain different types of fusion; at least one of the rings being an aromatic ring; and the ring system being optionally substituted with one or more radicals independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, nitro, cyano, and halogen.
    The known term "heteroaryl" refers to a ring system with 1-3 rings containing the number of carbon atoms specified in the description or claims, wherein one or more of the ring members, preferably 1,2 The 3,4-membered ring is selected from N, NH, O, and S; the rings being saturated, partially unsaturated, aromatic; and being condensed, bridged, or may contain different types of fusion; at least one of the rings being an aromatic ring; and the ring system being optionally substituted with one or more radicals independently selected from the group consisting of (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, nitro, cyano, and halogen.
    For the purposes of the present invention, in "fused" rings fusion occurs through a bond that is common to two contiguous rings; and in "bridged" rings fusion occurs through a sequence of atoms (bridgehead) that is common to two rings.
    The term "percentage (%) by weight" refers to the percentage of each component of the emulsion or alternatively of the composition in relation to the total weight.
    As mentioned above, one aspect of the present invention relates to a double water-in-oil-in-water emulsion (W1 / O / W2) comprising (a) an internal aqueous phase (W1) comprising one or more non-volatile biocidal active ingredients; (b) an oil phase intermediate (O) 5 between the internal aqueous phase and the external aqueous phase comprising one or more oil compounds; and (c) an external aqueous phase (W2) comprising one or more volatile biocidal active ingredients.
    Compared with the water-in-oil-in-water disinfectant double emulsion of the state of the art, the double emulsion of the present invention has a longer broad spectrum biocidal effect. As shown in section 5.2.3. and Tables 9 and 10 above, the double emulsion of the invention is stable having a remaining biocidal effect, even up to 72 hours after its application. This effect occurs even until re-contaminations occur, or after a prolonged storage period.
    In the double water-in-oil-in-water emulsion of the invention, the non-volatile biocidal active ingredient is selected from the group consisting of biguanides, tertiary amines, ethanolamines, quaternary ammonium compounds, and a mixture thereof.
    In one embodiment of the invention, the non-volatile biocidal active ingredient is a biguanide selected from the group consisting of chlorhexidine; octenidine; 25 alexidine; and polymeric biguanides selected from the group consisting of polyhexamethylene biguanide (PHMB), and polyaminopropylbiguanide; and salts and mixing them. Preferably, the non-volatile biocidal active ingredient is selected from chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine gluconate and polyhexamethylene biguanide. 30
    In another embodiment of the invention, the non-volatile biocidal active ingredient is a tertiary amine; preferably the tertiary amine is an N-oxide tertiary amine selected from the group selected from 1-dodecylpiperidine N-oxide, ethylenediaminetetraacetic acid (EDTA), EDTA with aminopolycarboxylic acid, 4-alkylmorpholine N-oxide, 4-N-oxide -decylmorpholine, 4-dodecylmorpholine N-oxide, 4- N-oxide
    tetradecylmorpholine and 4-hexadecylmorpholine N-oxide.
    In another embodiment of the invention, the non-volatile biocidal active ingredient is an ethanolamine; preferably ethanolamine is selected from 2- (N-amyl) ethanolamine, 2-cyclohexylethanolamine and N-butylethanolamine. 5
    In another embodiment of the invention, the non-volatile biocidal active ingredient is a quaternary ammonium compound (QAC). QAC is the common name of a group of compounds having the following formula R1R2R3R4N + X-. Depending on the nature of the R groups, the anion (X-) and the number of 10 quaternary nitrogen atoms present in the formula, QACs are normally classified as:
    (a) monoalkyltrimethylammonium compounds such as, for example, cetyltrimethylammonium bromide (CTAB); alkyltrimethylammonium chloride; alkylaryltrimethylammonium chloride; cetyldimethylethylammonium bromide; fifteen
    (b) monoalkyldimethylbenzylammonium salts such as, for example, alkyldimethylbenzylammonium chlorides; dodecyldimethyl-3,4-dichlorobenzylammonium chloride; and mixtures of substituted alkyldimethylbenzyl (ethylbenzyl) ammonium and alkyldimethylbenzylammonium chloride, dialkyldimethylammonium salts; twenty
    (c) dialkyldimethylammonium salts such as, for example, didecyldimethylammonium halides and octyldodecyldimethylammonium chlorides;
    (d) heteroarylammonium salts such as, for example, cetylpyridinium halide (CPC); 1- [3-chloroallyl] -3,5,7-triaza-1-azoniaadamantane; alkyl isoquinolinium bromide and alkyldimethylnaphthylmethylammonium chloride;
    (e) polysubstituted quaternary ammonium salts such as, for example, alkyldimethylbenzylammonium saccharinate and alkyldimethylethylbenzylammonium cyclohexylsulphamate; and
    (f) bisquaternary ammonium salts or 1,10-bis (2-methyl-4-30 aminoquinolinium chloride) -decane; bl, 6-bis [1-methyl-3- (2,2,6-trimethylcyclohexyl) -propyldimethylammonium chloride] hexane.
    In a preferred embodiment, the non-volatile biocidal active ingredient is a quaternary ammonium compound selected from the group consisting of monoalkyltrimethylammonium salts; monoalkyldimethylbenzylammonium salts; dialkyldimethylammonium salts; heterocyclic ammonium salts; you come out of
    polysubstituted quaternary ammonium, bisquaternary ammonium salt; and polymeric ammonium salts. In a more preferred embodiment, the quaternary ammonium compound is selected from the group consisting of benzalkonium chloride, decualinium chloride, laurolinium acetate; and hedaquinium chloride. 5
    In the water-in-oil-in-water double emulsion of the invention, the volatile biocidal active ingredient is selected from the group consisting of hypohalide salt; oxygen releasing compound; and mixing them.
    10
    In one embodiment of the invention, the volatile biocidal active ingredient is alkaline or alkaline earth salts of hypohalide; preferably alkali or alkaline earth salts of hypohalide compound selected from the group consisting of sodium hypochlorite, calcium hypochlorite and chlorine dioxide.
    fifteen
    In another embodiment of the invention, the volatile biocidal active ingredient is an oxygen releasing compound selected from the group consisting of hydrogen peroxide, perborate, perborates, percarbonate, organic peracid, inorganic peracid, organic persalt, inorganic persalt, monoperoxysulfate salt. , and mixing them; preferably, the oxygen releasing compound 20 is selected from hydrogen peroxide, peracetic acid, and potassium monoperoxysulfate.
    In one embodiment of the invention, the emulsion is one in which the non-volatile biocidal active ingredient is a biguanide and the volatile biocidal active ingredient is a hypohalide. In a preferred embodiment, the emulsion is one in which the non-volatile biocidal active ingredient is chlorhexidine, or salts thereof, and the volatile biocidal active ingredient is sodium hypochlorite; or alternatively the non-volatile biocidal active ingredient is polyhexamethylene biguanide and the volatile biocidal active ingredient is sodium hypochlorite.
    In another embodiment of the invention, the emulsion is one in which the non-volatile biocidal active ingredient is a biguanide and the volatile biocidal active ingredient is an oxygen-releasing compound. In a preferred embodiment, the emulsion is one in which the non-volatile biocidal active ingredient is chlorhexidine or salts thereof and the volatile biocidal active ingredient is
    hydrogen peroxide or potassium monoperoxysulfate; or alternatively the non-volatile biocidal active ingredient is polyhexamethylene biguanide and the volatile biocidal active ingredient is hydrogen peroxide or potassium monoperoxysulfate.
    5
    The water-in-oil-in-water double emulsion of the present invention comprises one or more hydrophilic surfactants having an HLB value equal to or greater than 10; preferably equal to or greater than 12; more preferably equal to or greater than 15. In one embodiment of the invention, the hydrophilic surfactant is selected from the group consisting of (C2-C8) diol, (C2-10 C8) glycol, polyglycols, and mixtures thereof. In a preferred embodiment, the hydrophilic surfactant is a polyglycol. Examples of suitable polyglycols for the present invention include, but are not limited to, ethylene glycol, propylene glycol, polyethylene glycols, polypropylene glycols, methoxypolyethylene glycols, polybutylene glycols, block copolymers of butylene oxide and ethylene oxide, and block copolymers of ethylene glycol and propylene glycol. In a preferred embodiment, the hydrophilic surfactant having an HLB value equal to or greater than 10 is a block copolymer of ethylene glycol and propylene glycol; more preferred is an ethylene glycol and propylene glycol block copolymer having a polypropylene glycol molar mass equal to or less than 2000 (g / mol); and 20 a percentage by weight of polyethylene glycol is comprised from 70 to 100. In a much more preferred embodiment, the hydrophilic surfactant having an HLB value equal to or greater than 10 is selected from Pluronic F127, Pluronic PE6800 and a mixture thereof.
    25
    The water-in-oil-in-water dual emulsions of the present invention comprise one or more lipophilic surfactants having an HLB value of less than 10; preferably equal to or less than 8; more preferably equal to or less than 5. In one embodiment of the invention, the lipophilic surfactant is selected from the group consisting of for the present invention include (C2-C8) diol, (C2-C8) glycol, polyglycols, and mixture of the themselves. In a preferred embodiment, the lipophilic surfactant is a polyglycol. Examples of polyglycols suitable for the present invention include, but are not limited to, ethylene glycol, propylene glycol, polyethylene glycols, polypropylene glycols, methoxypolyethylene glycols, polybutylene glycols, block copolymers of butylene oxide and ethylene oxide, and block copolymers of ethylene glycol and propylene glycol. In a preferred embodiment, the lipophilic surfactant having
    an HLB value of less than 10 is a block copolymer of ethylene glycol and propylene glycol; more preferred a block copolymer of ethylene glycol and propylene glycol having a polypropylene glycol molar mass equal to or greater than 2500 (g / mol); and a percentage by weight of polyethylene glycol ranging from 20 to 60. In a much more preferred embodiment, the lipophilic surfactant having an HLB value of less than 10 is selected from Pluronic P123, Pluronic PE10300, Pluronic PE10400, Pluronic PE10500, and mixture thereof. In a preferred embodiment, the lipophilic surfactant is a mixture, comprising Pluronic P123, Pluronic PE10300, Pluronic PE10400, and Pluronic PE10500. 10
    The oil phase of the water-in-oil-in-water double emulsion of the present invention comprises one or more oil compounds. In one embodiment, the oil compounds of the oil phase are selected from the group consisting of essential oil, fatty acid esters, and mixtures thereof.
    In one embodiment of the invention, the oil compounds of the oil phase are one or more essential oils. The term "essential oil" is a low volatile oil made from natural extracts that are compatible with the active biocidal ingredients of the emulsion. In one embodiment, the oil phase is an essential oil selected from the group consisting of citrus oil, a leaf oil; a spice oil; a seed oil; a peel oil, and a mixture of them. Examples of essential oil suitable for the present invention include, but are not limited to, oil such as lemon, orange, lime, grapefruit, and tangerine; peppermint, tea tree and peppermint oil; bergamot, lavender, eucalyptus and rosemary oil; flax seed oil and cranberry seed oil. In a preferred embodiment, the essential oil is lemon oil, tea tree oil, rosemary oil, lavender oil, and eucalyptus oil; more preferably lemon oil. 30
    In another alternative embodiment, the oil compounds of the oil phase is one or more fatty acid esters. The term "fatty acid" refers to any natural or synthetic carboxylic acid compound comprising an alkyl chain that may optionally be monounsaturated, or polyunsaturated; and it can also be substituted. The term "fatty acid ester" refers to any compound comprising at least one ester of
    a fatty acid. Examples of suitable fatty acid ester for the present invention include caprylic-capric triglyceride, isopropyl palmitate / myristate, ethylhexyl, palmitate / stearate / cocoate, propylene glycol dicaprylate / dicaprate; Polyethylene glycol 7 glycerylcocoate, cetearyl octanoate / isononanoate, cetyloctanoate / pamilitate, isononyl isononanoate, glycol 5 stearate / distearate, C12-C15-alkyl benzoate, glycerol esters, ethylhexanothylhexanoate. Preferably, the fatty acid ester is a mixture of caprylic and capric triglyceride (ie caprylic / capric triglyceride).
    10
    In another alternative embodiment, the oil compounds of the oil phase is a mixture of one or more essential oils and one or more fatty acid esters. Preferably, a mixture of lemon oil and caprylic / capric triglyceride. In a preferred embodiment, the weight ratio of essential oil to fatty acid esters is from 10:90 to 100: 0; preferably 50:50.
    In one embodiment of the invention, the double emulsion comprises one or more biguanides selected from chlorhexidine or salts thereof, and polyhexamethylene biguanide; one or more volatile biocidal active ingredients 20 selected from hypohalide and oxygen releasing compound; one or more lipophilic surfactants having an HLB of less than 10 selected from diol (C2-C8), glycol (C2-C8), polyglycols; preferably, the lipophilic surfactant is a block copolymer of ethylene glycol and propylene glycol; and one or more hydrophilic surfactants having an HLB value equal to or greater than 10 selected from diol (C2-C8), glycol (C2-C8), polyglycols; preferably, the lipophilic surfactant is a block copolymer of ethylene glycol and propylene glycol.
    The amount of non-volatile biocidal active principle is comprised from 0.4 to 3% by weight of the total weight of the double emulsion. In one embodiment of the invention, optionally in combination with one or more features of the various embodiments described above or below, the amount of the amount of non-volatile biocidal active ingredient is comprised from 0.6 to 1% by weight of the total weight of the double emulsion. 35
    The amount of the volatile biocidal active ingredient is comprised from 0.3
    up to 40% by weight of the total weight of the double emulsion. In one embodiment of the invention, optionally in combination with one or more features of the various embodiments described above or below, the amount of volatile biocidal active ingredient is comprised from 1 to 35% by weight of the total weight of the double emulsion; preferably it is comprised from 5 to 15% by weight of the total weight of the double emulsion.
    The amount of intermediate oil phase is comprised from 2.5 to 30% by weight of the total weight of the double emulsion. In one embodiment of the invention, optionally in combination with one or more features of the various embodiments described above or below, the amount of intermediate oil phase is from 5 to 20% by weight of the total weight of the double emulsion.
    fifteen
    In one embodiment of the invention, the double emulsion as defined above comprises:
    (a) from 5 to 30% by weight of the internal aqueous phase (W1) comprising, in relation to the total weight of the double emulsion:
    (a1) from 0.4 to 3% by weight of one or more non-volatile biocide active ingredients;
    (a2) from 0.125 to 0.5% by weight of one or more lipophilic surfactants; and
    (a3) from 3.8 to 21.5% water;
    (b) from 2.5 to 30% by weight of the intermediate oil phase in relation to the total weight of the double emulsion; and
    (c) from 40 to 87% by weight of the external aqueous phase (W2) comprising, in relation to the weight of the double emulsion:
    (c1) from 0.3 to 10% by weight of one or more volatile biocidal active ingredients; 30
    (c2) from 2 to 8% by weight of one or more hydrophilic surfactants; and
    (c3) from 37 to 80% by weight of water;
    the sum of the weight of the emulsion phases being 100%.
    35
    In another embodiment of the invention, the double emulsion comprises:
    (a) from 5 to 20% by weight of the internal aqueous phase (W1) which
    comprises, in relation to the total weight of the double emulsion:
    (a1) from 0.5 to 2% by weight of one or more non-volatile biocidal active ingredients;
    (a2) from 0.2 to 0.4% by weight of one or more lipophilic surfactants; and 5
    (a3) from 2.8 to 13.6% water;
    (b) from 3 to 15% by weight of the intermediate oil phase in relation to the total weight of the double emulsion; and
    (c) from 60 to 85% by weight of the external aqueous phase (W2) comprising in relation to the weight of the double emulsion: 10
    (c1) from 1 to 5% by weight of one or more volatile biocidal active ingredients;
    (c2) from 2 to 6% by weight of one or more hydrophilic surfactants; and
    (c3) from 57 to 74% by weight of water; fifteen
    the sum of the weight of the emulsion phases being 100%.
    In another embodiment of the invention, the double emulsion comprises:
    (a) from 5 to 15% by weight of the internal aqueous phase (W1) comprising, in relation to the total weight of the double emulsion: 20
    (a1) from 0.5 to 2% by weight of one or more non-volatile biocidal active ingredients;
    (a2) from 0.2 to 0.3% by weight of one or more lipophilic surfactants; and
    (a3) from 1.8 to 9.7% water; 25
    (b) from 3 to 10% by weight of the intermediate oil phase in relation to the total weight of the double emulsion; and
    (c) from 70 to 85% by weight of the external aqueous phase (W2) comprising in relation to the weight of the double emulsion:
    (c1) from 2 to 4% by weight of one or more volatile biocide active ingredients;
    (c2) from 3 to 5% by weight of one or more hydrophilic surfactants; and
    (c3) from 65 to 76% by weight of water;
    the sum of the weight of the emulsion phases being 100%. 35
    As shown in section 5.2.3., The double emulsion of this
    The invention, as defined above, is active for a long period of time after use on the surface or fabric, for example, up to 72 hours, and even after prolonged storage periods (see Table 10).
    5
    It is described in the state of the art that changes in the physical properties of the emulsion such as, for example, pH, viscosity, particle size and / or distribution of the emulsion can cause a destabilizing phenomenon such as creaming, flocculation, coalescence. total or partial, phase inversion and Ostwald ripening. As shown in sections 3 and 5.2.3., The double emulsion of the invention maintains its physical and chemical properties by protecting and stabilizing both biocidal active ingredients in the separate phases, even after long periods of storage.
    fifteen
    The mean particle size of the oil phase (discontinuous phase of the internal emulsion (W1 / O)) of the invention is comprised from 50 nm to 300 nm; preferably it is comprised from 100 to 200 nm; preferably 150 nm. The specific composition of the double emulsion of the invention in combination with the amount of the oil phase and the particle size of the discontinuous phase of the internal emulsion as mentioned above has the advantage of providing the appropriate number of drops with the in order to form a continuous film over the entire treated surface / fabric.
    25
    The term "mean particle size" means that 50% of the measurable particles in the oil phase have a larger equivalent diameter, and the other 50% of the particles have a smaller equivalent diameter. Additionally, the oil phase particles of the present invention have a dispersion index of from 0 to less than 1; 30 preferably from 0.1 to 0.5; more preferably 0.2. The dispersion index is defined as the ratio of the variance () with respect to the mean (µ) and is calculated by the following formula:
    35
    and is indicative of the "uniformity" of the particle size of the oil phase.
    The double emulsion of the present invention allows an immediate first disinfection on the tissue or object (surface) by the biocidal effect of the volatile biocidal active ingredient, followed by the subsequent release of the non-volatile biocidal active ingredient from the emulsion. The specific emulsion of the present invention allows a prolonged release profile of the non-volatile biocidal active ingredient from the internal aqueous phase. The concentration of the non-volatile active principle 10, which is in contact with the volatile active principle both in the double emulsion of the invention itself and in the gas phase after its release out of the emulsion, is constant and less than 15% by weight of the total weight of the double emulsion. It is advantageous because the low and constant concentration of the non-volatile active principle avoids the interaction between the two biocidal active principles both in the liquid and in the gaseous phase. In one embodiment of the invention, the double water-in-oil-in-water emulsion of the invention is one in which the concentration of the non-volatile biocidal active ingredient released from the internal aqueous phase is less than 15% by weight of the total weight. of the double emulsion. Particularly, the concentration 20 is less than 5% by weight of the total weight of the double emulsion; more particularly, the concentration is comprised from 0.5% to 1% by weight of the total weight of the double emulsion. Preferably, the concentration of the non-volatile biocidal active principle released from the internal aqueous phase is from 0.6% to 0.75 by weight of the total weight of the double emulsion.
    As mentioned above, another aspect of the present invention relates to a process for the preparation of the water-in-oil-in-water double emulsion (W1 / O / W2) as defined above. The process comprises two emulsion stages, the first stage to form an inverse emulsion of water in oil (W1 / O), followed by emulsification of this mixture in water (W2) using a combination of surfactants. In particular, the process comprises: (a) Mixing one or more oily compounds (O) and one or more non-volatile biocidal active principles to obtain a mixture; (b) Add a solution of one
    or more lipophilic surfactants in water to the mixture obtained in step (a) to obtain a water-in-oil emulsion (W1 / O) with an average particle size comprised from 5 µm to 20 µm; (c) Reducing the particle size of the water-in-oil emulsion obtained in step (b) to obtain a water-in-oil emulsion having a mean particle size ranging from 50 nm to 300 nm; and (d) Disperse the water-in-oil emulsion (W1 / O) obtained in step (c) in a mixture of the volatile biocidal active ingredient and one or more of the hydrophilic surfactant in water (W2) to obtain a water emulsion. -in oil-in water (W1 / O / W2). 10
    In particular, the reduction of the particle size of the water-in-oil emulsion obtained in step (b) can be carried out using any of the techniques commonly used in the state of the art to reduce the particle size of an emulsion. . Examples of suitable techniques for reducing particle size can be high speed homogenization, high pressure homogenization, ultrasound, jet milling, and cavitation. In one embodiment of the invention, step (c) is carried out by high pressure homogenization.
    twenty
    The aforementioned procedure makes it possible to control the particle size and the homogeneity of the oily droplets (W1 / O). In particular, this process makes it possible to form the emulsion of stable nanoscale droplets (or nanoparticles) of the invention having the specific composition of the surfactant system and comprising the 25 incompatible biocidal active principles in a single emulsion. This procedure is simple, safe and easy to scale up due to the reduction of almost any interaction between the incompatible biocidal active ingredients.
    30
    Also part of the invention is a double water-in-oil-in-water emulsion (W1 / O / W2) obtainable by (a) Mixing one or more oily compounds (O) and one or more non-volatile biocidal active ingredients to obtain a mixture; (b) Adding a solution of one or more lipophilic surfactants in water to the mixture obtained in step (a) to obtain a water-in-oil (W1 / O) emulsion with an average particle size ranging from 5 µm to 20 µm; (c) Reducing the particle size of the
    water-in-oil emulsion obtained in step (b) to obtain a water-in-oil emulsion having a particle size comprised from 50 nm to 300 nm; (d) Dispersing the water-in-oil emulsion (W1 / O) obtained in step (c) in a mixture of the volatile biocidal active ingredient and one or more of the hydrophilic surfactant in water (W2) to obtain a water emulsion -in oil-in water (W1 / O / W2).
    The terms "obtainable" and "obtained" have the same meaning and are used interchangeably. In any case, the term "obtainable" encompasses the term "obtained". 10
    As mentioned above, another aspect of the present invention relates to a composition comprising the double water-in-oil-in-water emulsion as defined above together with one or more appropriate excipients or carriers. fifteen
    Suitable excipients or vehicles for the present invention can be any commonly used in the antiseptic or disinfectant composition described in the state of the art. For example, excipients or vehicles can be selected from the group of colorants; aromas; solvents, for example glycols; diluents, for example water; surfactants, for example anionic surfactants; stabilizers; and rheological modifiers. In one embodiment, the composition further comprises one or more glycols selected from the group consisting of glycol derived ester and glycol derived ether. The term "glycol" or "vicinal diol" or "1,2-diols", which are used interchangeably, refer to aliphatic organic compounds in which two hydroxyl (OH) groups are attached to adjacent carbon atoms.
    In one embodiment of the invention, the composition further comprises one or more additional active ingredients. Examples of such active ingredients include, among others, cleaning compounds; and disinfectant compounds, for example, virucidal compounds, fungicidal compounds, bactericidal compounds, yeasticidal compounds, and sporicidal compounds.
    35
    As mentioned above, the double emulsion of the present invention can be used as a biocidal compound. Thus, the fourth aspect of the
    The present invention is the use of the water-in-oil-in-water double emulsion as defined above as a biocidal compound. In one embodiment, the use of the emulsion of the invention as a biocidal compound is selected from a disinfectant and antiseptic agent.
    5
    In one embodiment, the double emulsions of the invention can be used as a disinfectant. The term "disinfectant" refers to a product that kills microorganisms on inanimate objects. Examples of inanimate objects include hard surfaces, medical devices, and surgical equipment. 10
    In an alternative embodiment, the double emulsions of the invention can be used as an antiseptic. The term "antiseptic" refers to a product that inhibits the growth or destroys bacteria, or other microorganisms, in or on the living tissues of humans or animals such as, for example, on the skin.
    Throughout the description and claims, the word "comprise", and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise" encompasses the case of "consisting of". Additional objects, advantages, and features of the invention will be apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. Reference signs related to drawings and placed in parentheses in a claim are solely to attempt to increase the intelligibility of the claim, and should not be construed as limiting the scope of the claim. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein.
    EXAMPLES
    General considerations 35
    The reagents used in the following examples have been purchased from: Pluronic P123 (BASF); Pluronic PE10300 (BASF); Pluronic F127 (BASF);
    Pluronic PE6800 (BASF); chlorhexidine (Sparchim); CHLX / isopropanol (Sparchim / Sigma Aldrich); PHMB (Lonza); sodium hypochlorite (Henkel); Caroat (antiseptic); peracetic acid (FMC Foret); hydrogen peroxide (FMC Foret); chlorine dioxide (Pharmacal); benzylammonium chloride (multiBIND biotec GmbH); lemon oil (Sigma Aldrich); lemon oil / fatty acid ester (Sigma Aldrich / Sternchemie); lemon oil / Bergabest (Sigma Aldrich / Sternchemie); tea tree oil (Sigma Aldrich); water (distilled water).
    1. Double water-in-oil-in-water emulsions of the present invention
    1.A. Composition
    Tables 1-5 show the qualitative and quantitative composition of the water-in-oil-in-water emulsion of the present invention.
    The compositions of the present invention 1-20 described below have a mean particle size of 150 nm.
    twenty
    1 B. Preparation procedure
    The compositions of the present invention 1-20 described in section 1A were prepared following the procedure described below which comprises two emulsification steps. 5
    STAGE A: Preparation of the water-in-oil emulsion (W1 / O)
    (A1) The oil phase (O; 5 g); and the non-volatile biocidal active ingredient were mixed in a rotor-stator mixer (Ultraturrax) at 8000 rpm for 5 min.
    (A2) A solution of the lipophilic surfactant in water (5 g; 0.25 g of surfactant in 4.75 ml of water) was added to the mixture obtained in step (A1). The resulting mixture was mixed at 8000 rpm for 5 min. fifteen
    (A3) The emulsion resulting from step (A2) was homogenized under high pressure (microfluidizer) at 6 kPa to obtain the water-in-oil emulsion with a nano-average particle size.
    twenty
    STAGE B: Preparation of the water-in-oil-in-water emulsion (W1 / O / W2)
    (B1) Preparation of phase W1: The volatile biocidal active ingredient (5 g), the hydrophilic surfactant (4 g) and water (78 g) were mixed.
    25
    (B2) To phase W1 obtained in step (B1) the water-in-oil emulsion obtained in step (A3) was added under manual stirring for 1 min to obtain the double water-in-oil-in-water emulsion ( W1 / O / W2) of the present invention.
    30
    2. Comparative water-in-oil-in water double emulsion
    2.A. Composition
    Table 6 shows the qualitative and quantitative composition of the 35 comparative water-in-oil-in-water emulsions outside the scope of the present invention.
    Comparative compositions 1-4 described below have a mean particle size of 150 nm.
    2.B. Preparation procedure
    5
    Comparative compositions 1-4 described in section 2A were prepared following the procedure as defined in section 1A using the components specified in Table 6.
    3. Stability test 10
    3.1. Direct visual inspection
    A visual test of the emulsions of the invention (1-20) and the comparative emulsions (1-4) was carried out at room temperature (at 20-25 ° C) at zero time and every month for 1 year.
    Creaming was observed in the tested emulsions of the present inventive and comparative emulsion, it means that the dispersed phase has a lower density than the continuous phase. The effect of cremation is reversed after shaking and the initial state is recovered.
    Thus, the compositions of the invention can be considered visually stable. 25 3.2. Turbidity test
    The stability of the emulsions of the present invention was based on turbidity measurements using a Turbiscan Lab turbidimeter. Turbiscan technology consists of measuring backscatter and transmission intensities versus sample separation. A water-in-oil-in-water emulsion of the present invention (1-20) or a comparative emulsion (1-4) was placed in a vial and introduced into the turbidimeter during a routine predetermined scan. The stability index was carried out at 25 ° C.All the emulsions tested have a cloud index of less than 15. Therefore, the compositions of the invention can be considered stable.
    image 1
    3.2. Stability on the surface This study determines the visual stability and microbiological activity of the emulsions of the present invention after applying them on hard surfaces. 5Procedure:Water-in-oil-in-water emulsions of the present invention or comparative compositions were sprayed onto plastic and glass surfaces. They were then wiped with a cloth and dried at ambient conditions.Optical check: fifteen Macroscopic level: No visible residue of the sprayed emulsion was observed on the surface, even on glass.Microscopic level: Evenly distributed emulsion droplets were observed on the surface at the optical microscopic level. twenty3.3. Stability test conclusionThe compositions of the invention are stable during the preparation process and under storage conditions. 25
    4. Non-volatile biocide release profile
    This study determines the kinetic release profile of the non-volatile biocidal active ingredient from the internal aqueous phase (W1) of the emulsion in which a surface is impregnated with the tested composition and then dried.
    These tests were carried out with simplified models of the compositions of the invention that comprise testing simplified compositions 5'-11 '. The simplified compositions 5'-11 'contain all 35 components of the water-in-oil-in-water emulsions of Examples 5-11 of the present invention, in which the volatile biocide is removed and the
    amount of the volatile biocide has been replaced with the same amount of water. Therefore, the composition of the internal aqueous phase (W1) and the oil phase (O) of the comparative simplified compositions 5'-12 'is the same as shown in Tables 2-3 for compositions 5-12, respectively. , and the composition of the external aqueous phase (W2) comprises an amount of 4-5% of Pluronic F127 (as hydrophilic surfactant) and an amount of 81% of water.
    PROCESS
    10
    The simplified compositions tested were placed on styrene well plates, and the composition was held on the surface for 5 minutes and wiped with a cloth. Then the surface of the piece of cloth was allowed to dry for different times. For each time, the free non-volatile biocidal active ingredient was measured. fifteen
    The measurement was carried out by dissolving the dry film containing the non-volatile biocidal active ingredient in 0.3 ml of water and was analyzed by UV-visible spectroscopy at 235 nm.
    twenty
    Table 7 shows the kinetic release of PHMB from styrene surfaces.
    Time (h) Simplified compositions 5'-11 '
    PHMB concentration (%) Standard deviation
    0 0.73928 0.02885
    1 0.77723 0.01582
    2 0.81483 0.03952
    6 0.8454 0.01884
    2. 3 0.87807 0.02117
    24 0.88229 0.0454
    From the results of the kinetic release obtained from the simplified models of Examples 7-11 (see Table 7) it is deducible that the 25 compositions, which comprise the specific composition as defined in the present invention, allow to have a constant free concentration of the non-volatile biocidal active ingredient comprising 0.75 ± 0.05%
    for a 24 hour period on inert surfaces. The fact that the free non-volatile biocide has been detected on the treated surfaces for up to 24 hours has to be considered an advantage, indicating that the compositions of the invention have long-lived (carryover) biocidal activity against microorganisms. 5
    Therefore, the specific composition of the present invention makes it possible to have a prolonged and constant release profile of the non-volatile biocidal active principle to have an appropriate biocidal effective amount of free non-volatile biocide, and at the same time an appropriate free biocidal concentration to avoid the 10 interaction with the volatile biocide.
    5. Biocidal activity test
    Experiments were performed for both immediate and remnant effect 15 using:
    Bacteria:
    - Gram-positive bacteria: Staphylococcus aureus ATCC 6538; and
    Enterococcus hirae ATCC 10541 20
    - Gram-negative bacteria: Escherichia coli ATCC 10536; and
    Pseudomonas aeruginosa ATCC 15442
    Mushrooms:
    -Candida albicans ATCC 10231; and
    - Aspergillus brasiliensis ATCC 164049. 25
    Spores
    -Bacillus subtilis ATCC 6633
    The conditions and concentration of the microorganisms are those described in the standardized test protocols (European standards); and the strains were maintained according to the procedure described in EN 12353: 2013 (European Standardization Committee. EN 12353: 2013. Chemical disinfectants and antiseptics - Preservation of test organisms used for the determination of bactericidal (including Legionella), mycobactericidal, sporicidal, fungicidal and virucidal (including 35 bacteriophages) activity).
    Neutralizers:
    All neutralizers were validated for the residual antimicrobial activity of chemical disinfectants. For the immediate biocidal test, the membrane filtration procedure is used and the rinse liquid is 0.1% tryptone, 0.9% NaCl, 0.3% Na thiosulfate, 3.4% 5-dihydrogen phosphate. potassium and 0.5% polysorbate 80. The neutralizer used in the remaining biocide test is listed below:
    For chlorine derivatives (sodium hypochlorite and chlorine dioxide): 3% polysorbate 80, 3% saponin, 0.3% lecithin and 1.5% Na thiosulfate. 10
    For peracetic acid: 3% polysorbate 80, 3% saponin, 0.3% lecithin and 0.3% Na thiosulfate.
    For Caroat and hydrogen peroxide: 3% polysorbate 80, 3% saponin, 0.3% lecithin for chlorhexidine; and 3% saponin in sodium phosphate buffer. fifteen
    5.1. Immediate biocidal activity test
    5.1.1. Procedure
    twenty The procedures adopted to demonstrate immediate activity follow European standard protocols for bactericidal, fungicidal and sporicidal testing in the disinfecting conditions of medical areas and surfaces. Examples of such tests are EN 13727: 2012 (European Standardization Committee.
    EN 13727: 2012 + A1: 2014 Quantitative suspension 25 test for the evaluation of bactericidal activity in the medical area - Test method and requirements (phase 2, step 1)); EN 13624: 2013 (European Standardization Committee. EN 13624: 2013. Chemical disinfectants and antiseptics. Quantitative suspension test for the evaluation of fungicidal or yeasticidal activity in the medical area. Test method and requirements (phase 30 2, step 1) and EN 14347 : 2005, (European Standartization Committee. EN 14347: 2005. Chemical disinfectants and antiseptics. Basic sporicidal activity. Test method and requirements (phase 1, step 1 and EN 13704: 2002, (European Standartization Committee. EN 13704: 2002. Chemical disinfectants and antiseptics. Quantitative suspension test for the evaluation of sporicidal 35 activity of chemical disinfectants used in food, industrial, domestic and institutional areas. Test method and requirements (phase 2, step 1)). For all protocols, a sample of the product is added as administered and diluted with water (ready-to-use products) to a test suspension bacterium or other microorganism under clean conditions. Products will be tested at a concentration of 97% minus spores (80%). The mixture is kept at the contact temperature and time. At the end of this contact time, an aliquot is taken, and the biocidal action is immediately neutralized or suppressed (validated procedure). The number of surviving microorganisms in each dilution or sample is determined and the reduction calculated.
    10
    5.1.2. Results
    The amount of the volatile biocidal active ingredient in the external aqueous phase (W2) of the water-in-oil-in-water double emulsion (W1 / O / W2) of the present invention allows to have the effective biocidal amount of free volatile biocide in the 15 surface to be treated.
    The concentration of the free volatile biocidal active principle makes it possible to have the biocidal effect in a short contact time against the susceptible biocidal agents for each active principle. twenty
    The effective concentration of the free volatile biocidal active ingredient for each susceptible microorganism and the contact time has been defined in the state of the art (see Block SS, "Disinfection, Sterilization and Preservation", Lippincott Williams & Wilkins, 5th ed. Philadelphia, 2001, pp. 25 143-147, 187-199 and 530-531, and Zhu PC, "New Biocides Development. The combined Approach of Chemistry and Microbiology." ACS Symposium series 967. American Chemical Society, Washiton; 2007, p. 294-306 Russell et al., "Principles and Practice Disinfection, Preservation & Sterilization" Blackwell Publishing Ltd, 4th ed. Oxford (UK); 2004, pp. 32-33 These 30 effective concentrations for each free volatile biocidal active ingredient are listed below in Table 8:
    Table 8
    Volatile biocidal active ingredient Biocide effective amount Microorganism Contact time (min) Logarithm of reduction
    PHMB 0.75% S. aureus 5 ˃ 5 log
    E. hirae 5> 5 log
    P. aeruginosa 5> 5 log
    E. coli 5> 5 log
    C. albicans 5> 4 log
    Sodium hypochlorite 1000-1200 ppm S. aureus <5 ˃ 5 log
    E. hirae <5> 5 log
    P. aeruginosa <5> 5 log
    E. coli <5> 5 log
    C. albicans <5> 4 log
    Peracetic acid 0.3% S. aureus 5 ˃ 5 log
    E. hirae 5> 5 log
    P. aeruginosa 5> 5 log
    E. coli 5> 5 log
    C. albicans 5 - 10> 4 log
    B. subtilis 5 -10> 4 log
    Hydrogen peroxide 7% S. aureus 5 ˃ 5 log
    E. hirae 5> 5 log
    P. aeruginosa 5> 5 log
    E. coli 5> 5 log
    C. albicans 5> 3 log
    The number of live pathogens killed by a disinfectant is measured by the value of the decimal logarithm of reduction. A disinfectant is known to be effective against bacteria when the value of the logarithm of reduction is equal to or 5 greater than 5 (5 log reduction means reducing the number of microorganisms 100,000 times). In the case of molds, a disinfectant is considered effective when the log reduction value is equal to or greater than 4 (4 log reduction means reducing the number of fungi 10,000 times). And, in the case of bacterial spores, a disinfectant is considered effective when the value of the 10 log reduction is equal to or greater than 3 (3 log reduction means reducing the
    number of bacterial spores 1,000 times).
    5.2. Remaining biocidal activity test
    5.2.1. Remaining chip test 5
    The procedure is summarized as follows:
    The entire procedure has been carried out in a biological safety cabinet. Briefly, two hundred µl of each tested composition along with control sample (sterile distilled water) are placed in 48 sterile polystyrene microplate wells. There are 8 replicates for each sample tested and one control sample. They are left in contact for 10 minutes. After that, the product or water is removed and the microplate is dried for 20 min. The microplate is then covered and kept in the dark for the application time (24 hours). After that, 200 µl of the bacterial or fungal suspension (1.5-5x105 cfu / ml) is added to each well and incubated for 5 minutes at 37 ° C. Forty microliters of this suspension are transferred to a well of the 100-well microtiter plate containing 360 µl of tryptone soy broth (TSA) for bacteria or malt extract agar (MEA) for fungi. Bacterial or fungicidal growth is detected with a turbidimeter microplate reader. Turbidity measurement is recorded every 10 min using a 420-580 nm filter, at 37 ° C for a period of 18-24 hours for bacteria and 48 hours for fungi.
    25
    5.2.2. ASTM 2180 Test
    The procedure is summarized as follows:
    Each tested composition is spread on a stainless steel holder and 30 dried. Each composition is kept in the dark during the application time (0 and 24 h). There are 3 duplicates for each composition tested and a control sample (sterile distilled water). At the end of this time, 500 ml of the inoculated semi-solid agar suspension (bacterial, yeast and mold) (0.85% NaCl and 0.3% agar) are pipetted onto the support as a thin layer ( 1 mm of film) and is kept in the humidity chamber at 37 ° C for a contact time of 24 hours.
    Surviving microorganisms are recovered by eluting the inoculum from agar suspension. The supports are transferred to a container containing 10 ml of neutralizer. The container is then sonicated and vortexed for 1 minute at a time.
    5
    Serial ten-fold dilutions of the neutralized mixture are made in diluent (0.85% NaCl and 0.1% tryptone). A one ml sample of each dilution is spread, in duplicate, in TSA for bacterial plates or MEA for fungi and incubated for 24 hours at 37 ° C for bacteria or 48 hours at 30 ° C for fungi. 10
    Bacterial or fungal colonies (number of survivors) are counted and recorded. Finally, the percentage of bacterial / fungal reduction of treated samples versus untreated control is calculated.
    fifteen
    5.2.3. Results
    5.2.3.1. Remanent biocidal activity associated with the double water-in-oil-in-water emulsion (W1 / O / W2)
    twenty
    Table 9 shows the carryover effect of the biocidal activity of the compositions of the invention for compositions that have been freshly prepared prior to storage.
    Table 9 25
    Composition Bacteria Fungi
    S. aureus P. aeruginosa E. coli E. hirae C. albicans
    Ex. 1 + + NP NP NP
    Ex. 2 + + NP NP NP
    Ex 3 + + NP NP NP
    Ex. 4 + + + + +
    Ex. 5 + + + + +
    Ex. 6 + + + + +
    Ex. 7 + + + + +
    Ex. 8 + + + + +
    Ex. 9 + + + + +
    Composition Bacteria Fungi
    S. aureus P. aeruginosa E. coli E. hirae C. albicans
    Ex. 10 + + + + +
    Ex. 11 + + + + +
    Ex. 12 + + + + +
    Ex 13 + + + + +
    Ex. 14 + + + + +
    Ex. 15 + + + + +
    Ex. 16 + + + + +
    Ex. 17 + + + + +
    Ex. 18 + + + + +
    Ex. 19 + + + + +
    Ex. 20 + + + + +
    Comparative Example 1 - - - - -
    Comparative Example 2 - - - - -
    Comparative Example 3 - - - - -
    Comparative Ex 4 - - - - -
    NP: not tested; +: remnant effect (24 h); -: non-carryover effect.
    Table 10 shows the carryover effect of the biocidal activity of the compositions of the invention for compositions that have been stored for an extended period of time. Remaining positive biocidal activity was shown for the compositions tested after the storage period specified in the following table.
    Table 10
    Composition Storage period (month)
    S. aureus P. aeruginosa E. coli E. hirae C. albicans
    Ex. 6 7 7 7 7 7
    Ex. 15 2 2 2 2 2
    Ex. 16 6 6 6 6 2
    Ex. 17 6 6 6 6 2
    Ex. 19 2 2 2 2 2
    The results of Tables 8, 9 and 10 show that the compositions of the present invention, which comprise the double emulsion of water-in oil-in water (W1 / O / W2) defined above, allow to have a stable emulsion with biocidal activity dual immediate-remnant for a long period of time even after a long period of storage. It is shown that the specific compositions of the emulsions having the non-volatile active principle in the internal aqueous phase (W1) and the volatile active principle in the external aqueous phase (W2) are essential to have the remaining biocidal activity. 10
    6. Comparative water-in-oil-in-water double emulsion 5-8
    6.A Composition
    fifteen
    Table 11 shows the quantitative and qualitative composition of the comparative water-in-oil-in-water emulsions 5-8 outside the scope of protection of the present invention described in US patent application US20100158851 and Langmuir 2009, vol. 25 (23), pp. 13472-13480. Comparative compositions 5-8 comprise the non-volatile biocide in the inner aqueous phase rather than in the outer aqueous phase.
    These comparative compositions described below have a particle size of 560 nm.
    25
    Table 11
    6.B. Preparation procedure
    Comparative compositions 5-8 described in section 6A were prepared following the preparation procedure described in Examples 1-3 of US20100158851 and the experimental section on page 13473 of the scientific article Langmuir 2009 mentioned above.
    6C. Biocidal activity test 10
    Remaining biocidal activity test
    The remaining biocidal biological activity was determined by carrying out the remaining biocidal activity test defined in section 5.2.1. (test 15 micromethod remaining).
    Results
    Table 12 shows the remaining effect of the biocidal activity of the 20 comparative compositions 5-8 that have been between 15 and 30 days before performing the biocidal activity test.
    Table 12
    25
    Composition Fungus bacteria
    S. aureus p.aeruginosa E. coli E. hirae C. albicans
    Ex. 5 Comparative - - - - -
    Ex. 6 Comparative - - - - -
    Ex. 7 Comparative - - - - -
    Ex. 8 Comparative - - - - -
    +: remnant effect (24h); -: no carryover effect
    The results in Table 12 show that comparative compositions 5-8, comprising the double water-in-oil-in-water emulsion (W1 / O / W2) having the non-volatile biocide in the internal aqueous phase defined above do not it has a remaining biocidal activity. Therefore, it is shown that the specific compositions of the emulsions having the non-volatile active ingredient in the internal aqueous phase (W1) and the volatile active ingredient in the external aqueous phase are essential to have the remaining biocidal activity.
    10
    权利要求:
    Claims (14)
    [1]

    1. Double water-in-oil-in-water emulsion (W1 / O / W2) comprising:
    (a) an internal aqueous phase (W1) comprising: 5
    (a1) one or more non-volatile biocidal active ingredients;
    (a2) one or more lipophilic surfactants; and
    (a3) water;
    (b) an oil phase intermediate (O) between the internal aqueous phase (W1) and the external aqueous phase (W2) comprising one or more oil compounds; and
    (c) an external aqueous phase (W2) comprising:
    (c1) one or more volatile biocidal active ingredients;
    (c2) one or more hydrophilic surfactants; and 15
    (c3) water;
    in which:
    the amount of non-volatile biocidal active principle is comprised from 0.4 to 3% by weight of the total weight of the double emulsion;
    the amount of volatile biocidal active principle is comprised from 0.3 to 40% by weight of the total weight of the double emulsion;
    25
    the amount of intermediate oil phase (O) (b) is comprised from 2.5 to 30% by weight of the total weight of the double emulsion; and
    the mean particle size of the emulsion (W1 / O) ranges from 50 nm to 300 nm. 30

    [2]
    The double water-in-oil-in-water emulsion according to claim 1, comprising:
    (a) from 5 to 30% by weight of the internal aqueous phase (W1) comprising, in relation to the total weight of the double emulsion: 35
    (a1) from 0.4 to 8% by weight of one or more non-volatile biocidal active ingredients;
    (a2) from 0.125 to 0.5% by weight of one or more lipophilic surfactants; and
    (a3) from 3.8 to 21.5% water;
    (b) from 2.5 to 30% by weight of the intermediate oil phase (O) in relation to the total weight of the double emulsion; and 5
    (c) from 40 to 87% by weight of the external aqueous phase (W2) comprising, in relation to the total weight of the double emulsion:
    (c1) from 0.3 to 10% by weight of one or more volatile biocidal active ingredients; 10
    (c2) from 2 to 8% by weight of one or more hydrophilic surfactants; and
    (c3) from 37 to 81% by weight of water;
    the sum of the weight of the phases of the emulsion being 100%.
    fifteen
    [3]
    The water-in-oil-in-water double emulsion according to any of claims 1-2, wherein the volatile biocidal active ingredient is selected from the group consisting of oxygen releasing compound, hypohalide salt, and mixture of the same.
    twenty
    [4]
    4. The water-in-oil-in-water emulsion according to any of claims 1-3, wherein the non-volatile biocidal active ingredient is selected from the group consisting of biguanides, tertiary amines, ethanolamines, quaternary ammonium compounds and mixture thereof.
    25
    [5]
    The water-in-oil-in-water double emulsion according to any of claims 1-4, wherein the hydrophilic surfactant is selected from the group consisting of block copolymers of ethylene glycol and propylene glycol having an HLB value equal to or greater than 10, polyethylene glycol-20-sorbitan monostearate, polyethylene glycol-4-sorbitan monostearate, 30 polyethylene glycol-20-sorbitan monopalmitate, polyethylene glycol-20-sorbitan monostearate, polyethylene glycol-4-sorbitan monostearate, polyethylene glycol-4-sorbitan monostearate, polyethylene glycol-20 triesarate sorbitan, PEG-20-sorbitan monooleate, and 4-octylphenol polyethoxylate.
    35
    [6]
    6. The water-in-oil-in-water double emulsion according to any of claims 1-5, wherein the lipophilic surfactant is selected from the group
    consisting of ethylene glycol and propylene glycol block copolymers having an HLB value of less than 10, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, and sorbitan isostearate.
    5
    [7]
    7. The water-in-oil-in-water double emulsion according to any of claims 1-6, wherein the oil compound of the oil phase is selected from the group consisting of essential oils and fatty acid esters.
    10
    [8]
    8. The double water-in-oil-in-water emulsion according to any of claims 1-7, wherein the amount of non-volatile biocidal active ingredient released from the internal aqueous phase is less than 15% by weight of the total weight of the double emulsion.
    fifteen
    [9]
    The double water-in-oil-in-water emulsion according to claim 8, wherein the amount of non-volatile biocidal active ingredient released from the internal aqueous phase is compressed from 0.5 to 1% by weight.

    [10]
    10. A process for the preparation of the water-in-oil-in-water double emulsion as defined in any of claims 1-9 comprising:
    to. Mix one or more compounds (O) and one or more non-volatile biocidal active ingredients to obtain a mixture; 25
    b. Adding a solution of one or more lipophilic surfactants in water to the mixture obtained in step (a) to obtain a water-in-oil emulsion (W1 / O) with an average particle size ranging from 5 µm to 20 µm;
    c. Reduce the particle size of the water-in-oil emulsion obtained in step (b) to obtain a water-in-oil emulsion having a particle size comprised from 50 nm to 300 nm.
    d. Disperse the water-in-oil emulsion (W1 / O) obtained in step (c) in a mixture of the volatile biocidal active ingredient and one or more of the hydrophilic surfactant in water (W2) to obtain a water-in-oil emulsion -in water (W1 / O / W2).
    [11]
    11. A composition comprising the water-in-oil-in-water double emulsion as defined in any of claims 1-9 together with one or more appropriate excipients or carriers.

    [12]
    The composition according to claim 11, further comprising one or 5 more additional active compounds selected from the group consisting of cleaning compounds and disinfectant compounds.

    [13]
    13. Use of the double water-in-oil-in-water emulsion as defined in any of claims 1-9, as a biocidal compound. 10

    [14]
    14. Use of the water-in-oil according to claim 13, as a disinfectant.
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    同族专利:
    公开号 | 公开日
    EP3028568A1|2016-06-08|
    ES2642671B1|2018-11-13|
    ES2642671R1|2018-02-01|
    WO2016087630A1|2016-06-09|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB0009735D0|2000-04-19|2000-06-07|Zeneca Ltd|Formulation|
    US20100004124A1|2006-12-05|2010-01-07|David Taft|Systems and methods for delivery of materials for agriculture and aquaculture|
    DE102007044916A1|2007-09-19|2009-04-23|Bionorica Ag|Cosmetic or dermatological composition for topical use|
    US8741325B2|2008-12-18|2014-06-03|The Hong Kong University Of Science And Technology|Material for forming a multi-level antimicrobial surface coating and its preparation|CN111032060A|2017-06-28|2020-04-17|科利迪恩公司|Compositions, methods and uses for cleaning, disinfecting and/or sterilizing|
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    优先权:
    申请号 | 申请日 | 专利标题
    EP14382498.5A|EP3028568A1|2014-12-05|2014-12-05|Biocidal composition with dual inmediate and remnant activity|
    EP14382498|2014-12-05|
    PCT/EP2015/078622|WO2016087630A1|2014-12-05|2015-12-04|Biocidal composition with dual inmediate and remnant activity|
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