Chemical chamfering method

Abstract

A cytotoxic agent and its use in dehorning an animal or inhibiting horn growth in a young animal. The cytotoxic agent may be a hardener, a p53 activator, an antiprotozoal agent, an apoptosis inducer, or a local anesthetic.

Description

[0001] Related Applications

[0002] This application claims priority to Australian Provisional Patent Application No. 2022902547 filed on September 5, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention broadly relates to cytotoxic agents and their use in dehorning animals or inhibiting horn growth in young animals. In particular, the cytotoxic agent is a sclerosant, a p53 activator, an antiprotozoal agent, an apoptosis inducer and / or a local anesthetic. Background Art

[0004] Horn bud removal is a routine husbandry practice in most dairy herds around the world.

[0005] Dehorning is a procedure that uses a hot cautery (branding iron) device to remove or destroy the horn bud of a calf by burning and destroying the tissue surrounding the horn bud. Branding iron equipment used for dehorning is potentially dangerous due to the use of high temperatures. Successful dehorning requires experience and skill, and incorrect technique can result in injury to the animal and the operator.

[0006] Even when performed correctly, the iron dehorning procedure can be painful and stressful for the animal if carried out without appropriate anesthesia and analgesia. In New Zealand, it is illegal to dehorn a calf unless the calf is "under the influence of a properly placed and effective local anaesthetic" (Animal Welfare (Care and Procedures) Regulations 2018). The ideal welfare protocol for dehorning involves the administration of a sedative to reduce stress during the procedure, the injection of a local anaesthetic into the horn nerve to numb the horn bud and surrounding tissue, and the administration of a non-steroidal anti-inflammatory drug (NSAID) to reduce post-operative pain. However, the combination of these procedures still does not guarantee a comfortable experience for the animal. In most countries, there are barriers to the cost and availability of appropriate medications for animal keepers. The above recommended treatments also require experience and skills in administering an appropriate medication regimen. In particular, the correct administration of anaesthetic to the horn nerve requires training in the correct procedure.

[0007] Other less commonly used methods of dehorning include direct removal of the horn bud with a spatula or chisel, and chemical dehorning using caustic soda. It has been observed that removing the horn bud by cutting causes more pain and stress than using a soldering iron and leaves a large open wound.

[0008] There are reports in the literature of experimental methods of dehorning that have been tried. A 1976 paper (Koger LM. Dehorning by injection of calcium chloride. Vet Med Small Anim Clin 1976; 71(6):824-825) describes a method of injecting high concentrations of calcium chloride into the horn bud to cause tissue necrosis. This method also causes significant inflammation and is expected to cause considerable pain. The authors recommend the use of analgesics and sedatives.

[0009] The use of caustic soda has been tested. It is often inadvertently spread from the site of application to other areas of the animal and to other animals through contact, causing blindness in treated animals and adverse effects of rainfall.

[0010] Attempts have been made to use liquid nitrogen as a cryogenic liquid to destroy horn bud tissue, but this has been found to be almost completely ineffective.

[0011] Injection of clove oil (eugenol) under the horn bud to cause necrosis of the horn bud tissue has been trialed but found to be relatively ineffective, in many cases delaying rather than preventing horn growth, and is not recommended by the original investigators (Sutherland et al., Vet Sci. 2019 Dec;6(4):102).

[0012] Therefore, there is a need for an improved composition or method for preventing horn growth in young animals.

[0013] Purpose of the Invention

[0014] One or more embodiments of the present invention aim to solve one or more of the above problems. Alternatively, one or more embodiments of the present invention aim to provide a composition or method for chemical exfoliation to overcome or minimize the above mentioned disadvantages of known exfoliation methods. Alternatively, the present invention aims to provide the public with a useful choice. Summary of the invention

[0015] The present invention generally relates to cytotoxic agents and their use in dehorning animals.

[0016] According to a first aspect of the present invention, there is provided a method for chemical dehorning of young animals, the method being performed by administering at least one cytotoxic agent to the horn bud cells of the animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0017] According to a second aspect of the present invention, there is provided a use of at least one cytotoxic agent for chemical dehorning of young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0018] According to a third aspect of the present invention, there is provided at least one cytotoxic agent for or when used for chemical dehorning of a juvenile animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0019] According to a fourth aspect of the present invention, there is provided a use of at least one cytotoxic agent in the preparation of a medicament for chemical dehorning of young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0020] According to a fifth aspect of the present invention, there is provided a dehorning composition comprising at least one cytotoxic agent, which is formulated for administration to young animals and for chemical dehorning of young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0021] According to the sixth aspect of the present invention, a method for inhibiting horn growth in young animals is provided, the method being performed by administering at least one cytotoxic agent to the horn bud cells of the animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0022] According to a seventh aspect of the present invention, there is provided a use of at least one cytotoxic agent for inhibiting horn growth in young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0023] According to an eighth aspect of the present invention, there is provided at least one cytotoxic agent for or when used to inhibit horn growth in a juvenile animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0024] According to the ninth aspect of the present invention, there is provided the use of at least one cytotoxic agent in the preparation of a medicament for inhibiting horn growth in young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0025] According to the tenth aspect of the present invention, there is provided a composition comprising at least one cytotoxic agent, which is formulated for administration to a young animal and inhibiting horn growth of the young animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0026] According to the eleventh aspect of the present invention, there is provided a syringe containing at least one cytotoxic agent, wherein the cytotoxic agent is used for or when used to dehorn a young animal or inhibit horn growth of a young animal, wherein the syringe is capable of administering the at least one cytotoxic agent to the horn bud cells of the young animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0027] According to the twelfth aspect of the present invention, a kit is provided, which is used for or when used in a method for dehorning young animals or inhibiting horn growth of young animals, wherein the kit comprises: a syringe capable of administering at least one cytotoxic agent to horn bud cells of young animals; and at least one cytotoxic agent, wherein the at least one cytotoxic agent kills horn bud cells in a certain amount, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0028] According to the thirteenth aspect of the present invention, a composition is provided, which is formulated into a solution, a suspension, a dispersion, an emulsion, a low-viscosity gel or other sustained-release liquid preparation, the composition comprising at least one cytotoxic agent and one or more excipients, and capable of providing sustained release of the at least one cytotoxic agent, wherein the at least one cytotoxic agent includes at least one sclerosant, a p53 activator, an antiprotozoal agent, an apoptosis inducer and a local anesthetic.

[0029] According to the fourteenth aspect of the present invention, a composition is provided, which is formulated into a solution, suspension, dispersion, emulsion, low-viscosity gel or other sustained-release liquid preparation, and the composition comprises at least one cytotoxic agent in an amount capable of dehorning young animals or inhibiting the growth of horns of young animals, and one or more excipients, and is capable of providing sustained release of the at least one cytotoxic agent, wherein the at least one cytotoxic agent includes at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0030] According to a fifteenth aspect of the present invention, there is provided a composition formulated as a low viscosity injectable gel, the low viscosity injectable gel comprising: all in about % w / v,

[0031] 10% w / v of at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as mepacrine dihydrochloride, or mepacrine dihydrochloride dihydrate, at 11.8% w / v;

[0032] 40-85% w / v SAIB;

[0033] 0-2% w / v Tween 80;

[0034] 0-50% w / v triacetin;

[0035] 0-50%w / v DEGEE(Transcutol TM );and

[0036] Ethanol is made up to 100% volume, where:

[0037] The concentration of ethanol is 0-30% w / v; or

[0038] In the absence of other solvents and Tween, and at a SAIB level of 85% w / v, assuming a weight of 1.1 g per mL of composition formulation, the ethanol concentration is approximately 15% w / v.

[0039] According to a sixteenth aspect of the present invention, there is provided a composition formulated as a low viscosity injectable gel, the low viscosity injectable gel comprising: all in about % w / v,

[0040] 20% w / v of at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v, or mepacrine dihydrochloride dihydrate at 25.4% w / v;

[0041] 40-85% w / v SAIB;

[0042] 0-2% w / v Tween 80;

[0043] 0-50% w / v triacetin;

[0044] 0-50%w / v DEGEE(Transcutol TM );and

[0045] Ethanol is made up to 100% volume, where:

[0046] The concentration of ethanol is 0-30% w / v; or

[0047] In the absence of other solvents and Tween, and at 20% w / v imipenem base and 85% w / v SAIB level, assuming a weight of 1.1 g per mL of composition formulation, the ethanol concentration is 5% w / v, which may be too low, in which case the maximum concentration of SAIB must be reduced.

[0048] According to the seventeenth aspect of the present invention, there is provided a composition formulated as a low viscosity injectable gel, the low viscosity injectable gel comprising: all in about % w / v,

[0049] 10% w / v of at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride;

[0050] 70% w / v SAIB;

[0051] 1% w / v Tween 80;

[0052] 5% w / v triacetin;

[0053] 0%w / v DEGEE(Transcutol TM );and

[0054] Ethanol was made up to 100% volume, ie about 22% w / v ethanol assuming a weight of 1.1 g per mL of final formulation and assuming that mepacrine dihydrochloride was used.

[0055] According to the eighteenth aspect of the present invention, there is provided a composition formulated as a low viscosity injectable gel, the low viscosity injectable gel comprising: all in about % w / v,

[0056] 20% w / v of at least one cytotoxic agent, preferably mepacrine, more preferably 23.6% w / v of mepacrine dihydrochloride;

[0057] 70% w / v SAIB;

[0058] 1% w / v Tween 80;

[0059] 5% w / v triacetin;

[0060] 0%w / v DEGEE(Transcutol TM );and

[0061] Ethanol was made up to 100% volume, ie, approximately 10.4% w / v ethanol assuming a weight of 1.1 g per mL of the final formulation.

[0062] According to the nineteenth aspect of the present invention, there is provided a composition which is formulated into an injectable oily solution or suspension, the injectable oily solution or suspension comprising: all in about % w / v,

[0063] 10-15% w / v of at least one cytotoxic agent, preferably mepacrine or a salt thereof providing 10-15% w / v mepacrine, such as 11.8-17.7% w / v mepacrine dihydrochloride; and

[0064] At least one oily excipient.

[0065] It is to be understood that features cited for a particular aspect of the invention may be, or reframed as, features of any and all other aspects of the invention, where the context permits. For example, one or more features of a "method" (method, use, process, etc.) may be reframed as features of a "product" (cytotoxic agent, composition, medicament, formulation, syringe, kit, etc.), and vice versa, where the context permits.

[0066] "Cytotoxic agent" refers to an agent that is toxic to keratinocytes (especially dermis), which can be destroyed and / or inactivated by the cytotoxic agent. Unless otherwise indicated, "cytotoxic agent" refers to at least one type of agent, and in some embodiments, two, three, four or more different types of agents can be used together. For example, another suitable cytotoxic agent may be eugenol (clove oil). For example, eugenol can be used in combination with mepacrine.

[0067] In some embodiments, the cytotoxic agent can be in free acid or free base form, or a salt. Where the context permits, the term "cytotoxic agent" includes free acid or free base forms of the cytotoxic agent, and any salt or salts of the cytotoxic agent. For example, mepaline is a base / free base, so the use of "mepaline" throughout the specification and claims includes mepaline as a free base and any salt of mepaline, such as mepaline dihydrochloride or mepaline dihydrochloride dihydrate. Sometimes one or more salts of mepaline may be specifically mentioned to illustrate more clearly.

[0068] Although not always explicitly stated, it is understood that the cytotoxic agent is typically administered to the animal in the form of a composition, formulation or medicament.

[0069] It is to be understood that dehorning or inhibition of horn growth can be achieved by administering a cytotoxic agent directly to the horn bud cells (horn bud tissue) of an animal or in the vicinity of the horn bud cells. Preferably, dehorning or horn inhibition is performed while the horn bud is freely floating in the skin. Preferably, dehorning or horn inhibition is performed before the horn bud attaches to the skull. Preferably, the cytotoxic agent is administered under or around the horn bud, more preferably under the horn bud. Successful dehorning or horn inhibition requires inactivation or destruction of the horn-producing cells (dermis) of the horn bud (i.e., "horn bud cells").

[0070] Preferably, the cytotoxic agent is administered in an amount sufficient to prevent horn growth or significantly reduce horn growth (ie an "effective amount") such that the resulting horn / rudimentary horn / stub / sprout is not dangerous to other animals. Preferably, complete prevention of horn growth is achieved.

[0071] The inventors have discovered that young animals can be dehorned by applying at least one (one or more) hardening agent to the horn buds.

[0072] Any suitable sclerosing agent or agents may be used. Techniques for identifying and evaluating new potential sclerosing agents are known in the art, including in vitro assays. Sclerosing agents are generally used in sclerotherapy. In sclerotherapy procedures, a sclerosing agent generally refers to a substance that, when introduced into the lumen of a blood vessel, causes damage to the vessel wall, thereby causing occlusion of the vessel due to the resulting fibrosis. Sclerotherapy is often used to treat varicose veins.

[0073] Preferred sclerosing agents include mepacrine (quinacrine), chloroquine, polidocanol and quinine. Preferred sclerosing agents are those that also provide a local anesthetic effect, such as mepacrine, chloroquine and polidocanol.

[0074] Acridine hardening agents, such as mepacrine (quinacrine), are particularly preferred active agents.

[0075] The inventors have discovered that animals can be dehorned by administering one or more p53 activators to the horn buds.

[0076] Any suitable one or more p53 activators may be used. Suitable p53 activators that can be used in the present invention are known to the skilled person, particularly for potential use in cancer treatment. Protein p53, also known as tumor protein p53 and tumor suppressor p53, acts as a tumor suppressor in cells. Agents that lead to activation of the p53 protein are called p53 activators.

[0077] Preferred p53 activators are small molecules, including mepaline and chloroquine.

[0078] Acridine p53 activators, such as mepacrine (quinacrine), are particularly preferred agents.

[0079] Particularly preferred p53 activators provide a local anesthetic effect, such as mepacrine and chloroquine.

[0080] The inventors have discovered that animals can be dehorned by administering one or more antiprotozoal agents to the horn buds.

[0081] Any suitable antiprotozoal agent or agents may be used. Many antiprotozoal agents are known in the art. For example, suitable antiprotozoal agents may include antimalarial agents. Techniques for identifying and evaluating new potential antiprotozoal agents are known in the art.

[0082] Preferred antiprotozoal agents include mepacrine, chloroquine and quinine.

[0083] Acridine antiprotozoal agents, such as mepacrine (quinacrine), are particularly preferred agents.

[0084] Particularly preferred antiprotozoal agents are those that also provide a local anesthetic effect, such as mepacrine and chloroquine.

[0085] The inventors have discovered that animals can be dehorned by administering one or more apoptosis-inducing agents to the horn buds.

[0086] Any suitable one or more apoptosis inducers may be used. Suitable apoptosis inducers that can be used in the present invention are known to the skilled person. Preferred apoptosis inducers include mepacrine and cinchocaine.

[0087] Acridine apoptosis inducers, such as mepacrine (quinacrine), are particularly preferred active agents. Particularly preferred apoptosis inducers provide a local anesthetic effect, such as mepacrine and cinchocaine.

[0088] The inventors have discovered that animals can be dehorned by applying one or more anesthetics to the horn buds.

[0089] Any suitable one or more anesthetics can be used. Suitable anesthetics include amide anesthetics, ester anesthetics or non-ionic surfactant anesthetics. Suitable anesthetics include: lidocaine, chloroprocaine, mepivacaine, bupivacaine, articaine, etidocaine, levobupivacaine, tetracaine, prilocaine, benzocaine, ropivacaine, cocaine, hydroxyprocaine, hexocaine (hexocaine), dibucaine, perralcaine and procaine, and pharmaceutically acceptable acids, bases and salts thereof (including acid salts). In some embodiments, anesthetics exist in the form of acid salts or acidic solutions. (Local anesthetic solutions usually have acidic pH to maximize their water solubility. Suitable anesthetics include imipaline imipaline (quinacrine), polidocanol, cinchocaine, chloroquine and quinine.

[0090] For example, chloroquine diphosphate may be administered.

[0091] Preferably, the cytotoxic agent is mepacrine, polidocanol, cinchocaine, chloroquine or quinine. In addition to being cytotoxic, these agents also provide a local anesthetic effect.

[0092] The animal may be any type of animal that can grow true horns from horn buds. Such animals include, but are not limited to, Bos (cows or bulls), goats, sheep, bison, African buffalo, gazelles, musk oxen, and antelopes. The young animal is preferably a calf or kid.

[0093] Any suitable amount of one or more cytotoxic agents may be used, provided that it is cytotoxic to horn bud cells. The amount applied depends on the potency of the cytotoxic agent, and the size or volume of the horn bud area being treated. The amount of cytotoxic agent applied to horn bud cells is preferably in the range of about 5-1000 mg, including all values ​​between 5-1000. More preferably, the amount of cytotoxic agent applied to horn bud cells is in the range of about 20-400 mg, including all values ​​between 20-400, including 20, 21, 22, etc.

[0094] For mepaline, in some embodiments, at least about 100 mg (single injection or total amount of multiple injections) is administered. For mepaline, preferably about 100-300 mg is administered, preferably about 100-150 mg, more preferably about 100 mg, including all values ​​between 100-300 and 100-150 (100, 101, 102, etc.). For example, a salt of mepaline, such as mepaline dihydrochloride or mepaline dihydrochloride dihydrate, can be administered.

[0095] Typically, the cytotoxic agent will be administered to an animal in the form of a composition, formulation or medicament suitable for injection. Preferred compositions, formulations or medicaments are liquid compositions. Preferred liquid compositions, formulations or medicaments include solutions, suspensions, dispersions, emulsions, low viscosity gels and other sustained release formulations.

[0096] Preferred compositions (preparations or medicines) for administration are liquid compositions suitable for injection. Compositions for injection can be prepared by dissolving or mixing the cytotoxic agent in a suitable veterinary acceptable vehicle, carrier, solvent or excipient, etc., which may include other ingredients such as solubilizing agents, acids, bases, buffer salts, antioxidants and / or preservatives. These compositions can be sterilized, such as by heating, filtering or irradiation, or can be prepared aseptically. Compositions for injection can be prepared by methods and techniques known to those skilled in the art.

[0097] The composition (formulation or medicament) may include one or more of the following types of veterinary acceptable ingredients: vehicles; aqueous or oily diluents; carriers; excipients; bases; buffers; pH adjusters; suspending agents; flocculants; thickeners; viscosity building agents; gelling agents; solvents; cosolvents; solvent systems; emulsifiers; stabilizers; dispersants; solubilizers; fragrances; preservatives; surfactants; detergents, complexing agents; acids; bases; antioxidants; wetting agents; chelating agents; reducing agents; fillers; protective agents; osmotic pressure regulators; and colorants.

[0098] Examples of osmotic pressure regulators used in liquid injections include electrolytes, dextrose, glycerol, sodium chloride, glycerin, and mannitol.

[0099] Preservatives used in liquid injections include antioxidants, antimicrobial agents, and chelating agents, including ascorbic acid, acetylcysteine, sulfites (bisulfites, metabisulfites), monothioglycerol, phenol, m-cresol, benzyl alcohol, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric salts, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), and alpha-tocopherol.

[0100] Examples of solubilizers used in liquid injections include surfactants, solvents, and cosolvents, and include water, Tween, polysorbate, nonionic surfactants, polyoxyethylene sorbitan monooleate (Tween 80), EDTA, sorbitan monooleate, polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, polyoxyethylene copolymers (pluronics), propylene glycol, glycerol, ethanol, polyethylene glycol (300 and 400), sorbitol, dimethylacetamide, and cremophor EL.

[0101] Examples of complexing agents and dispersing agents used in liquid injections include cyclodextrins and modified cyclodextrins such as hydroxypropyl-b-cyclodextrin and sulfobutyl ether-b-cyclodextrin.

[0102] Examples of buffers used in liquid injections include phosphate, citrate, acetate, lactate, and tartrate buffers.

[0103] Suspensions (including aqueous or oily suspensions) can provide a more sustained release of the cytotoxic agent from the injection site compared to comparable solutions. Examples of excipients used in suspensions include flocculants / suspending agents, viscosity building agents, wetting agents, solvent systems, preservatives, antioxidants, chelating agents, buffers, and osmotic pressure regulators. Examples of excipients or oily suspensions used in oily suspensions include oils, preferably vegetable oils, such as castor oil, cottonseed oil, soybean oil, ethyl oleate, olive oil, peanut oil, sesame oil, sunflower seed oil, soybean oil, and safflower oil.

[0104] Examples of flocculants / suspending agents include electrolytes, surfactants, and hydrophilic colloids, including potassium / sodium chloride, potassium / sodium citrate, and potassium / sodium acetate.

[0105] Examples of viscosity building agents include sodium carboxymethylcellulose, gum arabic, gelatin, methylcellulose and polyvinylpyrrolidone.

[0106] Examples of wetting agents include glycerin, alcohol, propylene glycol, lecithin, polysorbate 20, polysorbate 80, Pluronic F-68, sorbitan trioleate.

[0107] Examples of the solvent include water, ethanol, glycerol, propylene glycol, n-lactamide, and polyethylene glycol (PEG).

[0108] In some embodiments, the composition (formulation or drug) is in the form of a low viscosity injectable gel that rapidly gels at the injection site to retain the cytotoxic agent for an appropriate period of time. In this way, relatively large amounts of cytotoxic agents can be delivered to horn bud cells (horn bud tissue).

[0109] The composition can be gelled in situ in any suitable manner. In some embodiments, the composition comprises one or more gelling agents. In some embodiments, the composition comprises one or more solvents or solvent systems. In some embodiments, the composition comprises one or more surfactants. In some embodiments, the composition comprises sucrose acetate isobutyrate (SAIB) and at least one type of solvent. In some embodiments, the composition comprises sucrose acetate isobutyrate (SAIB), at least one type of solvent and at least one type of surfactant. Once the composition containing SAIB preparation and solvent (and optional surfactant) is injected, the solvent can diffuse out, leaving a matrix that is both sticky and thick. The matrix can retain the cytotoxic agent in the horn bud cells for an effective time, rather than the cytotoxic agent being dispersed almost immediately.

[0110] The molecular weight of SAIB may be 846.9 (CAS No. 27216-37-1 or 126-13-6).

[0111] In some embodiments, the composition comprises about 30% to 90% w / v SAIB, preferably about 40% to 85% w / v SAIB, more preferably about 70% to 80% w / v SAIB, even more preferably about 70% w / v SAIB. 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 86, 87, 88, 89, and 90.

[0112] Any suitable solvent or solvents may be used provided that they produce a low viscosity injectable gel. Preferred solvents include ethanol, TM The solvents include diethylene glycol monoethyl ether (DEGEE), N-methylpyrrolidone (NMP), triacetin, benzyl benzoate, miglyol, propylene carbonate, benzyl alcohol, ethyl lactate, glycofurol, 2-pyrrolidone, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid and 1-dodecylazacycloheptan-2-one sold under the trademark TETRAZOL. The amount of the one or more solvents may be about 0-50% w / v, preferably about 10-30% w / v. These ranges include all values ​​and subranges between 0-50 and 10-30, including 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50.

[0113] Any suitable surfactant or surfactants may be used provided that they produce a low viscosity injectable gel. Preferred surfactants include nonionic surfactants, polysorbates, Tween, polyoxyethylene (20) sorbitan monooleate (Tween 80) or polyoxyethylene (20) sorbitan monolaurate (Tween 20). The amount of surfactant may be up to about 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75 or 3.0% w / v, or, for example, about 0-3% w / v, 0-2% w / v, 0-1% w / v, 1-3% w / v or 1-2% w / v. These ranges include all values ​​and subranges between 0-3, 0-2, 0-1, 1-3 and 1-2.

[0114] The concentration of the cytotoxic agent in the composition administered to an animal is preferably in the range of about 0.01% weight / volume (w / v) to about 100% w / v, depending on the potency of the cytotoxic agent, including all values ​​and subranges between 0.01-100, including about 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 2, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100.

[0115] The volume of the composition applied to the horn bud is preferably in the range of about 0.05 to about 10 mL, including all values ​​between 0.05 -10. A particularly preferred range is 0.1-2.0 mL, including all values ​​between 0.1-2.0. For example, an amount of about 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, or 1.5 mL of the composition may be applied to the horn bud. Up to about 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1 mL, 1.25 mL, or 1.5 mL of the composition is preferably injected.

[0116] The cytotoxic agent can be administered to the young animal in any suitable manner. Preferably, the cytotoxic agent is administered by injection. In some embodiments, a single injection is administered. In some embodiments, more than one injection is administered, such as 2, 3 or 4 injections are administered over a suitable period of time.

[0117] The animals are preferably injected (administered) using a syringe. It is preferred to use a syringe that is suitable for use in one hand so that the other hand can be used to stabilize the animal's head and locate the horn bud.

[0118] In some embodiments, the syringe is suitable for providing multiple doses, such as an auto-vaccinating syringe, a self-filling injection syringe, or a multi-dose auto-injector. An example of a suitable syringe is a McLintock syringe, commonly used for tuberculin testing, but can be configured to administer the desired dose volume.

[0119] Preferred embodiments of the present invention are defined in the following numbered paragraphs:

[0120] 1. A method for chemically removing the horns of young animals or inhibiting the growth of horns of young animals, the method being performed by administering at least one cytotoxic agent to the horn bud cells of the animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0121] 2. Use of at least one cytotoxic agent for chemical dehorning of young animals or inhibiting horn growth of young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0122] 3. At least one cytotoxic agent for use in or when used for chemically dehorning a young animal or inhibiting horn growth in a young animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0123] 4. Use of at least one cytotoxic agent in the preparation of a medicament for chemical dehorning of young animals or inhibiting horn growth of young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0124] 5. A composition comprising at least one cytotoxic agent, the composition being formulated for administration to a juvenile animal to chemically dehorn the juvenile animal or inhibit horn growth in the juvenile animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0125] 6. A syringe containing at least one cytotoxic agent, the cytotoxic agent is used or when used for dehorning a young animal or inhibiting horn growth of a young animal, wherein the syringe is capable of administering the at least one cytotoxic agent to the horn bud cells of the young animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0126] 7. A kit of parts for use in or when used in a method for dehorning a young animal or inhibiting horn growth of a young animal, wherein the kit of parts comprises: a syringe capable of administering at least one cytotoxic agent to horn bud cells of a young animal; and at least one cytotoxic agent, wherein the at least one cytotoxic agent kills the horn bud cells in a certain amount, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

[0127] 8. The method according to paragraph 1, the use according to paragraph 2, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to paragraph 3, the use according to paragraph 4, the composition according to paragraph 5, the syringe according to paragraph 6 or the kit according to paragraph 7, wherein the at least one cytotoxic agent is in the form of a free acid, a free base or a salt.

[0128] 9. The method according to paragraph 1 or 8, the use according to paragraph 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 3 or 8, the use according to paragraph 4 or 8, the composition according to paragraph 5 or 8, the syringe according to paragraph 6 or 8, or the kit according to paragraph 7 or 8, wherein the at least one cytotoxic agent comprises at least one sclerosing agent.

[0129] 10. The method according to paragraph 9, the use according to paragraph 9, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 9, the use according to paragraph 9, the composition according to paragraph 9, the syringe according to paragraph 9 or the kit according to paragraph 9, wherein:

[0130] The at least one sclerosing agent comprises imipaline (quinacrine), chloroquine, polidocanol or quinine;

[0131] The at least one hardener comprises an acridine, preferably mepacrine; or

[0132] The at least one hardening agent comprises mepacrine.

[0133] 11. The method according to paragraph 1 or 8, the use according to paragraph 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to paragraph 3 or 8, the use according to paragraph 4 or 8, the composition according to paragraph 5 or 8, the syringe according to paragraph 6 or 8 or the kit according to paragraph 7 or 8, wherein the at least one cytotoxic agent comprises at least one p53 activator.

[0134] 12. The method according to paragraph 11, the use according to paragraph 11, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 11, the use according to paragraph 11, the composition according to paragraph 11, the syringe according to paragraph 11 or the kit according to paragraph 11, wherein:

[0135] The at least one p53 activator comprises mepaline or chloroquine;

[0136] The at least one p53 activator comprises an acridine, preferably mepacrine; or

[0137] The at least one p53 activator comprises mepacrine.

[0138] 13. The method according to paragraph 1 or 8, the use according to paragraph 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 3 or 8, the use according to paragraph 4 or 8, the composition according to paragraph 5 or 8, the syringe according to paragraph 6 or 8, or the kit according to paragraph 7 or 8, wherein the at least one cytotoxic agent comprises at least one antiprotozoal agent.

[0139] 14. The method according to paragraph 13, the use according to paragraph 13, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 13, the use according to paragraph 13, the composition according to paragraph 13, the syringe according to paragraph 13 or the kit according to paragraph 13, wherein:

[0140] The at least one antiprotozoal agent comprises at least one antimalarial agent;

[0141] The at least one antiprotozoal agent comprises mepacrine, chloroquine, or quinine;

[0142] The at least one antiprotozoal agent comprises an acridine, preferably mepacrine; or

[0143] The at least one antiprotozoal agent comprises mepacrine.

[0144] 15. The method according to paragraph 1 or 8, the use according to paragraph 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to paragraph 3 or 8, the use according to paragraph 4 or 8, the composition according to paragraph 5 or 8, the syringe according to paragraph 6 or 8, or the kit according to paragraph 7 or 8, wherein the at least one cytotoxic agent comprises at least one apoptosis inducer.

[0145] 16. The method according to paragraph 15, the use according to paragraph 15, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 15, the use according to paragraph 15, the composition according to paragraph 15, the syringe according to paragraph 15 or the kit according to paragraph 15, wherein:

[0146] The at least one apoptosis inducer comprises mepacrine or cinchocaine;

[0147] The at least one apoptosis inducing agent comprises an acridine, preferably mepacrine; or

[0148] The at least one apoptosis inducer comprises mepacrine.

[0149] 17. The method according to paragraph 1 or 8, the use according to paragraph 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to paragraph 3 or 8, the use according to paragraph 4 or 8, the composition according to paragraph 5 or 8, the syringe according to paragraph 6 or 8 or the kit according to paragraph 7 or 8, wherein the at least one cytotoxic agent comprises at least one anesthetic.

[0150] 18. The method according to paragraph 17, the use according to paragraph 17, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 17, the use according to paragraph 17, the composition according to paragraph 17, the syringe according to paragraph 17 or the kit according to paragraph 17, wherein:

[0151] The at least one anesthetic agent comprises an amide anesthetic, an ester anesthetic, or a non-ionic surfactant anesthetic;

[0152] The at least one anesthetic agent comprises lidocaine, chloroprocaine, mepivacaine, bupivacaine, articaine, etidocaine, levobupivacaine, tetracaine, prilocaine, benzocaine, ropivacaine, cocaine, hydroxyprocaine, hexylcaine, dibucaine, perralcaine or procaine, or a pharmaceutically acceptable acid, base or salt thereof;

[0153] The at least one anesthetic agent comprises mepacrine, polidocanol, cinchocaine, chloroquine or quinine;

[0154] The at least one anesthetic comprises an acridine, preferably mepacrine; or

[0155] The at least one anesthetic agent comprises mepacrine.

[0156] 19. The method according to paragraph 1 or 8, the use according to paragraph 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to paragraph 3 or 8, the use according to paragraph 4 or 8, the composition according to paragraph 5 or 8, the syringe according to paragraph 6 or 8, or the kit according to paragraph 7 or 8, wherein the at least one cytotoxic agent comprises mepacrine, polidocanol, cinchocaine, chloroquine or quinine.

[0157] 20. The method according to paragraph 19, the use according to paragraph 19, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 19, the use according to paragraph 19, the composition according to paragraph 19, the syringe according to paragraph 19 or the kit according to paragraph 19, wherein:

[0158] The at least one cytotoxic agent is administered or administrable in an amount comprising about 100-400 mg of mepaline as a free base;

[0159] The at least one cytotoxic agent is administered or administrable in an amount comprising about 100-400 mg of mepacrine as a salt;

[0160] The at least one cytotoxic agent is administered or administrable in an amount comprising about 100-400 mg of mepaline dihydrochloride;

[0161] The at least one cytotoxic agent is administered or administrable in an amount comprising an amount equivalent to about 0.5 mL of polidocanol (95%-100%);

[0162] The at least one cytotoxic agent is administered or administrable in an amount comprising about 150-250 mg of chloroquine as a free base;

[0163] The at least one cytotoxic agent is administered or administrable in an amount comprising about 150-250 mg of chloroquine as a salt; or

[0164] The amount of at least one cytotoxic agent administered or administrable comprises about 150-250 mg of chloroquine diphosphate.

[0165] 21. A method according to any one of paragraphs 1 and 8-20, a use according to any one of paragraphs 2 and 8-20, at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to any one of paragraphs 3 and 8-20, a use according to any one of paragraphs 4 and 8-20, a composition according to any one of paragraphs 5 and 8-20, a syringe according to any one of paragraphs 6 and 8-20, or a kit according to any one of paragraphs 7 and 8-20, wherein the at least one cytotoxic agent is administered or can be administered to the young animal by one or more injections, preferably a single injection.

[0166] 22. A method according to any one of paragraphs 1 and 8-21, a use according to any one of paragraphs 2 and 8-21, at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to any one of paragraphs 3 and 8-21, a use according to any one of paragraphs 4 and 8-21, a composition according to any one of paragraphs 5 and 8-21, a syringe according to any one of paragraphs 6 and 8-21, or a kit according to any one of paragraphs 7 and 8-21, wherein the at least one cytotoxic agent is administered or can be administered to the young animal in the form of a liquid composition capable of providing sustained release of the at least one cytotoxic agent.

[0167] 23. The method according to paragraph 22, the use according to paragraph 22, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 22, the use according to paragraph 22, the composition according to paragraph 22, the syringe according to paragraph 22 or the kit according to paragraph 22, wherein the liquid composition is in the form of a solution, suspension, dispersion, emulsion or low viscosity gel.

[0168] 24. The method according to paragraph 23, the use according to paragraph 23, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to paragraph 23, the use according to paragraph 23, the composition according to paragraph 23, the syringe according to paragraph 23 or the kit according to paragraph 23, wherein the liquid composition is in the form of a low viscosity injectable gel, which is formulated to gel rapidly at the injection site and prolong the release of the at least one cytotoxic agent from the gel.

[0169] 25. The method according to paragraph 24, the use according to paragraph 24, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 24, the use according to paragraph 24, the composition according to paragraph 24, the syringe according to paragraph 24 or the kit according to paragraph 24, wherein the low viscosity injectable gel comprises one or more gelling agents, one or more solvents or solvent systems, and optionally one or more surfactants.

[0170] 26. The method according to paragraph 25, the use according to paragraph 25, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 25, the use according to paragraph 25, the composition according to paragraph 25, the syringe according to paragraph 25 or the kit according to paragraph 25, wherein the low viscosity injectable gel comprises:

[0171] Sucrose acetate isobutyrate (SAIB) and at least one solvent as the one or more gelling agents; or

[0172] SAIB as the one or more gelling agents, at least one solvent and at least one surfactant.

[0173] 27. The method according to paragraph 26, the use according to paragraph 26, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 26, the use according to paragraph 26, the composition according to paragraph 26, the syringe according to paragraph 26 or the kit according to paragraph 26, wherein the low viscosity injectable gel comprises:

[0174] About 30%-90% w / v SAIB;

[0175] About 40%-85% w / v SAIB;

[0176] About 70%-80% w / v SAIB; or

[0177] About 70% w / v SAIB.

[0178] 28. The method according to paragraph 26 or 27, the use according to paragraph 26 or 27, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 26 or 27, the use according to paragraph 26 or 27, the composition according to paragraph 26 or 27, the syringe according to paragraph 26 or 27 or the kit according to paragraph 26 or 27, wherein the low viscosity injectable gel comprises:

[0179] about 0-50% w / v of the at least one solvent; or

[0180] About 15-30% w / v of the at least one solvent.

[0181] 29. The method according to paragraph 28, the use according to paragraph 28, the at least one cytotoxic agent for or when used for chemically dehorning a young animal or inhibiting horn growth in a young animal according to paragraph 28, the use according to paragraph 28, the composition according to paragraph 28, the syringe according to paragraph 28 or the kit according to paragraph 28, wherein the at least one solvent comprises one or more of the following: ethanol, diethylene glycol monoethyl ether (DEGEE), N-methylpyrrolidone (NMP), triacetin, benzyl benzoate, miglyol, propylene carbonate, benzyl alcohol, ethyl lactate, tetraethylene glycol, 2-pyrrolidone, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid and 1-dodecylazacycloheptan-2-one.

[0182] 30. The method according to paragraph 26, 27, 28 or 29, the use according to paragraph 26, 27, 28 or 29, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 26, 27, 28 or 29, the use according to paragraph 26, 27, 28 or 29, the composition according to paragraph 26, 27, 28 or 29, the syringe according to paragraph 26, 27, 28 or 29 or the kit according to paragraph 26, 27, 28 or 29, wherein the low viscosity injectable gel comprises:

[0183] about 0-3% w / v of said at least one surfactant;

[0184] about 0-2% w / v of said at least one surfactant;

[0185] about 0-1% w / v of the at least one surfactant;

[0186] about 1-3% w / v of the at least one surfactant; or

[0187] About 1-2% w / v of the at least one surfactant.

[0188] 31. The method according to paragraph 30, the use according to paragraph 30, the at least one cytotoxic agent for chemically dehorning a young animal or inhibiting horn growth in a young animal according to paragraph 30, the use according to paragraph 30, the composition according to paragraph 30, the syringe according to paragraph 30 or the kit according to paragraph 30, wherein the at least one surfactant comprises one or more of the following: a nonionic surfactant, a polysorbate, Tween, polyoxyethylene (20) sorbitan monooleate (Tween 80) or polyoxyethylene (20) sorbitan monolaurate (Tween 20).

[0189] 32. The method according to paragraph 26, the use according to paragraph 26, the at least one cytotoxic agent for chemical dehorning of a young animal or inhibiting horn growth of a young animal according to paragraph 26, the use according to paragraph 26, the composition according to paragraph 26, the syringe according to paragraph 26 or the kit according to paragraph 26, wherein the low viscosity injectable gel comprises: all in about % w / v,

[0190] 10% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride;

[0191] 40-85% w / v SAIB;

[0192] 0-2% w / v Tween 80;

[0193] 0-50% w / v triacetin;

[0194] 0-50% w / v DEGEE; and

[0195] Ethanol is made up to 100% volume, where:

[0196] The concentration of ethanol is 0-30% w / v; or

[0197] In the absence of other solvents and Tween, and at 10% mepaline base and SAIB level of 80% w / v, assuming a weight of 1.1 g per mL of formulation, the ethanol concentration was 20% w / v.

[0198] 33. The method according to paragraph 26, the use according to paragraph 26, the at least one cytotoxic agent for chemically dehorning a young animal or inhibiting horn growth in a young animal according to paragraph 26, the use according to paragraph 26, the composition according to paragraph 26, the syringe according to paragraph 26 or the kit according to paragraph 26, wherein the low viscosity injectable gel comprises: all in about % w / v,

[0199] 20% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v;

[0200] 40-85% w / v SAIB;

[0201] 0-2% w / v Tween 80;

[0202] 0-50% w / v triacetin;

[0203] 0-50% w / v DEGEE; and

[0204] Ethanol is made up to 100% volume, where:

[0205] The concentration of ethanol is 0-30% w / v; or

[0206] In the absence of other solvents and Tween, and at 23.6% mepaline dihydrochloride and a SAIB level of 85% w / v, assuming a weight of 1.1 g per mL, the ethanol concentration would be 1.4% w / v, which may be too low, in which case the maximum SAIB concentration would have to be reduced.

[0207] 34. The method according to paragraph 26, the use according to paragraph 26, the at least one cytotoxic agent for chemical dehorning of a young animal or inhibiting horn growth of a young animal according to paragraph 26, the use according to paragraph 26, the composition according to paragraph 26, the syringe according to paragraph 26 or the kit according to paragraph 26, wherein the low viscosity injectable gel comprises: all in about % w / v,

[0208] 10% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride;

[0209] 70% w / v SAIB;

[0210] 1% w / v Tween 80;

[0211] 5% w / v triacetin;

[0212] 0% w / v DEGEE; and

[0213] The ethanol was made up to 100% volume, ie, 22.2% w / v ethanol, assuming a weight of 1.1 g per mL.

[0214] 35. The method according to paragraph 26, the use according to paragraph 26, the at least one cytotoxic agent for chemically dehorning a young animal or inhibiting horn growth in a young animal according to paragraph 26, the use according to paragraph 26, the composition according to paragraph 26, the syringe according to paragraph 26 or the kit according to paragraph 26, wherein the low viscosity injectable gel comprises: all in about % w / v,

[0215] 20% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v;

[0216] 70% w / v SAIB;

[0217] 1% w / v Tween 80;

[0218] 5% w / v triacetin;

[0219] 0% w / v DEGEE; and

[0220] The ethanol was made up to 100% volume, ie, assuming a weight of 1.1 g per mL, it was 10.4% w / v ethanol.

[0221] 36. A composition formulated as a solution, suspension, dispersion, emulsion, low viscosity gel or other sustained release liquid formulation, comprising at least one cytotoxic agent and one or more excipients and capable of providing sustained release of the at least one cytotoxic agent, wherein the at least one cytotoxic agent is one or more of a sclerosing agent, a p53 activator, an antiprotozoal agent, an apoptosis inducer and a local anesthetic.

[0222] 37. The composition according to paragraph 36, which is formulated as an injectable oily solution or suspension and comprises at least one oily excipient.

[0223] 38. The composition according to paragraph 37, comprising: all in about % w / v,

[0224] 10-15% w / v of at least one cytotoxic agent, preferably mepacrine or a salt thereof providing 10-15% w / v mepacrine, such as 11.8-17.7% w / v mepacrine dihydrochloride; and

[0225] Aqueous or oily suspension, preferably oily suspension.

[0226] 39. The composition of paragraph 36 formulated as a low viscosity injectable gel.

[0227] 40. The composition of paragraph 39, formulated to rapidly gel at the injection site in an animal and to prolong the release of the at least one cytotoxic agent from the gel.

[0228] 41. A composition according to paragraph 39 or 40, comprising: all in about % w / v,

[0229] 10-15% w / v of at least one cytotoxic agent, preferably mepacrine or a salt thereof providing 10-15% w / v mepacrine, such as 11.8-17.7% w / v mepacrine dihydrochloride.

[0230] 42. The composition of paragraph 39, 40 or 41, wherein the low viscosity injectable gel comprises one or more gelling agents, one or more solvents or solvent systems, and optionally one or more surfactants.

[0231] 43. A composition according to paragraph 42, wherein the low viscosity injectable gel comprises:

[0232] Sucrose acetate isobutyrate (SAIB) and at least one solvent as the one or more gelling agents; or

[0233] SAIB as the one or more gelling agents, at least one solvent and at least one surfactant.

[0234] 44. The composition according to paragraph 43, wherein the low viscosity injectable gel comprises:

[0235] About 30%-90% w / v SAIB;

[0236] About 40%-85% w / v SAIB;

[0237] About 70%-80% w / v SAIB; or

[0238] About 70% w / v SAIB.

[0239] 45. The composition according to paragraph 43 or 44, wherein the low viscosity injectable gel comprises:

[0240] about 0-50% w / v of the at least one solvent; or

[0241] About 15-30% w / v of the at least one solvent.

[0242] 46. ​​The composition of paragraph 45, wherein the at least one solvent comprises one or more of ethanol, diethylene glycol monoethyl ether (DEGEE), N-methylpyrrolidone (NMP), triacetin, benzyl benzoate, miglyol, propylene carbonate, benzyl alcohol, ethyl lactate, tetraethylene glycol, 2-pyrrolidone, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one.

[0243] 47. The composition of paragraph 42, 43, 44, 45 or 46, wherein the low viscosity injectable gel comprises:

[0244] about 0-3% w / v of said at least one surfactant;

[0245] about 0-2% w / v of said at least one surfactant;

[0246] about 0-1% w / v of the at least one surfactant;

[0247] about 1-3% w / v of the at least one surfactant; or

[0248] About 1-2% w / v of the at least one surfactant.

[0249] 48. A composition according to paragraph 47, wherein the at least one surfactant comprises one or more of the following: a nonionic surfactant, a polysorbate, Tween, polyoxyethylene (20) sorbitan monooleate (Tween 80) or polyoxyethylene (20) sorbitan monolaurate (Tween 20).

[0250] 49. The composition of paragraphs 41, 42, 43, 44, 45, 46, 47 or 48, wherein the low viscosity injectable gel comprises: all in about % w / v,

[0251] 10% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride;

[0252] 40-85% w / v SAIB;

[0253] 0-2% w / v Tween 80;

[0254] 0-50% w / v triacetin;

[0255] 0-50% w / v DEGEE; and

[0256] Ethanol is made up to 100% volume, where:

[0257] The concentration of ethanol is 0-30% w / v; or

[0258] In the absence of other solvents and Tween, and at a SAIB level of 80% w / v, assuming a weight of 1.1 g per mL of formulation, the ethanol concentration was 18.2% w / v.

[0259] 50. The composition of paragraph 41, 42, 43, 44, 45, 46, 47 or 48, wherein the low viscosity injectable gel comprises: all in about % w / v,

[0260] 20% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v;

[0261] 40-85% w / v SAIB;

[0262] 0-2% w / v Tween 80;

[0263] 0-50% w / v triacetin;

[0264] 0-50% w / v DEGEE; and

[0265] Ethanol is made up to 100% volume, where:

[0266] The concentration of ethanol is 0-30% w / v; or

[0267] In the absence of other solvents and Tween, and at a SAIB level of 85% w / v, assuming a weight of 1.1 g per mL, the ethanol concentration is 1.4% w / v, which may be too low, in which case the maximum SAIB concentration must be reduced.

[0268] 51. The composition of paragraph 41, 42, 43, 44, 45, 46, 47 or 48, wherein the low viscosity injectable gel comprises: all in about % w / v,

[0269] 10% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride;

[0270] 70% w / v SAIB;

[0271] 1% w / v Tween 80;

[0272] 5% w / v triacetin;

[0273] 0% w / v DEGEE; and

[0274] The ethanol was made up to 100% volume, ie, 22.2% w / v ethanol, assuming a weight of 1.1 g per mL.

[0275] 52. The composition of paragraphs 41, 42, 43, 44, 45, 46, 47 or 48, wherein the low viscosity injectable gel comprises: all in about % w / v,

[0276] 20% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v;

[0277] 70% w / v SAIB;

[0278] 1% w / v Tween 80;

[0279] 5% w / v triacetin;

[0280] 0% w / v DEGEE; and

[0281] The ethanol was made up to 100% volume, ie, assuming a weight of 1.1 g per mL, it was 10.4% w / v ethanol.

[0282] 53. The composition of any of paragraphs 36-52, wherein the at least one cytotoxic agent is mepaline dihydrochloride.

[0283] 54. The method of paragraph 1, the use of paragraph 2, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to paragraph 3, the use of paragraph 4, the syringe of paragraph 6 or the kit of parts of paragraph 7, wherein the at least one cytotoxic agent is formulated as a composition according to any one of paragraphs 36-53.

[0284] A composition, medicament or formulation as described herein (including the examples and claims, including any tables presented herein). BRIEF DESCRIPTION OF THE DRAWINGS

[0285] Further aspects of the invention will become apparent from the ensuing description, given by way of example only, and with reference to the accompanying drawings, in which:

[0286] Figure 1 - Related to Example 3. Chemical dehorning of calves using eugenol. Painless swelling at the site of eugenol injection.

[0287] Figure 2 - Related to Example 3. Representative images of different chemical dehorning treatments used on calves: 1) eugenol; 2) mepacrine; 3) eugenol + mepacrine in water (20:80); and 4) eugenol + mepacrine in water (80:20). Example

[0288] Example 1 - Chemical exfoliation using mepaline

[0289] A study was conducted to test the dehorning effect of applying mepaline dihydrochloride to horn buds compared to the traditional iron dehorning method. Mepaline dihydrochloride was applied as a composition comprising mepaline dihydrochloride suspended in water. The composition was prepared by dispersing mepaline dihydrochloride powder into water for injection. Immediately prior to application, the composition was shaken to resuspend the mepaline dihydrochloride.

[0290] The animals (calves) in the study were divided into multiple groups. Groups 1-4 were administered a single dose of 0.5 mL of the mepaline dihydrochloride composition, and each group was administered a composition having a different concentration of mepaline dihydrochloride, ranging from 50 mg / mL to 400 mg / mL.

[0291] Groups 5-8 were administered a split dose of 0.5 mL of the mepaline dihydrochloride composition, each group being administered a composition having a different concentration of mepaline dihydrochloride, ranging from 50 mg / mL to 400 mg / mL. Each split dose included 5 0.1 mL doses administered around the horn bud.

[0292] Administration of mepaline dihydrochloride was performed by injection of the mepaline dihydrochloride composition using a McLintock pre-set syringe configured to administer up to 0.5 mL. Single dose administration for Groups 1-4 was performed by injecting the composition directly into the horn bud. Split dose administration for Groups 5-8 was performed by injecting smaller multiple doses into the area immediately surrounding the horn bud. Animals in the control group, Group 9, were first treated with a 2% lidocaine injection as a horn nerve block and then dehorned using a conventional iron.

[0293] Each animal in the study underwent a dehorning procedure, i.e., dehorning with either mepaline dihydrochloride or iron, applied only to the right horn bud. The left horn bud of each animal was left untreated as a control.

[0294] The animals in the study were dairy cow calves that were gradually introduced into the study and treated at 7 days of age.

[0295] The study protocol and results are shown in Table 1. The success rate was based on the proportion of horn buds that were treated with no subsequent horn growth or with a rudimentary horn. A rudimentary horn is a deformed horn that is not attached to the skull. The rudimentary horn removal procedure was found to be most successful with the higher concentrations of imipaline dihydrochloride. In particular, the administration of 0.5 mL of 200 mg / mL and 400 mg / L imipaline dihydrochloride had a high success rate in both single injections and split doses using multiple injections. Every untreated horn bud developed into a horn in every animal.

[0296] Animals that received mepaline dehorning were observed to show very minimal pain responses. Animals that received injections showed discomfort during the injection procedure and no subsequent pain activity after the injection was completed.

[0297] Table 1: Mepaline dehorning studies

[0298]

[0299]

[0300] The high concentrations of 200 and 400 mg / mL had a higher success rate than the lower concentrations of 50 and 100 mg / mL. There was no clear advantage to dividing the dose into multiple injections.

[0301] The dehorning procedure by applying mepaline to each animal took less than 1 minute, whereas dehorning animals with a soldering iron takes 5-10 minutes. Animals treated with mepaline experienced little discomfort during the application and showed no pain reactions / behaviors.

[0302] Example 2 - Chemical exfoliation using chloroquine diphosphate and polidocanol

[0303] A study was conducted on calves to test the efficacy of dehorning with chloroquine diphosphate and polidocanol applied to horn buds.

[0304] Chloroquine diphosphate is administered as a composition comprising chloroquine diphosphate suspended in water. The composition is prepared by dispersing chloroquine diphosphate powder into water for injection. Immediately prior to administration, the composition is shaken to resuspend the chloroquine diphosphate.

[0305] Polidocanol was administered as undiluted polidocanol at 100% concentration at the time of administration, or as diluted solutions in 90%, 50% and 10% concentration groups diluted with water.

[0306] The animals in the study were divided into groups. Group 1 and Group 2 were administered with saline solution (0.9% sodium chloride) as a single dose for Group 1 and as split doses for Group 2. Each split dose consisted of 5 0.1 mL doses administered around the horn bud.

[0307] Groups 3 and 4 were administered 100 mg / mL or 300 mg / mL of chloroquine diphosphate, and groups 5-8 were administered different concentrations of polidocanol ranging from 100%-10% w / v.

[0308] The saline control group showed no change in normal horn growth. Chloroquine diphosphate showed some success at a concentration of 300 mg / mL, with half of the animals having no horn growth at all, while the others only formed rudimentary horns. Polidocanol was successful at the 100% and 10% concentrations, with less success at the other concentrations. It was observed that the higher concentration compositions had high viscosities, and the lack of success may be due to insufficient administration into the horn bud - for example, when applied at a 90% concentration.

[0309] Table 2: Chloroquine and polidocanol exfoliation studies

[0310]

[0311]

[0312] Example 3 - Chemical exfoliation using mepalene and eugenol

[0313] Methodology

[0314] Sixteen calves (4-6 days old) obtained from a commercial dairy farm were used in this study. The calves were randomly assigned to receive one of the four formulations (Table 3). The animals were gently restrained and the hair around the horn bud area was clipped. The formulations (0.3-0.5 mL) were then injected subcutaneously under or around the right horn bud using a McLintock syringe and needle (22G 11 / 64", 0.71*4.3 mm), delivering 0.1 mL per injection. The left horn bud served as a control. The details of the treatments are shown in Table 3 below. The animals were observed for pain-related behaviors during and after the injections. The difference in the growth rate of the left and right horn buds was determined by measuring the height of the horn buds regularly. Photos of the horn buds were taken at the same time. After 4 months, the calves were euthanized by intravenous injection of sodium pentobarbital (100 mg / kg body weight) for gross pathology and histopathology of the horn buds.

[0315] Table 3: Details of the treatments

[0316]

[0317]

[0318] Eugenol-Sigma Aldrich (Lot#STBG9481); Mepaline or Quinacrine dihydrochloride-Sigma Aldrich (Lot#BCBR3327)

[0319] result

[0320] The calves showed minimal resistance during the injection of the formulation. Each injection took less than one second, and the total injection time after restraining the calves was less than one minute. No behavioral signs related to pain, such as shaking the head or scratching the head, were observed in any animal after injection of the formulation. Swelling around the horn buds was observed after injection of eugenol and eugenol + mepacrine aqueous solutions (80:20). The swelling was painless to the touch and subsided after a few days. In addition, scars and depressions were observed at the injection sites of animals receiving eugenol and eugenol + mepacrine (80:20). No such adverse reactions were observed in the other two groups. The growth rate of horn buds is shown in Table 4.

[0321] Table 4: Growth rate of horn buds after injection of the formulation into the right horn bud

[0322]

[0323] Summarize

[0324] Table 5: Subjective evaluation of efficacy

[0325]

[0326]

[0327] Discovery of Example 3

[0328] The dehorning technique of this embodiment appears to be simple, quick, and effective, and does not require postoperative pain relief.

[0329] Key findings:

[0330] 1) Injection of the preparation using a McLintock syringe and needle is quick, easy and causes minimal pain.

[0331] 2) All formulations appeared to arrest growth when injected beneath the horn bud.

[0332] 3) Injection around the horn bud reduced growth but failed to completely prevent it in most animals.

[0333] 4) Eugenol and its combination (eugenol + mepacrine aqueous solution (80:20)) produced slight swelling and scarring at the injection site. No such effects were observed after injection of mepacrine aqueous solution or eugenol + mepacrine aqueous solution (20:80).

[0334] 5) The absence of behavioral signs related to pain after injection may mean that postoperative pain relief is not required if these preparations are used.

[0335] General conclusions

[0336] The inventors have discovered that mepacrine, polidocanol and chloroquine act as effective chemical exfoliants, thereby overcoming or reducing many of the disadvantages of previously known exfoliation procedures.

[0337] The animals appear to tolerate injections of these chemical exfoliants well.

[0338] These chemical exfoliants are safer and easier to apply than traditional exfoliation techniques.

[0339] A single injection of these chemical dehorning agents can remove the horns from an animal.

[0340] These chemical exfoliants target the horn bud cells / horn buds / horn bud tissue and therefore cause much less collateral damage to surrounding tissue than some traditional exfoliation techniques.

[0341] These chemical exfoliants provide a local anesthetic effect, thus eliminating the need for post-operative pain relief.

[0342] Unlike eugenol, these chemical exfoliants do not cause swelling at the injection site.

[0343] Unlike eugenol, these chemical exfoliants do not create open wounds or scars at the injection site, reducing the chance of infection.

[0344] Example 4 - Low viscosity injectable gel formulation: SAIB + cytotoxic agent

[0345] It is believed that the composition that provides extended cytotoxic agent release from the injection site can provide the same or better dehorning results. It is believed that a lower amount of cytotoxic agent can be used in the composition of the injectable extended release compared with the cytotoxic agent tested. It is envisioned that the composition used can be in the form of a low-viscosity injectable gel (solution or suspension), which quickly gels at the injection site to retain the cytotoxic agent for an appropriate (effective treatment) time. In this way, a relatively large amount of cytotoxic agent can be delivered to horn bud cells (horn bud tissue). It is believed that a composition containing a cytotoxic agent, sucrose acetate isobutyrate (SAIB) and a solvent can achieve this. Once a composition containing a SAIB preparation and a solvent is injected, the solvent will diffuse out, leaving a matrix that is both sticky and thick. The matrix can retain the cytotoxic agent in the horn bud cells for a period of time, rather than the cytotoxic agent dispersing immediately.

[0346] Preferred cytotoxic agent + SAIB formulations are described below.

[0347] Ingredient Range

[0348] Although the solvents triacetin, Transcutol TM(diethylene glycol monoethyl ether) and ethanol, but other solvents may be used instead of or in addition to these solvents. The inventors' research principle is that they need 40-85% SAIB and up to 30% ethanol to adjust the release rate of the cytotoxic agent.

[0349] Table 6: Cytotoxic agent + SAIB formulation composition range

[0350] Element g %w / v Cytotoxic agents** 0.1 10 SAIB 0.4-0.85 40-85 Tween 80 0.0-0.02 0-2 Triacetin 0-0.5 0-50 <![CDATA[Transcutol TM ]]> 0-0.5 0-50 Ethanol to make up to* 1.0mL 100

[0351] **Mepaline dihydrochloride is used as an example.

[0352] *The mass of ethanol varies from 0-0.3 g, i.e., 0-30% w / v, and in the absence of other solvents and Tween, at a SAIB level of 0.85 g (85%), assuming a weight of 1.1 g per mL of formulation, the ethanol is 0.15 g (15% w / v).

[0353] Table 7: Cytotoxic agent + SAIB formulation composition range

[0354]

[0355]

[0356] **Mepaline dihydrochloride is used as an example.

[0357] *The mass of ethanol can vary from 0-0.45 g, i.e., 0-30% w / v, and in the absence of other solvents and Tween, at a SAIB level of 1.275 g (85%), the ethanol is 0.075 g (5%), which may be too low, in which case the maximum concentration of SAIB must be reduced.

[0358] Table 8: Preferred cytotoxic agent + SAIB formulations

[0359] Element g %w / v Cytotoxic agents** 0.1 10 SAIB 0.7 70 Tween 80 0.01 1 Triacetin 0.05 5 <![CDATA[Transcutol TM ]]> 0 0 Ethanol to make up to* 1.0mL 100 (i.e., about 24% w / v)

[0360] ** Taking mepacrine as dihydrochloride as an example, therefore, 0.118 g of mepacrine dihydrochloride.

[0361] *The mass of ethanol required is 0.22 g or 22% w / v (assuming a weight of 1.1 g per mL).

[0362] Table 8: Preferred cytotoxic agent + SAIB formulations

[0363] Element g %w / v Cytotoxic agents** 0.3 20 SAIB 0.975 65 Tween 80 0.015 1 Triacetin 0.075 5 <![CDATA[Transcutol TM ]]> 0 0 Ethanol to make up to* 1.5mL 100 i.e. about 19% w / v)

[0364] ** Taking mepacrine as dihydrochloride as an example, therefore 0.355 g of mepacrine dihydrochloride.

[0365] *The mass of ethanol required is 0.23 g or 15.3% w / v (assuming a weight of 1.1 g per mL of formulation).

[0366] All estimates of % w / v ethanol assume a weight of 1.1 g per mL of formulation. Actual values ​​will vary, for example, the weight per mL may be lower as the SAIB content decreases. Actual values ​​will be determined experimentally using well-known methods.

[0367] Various aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope defined in the appended claims.

[0368] All references, including any patents or patent applications cited in this specification, are incorporated herein by reference. No admission is made that any reference constitutes prior art. It is to be clearly understood that, although a number of prior art publications are cited herein, this citation does not constitute an admission that any of these documents constitute part of the common general knowledge in the art in any country.

[0369] Throughout this specification, the word "comprise" or variations thereof (such as "includes" or "comprising") will be understood to imply the inclusion of stated elements, integers or steps, or groups of elements, integers or steps, but not the exclusion of any other elements, integers or steps, or groups of elements, integers or steps.

[0370] The terms "about" or "approximately" generally, where the context permits, mean plus or minus 10% of the recited number, but this is not necessarily the case.

Claims

1. A method for chemically dehorning or inhibiting horn growth in young animals by administering at least one cytotoxic agent to horn bud cells of the animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

2. Use of at least one cytotoxic agent for chemical dehorning of young animals or inhibiting horn growth of young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

3. At least one cytotoxic agent for use in or when used for chemically dehorning a young animal or inhibiting horn growth in a young animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

4. Use of at least one cytotoxic agent in the preparation of a medicament for chemical dehorning of young animals or inhibiting horn growth of young animals, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

5. A composition comprising at least one cytotoxic agent, the composition being formulated for administration to a juvenile animal and for chemically dehorning the juvenile animal or inhibiting horn growth in the juvenile animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

6. A syringe containing at least one cytotoxic agent, the cytotoxic agent is used or when used for dehorning a young animal or inhibiting horn growth of a young animal, wherein the syringe is capable of administering the at least one cytotoxic agent to the horn bud cells of the young animal, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer or local anesthetic.

7. A kit of parts for use in or when used in a method of dehorning or inhibiting horn growth in a young animal, wherein the kit of parts comprises: a syringe capable of administering at least one cytotoxic agent to horn bud cells of a juvenile animal; and at least one cytotoxic agent in an amount that kills keratinocytes, wherein the at least one cytotoxic agent comprises at least one sclerosant, p53 activator, antiprotozoal agent, apoptosis inducer, or local anesthetic.

8. The method according to claim 1, the use according to claim 2, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to claim 3, the use according to claim 4, the composition according to claim 5, the syringe according to claim 6 or the kit according to claim 7, wherein the at least one cytotoxic agent is in the form of a free acid, a free base or a salt.

9. The method according to claim 1 or 8, the use according to claim 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to claim 3 or 8, the use according to claim 4 or 8, the composition according to claim 5 or 8, the syringe according to claim 6 or 8 or the kit according to claim 7 or 8, wherein the at least one cytotoxic agent comprises at least one sclerosing agent.

10. The method according to claim 9, the use according to claim 9, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 9, the use according to claim 9, the composition according to claim 9, the syringe according to claim 9 or the kit according to claim 9, wherein: The at least one sclerosing agent comprises imipaline (quinacrine), chloroquine, polidocanol or quinine; The at least one hardener comprises an acridine, preferably mepacrine; or The at least one hardening agent comprises mepacrine.

11. The method according to claim 1 or 8, the use according to claim 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to claim 3 or 8, the use according to claim 4 or 8, the composition according to claim 5 or 8, the syringe according to claim 6 or 8 or the kit according to claim 7 or 8, wherein the at least one cytotoxic agent comprises at least one p53 activator.

12. The method according to claim 11, the use according to claim 11, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 11, the use according to claim 11, the composition according to claim 11, the syringe according to claim 11 or the kit according to claim 11, wherein: The at least one p53 activator comprises mepaline or chloroquine; The at least one p53 activator comprises an acridine, preferably mepacrine; or The at least one p53 activator comprises mepacrine.

13. The method according to claim 1 or 8, the use according to claim 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to claim 3 or 8, the use according to claim 4 or 8, the composition according to claim 5 or 8, the syringe according to claim 6 or 8 or the kit according to claim 7 or 8, wherein the at least one cytotoxic agent comprises at least one antiprotozoal agent.

14. The method according to claim 13, the use according to claim 13, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 13, the use according to claim 13, the composition according to claim 13, the syringe according to claim 13 or the kit according to claim 13, wherein: The at least one antiprotozoal agent comprises at least one antimalarial agent; The at least one antiprotozoal agent comprises mepacrine, chloroquine, or quinine; The at least one antiprotozoal agent comprises an acridine, preferably mepacrine; or The at least one antiprotozoal agent comprises mepacrine.

15. The method according to claim 1 or 8, the use according to claim 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to claim 3 or 8, the use according to claim 4 or 8, the composition according to claim 5 or 8, the syringe according to claim 6 or 8 or the kit according to claim 7 or 8, wherein the at least one cytotoxic agent comprises at least one apoptosis inducer.

16. The method according to claim 15, the use according to claim 15, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 15, the use according to claim 15, the composition according to claim 15, the syringe according to claim 15 or the kit according to claim 15, wherein: The at least one apoptosis inducer comprises mepacrine or cinchocaine; The at least one apoptosis inducer comprises an acridine, preferably mepacrine; or The at least one apoptosis inducer comprises mepacrine.

17. The method according to claim 1 or 8, the use according to claim 2 or 8, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to claim 3 or 8, the use according to claim 4 or 8, the composition according to claim 5 or 8, the syringe according to claim 6 or 8 or the kit according to claim 7 or 8, wherein the at least one cytotoxic agent comprises at least one anesthetic agent.

18. The method according to claim 17, the use according to claim 17, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 17, the use according to claim 17, the composition according to claim 17, the syringe according to claim 17 or the kit according to claim 17, wherein: The at least one anesthetic agent comprises an amide anesthetic, an ester anesthetic, or a non-ionic surfactant anesthetic; The at least one anesthetic agent comprises lidocaine, chloroprocaine, mepivacaine, bupivacaine, articaine, etidocaine, levobupivacaine, tetracaine, prilocaine, benzocaine, ropivacaine, cocaine, hydroxyprocaine, hexylcaine, dibucaine, perralcaine or procaine, or a pharmaceutically acceptable acid, base or salt thereof; The at least one anesthetic agent comprises mepacrine, polidocanol, cinchocaine, chloroquine or quinine; The at least one anesthetic comprises an acridine, preferably mepacrine; or The at least one anesthetic agent comprises mepacrine.

19. The method according to claim 1 or 8, the use according to claim 2 or 8, the at least one cytotoxic agent for chemical dehorning of young animals or inhibiting horn growth of young animals according to claim 3 or 8, the use according to claim 4 or 8, the composition according to claim 5 or 8, the syringe according to claim 6 or 8 or the kit according to claim 7 or 8, wherein the at least one cytotoxic agent comprises mepacrine, polidocanol, cinchocaine, chloroquine or quinine.

20. The method according to claim 19, the use according to claim 19, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 19, the use according to claim 19, the composition according to claim 19, the syringe according to claim 19 or the kit according to claim 19, wherein: The at least one cytotoxic agent is administered or administrable in an amount comprising about 100-400 mg of mepaline as a free base; The at least one cytotoxic agent is administered or administrable in an amount comprising about 100-400 mg of mepacrine as a salt; The amount of at least one cytotoxic agent administered or administrable comprises about 100-400 mg of mepaline as the dihydrochloride salt; The at least one cytotoxic agent is administered or administrable in an amount comprising an amount equivalent to about 0.5 mL of polidocanol (95%-100%); The at least one cytotoxic agent is administered or administrable in an amount comprising about 150-250 mg of chloroquine as a free base; The at least one cytotoxic agent is administered or administrable in an amount comprising about 150-250 mg of chloroquine as a salt; or The amount of at least one cytotoxic agent administered or administrable comprises about 150-250 mg of chloroquine diphosphate.

21. The method according to any one of claims 1 and 8-20, the use according to any one of claims 2 and 8-20, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to any one of claims 3 and 8-20, the use according to any one of claims 4 and 8-20, the composition according to any one of claims 5 and 8-20, the syringe according to any one of claims 6 and 8-20 or the kit according to any one of claims 7 and 8-20, wherein the at least one cytotoxic agent is administered or can be administered to the young animal by one or more injections, preferably a single injection.

22. The method according to any one of claims 1 and 8-21, the use according to any one of claims 2 and 8-21, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to any one of claims 3 and 8-21, the use according to any one of claims 4 and 8-21, the composition according to any one of claims 5 and 8-21, the syringe according to any one of claims 6 and 8-21 or the kit according to any one of claims 7 and 8-21, wherein the at least one cytotoxic agent is administered or is administerable to the young animal in the form of a liquid composition capable of providing a sustained release of the at least one cytotoxic agent.

23. The method according to claim 22, the use according to claim 22, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to claim 22, the use according to claim 22, the composition according to claim 22, the syringe according to claim 22 or the kit according to claim 22, wherein the liquid composition is in the form of a solution, a suspension, a dispersion, an emulsion or a low viscosity gel.

24. The method of claim 23, the use of claim 23, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal, the use of claim 23, the composition of claim 23, the syringe of claim 23 or the kit of parts of claim 23, wherein the liquid composition is in the form of a low viscosity injectable gel formulated to gel rapidly at the injection site and to prolong the release of the at least one cytotoxic agent from the gel.

25. The method according to claim 24, the use according to claim 24, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 24, the use according to claim 24, the composition according to claim 24, the syringe according to claim 24 or the kit of parts according to claim 24, wherein the low viscosity injectable gel comprises one or more gelling agents, one or more solvents or solvent systems, and optionally one or more surfactants.

26. The method according to claim 25, the use according to claim 25, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 25, the use according to claim 25, the composition according to claim 25, the syringe according to claim 25 or the kit according to claim 25, wherein the low viscosity injectable gel comprises: Sucrose acetate isobutyrate (SAIB) and at least one solvent as the one or more gelling agents; or SAIB as the one or more gelling agents, at least one solvent and at least one surfactant.

27. The method according to claim 26, the use according to claim 26, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal, the use according to claim 26, the composition according to claim 26, the syringe according to claim 26 or the kit according to claim 26, wherein the low viscosity injectable gel comprises: About 30%-90% w / v SAIB; About 40%-85% w / v SAIB; About 70%-80% w / v SAIB; or About 70% w / v SAIB.

28. The method according to claim 26 or 27, the use according to claim 26 or 27, the at least one cytotoxic agent for or when used for chemical dehorning of young animals or inhibiting horn growth in young animals according to claim 26 or 27, the use according to claim 26 or 27, the composition according to claim 26 or 27, the syringe according to claim 26 or 27 or the kit according to claim 26 or 27, wherein the low viscosity injectable gel comprises: about 0-50% w / v of the at least one solvent; or About 15-30% w / v of the at least one solvent.

29. The method of claim 28, the use of claim 28, the at least one cytotoxic agent for or when used for chemically dehorning a young animal or inhibiting horn growth in a young animal, the use of claim 28, the composition of claim 28, the syringe of claim 28 or the kit of parts of claim 28, wherein the at least one solvent comprises one or more of ethanol, diethylene glycol monoethyl ether (DEGEE), N-methylpyrrolidone (NMP), triacetin, benzyl benzoate, miglyol, propylene carbonate, benzyl alcohol, ethyl lactate, tetraethylene glycol, 2-pyrrolidone, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid and 1-dodecylazacycloheptan-2-one.

30. The method of claim 26, 27, 28 or 29, the use of claim 26, 27, 28 or 29, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal, the use of claim 26, 27, 28 or 29, the composition of claim 26, 27, 28 or 29, the syringe of claim 26, 27, 28 or 29 or the kit of parts of claim 26, 27, 28 or 29, wherein the low viscosity injectable gel comprises: about 0-3% w / v of said at least one surfactant; about 0-2% w / v of said at least one surfactant; about 0-1% w / v of the at least one surfactant; about 1-3% w / v of the at least one surfactant; or About 1-2% w / v of the at least one surfactant.

31. The method according to claim 30, the use according to claim 30, the at least one cytotoxic agent for chemically dehorning a young animal or inhibiting horn growth in a young animal according to claim 30, the use according to claim 30, the composition according to claim 30, the syringe according to claim 30 or the kit according to claim 30, wherein the at least one surfactant comprises one or more of the following: a nonionic surfactant, a polysorbate, Tween, polyoxyethylene (20) sorbitan monooleate (Tween 80) or polyoxyethylene (20) sorbitan monolaurate (Tween 20).

32. The method of claim 26, the use of claim 26, the at least one cytotoxic agent for chemical dehorning of a young animal or inhibiting horn growth of a young animal, the use of claim 26, the composition of claim 26, the syringe of claim 26 or the kit of parts of claim 26, wherein the low viscosity injectable gel comprises: all in about % w / v, 10% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride; 40-85% w / v SAIB; 0-2% w / v Tween 80; 0-50% w / v triacetin; 0-50% w / v DEGEE; and Ethanol is made up to 100% volume, where: The concentration of ethanol is 0-30% w / v; or In the absence of other solvents and Tween, and at a SAIB level of 80% w / v, assuming a weight of 1.1 g per mL of formulation, the ethanol concentration was 18.2% w / v.

33. The method of claim 26, the use of claim 26, the at least one cytotoxic agent for chemical dehorning of a young animal or inhibiting horn growth of a young animal, the use of claim 26, the composition of claim 26, the syringe of claim 26 or the kit of parts of claim 26, wherein the low viscosity injectable gel comprises: all in about % w / v, 20% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v; 40-85% w / v SAIB; 0-2% w / v Tween 80; 0-50% w / v triacetin; 0-50% w / v DEGEE; and Ethanol is made up to 100% volume, where: The concentration of ethanol is 0-30% w / v; or In the absence of other solvents and Tween, and at a SAIB level of 85% w / v, assuming a weight of 1.1 g per mL, the ethanol concentration is 1.4% w / v, which may be too low, in which case the maximum SAIB concentration must be reduced.

34. The method of claim 26, the use of claim 26, the at least one cytotoxic agent for chemical dehorning of a young animal or inhibiting horn growth of a young animal, the use of claim 26, the composition of claim 26, the syringe of claim 26 or the kit of parts of claim 26, wherein the low viscosity injectable gel comprises: all in about % w / v, 10% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride; 70% w / v SAIB; 1% w / v Tween 80; 5% w / v triacetin; 0% w / v DEGEE; and The ethanol was made up to 100% volume, ie, 22.2% w / v ethanol, assuming a weight of 1.1 g per mL.

35. The method of claim 26, the use of claim 26, the at least one cytotoxic agent for chemical dehorning of a young animal or inhibiting horn growth of a young animal, the use of claim 26, the composition of claim 26, the syringe of claim 26 or the kit of parts of claim 26, wherein the low viscosity injectable gel comprises: all in about % w / v, 20% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v; 70% w / v SAIB; 1% w / v Tween 80; 5% w / v triacetin; 0% w / v DEGEE; and The ethanol was made up to 100% volume, ie, assuming a weight of 1.1 g per mL, it was 10.4% w / v ethanol.

36. A composition formulated as a solution, suspension, dispersion, emulsion, low viscosity gel or other sustained release liquid preparation, comprising at least one cytotoxic agent and one or more excipients and capable of providing sustained release of the at least one cytotoxic agent, wherein the at least one cytotoxic agent comprises one or more of a sclerosant, a p53 activator, an antiprotozoal agent, an apoptosis inducer and a local anesthetic.

37. The composition according to claim 36, which is formulated as an injectable oily solution or suspension and comprises at least one oily excipient.

38. The composition of claim 37, comprising: all in about % w / v, 10-15% w / v of at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10-15% w / v mepacrine, such as 11.8-17.7% w / v mepacrine dihydrochloride; and Aqueous or oily suspension, preferably oily suspension.

39. The composition of claim 36 formulated as a low viscosity injectable gel.

40. The composition of claim 39, formulated to rapidly gel at the injection site in an animal and to prolong the release of the at least one cytotoxic agent from the gel.

41. A composition according to claim 39 or 40 comprising: in total about % w / v, 10-15% w / v of at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10-15% w / v mepacrine, such as 11.8-17.7% w / v mepacrine dihydrochloride.

42. The composition of claim 39, 40 or 41, wherein the low viscosity injectable gel comprises one or more gelling agents, one or more solvents or solvent systems, and optionally one or more surfactants.

43. The composition of claim 42, wherein the low viscosity injectable gel comprises: Sucrose acetate isobutyrate (SAIB) and at least one solvent as the one or more gelling agents; or SAIB as the one or more gelling agents, at least one solvent and at least one surfactant.

44. The composition of claim 43, wherein the low viscosity injectable gel comprises: About 30%-90% w / v SAIB; About 40%-85% w / v SAIB; About 70%-80% w / v SAIB; or About 70% w / v SAIB.

45. The composition of claim 43 or 44, wherein the low viscosity injectable gel comprises: about 0-50% w / v of the at least one solvent; or About 15-30% w / v of the at least one solvent.

46. ​​The composition of claim 45, wherein the at least one solvent comprises one or more of ethanol, diethylene glycol monoethyl ether (DEGEE), N-methylpyrrolidone (NMP), triacetin, benzyl benzoate, miglyol, propylene carbonate, benzyl alcohol, ethyl lactate, tetraethylene glycol, 2-pyrrolidone, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one.

47. The composition of claim 42, 43, 44, 45 or 46, wherein the low viscosity injectable gel comprises: about 0-3% w / v of said at least one surfactant; about 0-2% w / v of said at least one surfactant; about 0-1% w / v of the at least one surfactant; about 1-3% w / v of the at least one surfactant; or About 1-2% w / v of the at least one surfactant.

48. The composition of claim 47, wherein the at least one surfactant comprises one or more of the following: a nonionic surfactant, a polysorbate, Tween, polyoxyethylene (20) sorbitan monooleate (Tween 80), or polyoxyethylene (20) sorbitan monolaurate (Tween 20).

49. The composition of claim 41, 42, 43, 44, 45, 46, 47 or 48, wherein the low viscosity injectable gel comprises: all in about % w / v, 10% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride; 40-85% w / v SAIB; 0-2% w / v Tween 80; 0-50% w / v triacetin; 0-50% w / v DEGEE; and Ethanol is made up to 100% volume, where: The concentration of ethanol is 0-30% w / v; or In the absence of other solvents and Tween, and at a SAIB level of 80% w / v, assuming a weight of 1.1 g per mL of formulation, the ethanol concentration was 18.2% w / v.

50. The composition of claim 41, 42, 43, 44, 45, 46, 47 or 48, wherein the low viscosity injectable gel comprises: all in about % w / v, 20% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v; 40-85% w / v SAIB; 0-2% w / v Tween 80; 0-50% w / v triacetin; 0-50% w / v DEGEE; and Ethanol is made up to 100% volume, where: The concentration of ethanol is 0-30% w / v; or In the absence of other solvents and Tween, and at a SAIB level of 85% w / v, assuming a weight of 1.1 g per mL, the ethanol concentration is 1.4% w / v, which may be too low, in which case the maximum SAIB concentration must be reduced.

51. The composition of claim 41, 42, 43, 44, 45, 46, 47 or 48, wherein the low viscosity injectable gel comprises: all in about % w / v, 10% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 10% w / v mepacrine, such as 11.8% w / v mepacrine dihydrochloride; 70% w / v SAIB; 1% w / v Tween 80; 5% w / v triacetin; 0% w / v DEGEE; and The ethanol was made up to 100% volume, ie, 22.2% w / v ethanol, assuming a weight of 1.1 g per mL.

52. The composition of claim 41, 42, 43, 44, 45, 46, 47 or 48, wherein the low viscosity injectable gel comprises: all in about % w / v, 20% w / v of the at least one cytotoxic agent, preferably mepacrine or a mepacrine salt providing 20% ​​w / v mepacrine, such as mepacrine dihydrochloride at 23.6% w / v; 70% w / v SAIB; 1% w / v Tween 80; 5% w / v triacetin; 0% w / v DEGEE; and The ethanol was made up to 100% volume, ie, assuming a weight of 1.1 g per mL, it was 10.4% w / v ethanol.

53. The composition of any one of claims 36-52, wherein the at least one cytotoxic agent is mepaline dihydrochloride.

54. The method of claim 1, the use of claim 2, the at least one cytotoxic agent for or when used for chemical dehorning of a young animal or inhibiting horn growth in a young animal according to claim 3, the use of claim 4, the syringe of claim 6 or the kit of parts according to claim 7, wherein the at least one cytotoxic agent is formulated as a composition according to any one of claims 36-53.

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