Medetomidine-containing particles and uses thereof

Abstract

Solid particles comprising a coprecipitate of a metal or metalloid compound with medetomidine or an enantiomer or salt of medetomidine, antifouling and antifouling paint formulations containing such particles, antifouling coatings obtained by use of the paint formulations, and objects having a coating on at least a portion of their surface. Methods for preparing the particles and formulations.

Description

[Technical Field]

[0001] The present invention relates generally to novel medetomidine-containing products useful as antifouling agents, methods for preparing such products, and the use of such products as additives, for example, in marine paints. [Background technology]

[0002] Biofouling is a natural process involving the accumulation and growth of microorganisms, algae, plants, and small animals on any natural or artificial wet surface, often resulting in serious economic harm to marine and other aquatic industries. For example, the attachment of organisms such as barnacles, algae, and tubeworms to a ship's hull requires regular cleaning, resulting in reduced fuel efficiency and lost useful time. Meanwhile, the attachment of such organisms to cooling water systems reduces thermal conductivity, ultimately reducing the cooling power of the system and increasing costs. Significant problems with marine biofouling also exist in facilities such as aquaculture equipment, marine sensors, marine renewable energy and floating equipment, and offshore oil and gas facilities.

[0003] To combat biofouling, antifouling strategies have been devised, including various types of antifouling paints and coatings. Biocidal antifouling paints are paint coatings that repel biofouling organisms by forming a bioactive boundary layer in the immediate vicinity of the coated surface. One type of antifouling paint is biocide-releasing antifouling paint, which can be broadly classified into three main categories: contact leaching coatings, controlled depletion polymer (CDP) coatings, and self-polishing copolymer (SPC) coatings, all of which are based on the controlled, sustained release of bioactive molecules incorporated into a polymer matrix.

[0004] Contact leaching coatings rely on a high-molecular-weight polymer matrix that is insoluble in seawater and is made from polymers such as acrylic, epoxy, vinyl polymers, or chlorinated rubber polymers. Bioactive compounds present in the matrix are released into the surrounding environment, forming pores that allow water to permeate the coating, thereby dissolving more of the bioactive compounds. CDP coatings are soluble matrix paints containing a biocide mixed with a water-soluble binder. These paints are typically formulated using a blend of relatively fast-dissolving natural rosin and slower-dissolving synthetic organic resins, which control the hydration and dissolution of the soluble binder. When water passes through the surface of the coating, the soluble binder and the incorporated biocide dissolve and are released together. SPC coatings are based on polymer binders to which leaving group moieties are chemically bonded, and the leaving group bonds to the polymer backbone are gradually hydrolyzed by water, thereby washing away or eroding the water-soluble or water-dispersible polymer matrix at the surface of the coating layer. An example of a self-polishing antifouling paint system is a silyl ester copolymer-based paint.

[0005] There are also antifouling coatings, so-called Foul Release Coatings (FRCs), that do not essentially function by releasing biocides, but function primarily by providing a low-friction, ultra-smooth surface that prevents the attachment of biofouling and promotes the detachment of attached biofouling from the surface under the shear flows caused by the movement of the ship. These types of coatings are primarily based on fluoropolymers and silicon.

[0006] A variety of compounds are known in the prior art as active biocides in antifouling formulations, including, for example, copper(I) oxide, copper(I) thiocyanate, copper(II) pyrithione, zinc(II) pyrithione, DCOIT (4,5-dichloro-2-n-octyl-4-isothiazolin-3-one), tralopyril (4-bromo-2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile), and zineb (zinc ethane-1,2-diylbis(dithiocarbamate)). In many cases, antifouling paint formulations contain more than one of these biocides, for example, two, three, or four biocidal compounds are used in combination. Nominal bactericidal concentrations (mean ± standard deviation) in antifouling paint formulations have been reported, for example, as 35.9 ± 12.8% w / w for copper(I) oxide and 18.1 ± 8.02% w / w for copper(I) thiocyanate.

[0007] A further biocidal compound effective against barnacle biofouling on marine surfaces is the compound medetomidine, which has the chemical name (±)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (or (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, also known as RS)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole). Medetomidine is an alpha(2)-adrenergic receptor agonist and has been found to inhibit the settling process of barnacle larvae, making it useful as an antifouling agent in paint formulations.

[0008] Generally, the most established method for formulating antifouling paints containing medetomidine is to add it to the wet paint as a dry powder or as a solution with a solvent. In this method, medetomidine is preferably added early in the paint manufacturing process, when there is a high probability that medetomidine will adsorb to the surface of any other paint components, such as pigments. Later in the process, most potential adsorption sites for medetomidine are already occupied by other molecules, at which point the probability that medetomidine will adsorb to anything is low, and therefore the compound remains largely free in the wet paint.

[0009] However, if medetomidine is not adsorbed onto any carrier, there is a high risk that medetomidine will leach out of the paint matrix more rapidly than would be desirable, and therefore only provide short-term contamination protection. Furthermore, free medetomidine can lead to a decrease in the in-can stability of wet paints. Indeed, free organic biocides such as medetomidine can promote an increase in viscosity (gelation) of paint binders that have ester and / or silyl ester functional groups as part of the polymer chain, which not only shortens shelf life but can also affect the self-polishing and antifouling performance of the paint system.

[0010] One prior art method for controlling the release rate of medetomidine from a dried coating is described in U.S. Patent No. 7,311,766, in which pre-formed nanoparticles of various common paint pigments are added to a medetomidine / o-xylene solution to adsorb medetomidine onto the surface of the nanoparticles, and the nanoparticles with adsorbed medetomidine can then be mixed with other paint ingredients to provide a paint formulation with long-term antifouling efficacy.

[0011] There remains a need for marine antifouling additives that are easy to manufacture and provide high and long-term antifouling efficacy. There is also a need for antifouling paint formulations that have suitable in-can stability (shelf life) and that, when added to a paint formulation, do not unduly shorten its shelf life. In particular, it would be a great advantage to provide a paint formulation that has sufficient in-can stability and can provide long-term antifouling efficacy against, for example, barnacle attachment, when applied as a coating to a surface in a marine environment. Summary of the Invention

[0012] The first aspect is (i) a metal or semimetal compound; (ii) Particles comprising a coprecipitate of medetomidine or an enantiomer or salt of medetomidine.

[0013] A further embodiment is a method for preparing solid particles containing medetomidine or an enantiomer or salt of medetomidine by co-precipitation of (i) a metal or metalloid compound and (ii) medetomidine or an enantiomer or salt of medetomidine.

[0014] The medetomidine formulations provided herein differ from those disclosed in U.S. Patent No. 7,311,766, which describes pre-formed pigment particles having a biocide adsorbed to the surface. In contrast, the present invention herein relates to particles having medetomidine incorporated within the particle matrix.

[0015] The prepared medetomidine-containing particles can be added as an antifouling additive to any type of paint formulation, such as a silicon-based FRC formulation and / or a silyl acrylate-based SPC formulation. Due to the biological effect of medetomidine, the particles of the present invention can be used, in particular, against barnacle fouling of any solid surface that comes into contact with an aquatic environment where barnacles can grow (e.g., in seawater).

[0016] A still further aspect is an antifouling additive comprising a particle as defined herein or prepared by the methods disclosed herein, and optionally a liquid carrier.

[0017] Because the majority of medetomidine remains within the particles, the antifouling additive of the present invention, when added to a wet paint, limits the concentration of free medetomidine molecules in the wet paint. This reduces the possibility of undesirable interactions and / or reactions between free medetomidine and other paint components, thereby improving the shelf life and self-polishing and antifouling performance of the paint system. Furthermore, binders having ester and / or silyl ester functional groups can be combined with the medetomidine-containing particles of the present invention to improve the in-can stability of wet paint formulations.

[0018] A still further aspect is an antifouling coating composition comprising particles disclosed herein or prepared by the methods defined herein and a surface coating material.

[0019] A further aspect is an antifouling coating composition comprising an antifouling additive as defined herein or prepared by the methods disclosed herein, and a surface coating material.

[0020] A still further aspect is an antifouling coating film formed from the antifouling paint disclosed herein.

[0021] A further aspect is a method of preventing marine biofouling of a surface by applying an antifouling coating formulation to or near the surface.

[0022] A further aspect is an object, such as a ship, boat, marine sensor, floating device, buoy, fish cage, etc., having on at least a portion of its surface an antifouling coating according to the present invention.

[0023] The use of the medetomidine formulations of the present invention provides a reduced leaching rate of medetomidine from the coating matrix, which correlates with long-lasting barnacle protection of the coating surface. This effect is particularly important for silicon-based FRCs. Thus, the present invention further includes novel methods for improving the protective effect of FRCs and other types of antifouling coatings against barnacle attachment.

[0024] Further aspects and embodiments, as well as advantages associated with the present invention, will become apparent from the following detailed description and are illustrated by the non-limiting examples provided herein. [Brief explanation of the drawings]

[0025] [Figure 1]Photographs of silicon-based foul release coatings (FRCs) after 71 days of immersion in seawater in Tjarno, Sweden. Top area: undamaged; middle area: cross-cut with knife; bottom area: roughened with sandpaper. Left to right: 0.1% medetomidine added as a solution, 0.1% medetomidine incorporated in zinc(II) oxide (ZnO), and 0.1% medetomidine incorporated in copper(II) pyrithione (CuPT).

[0026] [Figure 2] 1 is a graph showing the viscosity of the silyl acrylate-based coating formulations of Example 4 as a function of time, i.e., formulations A (-), B (□), C (×), D (Δ), E (●), F (Ψ), G (○), and H (◆). The medetomidine concentration in formulations B, C, E, and G was 0.3 wt %. The other samples did not contain medetomidine.

[0027] [Figure 3] 1 is a graph showing the viscosity as a function of time for the silyl acrylate-based coating formulations of Example 5, i.e., the formulations are Formulation I (-), J (□), K (●), L (◇), M (◆), N (Ψ), and O (■). The medetomidine concentration in Formulation J, Formulation K, Formulation L, Formulation M, Formulation N, and Formulation O was 0.3 wt %. Formulation I did not contain medetomidine. BEST MODE FOR CARRYING OUT THE INVENTION

[0028] It is understood that the invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0029] Those skilled in the art should understand that the terminology used in the description herein is for the purpose of describing particular embodiments only, and is not intended to be limiting of the invention. Unless otherwise defined, all terms, including technical and scientific terms, used herein have the same meaning as generally understood by one of ordinary skill in the art to which this invention belongs.

[0030] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly dictates otherwise. Such references may therefore be replaced with a reference to "one or more," e.g., one, of the associated components or integers. As used herein, all references to "one or more" of a particular component or integer will be understood to refer to one to a plurality, e.g., two, three, or four, of such components or integers. References to "one or more" of a particular component or integer will be understood to include a specific reference to one such integer.

[0031] As used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items.

[0032] As used herein, the term "about," when referring to a measurable value, such as an amount of a compound, a dosage, a time, a temperature, and the like, refers to a variation of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the particular amount. When a range is used, e.g., a range from x to y, it means that the measurable value is in the range from about x to about y, or any range or value therein, inclusive of x and y. It will be further understood that the terms "comprises" and / or "comprising," as well as similar expressions such as "contains," "includes," "containing," and the like, when used herein, unless otherwise specified or clear from the context, specify the presence of stated features, integers, steps, operations, elements, components, and / or groups, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0033] As used herein, "surface coating material" or "coating material" or similar expressions refer to a material or compound or composition that adheres to a surface to provide a coating thereon. Surface coating materials are known in the art of paints.

[0034] As used herein, "effective," for example, with respect to the amount of a compound, composition and / or formulation, means sufficient to produce a desired effect.

[0035] All patents, patent applications, and publications mentioned herein are incorporated by reference in their entirety. In the event of a conflict of terminology, the present specification will control unless the context clearly dictates otherwise.

[0036] The present embodiment relates to particles with medetomidine incorporated therein. This differs from the teachings of U.S. Patent No. 7,311,766, which describes pre-formed pigment particles with a biocide adsorbed on the surface. In contrast, the present invention relates to particles with a biocide incorporated within the particle matrix.

[0037] The present invention is based on the use of medetomidine, or an enantiomer or salt thereof, as a biocide present in the matrix of solid particles, such as pigment particles.

[0038] As used herein, the term medetomidine refers to the compound having the structural formula (±)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (which may also be referred to as, for example, (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, or (RS)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole).

[0039] [ka]

[0040] Unless otherwise stated or clear from the context, the term medetomidine also includes salts thereof, or its enantiomers, or salts of its enantiomers.

[0041] Medetomidine-containing particles In a first embodiment, the solid particles are (i) a metal compound or a metalloid compound (“component (i)”); (ii) Co-precipitates with medetomidine or an enantiomer or salt of medetomidine.

[0042] The metal of component (i) may be, for example, a metal capable of forming a multivalent salt or oxide, and is selected from alkaline earth metals and transition metals, such as Mg, Ca, Ba, Ti, Fe, Cu, Zn, and Al.

[0043] Metalloids are chemical elements that have physical and chemical properties that are between those of chemical elements defined as metals and nonmetals. The metalloid of component (i) may be, for example, Si. Preferably, component (i) is not excessively toxic to the environment at use levels.

[0044] The metal or semi-metal compound may be, for example, an oxide, a salt, or a coordination complex, such as an oxide, pyrithione, thiocyanate, sulfate, carboxylate, or carbonate.

[0045] In some embodiments, component (i) is a metal compound, such as a metal oxide, metal salt, or metal coordination complex, such as a metal oxide, metal pyrithione, metal thiocyanate, metal sulfate, metal carboxylate, or metal carbonate.

[0046] Non-limiting examples of metal and metalloid compounds for use herein include: zinc (II) oxide, iron (II) oxide, iron (III) oxide, copper (I) oxide, copper (II) oxide, titanium (IV) oxide, silicon (IV) oxide, copper (II) pyrithione, zinc (II) pyrithione, copper (I) thiocyanate, barium (II) sulfate, calcium (II) sulfate, magnesium (II) carbonate, calcium (II) carbonate, barium (II) carbonate, iron (II) carbonate, zinc (II) carbonate, and / or metal salts of C2 to C24 carboxylic acids.

[0047] In some embodiments, metal and metalloid compounds for use herein include zinc (II) oxide, iron (II) oxide, iron (III) oxide, copper (I) oxide, copper (II) oxide, titanium (IV) oxide, copper (II) pyrithione, zinc (II) pyrithione, copper (I) thiocyanate, calcium (II) sulfate, barium (II) sulfate, barium (II) oxalate, magnesium (II) carbonate, calcium (II) carbonate, barium (II) carbonate, iron (II) carbonate, zinc (II) carbonate, and / or silicon (IV) oxide.

[0048] In some embodiments, the metal or semi-metal compound is more specifically a metal compound selected from zinc(II) oxide, copper(I) oxide, copper(II) pyrithione, and barium(II) sulfate.

[0049] In some embodiments, the metal compound is a metal oxide, such as those exemplified hereinabove. In some embodiments, component (i) is a polyvalent metal oxide, such as copper(II) oxide (CuO) or a divalent metal oxide, such as zinc(II) oxide (ZnO).

[0050] In some embodiments, the metal oxide is copper(I) oxide or copper(II) oxide. In some embodiments, the metal oxide is copper(I) oxide.

[0051] In some embodiments, component (i) is a metal salt, such as a metal salt exemplified herein. In some embodiments, when the metal compound is a metal salt, the metal salt is selected from polyvalent metal salts such as CuPT and barium(II) sulfate (BaSO). In some embodiments, when the metal compound is a metal salt, the metal salt is CuPT. In some other embodiments, when the metal compound is a metal salt, the metal salt is BaSO.

[0052] In some embodiments, the metal compound is selected from CuPT, ZnO, and BaSO4.

[0053] In some embodiments, the metal compound is a metal pyrithione, such as zinc(II) pyrithione (ZnPT) or CuPT. In CuPT and ZnPT, a divalent metal (Cu(II) or Zn(II)) and two 2-thioxopyridine-1(2H)-oleate moieties, respectively, are represented by the formula

[0054] [ka] where M represents Zn or Cu.

[0055] Although referred to herein as metal salts, pyrithiones may also be referred to as metal coordination complexes or compounds, and have the formula

[0056] [ka] where M represents either Zn or Cu.

[0057] Thus, in the present context, reference to metal salts may also include metal coordination complexes, ie component (i) may be selected from metal oxides, metal salts, and metal coordination complexes.

[0058] In some embodiments, the metal compound for use herein is copper(I) thiocyanate, sometimes referred to as copper(I) thiocyanate, which is a coordination polymer with the chemical formula CuSCN.

[0059] Other types of metal salts include salts with carboxylic acids, such as C2 to C24 carboxylic acids, e.g., C2 to C20 carboxylic acids, C2 to C16 carboxylic acids, C2 to C12 carboxylic acids, C2 to C8 carboxylic acids, or C2 to C6 carboxylic acids, including monocarboxylic and polycarboxylic acids, such as monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids, e.g., oxalic acid.

[0060] In some embodiments, component (i) may have biocidal activity itself, which may act to enhance the overall antifouling effect of medetomidine.

[0061] By co-precipitating with medetomidine, component (i) forms a matrix in which medetomidine is included. Component (i) is preferably somewhat water-soluble so that it dissolves over time when immersed in water, e.g., seawater. As the matrix formed by component (i) dissolves, the incorporated medetomidine is gradually exposed to water, and medetomidine is released as the matrix containing it dissolves. The released medetomidine thereby becomes available at and / or near the surface of the antifouling coating of the present invention, preventing or at least significantly reducing barnacle attachment and growth on the coated surface and on surfaces near the coating.

[0062] The metal or metalloid compound forming the medetomidine-containing matrix preferably has low water solubility. In particular, the water solubility of the compound is preferably such that the compound can be prepared by precipitation in water and / or other polar solvents and / or mixtures of water and other polar solvents. It is also preferred that the water solubility be such that, upon contact with water, dissolution of the matrix proceeds slowly over time, resulting in medetomidine being released from the coating over its entire lifespan. It should be understood that the total release of medetomidine from the coating also depends on other factors, such as the permeability of water through the coating, the rate of abrasion of the coating surface, and / or erosion of the coating surface. Coatings containing medetomidine-containing particles must allow some water to contact the particles to allow dissolution of the particle matrix and release of medetomidine.

[0063] If the aqueous solubility of the matrix formed by component (i) is higher than desired, the matrix may dissolve too quickly when the coating is submerged in water. This increases the exposure of medetomidine to water, thereby increasing the rate at which medetomidine leaches out of the coating. Thus, a high aqueous solubility of component (i) carries the risk of premature medetomidine depletion when the coating is submerged in water. Thus, the metal or metalloid compounds (including salts, coordination compounds and complex compounds, or oxides) used in accordance with the present invention preferably have low water solubility, at most 150 mg / L, at most 125 mg / L, at most 100 mg / L, at most 75 mg / L, at most 50 mg / L, at most 40 mg / L, at most 30 mg / L, at most 25 mg / L, at most 20 mg / L, at most 15 mg / L, at most 10 mg / L, at most 8 mg / L, at most 5 mg / L, at most 4 mg / L, at most 3 mg / L, at most 2 mg / L, or at most 1 mg / L (equilibrium solubility measured at pH 7 and 20°C).

[0064] Preferably, the water solubility of component (i) is not too low, as this may result in a too low medetomidine leaching rate, which may affect antifouling efficiency. Thus, the metal or metalloid compounds used in accordance with the present invention preferably have an aqueous solubility (equilibrium solubility measured at pH 7 and 20°C) of at least 0.01 mg / L, at least 0.02 mg / L, at least 0.05 mg / L, at least 0.08 mg / L, at least 0.1 mg / L, at least 0.2 mg / L, at least 0.3 mg / L, at least 0.4 mg / L, at least 0.5 mg / L, at least 0.6 mg / L, at least 0.7 mg / L, at least 0.8 mg / L, at least 0.9 mg / L, or at least 1 mg / L.

[0065] In some embodiments, component (i) has a water solubility in the range of 0.01 mg / L to 150 mg / L, e.g., 0.01 mg / L to 125 mg / L, 0.01 mg / L to 100 mg / L, 0.01 mg / L to 75 mg / L, 0.01 mg / L to 50 mg / L, 0.01 mg / L to 40 mg / L, 0.01 mg / L to 30 mg / L, 0.01 mg / L to 25 mg / L, 0.01 mg / L to 20 mg / L, 0.01 mg / L to 15 mg / L, 0.01 mg / L to 10 mg / L, 0.01 mg / L to 8 mg / L, or 0.01 mg / L to 5 mg / L.

[0066] In some embodiments, component (i) has a water solubility in the range of 0.02 mg / L to 150 mg / L, e.g., 0.02 mg / L to 125 mg / L, 0.02 mg / L to 100 mg / L, 0.02 mg / L to 75 mg / L, 0.02 mg / L to 50 mg / L, 0.02 mg / L to 40 mg / L, 0.02 mg / L to 30 mg / L, 0.02 mg / L to 25 mg / L, 0.02 mg / L to 20 mg / L, 0.02 mg / L to 15 mg / L, 0.02 mg / L to 10 mg / L, 0.02 mg / L to 8 mg / L, or 0.02 mg / L to 5 mg / L.

[0067] In some embodiments, component (i) has a water solubility in the range of 0.05 mg / L to 150 mg / L, e.g., 0.05 mg / L to 125 mg / L, 0.05 mg / L to 100 mg / L, 0.05 mg / L to 75 mg / L, 0.05 mg / L to 50 mg / L, 0.05 mg / L to 40 mg / L, 0.05 mg / L to 30 mg / L, 0.05 mg / L to 25 mg / L, 0.05 mg / L to 20 mg / L, 0.05 mg / L to 15 mg / L, 0.05 mg / L to 10 mg / L, 0.05 mg / L to 8 mg / L, or 0.05 mg / L to 5 mg / L.

[0068] In some embodiments, component (i) has a water solubility in the range of 0.08 mg / L to 150 mg / L, e.g., 0.08 mg / L to 125 mg / L, 0.08 mg / L to 100 mg / L, 0.08 mg / L to 75 mg / L, 0.08 mg / L to 50 mg / L, 0.08 mg / L to 40 mg / L, 0.08 mg / L to 30 mg / L, 0.08 mg / L to 25 mg / L, 0.08 mg / L to 20 mg / L, 0.08 mg / L to 15 mg / L, 0.08 mg / L to 10 mg / L, 0.08 mg / L to 8 mg / L, or 0.08 mg / L to 5 mg / L.

[0069] In some embodiments, component (i) has a water solubility in the range of 0.1 mg / L to 150 mg / L, e.g., 0.1 mg / L to 125 mg / L, 0.1 mg / L to 100 mg / L, 0.1 mg / L to 75 mg / L, 0.1 mg / L to 50 mg / L, 0.1 mg / L to 40 mg / L, 0.1 mg / L to 30 mg / L, 0.1 mg / L to 25 mg / L, 0.1 mg / L to 20 mg / L, 0.1 mg / L to 15 mg / L, 0.1 mg / L to 10 mg / L, 0.1 mg / L to 8 mg / L, or 0.1 mg / L to 5 mg / L.

[0070] In some embodiments, component (i) has a water solubility in the range of 0.2 mg / L to 150 mg / L, e.g., 0.2 mg / L to 125 mg / L, 0.2 mg / L to 100 mg / L, 0.2 mg / L to 75 mg / L, 0.2 mg / L to 50 mg / L, 0.2 mg / L to 40 mg / L, 0.2 mg / L to 30 mg / L, 0.2 mg / L to 25 mg / L, 0.2 mg / L to 20 mg / L, 0.2 mg / L to 15 mg / L, 0.2 mg / L to 10 mg / L, 0.2 mg / L to 8 mg / L, or 0.2 mg / L to 5 mg / L.

[0071] In some embodiments, component (i) has a water solubility in the range of 0.5 mg / L to 150 mg / L, e.g., 0.5 mg / L to 125 mg / L, 0.5 mg / L to 100 mg / L, 0.5 mg / L to 75 mg / L, 0.5 mg / L to 50 mg / L, 0.5 mg / L to 40 mg / L, 0.5 mg / L to 30 mg / L, 0.5 mg / L to 25 mg / L, 0.5 mg / L to 20 mg / L, 0.5 mg / L to 15 mg / L, 0.5 mg / L to 10 mg / L, 0.5 mg / L to 8 mg / L, or 0.5 mg / L to 5 mg / L.

[0072] In some embodiments, component (i) has a water solubility in the range of 0.8 mg / L to 150 mg / L, e.g., 0.8 mg / L to 125 mg / L, 0.8 mg / L to 100 mg / L, 0.8 mg / L to 75 mg / L, 0.8 mg / L to 50 mg / L, 0.8 mg / L to 40 mg / L, 0.8 mg / L to 30 mg / L, 0.8 mg / L to 25 mg / L, 0.8 mg / L to 20 mg / L, 0.8 mg / L to 15 mg / L, 0.8 mg / L to 10 mg / L, 0.8 mg / L to 8 mg / L, or 0.8 mg / L to 5 mg / L.

[0073] In some embodiments, component (i) has a water solubility in the range of 1 mg / L to 150 mg / L, e.g., 1 mg / L to 125 mg / L, 1 mg / L to 100 mg / L, 1 mg / L to 75 mg / L, 1 mg / L to 50 mg / L, 1 mg / L to 40 mg / L, 1 mg / L to 30 mg / L, 1 mg / L to 25 mg / L, 1 mg / L to 20 mg / L, 1 mg / L to 15 mg / L, 1 mg / L to 10 mg / L, 1 mg / L to 8 mg / L, or 1 mg / L to 5 mg / L.

[0074] As used herein, "water solubility" refers to equilibrium water solubility. For example, the (equilibrium) water solubility of CuPT is less than 0.039 mg / L, the water solubility of ZnO is 1.6 mg / L, and the water solubility of BaSO is 2.5 mg / L.

[0075] The medetomidine content of the medetomidine-containing particles is preferably in the range of 1 to 50% by weight of the particles, e.g., 1 to 40%, 1 to 30%, 1 to 25%, 1 to 20%, or 1 to 15% by weight. In some embodiments, the medetomidine content is in the range of 2 to 50% by weight of the particles, e.g., 2 to 40%, 2 to 30%, 2 to 25%, 2 to 20%, or 2 to 15% by weight. In some embodiments, the medetomidine content is in the range of 5 to 50% by weight of the particles, e.g., 5 to 40%, 5 to 30%, 5 to 25%, 5 to 20%, or 5 to 15% by weight.

[0076] The size of the medetomidine-containing particles may range from nm size to μm size or larger, for example, the average particle diameter may be within the range of about 5 nm to about 500 μm, e.g., about 10 nm to about 100 μm, about 50 nm to about 50 μm, or about 100 nm to about 10 μm, e.g., about 500 nm to about 5 μm.

[0077] In some embodiments, the metal compound of the medetomidine-containing particles is a compound useful as a pigment, in which case the medetomidine-containing particles may be referred to as medetomidine-containing pigment particles.

[0078] As described herein, medetomidine may be used in its free base form or as a salt, for example, an acid addition salt, for example, a salt with a strong mineral acid, such as HCl.

[0079] Method for producing medetomidine-containing particles Also provided herein is a method for preparing particles containing medetomidine or an enantiomer or salt of medetomidine by co-precipitation of (i) a metal or metalloid compound ("component (i)") with (ii) medetomidine or an enantiomer or salt of medetomidine (which may also be collectively referred to herein as "medetomidine"). The resulting particles comprise a co-precipitate of medetomidine and component (i), the latter forming a "matrix" containing medetomidine.

[0080] Co-precipitation of component (i) and medetomidine can be achieved by preparing a solution of the two components under conditions in which both components form a solution, and then changing the conditions, for example, changing the solvent system, solution pH, or solution temperature, to precipitate the components and form a coprecipitate of component (i) and medetomidine.

[0081] In some embodiments, component (i) is a metal compound described herein.

[0082] In some embodiments, a matrix of medetomidine may be prepared by mixing two solutions of different soluble precursor compounds, e.g., precursor salts, to form a less soluble ion pair that precipitates to form the matrix, and medetomidine may be incorporated into the pigment matrix by co-precipitation of component (i) with medetomidine.

[0083] Co-precipitation can be achieved by dissolving medetomidine together with one or both of the precursor compounds, or by mixing a solution of medetomidine with one or both of the precursor compound solutions to co-precipitate medetomidine with matrix-forming component (i).

[0084] Thus, in some embodiments, a method for preparing solid particles comprising a co-precipitate of (i) a metal or metalloid compound as defined herein and (ii) medetomidine or an enantiomer or salt of medetomidine comprises: - mixing two liquid phase solutions of the different salts in the presence of medetomidine or an enantiomer or salt of medetomidine to form a metal or metalloid compound that has a lower solubility in the liquid phase than either of the different salts; - co-precipitating said metal or metalloid compound and said medetomidine or medetomidine enantiomer or salt from the resulting liquid mixture.

[0085] In some embodiments, medetomidine or an enantiomer or salt of medetomidine is mixed with at least one of the liquid phase solutions prior to mixing the solutions. In some embodiments, the required amount of medetomidine is dissolved in a suitable liquid solvent or solvent mixture, for example, an organic solvent or solvent mixture such as xylene, ethanol, methanol, and / or 1-methoxy-2-propanol and / or water, and the medetomidine-containing solution is mixed with at least one of the liquid phase solutions prior to mixing and co-precipitation.

[0086] The solvent used for precipitation is preferably a polar solvent or a mixture of several polar solvents. Preferably, water and / or other polar solvents are used, such as, but not limited to, methanol, ethanol, and / or 1-methoxy-2-propanol. The type and / or blend of solvents, pH, and / or temperature may be adjusted to optimize the solubility of the components used for co-precipitation. In some embodiments, precipitation is carried out in an aqueous phase, for example, in water.

[0087] It is believed to be well within the knowledge of one skilled in the art to select suitable components and reaction conditions to form and precipitate the desired metal or metalloid compound. Information on suitable reactants and reaction conditions can be found in various texts, for example: Reece H. Vallance, Douglas F. Twiss, and Miss Annie R. Russell (1931). J. Newton Friend (ed.). Textbook of Inorganic Chemistry. Charles Griffin & Company Ltd.

[0088] For example, to obtain a desired metal oxide, a solution of a soluble salt of the metal of that oxide can be mixed with a solution of a strong base, such as aqueous NaOH. Similarly, to obtain a desired metal sulfate, a solution of a soluble salt of the metal of that sulfate can be mixed with a solution of a soluble sulfate, such as an aqueous solution of Na2SO4. To obtain a desired metal pyrithione, a solution of a soluble salt of the metal can be mixed with a solution of a soluble metal pyrithione, such as sodium pyrithione.

[0089] The precipitated medetomidine-containing particles may be separated from the solvent using any suitable separation method, such as, for example, filtration, vacuum filtration, sedimentation, decantation, centrifugation, evaporation, or any other separation method. The separated product may then be dried, preferably, but not limited to, within a temperature range of 10 to 150°C.

[0090] Antifouling additives Provided herein are antifouling additives comprising medetomidine-containing particles of the present invention and, optionally, a liquid carrier. If present, the liquid carrier should be one in which the particles of the present invention are essentially insoluble, at least for a time sufficient to allow the antifouling additive to be mixed with a paint formulation. For example, the liquid carrier may be an organic solvent such as xylene. In some embodiments, the antifouling additive does not include a liquid carrier, or is mixed with a liquid carrier prior to, e.g., immediately before, mixing the additive with the paint formulation. In some embodiments, the antifouling additive is a powder comprising medetomidine-containing particles of the present invention, optionally in admixture with one or more additional dry ingredients, such as pigment particles and / or additional biocides.

[0091] The medetomidine-containing particles of the present invention, or antifouling additives containing said particles, may be added to coating formulations, for example wet paint formulations, which may further be applied onto marine surfaces at risk of barnacle attachment.

[0092] For example, the particles of the present invention can be added to any type of antifouling coating formulation, but preferably to FRC formulations, CDP formulations, or SPC formulations. Even more preferably, the particles can be added to silicon-based FRC formulations and / or silyl acrylate-based SPC formulations.

[0093] Antifouling coating formulations Also provided herein is an antifouling coating formulation comprising the medetomidine-containing particles of the present invention in a surface coating formulation, which may include conventional ingredients such as binders, water scavengers, pigments, plasticizers, and optionally additional biocides.

[0094] The antifouling coating formulation may be, for example, a conventional contact leaching coating formulation, a CDP coating formulation, an SPC coating formulation such as a silyl acrylate-based SPC coating formulation, or an FRC formulation such as a silicon-based FRC formulation, containing the particles of the present invention. In some embodiments, the coating formulation is a CDP coating formulation, an SPC coating formulation, or an FRC formulation. In some embodiments, the coating formulation is an SPC coating formulation or an FRC formulation. In some embodiments, the coating formulation is an SPC coating formulation. In some embodiments, the coating formulation is an FRC formulation. The compositions of the foregoing coating formulations are known in the art, and one of ordinary skill in the art can select suitable components such as binders, water scavengers, pigments, plasticizers, and optionally additional biocides.

[0095] Non-limiting examples of biocides that may be used in accordance with embodiments include chlorothalonil (2,4,5,6-tetrachlorobenzene-L,3-dicarbonitrile), dichlofluanid (N-{[dichloro(fluoro)methyl]sulfanyl}-N'N'-dimethyl-N-phenylsulfuric acid diamide), DCOIT (4,5-dichloro-2-n-octyl-4-isothiazolin-3-one), sibutrin (2-N-tert-butyl-4-N-cyclopropyl-6-methylsulfanyl-L,3,5-triazine-2,4-diamine), DCMU (3-(3,4-dichlorophenyl)-1,1-dimethylurea), tolylfluanid (N-[dichloro(fluoro)methyl]sulfanyl-N-(dimethylsulfamoyl)-4-methylaniline), and the like. thiocyanate, copper oxide, sibutrin (2-N-tert-butyl-4-N-cyclopropyl-6-methylsulfanyl-1,3,5-triazine-2,4-diamine), zineb (zinc ethane-1,2-diylbis(dithiocarbamate)), ziram (zinc bis(dimethyldithiocarbamate)), maneb (manganese ethylene-1,2-bisdithiocarbamate polymer), tralopyril (4-bromo-2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile), and mixtures thereof.

[0096] To achieve an effective antifouling effect, the amount of medetomidine-containing particles added should be such that medetomidine constitutes at least 0.01 wt. % of the wet coating formulation, or more preferably at least 0.1 wt. % of the wet coating formulation. For example, medetomidine may constitute 0.01-5%, 0.01-2%, 0.01-1%, 0.01-0.5%, or 0.01-0.2% of the wet coating formulation. For example, medetomidine may constitute 0.1-5 wt. %, 0.1-2 wt. %, 0.1-1 wt. %, 0.1-0.5 wt. %, or 0.1-0.2 wt. % of the wet coating formulation. The particles of the present invention can be added to any type of antifouling coating formulation, but are preferably added to FRC, CDP, or SPC formulations. Even more preferably, the particles are added to silicon-based FRC and / or silyl acrylate-based SPC formulations.

[0097] The antifouling effect includes the prevention of barnacle adhesion and possibly other types of hard fouling on the surface of the coating where the medetomidine-containing particles are present.

[0098] Antifouling coating Also provided herein is an antifouling paint (or antifouling coating film) obtained by applying the wet antifouling coating formulation of the present invention to a solid surface and allowing the formulation to dry on the surface. The coating formulation can be applied by any means, such as spray coating, brush, or roller. The resulting dried coating generally has a thickness of about 0.05 mm to about 5 mm.

[0099] The antifouling coatings of the present invention are useful in methods for preventing aquatic (e.g., marine) biofouling. Accordingly, provided are methods for preventing marine biofouling of a surface, comprising applying an antifouling coating formulation as defined herein to or near the surface. In some embodiments, the methods comprise applying the antifouling coating formulation to a surface. In some embodiments, the methods comprise applying the antifouling coating formulation to an object near the surface to provide an antifouling effect to the surface. Accordingly, in some embodiments, methods are provided in which medetomidine is released from an object having the antifouling coating of the present invention when the object is immersed near the surface to be protected.

[0100] Coated objects Also provided herein is an object having the antifouling coating disclosed herein on at least a portion of its surface. The object may be any type of object that is in contact with water and susceptible to biofouling, for example, any type of object that is at least partially submerged in water, e.g., seawater. In some embodiments, the object is, or is part of, a water vehicle such as a boat or ship, an offshore oil or gas installation, an aquaculture installation, a marine sensor, or a floating device.

[0101] Compared to the use of pure medetomidine in paint formulations or the use of prior art particles as described in U.S. Patent No. 7,311,766, the use of medetomidine-containing particles of the present invention results in a lower concentration of free medetomidine in the wet paint. Therefore, the potential for undesirable interactions and / or reactions between medetomidine and other paint components is lower. As an example, the low levels of free medetomidine in the wet paint obtained according to the present invention may extend the shelf life and improve the in-can stability of paints containing binders with ester and / or silyl ester functional groups as part of the polymer chain. This is demonstrated by the data provided herein, which show the viscosity increase, i.e., gelation, over time of silyl acrylate-based formulations containing pure medetomidine and corresponding formulations with medetomidine-containing particles according to the present invention.

[0102] Another advantage of the present invention lies in the fact that as medetomidine is combined with the particle formulation, it becomes more diluted, and therefore any dosage error during paint manufacture will result in a smaller percentage error in medetomidine content compared to when pure medetomidine is used. [Example]

[0103] The present invention is further described in the following non-limiting examples.

[0104] Example 1, Medetomidine-containing ZnO particles A solution of 14.00 g of Zn(CH3COO)22H2O dissolved in 90 mL of liquid phase (50% HO and 50% CH3OH by volume) was slowly added to another solution containing 0.58 g of medetomidine and 200 mL of liquid phase (50% HO and 50% CH3OH by volume). Subsequently, an NaOH solution (5.20 g NaOH, 50 mL HO) was added dropwise, forming a white precipitate. The precipitate was separated from the liquid phase by vacuum filtration. The powder was washed several times with water and finally dried at room temperature. The resulting pigment particles contained up to 10% medetomidine by weight.

[0105] Reference Example 1, ZnO particles ZnO powder was obtained according to the method of Example 1, except that medetomidine was not added.

[0106] Example 2: Medetomidine-containing CuPT particles To a solution of 2.98 g of CuSO4 and 400 mL of water, medetomidine (0.60 g) was added. Then, sodium pyrithione solution (12.67 g of 2-mercaptopyridine-N-oxide, sodium salt, 40 wt% aqueous solution, diluted with an additional 100 mL of HO) was added dropwise, resulting in a green precipitate. The precipitate was washed several times with water and finally dried at room temperature. The resulting pigment particles contained up to 10 wt% medetomidine.

[0107] Reference example 2, CuPT particles CuPT powder was obtained according to the method of Example 2, except that medetomidine was not added.

[0108] Example 3: Medetomidine-containing BaSO4 particles Medetomidine (0.75 g) was dissolved in 260 mL of liquid phase (42% by volume CH3OH and 58% by volume HO). Then, another solution consisting of 6.00 g of BaCl2 in 100 mL of liquid phase (42% by volume CH3OH and 58% by volume HO) was added to the medetomidine solution. Then, Na2SO4 solution (4.09 g of Na2SO4, 143 mL of liquid phase, 42% by volume CH3OH, and 58% by volume HO) was added dropwise, resulting in the gradual formation of a white precipitate. The liquid phase was removed by decantation and evaporation at room temperature. The precipitate was washed several times with water and finally dried at room temperature. The resulting pigment particles contained up to 10% by weight of medetomidine.

[0109] Reference Example 3, BaSO4 particles BaSO4 powder was obtained according to the method of Example 3, except that medetomidine was not added.

[0110] Example 4. Silyl acrylate-based antifouling paint formulation containing medetomidine pigment prepared by coprecipitation Silyl acrylate-based paint formulations were prepared containing a water-soluble binder (rosin), an insoluble binder (silyl acrylate), a water scavenger (tetraethyl orthosilicate, TEOS), a biocide (CuO), a pigment (ZnO), and a solvent (xylene), and further containing either the medetomidine-containing pigment particles prepared in Examples 1 to 3, the "empty" pigment particles of Reference Examples 1 to 3, or pure medetomidine, or no such further additives.

[0111] All ingredients except the TEOS and silyl acrylate solution were added to a 125 mL paint can and mixed together using a spatula. The silyl acrylate solution and TEOS were then added, followed by another spatula mix. The paint can was shaken in a paint can shaker for 5 minutes until the paint ingredients were homogeneously distributed throughout the can. The ingredients and their amounts (g) in the prepared formulations (A-H) are listed in Table 1, where Formulations A, D, F, and H are reference formulations containing no medetomidine, Formulation B is a comparative formulation, and Formulations C, E, and G are in accordance with the present invention.

[0112] [Table 1] (1) 65% in xylene, (2) 50% in xylene / butanol

[0113] It should be noted that a higher concentration of medetomidine was used here than is typically used in antifouling paints to accelerate the gelation test: usually, about 0.1 wt. % medetomidine is sufficient to provide effective barnacle protection.

[0114] The viscosity of the paint samples was measured using a Krebs Viscometer (TQC Sheen). The paint samples were shaken in a paint can shaker for 5 minutes before viscosity measurement to ensure uniform distribution of the paint components.

[0115] Comments on the results: The results are shown in Figure 2. A comparison of Formulation A and Formulation B clearly shows that free medetomidine accelerates the viscosity increase (gelation) of silyl acrylate-based formulations. However, the results obtained for Formulations C, E, and G clearly demonstrate that incorporating medetomidine into pigments effectively reduces gelation of silyl acrylate-based paints. Formulations E and G still showed no significant gelation at the time of testing, 317 days after preparation, whereas the viscosity of Formulation C increased to approximately 2000 cP after 56 days. However, this should be compared with reference Formulation B, which contains free medetomidine and already reached 2000 cP 7 days after preparation. The reduced gelation of Formulations C, E, and G is explained by the lower amount of free medetomidine in the wet paint formulation when medetomidine is incorporated into the pigment. Thus, the present invention provides a novel method for formulating medetomidine-containing silyl acrylate-based paints with preserved or significantly extended shelf life. It should also be noted that the reference pigments without medetomidine (Formulas D, F, and H) showed no effect on silyl acrylate gelation when examined 317 days after preparation.

[0116] Example 5. Silyl acrylate-based antifouling paint formulations comparing medetomidine-containing pigments prepared by coprecipitation and adsorption It is known in the prior art (U.S. Pat. No. 7,311,766) that the release rate of medetomidine from a coating can be controlled by pre-adsorbing medetomidine onto the surface of carrier particles, such as ZnO particles. This example illustrates the difference between using the prior art method of pre-adsorbing medetomidine onto the surface of ZnO particles and using medetomidine incorporated into ZnO particles by co-precipitation, as described herein.

[0117] Silyl acrylate-based paint formulations were prepared containing a water-soluble binder (rosin), an insoluble binder (silyl acrylate), a water scavenger (TEOS), a biocide (CuO), a pigment (ZnO), and a solvent (xylene), and further containing either medetomidine-loaded pigmented ZnO particles as prepared in Example 1, medetomidine-loaded ZnO particles prepared by adsorption as described herein below, pure medetomidine, or no such further additives.

[0118] Adsorption of medetomidine onto ZnO surfaces was carried out by stirring medetomidine, solvent, and ZnO in a sealed Erlenmeyer flask at room temperature for 24 hours. The solvent volume was 100 mL per 1.0 g of medetomidine. The suspension was then transferred to an open beaker, allowing the solvent to evaporate. The dried solid was ground to a fine powder. Medetomidine was adsorbed onto either commercially available ZnO (White Seal, Umicore Zinc Chemicals, Larvik, Norway), ZnO nanoparticles (particle diameter <100 nm, Sigma-Aldrich, Stockholm, Sweden), or ZnO particles prepared as in Reference Example 1. Adsorption was carried out using either xylene or 1-methoxy-2-propanol as the solvent, and the final powder contained up to 10 wt% medetomidine. Details of each sample prepared are listed in Table 2.

[0119] All ingredients except the TEOS and silyl acrylate solution were added to a 125 mL paint can and mixed together using a spatula. The silyl acrylate solution and TEOS were then added, followed by another spatula mix. The paint can was shaken in a paint can shaker for 5 minutes until the paint ingredients were homogeneously distributed throughout the can. The ingredients and their amounts (g) in the prepared formulations (I-O) are listed in Table 2, where Formulation I is a reference formulation containing no medetomidine, Formulation J, Formulation L, Formulation M, Formulation N, and Formulation O are comparative formulations, and Formulation K is a formulation according to the present invention.

[0120] [Table 2] (1) 65% in xylene, (2) 50% in xylene / butanol, (3) ZnO nanoparticles (particle size <100 nm, Sigma-Aldrich, Stockholm, Sweden), (4) Commercially available ZnO (White Seal, Umicore Zinc Chemicals, Larvik, Norway); (5) ZnO was prepared as in Reference Example 1.

[0121] It should be noted that a higher concentration of medetomidine was used here than is typically used in antifouling paints to accelerate the gelation test: usually, about 0.1 wt. % medetomidine is sufficient to provide effective barnacle protection.

[0122] The viscosity of the paint samples was measured using a Krebs Viscometer (TQC Sheen). The paint samples were shaken in a paint can shaker for 5 minutes before viscosity measurement to ensure uniform distribution of the paint components. The results are shown in Figure 3.

[0123] Comments on the results: A comparison of Formulation J and Formulation K in Figure 3 reveals that the use of coprecipitated medetomidine / ZnO (prepared in Example 1) instead of adding pure medetomidine significantly inhibits gelation of silyl acrylate paints. Using pre-prepared ZnO with pre-adsorbed medetomidine can also mitigate gelation to some extent (see Formulations L through O in Figure 3). However, using coprecipitated medetomidine / ZnO (i.e., Example 1), as in Formulation K, is by far the most efficient method for controlling the in-can viscosity of medetomidine-containing silyl acrylate paints. For example, after 30 days, the viscosity of Formulation K was approximately 1200 cP, while the viscosities of the formulations prepared with medetomidine adsorbed on surface ZnO (Formulations L through O) ranged from 3500 to 5300 cP. This represents a significant difference between particles carrying medetomidine adsorbed to the particle surface, as disclosed in U.S. Pat. No. 7,311,766, and the particles of the present invention, which have medetomidine incorporated within the particle matrix.

[0124] Example 6. Silicon-based FRC antifouling paint formulation The medetomidine-containing pigments of Examples 1 to 3 were added as antifouling additives to a commercially available silicon-based FRC paint (Hempel Silic One Topcoat). For comparison, the commercially available silicon-based FRC paint was mixed with the "blank" pigments of Reference Examples 1 to 3, or with a medetomidine solution (medetomidine / 1-methoxy-2-propanol), or used without any of the mentioned additives. For each paint formulation, the components were weighed into a 125 mL paint can and then shaken in a paint can shaker for 5 minutes, i.e., until the paint components were uniformly distributed.

[0125] The ingredients and their amounts (g) in the prepared formulations (P to W) are shown in Table 3, where Formulation P, Formulation S, Formulation U, and Formulation W are reference formulations not containing medetomidine, Formulation Q is a comparative formulation, and Formulation R, Formulation T, and Formulation V are according to the invention.

[0126] [Table 3] (1) 20% solution in 1-methoxy-2-propanol

[0127] The topcoat was applied in two layers by brush onto a poly(methyl methacrylate) (PMMA) panel precoated with Hempel Light Primer and Hempel Silic One Tiecoat. The fully cured topcoat was divided into three separate pieces: one was left intact, one was cross-cut with a knife, and one was roughened with sandpaper.

[0128] Antifouling tests were performed at a test site in Tjarno, Sweden, by prolonged immersion of treated panels in seawater. All panels were submerged in water in June. Panels were inspected periodically and barnacle fouling was visually rated according to the scale shown in Table 4.

[0129] [Table 4]

[0130] Table 5 shows the results in terms of antifouling rating after 71 and 150 days, respectively, of immersion of treated panels in the sea at Tjarno.

[0131] [Table 5] * Due to heavy contamination by other species, it is not possible to assess barnacle coverage.

[0132] Comments on the results: The results show that silicon-based FRC is sensitive to damage, such as abrasion and scratching. The coating obtained using reference formulation P, i.e., Hempel Silic One Topcoat without any additives, was contaminated with barnacles on the sanded areas and in the knife cuts. Therefore, while undamaged silicon-based FRC can be effective against barnacle growth, the damaged areas of such coatings are easily contaminated by barnacles.

[0133] The coating obtained using Comparative Formulation Q was also contaminated with barnacles on the damaged areas. A reasonable explanation for this is the rapid release of medetomidine when the coating is submerged in water. This is not unusual when medetomidine is added late in the paint manufacturing process, as there are fewer adsorption sites available for medetomidine on other paint components.

[0134] The coatings obtained using Inventive Formulations R and T provided excellent barnacle protection for damaged FRC. This means that medetomidine was slowly released during the period of seawater submersion. This also means that this type of medetomidine-containing particle is suitable for post-addition to ready-made paints without the risk of premature depletion of medetomidine from the coating. For the coatings obtained using Inventive Formulation V and the coatings obtained using Reference Formulations S, U, and W, no or very limited barnacle fouling effect was observed.

[0135] Example 7, Rosin-Based Paint Formulation Rosin-based paint formulations were prepared containing a water-soluble binder (rosin), an insoluble binder (poly(butyl methacrylate-co-methyl methacrylate) (PBMA)), a plasticizer (Phosphlex® 71B), a pigment (ZnO), a rheological additive (Bentone SD1®), a thickener (fumed silica), a filler (BaSO), and a solvent (xylene), with or without the medetomidine-containing pigment of Examples 1-3 as an antifouling additive, the "blank" pigment of Reference Examples 1-3, or a medetomidine solution (medetomidine / 1-methoxy-2-propanol). For each formulation, the components were weighed into a 125 mL paint can along with 10 mL of ceramic beads. The paint can was shaken in a paint can shaker for 5 minutes, or until the paint components were uniformly distributed. The compositions of the formulations (X-AE) thus prepared are shown in Table 6, where Formulation X, Formulation AA, Formulation AC, and Formulation AE are reference formulations not containing medetomidine, Formulation Y is a comparative formulation, and Formulation Z, Formulation AB, and Formulation AD are according to the invention.

[0136] [Table 6] (1) 65% xylene solution, (2) 35% xylene solution, (3) Manufactured by ICL Industrial Products Ltd, Beer Sheva, Israel (4) Elementis GmbH, Cologne, Germany (5) 20% 1-methoxy-2-propanol solution

[0137] The paints were applied at a wet film thickness of 150 μm onto PMMA panels, and antifouling tests were performed at the Tjarno test site (Sweden) by immersing the treated panels in seawater for extended periods. All panels were submerged in June. The panels were inspected periodically and visually assessed for barnacle fouling. The overall antifouling efficiency of the formulations was rated according to the scale shown in Table 4. Table 7 shows the results of the panels at the Tjarno test site after 71, 287, and 449 days of submersion.

[0138] [Table 7]

[0139] Comments on the results: The addition of medetomidine to rosin-based paints provides excellent barnacle protection. This is evident by comparing panels coated with Formulation X (containing no medetomidine) and Formulation Y (containing medetomidine). Note that Formulation Y was prepared by adding medetomidine as a solution early in the paint manufacturing process. Therefore, medetomidine may have been adsorbed onto another paint component, such as the pigment. Adsorption of medetomidine onto the surface of pigments in paints is known to promote sustained release of medetomidine and efficient barnacle protection.

[0140] The results in Table 7 also show that the addition of medetomidine-containing particles prevents or makes significantly more difficult barnacles from attaching to the coating surface. Medetomidine incorporated into ZnO or CuPT (Formulations Z and AB) provides antifouling efficacy comparable to when medetomidine is added as a solution at an earlier formulation stage (Formulation Y). BaSO4-based particles (Formulation AD) were less effective. Corresponding particles without medetomidine (Formulations AA, AC, and AE) were less active against barnacles or not at all. From the results, it can be concluded that the medetomidine-containing particles of the present invention generally provide effective protection against barnacle deposition on the surface of rosin-based coatings.

[0141] Example 8: Medetomidine-containing CuO particles A solution of 20 mL of HO, 2.146 g of citric acid, 0.288 g of CuSO4 5HO, and 1.341 g of NaOH was stirred for 5 minutes. Then, a solution of 20 mL of HO and 1.667 g of Na2CO3 was added to the above solution. A solution containing 6.600 g of sucrose, 20 mL of HO, and 1.000 g of citric acid was heated in a boiling water bath for 10 minutes, then cooled to room temperature and added to the solution containing CuSO4 5HO. Then, 0.026 g of medetomidine was dissolved in 10 mL of CH3OH, and then 10 mL of HO was added. The medetomidine solution was added to a solution containing CuSO4 5H2O and placed in a boiling water bath for 15 minutes. Then, 20 mL of 0.5 M NaOH was added dropwise to the CuSO4 5H2O solution until the solution color changed from blue to orange. After the color change, the solution was placed in the water bath for 5 minutes and then added to Falcon® tubes and centrifuged at 4000 rpm for 30 minutes. The supernatant was discarded, and 40 mL of H2O was added to each tube to wash the coprecipitates. The Falcon® tubes were then centrifuged using the same procedure. The supernatant was discarded, and the coprecipitates were removed from the tubes, placed on filter paper, and allowed to dry at room temperature. 10% of the final product was dissolved in 1 g of CH3OH, shaken for 10 minutes, and placed on a roller table for 1 hour. The samples were then centrifuged, and the supernatant was extracted and examined by gas chromatography, which indicated that medetomidine was present in the samples.

Claims

1. (i) a metal or semi-metal compound; (ii) Solid particles comprising a coprecipitate of medetomidine or an enantiomer or salt of medetomidine.

2. 2. The particles of claim 1, wherein the metal compound or the metalloid compound has a water solubility of 0.01 to 150 mg / L, preferably 0.01 to 100 mg / L, more preferably 0.01 to 50 mg / L, even more preferably 0.01 to 10 mg / L, and most preferably 0.01 to 5 mg / L at pH 7 and 20°C.

3. 3. The particle according to claim 1 or 2, wherein the metal in the metal compound is selected from Mg, Ca, Ti, Fe, Cu, Zn, Al, and Ba, and the metalloid in the metalloid compound is Si.

4. 4. The particles according to claim 1, wherein the metal compound or the metalloid compound is a metal oxide or metalloid oxide, a metal salt or metalloid salt, or a metal coordination complex or metalloid coordination complex, preferably selected from zinc (II) oxide, iron (II) oxide, iron (III) oxide, copper (I) oxide, copper (II) oxide, titanium (IV) oxide, silicon (IV) oxide, copper (II) pyrithione, zinc (II) pyrithione, copper (I) thiocyanate, barium (II) sulfate, calcium (II) sulfate, magnesium (II) carbonate, calcium (II) carbonate, barium (II) carbonate, iron (II) carbonate, zinc (II) carbonate, and metal salts of C2 to C24 carboxylic acids, more preferably selected from zinc (II) oxide, copper (I) oxide, copper (II) pyrithione, and barium (II) sulfate.

5. 5. The particles according to any one of claims 1 to 4, comprising 1 to 50% by weight of said medetomidine or said enantiomer or salt of said medetomidine, preferably 5 to 15% by weight of said medetomidine or said enantiomer or salt of said medetomidine.

6. 6. A method for preparing solid particles according to any one of claims 1 to 5 by co-precipitation of (i) a metal or semi-metal compound and (ii) medetomidine or an enantiomer or salt of medetomidine.

7. mixing two liquid phase solutions of a different salt in the presence of medetomidine or an enantiomer or salt of medetomidine to form a metal or metalloid compound that has a lower solubility in the liquid phase than either of the different salts; and co-precipitating the metal or metalloid compound and the medetomidine or an enantiomer or salt of medetomidine from the resulting liquid mixture.

8. 8. The method of claim 7, wherein the medetomidine or an enantiomer or salt of the medetomidine is present as a solute in at least one of the liquid phase solutions.

9. 9. The method of any one of claims 6 to 8, comprising separating the coprecipitate from the liquid phase and, optionally, drying the separated coprecipitate.

10. An antifouling additive comprising particles as defined in any one of claims 1 to 5 or particles prepared by the method of any one of claims 6 to 9, and optionally a liquid carrier.

11. An antifouling coating formulation comprising particles as defined in any one of claims 1 to 5 or prepared by the method of any one of claims 6 to 9, and a surface coating material.

12. 12. An antifouling coating formulation according to claim 11, wherein the formulation contains said particles in an amount sufficient to provide a medetomidine content in the formulation of at least 0.01% by weight of the formulation, preferably at least 0.1% by weight.

13. 13. An antifouling coating film formed from the antifouling coating formulation defined in claim 11 or 12.

14. 13. A method for preventing marine biofouling of a surface by applying an antifouling coating formulation as defined in claim 11 or 12 to or in the vicinity of said surface.

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