Compositions and methods for inducing luteolysis

Abstract

An injectable sustained release composition comprising a prostaglandin, which is formulated to release the prostaglandin in a sustained manner, and a method of inducing luteolysis of a functional luteum in an animal by sustained administration of a prostaglandin, such as PGF2 [alpha], preferably cloprostenol.

Description

[0001] Related applications

[0002] This application claims priority to Australian patent application number 2023901142 filed on 18 April 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] In particular, the present invention relates to a method of inducing luteolysis in an animal and to inducing luteolysis of a functional corpus luteum in an animal by sustained administration of prostaglandins.

[0004] background

[0005] In modern dairy production systems, reproductive performance is currently considered one of the main goals for improving farm profitability and is influenced by many metabolic, physiological, and immunological factors during the early postpartum period. Many reproductive performance indicators are used to evaluate cow fertility, but pregnancy rate is considered the most important indicator for ensuring good farm profitability.

[0006] Considerable research has been devoted to developing reproductive protocols that ensure that estrus is synchronized when desired and that reproductive rates are high within a herd. These protocols typically involve the introduction of hormones in various forms and in phases. These treatments are time-consuming and expensive to implement, especially considering that a typical large herd often has hundreds of cows, and the costs can be exponentially higher.

[0007] A basic method of synchronizing estrus is to inject every cow in the herd with a prostaglandin, which is expected to cause about 75% of cycling animals to come into estrus within the next 2 to 5 days. This method is ineffective in anestrous cows because they do not have a corpus luteum in their ovaries.

[0008] A more complex approach involves multiple interactions. For example, treatment may begin with injections of an equivalent of endogenous gonadotropin-releasing hormone (GnRH), which stimulates follicular maturation, ovulation, and corpus luteum development.

[0009] In one version of a typical breeding protocol, the next stage is to then inject the cows with an analog of prostaglandin F2α (PGF2α) seven days later. This causes luteolysis (degradation) of the corpus luteum. Next, cows that appear to be in estrus are mated. Cows that do not appear to be in estrus are given another dose of GnRH and then inseminated shortly thereafter.

[0010] A shorter follicular dominant phase has been shown to improve embryo quality. Therefore, a shorter regimen has been proposed, in which PGF2α is administered only five days after GnRH administration. Because this five-day regimen includes PGF2α administration earlier than the more traditional seven-day regimen, incomplete luteolysis may occur, as some corpora lutea may not fully respond to the effects of PGF2α. This can result in high progesterone concentrations around the time of the second GnRH injection, reducing ovulation rates and, consequently, pregnancy rates.

[0011] Recent studies have shown that a second administration of PGF2α at least 6 hours (but usually 24 hours) after the first injection of PGF2α can enhance luteolysis success by targeting the corpus luteum, which did not respond to treatment at the time of the first injection but has developed receptors by the time of the second injection. However, the addition of a second administration of PGF2α increases the complexity of the protocol and increases the handling of the animals.

[0012] There is a need in the art for improvements to current breeding programs for animals, particularly dairy cattle.

[0013] Disclosure of the Invention

[0014] It is an object of one or more embodiments of the present invention to address the foregoing problems, or at least to provide the public with a useful choice.

[0015] According to a first aspect of the present invention, there is provided a sustained release composition formulated for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in an animal herd; synchronizing ovulation in an animal herd; or for use in a reproduction and breeding program, wherein the composition comprises a prostaglandin.

[0016] According to a second aspect of the present invention, there is provided the use of a prostaglandin in the preparation of a medicament or composition for: inducing luteolysis of a functional corpus luteum in an animal; improving the fertility of an animal; improving the conception rate of an animal herd; synchronizing ovulation in an animal herd; or for use in a breeding program, wherein the medicament or composition provides a sustained release of the prostaglandin.

[0017] According to a third aspect of the present invention, there is provided a sustained release composition for use in, or when used in, a method for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in an animal herd; synchronizing ovulation in an animal herd; or for use in a reproduction breeding program, wherein the composition comprises a prostaglandin.

[0018] According to a fourth aspect of the present invention, there is provided a method for inducing luteolysis of a functional corpus luteum in an animal; improving the fertility of an animal; improving the conception rate of an animal group; or synchronizing ovulation in an animal group; wherein the method comprises administering to the animal a sustained-release composition comprising a prostaglandin.

[0019] According to a fifth aspect of the present invention, there is provided a sustained release composition comprising a prostaglandin for use in: inducing luteolysis of a functional corpus luteum in an animal; improving the fertility of an animal; improving the conception rate of an animal herd; synchronizing ovulation in an animal herd; or for use in a breeding program.

[0020] According to a sixth aspect of the present invention, a kit is provided for: inducing luteolysis of a functional corpus luteum in an animal; improving the fertility of an animal; improving the conception rate of an animal herd; synchronizing ovulation in an animal herd; breeding programs; or controlling estrus in an animal, wherein the kit comprises a sustained-release composition comprising a prostaglandin.

[0021] According to a seventh aspect of the present invention, there is provided a kit for use in a method of controlling estrus in an animal, wherein the kit comprises a sustained-release composition of a prostaglandin.

[0022] According to an eighth aspect of the present invention, there is provided a method for preparing a sustained-release composition of a prostaglandin, the method comprising the steps of: mixing a therapeutic amount of a prostaglandin with a carrier capable of providing sustained release of the prostaglandin such that the terminal half-life of the prostaglandin plasma concentration versus time curve is approximately 3.5 hours or longer.

[0023] According to a ninth aspect of the present invention, there is provided an injectable sustained release composition comprising a prostaglandin, which is formulated to release the prostaglandin in a sustained manner.

[0024] According to a tenth aspect of the present invention, there is provided a sustained release composition comprising a prostaglandin and a carrier, which is formulated to release the prostaglandin in a sustained manner.

[0025] Where the context permits, the following features relate to all aspects of the invention described above. Where the context permits, features described with respect to the composition / formulation / medicament may also relate to the method / use, and vice versa. It will be understood that where the context permits, the terms "formulation," "medicament," and "composition" may be used interchangeably.

[0026] Prostaglandins

[0027] Any suitable type of prostaglandin can be used in the composition or the method / purpose. Naturally occurring prostaglandins are 20 carbon unsaturated fatty acids consisting of a cyclopentane ring and two aliphatic side chains. Prostaglandins are divided into nine major groups, A to I, by structure, with each group comprising subgroups represented by subscripts 1, 2, and 3. These include prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), prostaglandin F 2α (PGF 2α ), prostacyclin (PGI2) and thromboxane (TXA2). In domestic animals, prostaglandin F 2α (PGF 2α or PGF2α) is a prostaglandin specifically associated with the reproductive process.

[0028] As used herein (including in the claims), the term "prostaglandin" ("PG") means any prostaglandin or prostaglandin analog, whether naturally occurring or synthetically produced, which possesses and / or exerts the desired characteristics when used, including pharmaceutically acceptable salts or esters thereof, or solvated forms thereof, if the context permits.

[0029] As used herein (including in the claims), the term "PGF2α" means prostaglandin F2α or an analog thereof, including a pharmaceutically acceptable salt or ester thereof or a solvated form thereof, if the context permits. For example, cloprostenol is a functional synthetic analog of naturally occurring PGF2α. For example, dinoprost is a naturally occurring PGF2α.

[0030] One of the known functions of PGF2α in the bovine estrous cycle is to cause the corpus luteum to degenerate, a process known as luteolysis. Luteolysis results in a decrease in progesterone, which allows the dominant follicle from the last wave of follicles to emerge and mature. The dominant follicle is then able to produce enough estrogen to induce estrus.

[0031] A preferred prostaglandin for use in one or more compositions, medicaments, methods or uses of the present invention is PGF2α. A preferred PGF2α is the synthetic analog cloprostenol. A particularly preferred PGF2α is the sodium salt, cloprostenol sodium (anhydrous). Other potentially suitable salts include, for example, cloprostenol sodium hydrate, cloprostenol potassium, cloprostenol lithium, and cloprostenol calcium. A potentially suitable ester is isopropyl cloprostenol. Stearyl cloprostenol in an oily injection may have a sustained effect, as do other esters made using fatty alcohols.

[0032] Another preferred PGF2α is dinoprost, which is a naturally occurring PGF2α. A particularly preferred PGF2α is the dinoprost salt, dinoprost tromethamine.

[0033] As used herein, including in the claims, the term "cloprostenol" includes within its scope solvated forms of cloprostenol, as well as salts and esters thereof, if the context so permits.

[0034] As used herein, including in the claims, the term "dinoprost" includes within its scope solvated forms of dinoprost, as well as salts and esters thereof, if the context so permits.

[0035] Sustained release composition

[0036] Preferably, the sustained-release composition is formulated to provide a biologically active amount or concentration of the prostaglandin to an animal over a sufficient period of time for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; controlling estrus in an animal; or for use in a breeding program.

[0037] The phrase "releasing the prostaglandin in a sustained manner" and similar expressions refer to the ability of a sustained release composition to release a biologically active concentration of the prostaglandin from the composition or from a carrier of the composition over a specific period of time.

[0038] In certain embodiments, prepare described sustained release composition to provide the prostaglandin (PG) of bioactive concentration approximately at least 8 hours after using.In certain embodiments, prepare described sustained release composition to provide the prostaglandin (PG) of bioactive concentration approximately at least 12 hours after using.For example, prepare described sustained release composition to provide the prostaglandin (PG) of bioactive concentration approximately at least 8 hours after using.

[0039] In certain embodiments, the sustained release composition / drug / formulation can provide sustained release of the prostaglandin such that the terminal half-life of the prostaglandin plasma concentration versus time curve is about 3.5 hours or longer. (The terminal half-life is measured as the slope of the curve relative to time after the drug concentration in the blood reaches a peak. For sustained release formulations, the terminal half-life is primarily determined by the absorption rate when the absorption rate at the injection site is significantly slower than the clearance rate (the so-called trigger effect).

[0040] Typically, the sustained release composition will be administered to an animal in an injectable form. That is, in certain embodiments, the composition is formulated for injection, or administering the composition to an animal includes the step of injecting the animal with the composition. In certain embodiments, the composition is injected subcutaneously. In certain embodiments, the composition is injected intramuscularly.

[0041] In certain embodiments, described sustained release composition is a liquid preparation.In certain embodiments, described sustained release composition is solution, suspension, dispersion, emulsion or (low viscosity) gel that are suitable for injection.In certain embodiments, described sustained release composition comprises the prostaglandin of water-insoluble form, such as water-fast salt, and / or the prostaglandin of encapsulated solid form.

[0042] Typically, the sustained release composition comprises at least one type of carrier or carrier carrying the prostaglandin. The carrier may comprise one or more components.

[0043] In certain embodiments, the composition can comprise an emulsion, or a form of an emulsion, or a carrier that contains an emulsion, or a carrier that contains an emulsifying agent or an emulsifying agent. In certain embodiments, the composition or carrier can comprise an oil-in-water emulsion or a water-in-oil emulsion.

[0044] The release of active substances from water-in-oil compositions can be achieved by several mechanisms, including partitioning from water into the oil, diffusion through the oil, partitioning from the oil into the release medium (in vitro), or partitioning into the extracellular fluid (in vivo). Thus, the release rate can be controlled by varying the type of oil (chemical and physical properties, such as viscosity), additives (surfactants, gelling agents), the characteristics of the active substance, and the water-to-oil ratio.

[0045] In certain embodiments, the composition comprises an oily suspension of a prostaglandin (such as an ester of cloprostenol) in an oily vehicle or carrier. In certain embodiments, the carrier comprises the oil of at least one type. The oily suspension of active substance is a suspension of active substance particles in an oily vehicle or carrier. Preferably, the oily vehicle or carrier are veterinarily acceptable. Such oil can include sesame oil, medium chain triglycerides such as caprylic / capric triglyceride, capric acid, caprylic acid, propane-1,2,3-triol (Miglyol 812), propane-1,2-diol (Miglyol 840), cottonseed oil, soybean oil, peanut oil, corn oil and triacetin.

[0046] Gelled compositions can be used to provide sustained release of active substances. One method of forming a gel is to incorporate a gelling agent into a suitable vehicle or carrier that can be used to accommodate the active substance. In certain embodiments, the composition can comprise a gel, or be in the form of a gel, or can comprise a carrier in the form of a gel, or can comprise a carrier containing at least one type of gelling agent.

[0047] Another example of a gel composition is a sucrose acetate isobutyrate (SAIB) in situ gel composition. SAIB is soluble in certain water-miscible organic solvents, but has poor solubility in water. When a solution of SAIB in a water-miscible organic solvent contacts an aqueous environment, the organic solvent is diluted by water, resulting in the precipitation of SAIB and the formation of a gel-like substance. The release of the active substance from the gel-like substance is restricted (continuous). This is the basis of the so-called in situ gelling system. The active substance can be suspended or dissolved in a water-miscible organic solvent. The release characteristics of the formulation may vary by the selection and concentration of the water-miscible organic solvent, other additives, and the characteristics of the active substance. Preferably, the water-miscible solvent is veterinarily acceptable. Suitable solvents may include ethanol, Transcutol (diethylene glycol monoethyl ether), triacetin, propylene glycol. In certain embodiments, the composition comprises SAIB, or may comprise a carrier comprising SAIB. In certain embodiments, the composition comprises at least one type of solvent or solvent system, or may comprise a carrier comprising at least one type of solvent or solvent system.

[0048] The composition for injection can be prepared by dissolving the prostaglandin with a carrier or mixing it with the carrier. Preferably, the carrier is veterinarily acceptable. The composition can be sterilized by methods such as heating, filtering or irradiation, or prepared in an aseptic manner. The composition for injection can be prepared by methods and techniques known to those skilled in the art.

[0049] The at least one type of carrier or vehicle (or additive or ingredient) may comprise one or more of the following types of veterinarily acceptable ingredients / excipients / additives: vehicles; aqueous or oily diluents; bases; buffers; pH adjusters; suspending agents; flocculants; thickeners; viscosity builders; gelling agents; solvents; organic solvents; co-solvents; solvent systems; emulsifiers; stabilizers; dispersants; detergents; solubilizers; fragrances; preservatives; surfactants; acids; bases; antioxidants; wetting agents; chelating agents; reducing agents; fillers; protective agents; tonicity regulators; and colorants.

[0050] Examples of tonicity adjusting agents used in liquid injections or vehicles include electrolytes, dextrose, glycerol, sodium chloride, glycerol, and mannitol.

[0051] Examples of preservatives used in liquid injections / vehicles include antioxidants, antimicrobials, and chelating agents, including ascorbic acid, acetylcysteine, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sulfites (bisulfite, metabisulfite), monothioglycerol, phenol, m-cresol, benzyl alcohol, gallates, parabens (methyl, propyl, butyl), benzalkonium chloride, chlorobutanol, thimerosal, and phenylmercuric salts.

[0052] Examples of solubilizers used in liquid injections or vehicles include surfactants, solvents, and cosolvents, and include water, polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate, polyoxyethylene sorbitan monolaurate (Tween 20), lecithin, polyoxyethylene copolymers (pluronics), propylene glycol, glycerol, organic solvents, ethanol, polyethylene glycol (300 and 400), sorbitol, dimethylacetamide, and cremophor EL.

[0053] Examples of complexing agents and dispersing agents used in liquid injections or carriers include cyclodextrins and modified cyclodextrins such as hydroxypropyl-b-cyclodextrin and sulfobutyl ether-b-cyclodextrin.

[0054] Examples of buffers used in liquid injections or vehicles include phosphate, citrate, acetate, lactate and tartrate buffers.

[0055] Suspensions can provide a more sustained release of prostaglandins from the injection site compared to comparable solutions. Examples of additives / ingredients / excipients / carriers used in suspensions include flocculants or suspending agents, viscosity building agents, wetting agents, solvents, solvent systems, preservatives, antioxidants, chelating agents, buffers, surfactants, and tonicity adjusting agents.

[0056] Examples of flocculants or suspending agents include electrolytes, surfactants, and hydrophilic colloids, including potassium / sodium chloride, potassium / sodium citrate, and potassium / sodium acetate.

[0057] Examples of viscosity building agents include sodium carboxymethylcellulose, gum arabic, gelatin, methylcellulose and polyvinylpyrrolidone.

[0058] Examples of wetting agents include glycerin, alcohol, propylene glycol, lecithin, polysorbate 20, polysorbate 80, pluronic F-68, sorbitan, and trioleate.

[0059] Examples of solvents (including organic solvents) include water, ethanol, glycerol, propylene glycol, lactamide, polyethylene glycol (PEG), dimethyl sulfoxide, glycofurol, glycerol acetone, acetone, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, dimethyl isosorbide, ethyl lactate, diethylene glycol monoethyl ether (DEGEE) (e.g., sold under the trademark Transcutol), N-methylpyrrolidone (NMP), triacetin, benzyl benzoate, miglyol, propylene carbonate, benzyl alcohol, ethyl lactate, 2-pyrrolidone, propylene glycol, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid, and 1-dodecaazacycloheptan-2-one.

[0060] In certain embodiments, the composition or carrier is in the form of a low viscosity injectable gel that gels rapidly at the injection site to provide sustained release of the prostaglandin over an appropriate period of time.

[0061] In certain embodiments, described composition or carrier can be made to form gel in original position (in animal body) in any suitable manner.In certain embodiments, described composition or carrier can comprise one or more gelling agents.In certain embodiments, described composition or carrier comprise one or more solvents or solvent systems, such as one or more organic solvents.In certain embodiments, described composition or carrier comprise sucrose acetic isobutyrate (SAIB) and one or more solvents or solvent systems.In case injection contains the composition of SAIB and solvent or solvent system, solvent just can diffuse out, and stays not only viscosity but also thickness matrix.Described matrix can keep prostaglandin at injection site for a long period of time, rather than prostaglandin almost disperses completely immediately.

[0062] In certain embodiments, the composition or carrier comprises SAIB in the approximate range of 30% to 90%, 35% to 90%, 40% to 90%, 45% to 90%, 50% to 90%, 30% to 85%, 35% to 85%, 40% to 85%, 45% to 85%, 50% to 85%, 30% to 80%, 35% to 80%, 40% to 80%, 45% to 80%, 50% to 80%, 30% to 75%, 35% to 75%, 40% to 75%, 45% to 75%, 50% to 75%, 30% to 70%, 35% to 70%, 40% to 70%, 45% to 70%, or 50% to 70% w / v SAIB, including all numbers between 30 and 90, including about 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, 85, 86, 87, 88, 89 and 90. In certain embodiments, the composition or carrier comprises from about 70% to about 80% w / v SAIB. In certain embodiments, the composition or carrier comprises about 70% or about 80% w / v SAIB.

[0063] Any suitable solvent or solvent system can be used, as long as it / they produce a low viscosity injectable gel. Preferred solvents for the composition or vehicle include ethanol, diethylene glycol monoethyl ether (DEGEE) sold under the trademark Transcutol, 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-dodecaazacycloheptan-2-one or any mixture of these. In certain embodiments, the solvent of the composition or vehicle may comprise a mixture of ethanol, triacetin and diethylene glycol monoethyl ether in any suitable proportion and amount. The solvent may be present in the composition or vehicle in an amount of about 9% to 60% w / v, preferably about 15 to 30% w / v. These ranges include all numbers between 9 and 60 and 15 and 30, including about 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, 51, 52, 53, 54, 55, 56, 57, 58, 59, and 60. In certain embodiments, the solvent comprises Transcutol. In certain embodiments, the solvent comprises Transcutol and triacetin. In certain embodiments, the solvent comprises ethanol.

[0064] In certain embodiments, the composition or carrier comprises a surfactant, detergent or emulsifier to assist in the release of the prostaglandin. Any suitable type of surfactant, detergent or emulsifier can be used. Suitable examples include nonionic surfactants such as polysorbates. Span 80 (sorbitan monooleate, sorbitan oleate, CAS number: 1338-43-8) and Tween 80 (POE (20) sorbitan monooleate, polyethylene glycol sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate 80; CAS number: 9005-65-6) are particularly preferred. The surfactant can be present in the composition or carrier in an amount of about 0.01% to 10% w / v, preferably about 0.01% to 0.1% w / v and more preferably about 0.05% w / v. These ranges include all numbers between 0.01 and 10, 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, and 0.1). In certain embodiments, the composition or carrier comprises about 0.05% w / v surfactant, preferably Span 80.

[0065] In certain embodiments, the composition or carrier comprises at least one type of antioxidant. Any suitable type of one or more antioxidants can be used. Examples of suitable antioxidants include phenolic antioxidants, such as butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA). BHT is particularly preferred. The antioxidant can be present in the composition or carrier in an amount of about 0.01% to 10% w / v, preferably about 0.05% to 5% w / v. These ranges include all values ​​between 0.01 and 10 and between 0.05 and 5, 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, 1.0 ... etc.). In certain embodiments, the composition or vehicle comprises about 0.1% w / v of an antioxidant, preferably BHT.

[0066] The prostaglandin concentration in the composition / preparation / medicine or the carrier is preferably in the scope of about 0.0001%w / v to 10%w / v, depending on the effectiveness of the prostaglandin, included in all numerical values ​​between 0.0001 to 10 (comprising about 0.0001 ... 0.001 ... 0.01 ... 0.1 ... 1.0 ... 10). In certain embodiments, the prostaglandin exists with the amount of at least about 0.05%w / v. In certain embodiments, the prostaglandin exists with the amount of at least about 0.15%w / v. In certain embodiments, prostaglandin exists with the amount of about 0.05% to 0.5%w / v, preferably about 0.15%w / v, be included in all numerical values ​​and subranges between 0.05 to 0.5 (comprising for example about 0.05 ... 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2 ... 0.25 ... 0.3 ... 0.35 ... 0.4 ... 0.45 ... 0.5, and subrange 0.1 and 0.2%w / v).In certain embodiments, described prostaglandin is PGF2α.In certain embodiments, described prostaglandin is cloprostenol.In certain embodiments, described prostaglandin is dinoprost. In certain embodiments, the composition or vehicle comprises about 0.05% to 0.5% w / v prostaglandin, PGF2α, cloprostenol, or dinoprost, particularly about 0.15% w / v cloprostenol (as the sodium salt).

[0067] In certain embodiments, the sustained release composition comprises a prostaglandin or PGF2α, such as cloprostenol or cloprostenol sodium, in a SAIB carrier.

[0068] In certain embodiments, the sustained release composition comprises a prostaglandin or PGF2α, such as dinoprost, in a SAIB carrier.

[0069] In certain embodiments, described sustained release composition is included in the prostaglandin, PGF2α, cloprostenol or dinoprost in gel formation carrier, and described gel formation carrier comprises SAIB and water miscible or partially water miscible solvent.Such solvent comprises one or more in Transcutol, triacetine (1,2,3-triacetoxypropane, 1,2,3-triacetyl glycerol, triacetin) and ethanol.

[0070] In certain embodiments, the sustained release composition comprises a prostaglandin, PGF2α, cloprostenol, or dinoprost, preferably a cloprostenol ester, in a suspension comprising an oily vehicle, such as sesame oil.

[0071] In some embodiments, the composition of any suitable dose can be used to animal. In certain embodiments, the dosage may depend on the effectiveness of prostaglandin (PG), body weight or blood flow of animal and drug metabolism rate. In certain embodiments, use approximately 0.5 to approximately 10 μ g / kg animal body weight, more preferably approximately 2.5 to approximately 10 μ g / kg animal body weight, and even more preferably approximately 3.3 μ g / kg animal body weight (comprising approximately 0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5,8,8.5,9,9.5 and 10). In certain embodiments, an absolute dose is administered, such as, for example, about 10 μg to about 10 mg, preferably about 50 μg to about 5.0 mg, more preferably about 2.0 mg to about 3.0 mg (including about 0.01, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, and 10 mg), regardless of the animal's body weight.

[0072] The amount of composition administered is preferably in the range of about 0.5 to about 10 ml, including all values ​​between 0.5 and 10 (including about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, and 10). A particularly preferred range is from about 1.0 ml to 5 ml, including all values ​​between 1.0 and 5 (including about 0.1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5), and even more preferably up to about 2 ml. Preferably, the injection (administration) is performed on the animal using a syringe.

[0073] Particularly preferred compositions / formulations are shown below:

[0074] Formulation 1 (all % are approximate):

[0075] Prostaglandins or PGF2α (eg, cloprostenol or dinoprost) 0.05% to 0.5% w / v

[0076] SAIB 80% w / v

[0077] Solvent, such as Transcutol Appropriate amount (Appropriate amount)

[0078] Formulation 1A (all % are approximate):

[0079] Prostaglandin or PGF2α, such as cloprostenol 0.15% w / v (as sodium salt)

[0080] SAIB 80% w / v

[0081] Solvent, such as Transcutol q.s.

[0082] Formulation 1B (all % are approximate):

[0083] Cloprostenol 0.15% w / v (as sodium salt)

[0084] SAIB 80% w / v

[0085] Transcutol appropriate amount

[0086] Formulation 2 (all % are approximate):

[0087]

[0088] Formulation 2A (all % are approximate):

[0089]

[0090] Formulation 2B (all % are approximate):

[0091]

[0092] Formulation 3 (all % are approximate):

[0093] Prostaglandins or PGF2α (eg, cloprostenol or dinoprost) 0.05% to 0.5% w / v

[0094] SAIB 70% w / v

[0095] Solvent, such as ethanol

[0096] Formulation 3A

[0097] Prostaglandins, such as cloprostenol 0.15% w / v (as sodium salt)

[0098] SAIB 70% w / v

[0099] Solvent, such as ethanol

[0100] Formulation 3B

[0101] Cloprostenol 0.15% w / v (as sodium salt)

[0102] SAIB 70% w / v

[0103] Ethanol in moderation

[0104] Formulation 4 (all % are approximate):

[0105] Prostaglandins or PGF2α (eg, cloprostenol or dinoprost) 0.05% to 0.5% w / v

[0106] Emulsifier or detergent, such as Span 80 0.05% w / v

[0107] Oil, such as sesame oil

[0108] Formulation 4A (all % are approximate):

[0109] Prostaglandins, such as cloprostenol 0.15% w / v (as sodium salt)

[0110] Emulsifier or detergent, such as Span 80 0.05% w / v

[0111] Oil, such as sesame oil

[0112] Formulation 4B (all % are approximate):

[0113] Cloprostenol 0.15% w / v (as sodium salt)

[0114] Span 80 0.05% w / v

[0115] Sesame oil as needed

[0116] Studies by the authors have shown that a typical dose of 0.5 mg of cloprostenol as a sodium salt in a rapid-release aqueous composition results in an estimated half-life of cloprostenol in plasma of 15 to 60 minutes. The literature has reported that the half-life of cloprostenol is approximately 90 minutes, with maximum concentrations reached approximately 10 to 20 minutes after administration.

[0117] We performed simulations to estimate the plasma profile of cloprostenol based on an assumed elimination half-life of 60 minutes and first-order absorption at the injection site with varying absorption half-lives of 10 minutes, 4 hours, and 8 hours. From these simulations, it was determined that a sustained-release composition of cloprostenol with a duration of action of 12-24 hours would require an estimated 3 mg dose of cloprostenol with a sustained-release absorption half-life of 4 hours or longer.

[0118] The inventors have also used various models to describe the absorption kinetics of cloprostenol. The latest model describes the release from the SAIB formulation as a sudden release of a certain percentage of the dose, followed by a release rate proportional to the square root of time. In animal experiments, the inventors calculated the terminal slope of the plasma concentration vs. time curve. If absorption is very fast, that is, from a standard cloprostenol injection, Ovuprost TM, this terminal slope is related to the elimination half-life of cloprostenol. The inventors found that this half-life is 1 hour. The literature reports that the elimination half-life of cloprostenol is 1.5-3 hours. If absorption is slow, then the terminal slope is related to the absorption rate of cloprostenol from injection. The inventors found that the half-life of SAIB preparation is greater than 3.5 hours.

[0119] According to Greco et al. 2018, endogenous PGF2α is secreted in a pulsatile manner. Generally, cows undergoing luteolysis have two pulses of PGF metabolite (PGFM) during the pre-luteolysis phase, two pulses during the luteolysis phase, and one pulse during the post-luteolysis phase. In most cows, the luteolysis phase is characterized by at least two major pulses of PGFM, however, reliability measurements indicate that a minimum of three pulses of PGF2α are required to induce CL resolution. Greco determined endogenous pulses of PGFM in plasma during the luteolysis phase to be 200-300 pg / ml, while McCracken, Custer, and Lamsa 1999 determined it to be approximately 300-600 pg / ml.

[0120] Endogenous PGF2α is secreted in the uterus and transported to the ovary via a local pathway involving close integration of the uterine efferent vessels (venous and lymphatic) with the ovarian arterial vessels, and delivery to the ovary from the systemic circulation has been proposed to occur in cows (McCracken, Custer, and Lamsa 1999), but the effective luteolytic dose of PGF when administered systemically is approximately 20 times higher than when administered to the uterus (Inskeep 1973).

[0121] It is reported that PGF2α has a short half-life of approximately 8 minutes. Baseline PGF2α concentrations have been reported to be approximately 80 pg / ml (Shrestha et al. 2012), and baseline PGFM concentrations to be approximately 36-50 pg / ml. PGFM is inactive, and therefore, applying this ratio to peak PGFM levels indicates that the systemic PGF2α concentration required to provide luteolytic activity can be estimated to be approximately 400-1200 pg / ml (0.4-1.2 ng / ml). This is approximately 5-10 times the baseline concentration.

[0122] In cattle, the conventional intramuscular dose of native PGF2α is 25 mg, while the intramuscular dose of cloprostenol is 0.5 mg. PGF2α has a half-life of approximately 8-10 minutes, while the half-life of cloprostenol is approximately 1 hour, as determined by the authors' studies and reported elsewhere as 1.5-3 hours.

[0123] It is assumed that cloprostenol and PGF2α (dinoprost) have the same affinity and potency for luteal cell membrane receptors; therefore, the target peak systemic (plasma) cloprostenol concentration is also 0.4-1.2 ng / ml.

[0124] In some embodiments, the prostaglandin (PG) plasma concentration provided by long-term administration is at least about 0.1ng / ml.For example, the approximate prolongation bioactivity plasma concentration of the prostaglandin (PG) provided by long-term administration is at least 0.1ng / ml, at least 0.2ng / ml, at least 0.3ng / ml, at least 0.4ng / ml, at least 0.5ng / ml, at least 0.6ng / ml, at least 0.7ng / ml, at least 0.8ng / ml, at least 0.9ng / ml, at least 1.0ng / ml or at least 1.14ng / ml.In certain embodiments, the prostaglandin (PG) plasma concentration provided by long-term administration is about 0.1-1.2ng / ml, more preferably from about 0.4-1.2ng / ml.

[0125] Long-term administration of prostaglandins can be performed as part of a breeding program. For example, a breeding program can include timed administration of GnRH and / or timed administration of progesterone.

[0126] In a breeding program, GnRH is used to each animal, and after about five days, prostaglandins are administered for a long time. Preferably, the long-term administration of prostaglandins is the administration of the sustained-release composition of PGF2α. The sustained-release composition of cloprostenol or dinoprost is particularly preferred. The long-term administration of prostaglandins can replace the conventional administration of prostaglandins injected twice at intervals of 1 day.

[0127] In another breeding program, a second GnRH injection was administered 3 days after progesterone. In another breeding program, progesterone was administered before the first GnRH injection.

[0128] As used herein, the term "GnRH" means gonadotropin-releasing hormone or an equivalent of endogenous gonadotropin-releasing hormone, such as gonadorelin.

[0129] The present invention is primarily discussed with respect to use with cattle, but it will be understood that the present invention may also be used with other animal species, including any type of domesticated livestock or farm animal, including sheep, horses (e.g., mares), goats, pigs (e.g., sows), and dogs.

[0130] In certain embodiments, the composition / medicament is for luteolysis of a functional corpus luteum in a cow, mare, or sow.

[0131] Exemplary Uses

[0132] Dairy and beef cows

[0133] For use in fixed-time artificial insemination programs for cycling cows with normal estrous cycles. One PG injection can replace two PG injections.

[0134] Approximate dosage: 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg / kg animal body weight.

[0135] Preferred: approximately 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg / kg animal body weight.

[0136] Used to treat estrus in cows. One PG injection can replace two PG injections.

[0137] Approximate dosage: 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg / kg animal body weight.

[0138] Preferably: about 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg / kg animal body weight.

[0139] Dairy and beef heifers

[0140] For fixed-time artificial insemination programs in heifers. One PG injection can replace two PG injections.

[0141] Used for synchrony of production in heifers. One PG injection can replace two PG injections.

[0142] Approximate dosage: 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg / kg animal body weight.

[0143] Preferably: about 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg / kg animal body weight.

[0144] For use in luteolysis, synchronized or timed artificial insemination (TAI) programs, and treatment of anestrus, the dosage is as described in the above paragraph.

[0145] Regarding the seventh aspect of the present invention, the kit may further comprise progesterone. In one embodiment, the kit may further comprise GnRH.

[0146] Preferred embodiments of the present invention are defined in the following paragraphs:

[0147] 1. A sustained-release composition formulated for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in an animal herd; synchronizing ovulation in an animal herd; or for use in a reproductive breeding program, wherein the composition comprises a prostaglandin.

[0148] 2. Use of a prostaglandin in the preparation of a medicament or composition for: inducing luteolysis of a functional corpus luteum in an animal; improving the fertility of an animal; improving the conception rate of an animal herd; synchronizing ovulation in an animal herd; or for use in a breeding program, wherein the medicament or composition provides sustained release of the prostaglandin.

[0149] 3. A sustained release composition for use in, or when used in, a method for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; or for use in a reproductive breeding program, wherein the composition comprises a prostaglandin.

[0150] 4. A method of: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; or synchronizing ovulation in a herd of animals; wherein the method comprises administering to the animal a sustained-release composition comprising a prostaglandin.

[0151] 5. A sustained release composition comprising a prostaglandin for use in: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in an animal herd; synchronizing ovulation in an animal herd; or in a breeding program.

[0152] 6. A kit for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in an animal herd; synchronizing ovulation in an animal herd; propagating a breeding program; or controlling estrus in an animal, wherein the kit comprises a sustained-release composition comprising a prostaglandin.

[0153] 7. A kit for use in a method of controlling estrus in an animal, wherein the kit comprises a sustained release composition of a prostaglandin.

[0154] 8. A method for preparing a sustained release composition of a prostaglandin, said method comprising the steps of: mixing a therapeutic amount of a prostaglandin with a carrier capable of providing sustained release of the prostaglandin such that the terminal half-life of the prostaglandin plasma concentration versus time curve is about 3.5 hours or longer.

[0155] 9. A composition, method, use or kit as defined in any preceding paragraph (if the context permits), wherein the prostaglandin is a prostaglandin or a prostaglandin analogue, which is naturally occurring or synthetically produced.

[0156] 10. A composition, method, use or kit as defined in any preceding paragraph (if the context permits), wherein the prostaglandin is prostaglandin F2α or an analogue thereof, including a pharmaceutically acceptable salt or ester thereof, such as dinoprost, cloprostenol or cloprostenol sodium salt.

[0157] 11. A composition, method, use or kit as defined in any preceding paragraph (if the context permits), wherein the composition or medicament comprises or consists of Formulation 1 (1, 1A, 1B) as described herein, Formulation 2 (2, 2A, 2B) as described herein, Formulation 3 (3, 3A, 3B) as described herein, Formulation 4 (4, 4A, 4B) as described herein, a formulation as described in Table 4, a formulation as described in Table 5, a formulation as described in Table 7, a formulation as described in Table 8, a formulation as described in Table 11, or a composition, formulation or medicament described elsewhere in this specification.

[0158] 12. A composition, method, use or kit as defined in any preceding paragraph (as the context permits) for treating a condition in an animal or group of animals as described in Table 11 or elsewhere in the specification.

[0159] Further preferred embodiments of the present invention are defined in the following paragraphs:

[0160] 1. An injectable sustained-release composition comprising a prostaglandin, which is formulated to release the prostaglandin in a sustained manner.

[0161] 2. The composition of paragraph 1, wherein the prostaglandin is selected from prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), prostaglandin F 2α (PGF 2α / PGF2α), prostacyclin (PGI2) and thromboxane (TXA2).

[0162] 3. The composition of paragraph 2, wherein the prostaglandin is PGF2α, preferably cloprostenol or dinoprost.

[0163] 4. The composition of paragraph 3, wherein the PGF2α is the synthetic analog cloprostenol.

[0164] 5. The composition of paragraph 4, wherein the cloprostenol is a cloprostenol salt such as cloprostenol sodium.

[0165] 6. The composition of any of paragraphs 1 to 5, wherein the composition comprises about 0.0001% w / v to 10% w / v prostaglandin such as PGF2α, or about 0.05% to 0.5% w / v prostaglandin such as PGF2α.

[0166] 7. The composition of any of paragraphs 1 to 6, wherein the composition is in the form of a liquid, solution, suspension, dispersion, emulsion or gel.

[0167] 8. The composition of paragraph 7, wherein the composition is in the form of an injectable gel that is capable of rapidly gelling at the injection site to provide sustained release of the prostaglandin.

[0168] 9. The composition of paragraph 8, wherein the composition comprises at least one gelling agent and at least one water-miscible or partially water-miscible solvent or solvent system.

[0169] 10. The composition of paragraph 9, wherein the at least one gelling agent comprises sucrose acetate isobutyrate (SAIB).

[0170] 11. The composition of paragraph 10, wherein the composition comprises about 70% to about 80% w / v SAIB.

[0171] 12. The composition of paragraph 11, wherein the composition comprises about 70% or about 80% w / v SAIB.

[0172] 13. The composition of paragraph 9, 10, 11 or 12, wherein the at least one solvent or solvent system comprises one or more of diethylene glycol monoethyl ether (Transcutol), triacetin and ethanol.

[0173] 14. The composition of paragraph 9, 10, 11, 12, or 13, wherein the composition comprises from about 15% to about 30% w / v of at least one solvent or solvent system.

[0174] 15. The composition of paragraph 7, wherein the composition is in the form of an injectable suspension capable of providing sustained release of the prostaglandin.

[0175] 16. The composition of paragraph 15, wherein the composition comprises a suspension of a prostaglandin (such as a cloprostenol ester) in at least one oily vehicle.

[0176] 17. The composition of paragraph 16, wherein the at least one oily vehicle comprises sesame oil, medium chain triglycerides, capric acid, caprylic acid, propane-1,2,3-triol (Miglyol 812), propane-1,2-diol (Miglyol 840), cottonseed oil, soybean oil, peanut oil, corn oil, or triacetin.

[0177] 18. The composition of paragraph 17, wherein the at least one oily carrier comprises sesame oil.

[0178] 19. The composition of paragraph 16, 17 or 18, wherein the composition comprises at least one surfactant, detergent or emulsifier, preferably from about 0.01% to 10% w / v.

[0179] 20. The composition of paragraph 19, wherein the at least one surfactant, detergent, or emulsifier comprises a polysorbate.

[0180] 21. The composition of paragraph 21, wherein the polysorbate comprises sorbitan monooleate or sorbitan oleate.

[0181] 22. The composition of any of paragraphs 1 to 21, wherein the composition comprises about 0.05% to 0.5% w / v of a prostaglandin, such as PGF2α, such as cloprostenol, preferably about 0.15% w / v cloprostenol (as the sodium salt).

[0182] 23. The composition of paragraph 1 or any other preceding paragraph (as the context permits), comprising a formulation selected from the group consisting of the following formulations, wherein all ingredient percentages are approximate:

[0183] Preparation 1

[0184] Prostaglandins or PGF2α (e.g., cloprostenol or dinoprost) 0.05% to 0.5% w / v;

[0185] SAIB 80% w / v; and

[0186] Solvent, such as Transcutol q.s., or

[0187] Formulation 1A

[0188] Prostaglandins or PGF2α, such as cloprostenol 0.15% w / v (as the sodium salt);

[0189] SAIB 80% w / v; and

[0190] Solvent, such as Transcutol q.s., or

[0191] Formulation 1B

[0192] Cloprostenol 0.15% w / v (as sodium salt);

[0193] SAIB 80% w / v; and

[0194] Transcutol appropriate amount, or

[0195] Preparation 2

[0196]

[0197] Formulation 2A

[0198] Prostaglandins, such as cloprostenol 0.15% w / v (as the sodium salt);

[0199] SAIB 70% w / v;

[0200] A partially water-miscible solvent, such as triacetin 15% w / v; and

[0201] Solvent, such as Transcutol, or

[0202] Formulation 2B

[0203]

[0204] Preparation 3

[0205] Prostaglandins or PGF2α (e.g., cloprostenol or dinoprost) 0.05% to 0.5% w / v;

[0206] SAIB 70% w / v; and

[0207] A suitable amount of solvent, such as ethanol, or

[0208] Formulation 3A

[0209] Prostaglandins, such as cloprostenol 0.15% w / v (as the sodium salt);

[0210] SAIB 70% w / v; and

[0211] A suitable amount of solvent, such as ethanol, or

[0212] Formulation 3B

[0213] Cloprostenol 0.15% w / v (as sodium salt);

[0214] SAIB 70% w / v; and

[0215] Ethanol, or

[0216] Preparation 4

[0217] Prostaglandins or PGF2α (e.g., cloprostenol or dinoprost) 0.05% to 0.5% w / v;

[0218] an emulsifier or detergent, such as Span 80 0.05% w / v; and

[0219] Oil, such as sesame oil, or

[0220] Formulation 4A

[0221] Prostaglandins, such as cloprostenol 0.15% w / v (as the sodium salt);

[0222] an emulsifier or detergent, such as Span 80 0.05% w / v; and

[0223] Oil, such as sesame oil, or

[0224] Formulation 4B

[0225] Cloprostenol 0.15% w / v (as sodium salt);

[0226] Span 80 0.05% w / v; and

[0227] Appropriate amount of sesame oil.

[0228] 24. A sustained-release composition as defined in any of paragraphs 1 to 23, formulated for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; or for use in a reproductive breeding program.

[0229] 25. Use of a sustained release composition as defined in any one of paragraphs 1 to 23 in the preparation of a medicament for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in an animal herd; synchronizing ovulation in an animal herd; or for use in a breeding program.

[0230] 26. A sustained-release composition as defined in any one of paragraphs 1 to 23 for use in, or when used in, a method for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; or for use in a reproductive breeding program.

[0231] 27. A method of: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; or synchronizing ovulation in a herd of animals; wherein the method comprises administering to the animal a sustained-release composition as defined in any one of paragraphs 1 to 23.

[0232] 28. Use of a sustained-release composition as defined in any one of paragraphs 1 to 23 for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; or for use in a breeding program.

[0233] 29. A kit for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; propagating a breeding program; or controlling estrus in an animal, wherein the kit comprises a sustained-release composition as defined in any one of paragraphs 1 to 23.

[0234] 30. A kit for use in a method of controlling estrus in an animal, wherein the kit comprises a sustained release composition as defined in any one of paragraphs 1 to 23.

[0235] 31. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28, wherein the animal or group of animals is a domesticated livestock or farm animal, preferably a sheep, horse, goat, pig, or dog.

[0236] 32. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28, wherein the sustained-release composition is formulated to provide, or will provide, a biologically active concentration of the prostaglandin, preferably cloprostenol, for at least about 8 hours after administration or for at least about 12 hours after administration.

[0237] 33. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28, wherein the sustained release composition is capable of providing, or will provide, a prostaglandin, preferably cloprostenol, in a sustained release manner such that the terminal half-life of the prostaglandin plasma concentration versus time curve is about 3.5 hours or longer.

[0238] 34. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28, wherein about 0.5 to about 10 μg of a prostaglandin, preferably cloprostenol, is administered per kilogram of animal body weight, more preferably about 2.5 to about 10 μg per kilogram of animal body weight, and even more preferably about 3.3 μg per kilogram of animal body weight.

[0239] 35. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28, wherein an absolute dose of the composition is administered regardless of the body weight of the animal, preferably from about 10 μg to about 10 mg, or from about 50 μg to about 5.0 mg, or from about 2.0 mg to about 3.0 mg.

[0240] 36. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28, wherein the amount of the composition administered is in the range of about 0.5 to about 10 ml.

[0241] 37. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28, wherein the biologically active plasma concentration of the prostaglandin, preferably cloprostenol or dinoprost, provided by chronic administration is at least about 0.1 ng / ml, or between about 0.1-1.2 ng / ml, more preferably about 0.4-1.2 ng / ml.

[0242] 38. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28, wherein the reproduction breeding program further comprises timed administration of GnRH and / or timed administration of progesterone.

[0243] 39. The composition of paragraph 38, the use of paragraph 38 or the method of paragraph 38, wherein for said breeding program each animal is administered a first dose of GnRH and, after about five days, is followed by chronic administration of a prostaglandin, preferably cloprostenol, using said sustained release composition.

[0244] 40. The composition of paragraph 39, the use of paragraph 39, or the method of paragraph 39, wherein the second GnRH injection is administered 3 days after the prostaglandin.

[0245] 41. The composition of paragraph 39, the use of paragraph 39, or the method of paragraph 39, wherein the progesterone is administered before the first GnRH injection.

[0246] 42. The composition of paragraph 39, the use of paragraph 39, or the method of paragraph 39, wherein the progesterone is administered before the first GnRH injection.

[0247] 43. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28 for luteolysis of a functional corpus luteum in a cow, mare, or sow.

[0248] 44. The composition of paragraph 24, the use of paragraph 25, the composition of paragraph 26, the method of paragraph 27, or the use of paragraph 28:

[0249] - for fixed-time artificial insemination programs in cows with normal estrous cycles, at an approximate dose of 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg per kilogram of animal body weight; or at an approximate dose of 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg per kilogram of animal body weight; or

[0250] - for the treatment of anestrus in cows, an approximate dose of 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg per kilogram of animal body weight; or an approximate dose of 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg per kilogram of animal body weight; or

[0251] - a fixed-time artificial insemination program for heifers; or

[0252] - For synchronous delivery of heifers, the approximate dose is 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg per kilogram of animal body weight; or the approximate dose is 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg per kilogram of animal body weight.

[0253] 45. A treatment regimen selected from the following:

[0254]

[0255]

[0256]

[0257] Each of the formulations described herein contains the following ingredients, and all ingredient percentages are approximate:

[0258] Preparation 1

[0259] Prostaglandins or PGF2α (e.g., cloprostenol or dinoprost) 0.05% to 0.5% w / v;

[0260] SAIB 80% w / v; and

[0261] Solvent, such as Transcutol q.s.

[0262] Formulation 1A

[0263] Prostaglandins or PGF2α, such as cloprostenol 0.15% w / v (as the sodium salt);

[0264] SAIB 80% w / v; and

[0265] Solvent, such as Transcutol q.s.

[0266] Formulation 1B

[0267] Cloprostenol 0.15% w / v (as sodium salt);

[0268] SAIB 80% w / v; and

[0269] Transcutol appropriate amount,

[0270] Preparation 2

[0271]

[0272] Formulation 2A

[0273]

[0274] Formulation 2B

[0275]

[0276] Preparation 3

[0277] Prostaglandins or PGF2α (e.g., cloprostenol or dinoprost) 0.05% to 0.5% w / v;

[0278] SAIB 70% w / v; and

[0279] A suitable amount of solvent, such as ethanol,

[0280] Formulation 3A

[0281] Prostaglandins, such as cloprostenol 0.15% w / v (as the sodium salt);

[0282] SAIB 70% w / v; and

[0283] A suitable amount of solvent, such as ethanol,

[0284] Formulation 3B

[0285] Cloprostenol 0.15% w / v (as sodium salt);

[0286] SAIB 70% w / v; and

[0287] Ethanol in appropriate amount,

[0288] Preparation 4

[0289] Prostaglandins or PGF2α (e.g., cloprostenol or dinoprost) 0.05% to 0.5% w / v;

[0290] an emulsifier or detergent, such as Span 80 0.05% w / v; and

[0291] Oil, such as sesame oil,

[0292] Formulation 4A

[0293] Prostaglandins, such as cloprostenol 0.15% w / v (as the sodium salt);

[0294] an emulsifier or detergent, such as Span 80 0.05% w / v; and

[0295] Oil, such as sesame oil, and

[0296] Formulation 4B

[0297] Cloprostenol 0.15% w / v (as sodium salt);

[0298] Span 80 0.05% w / v; and

[0299] Sesame oil as needed

[0300] 46. ​​A method of preparing a sustained release composition as defined in any one of paragraphs 1 to 23, said method comprising the step of mixing a therapeutic amount of a prostaglandin with a carrier capable of providing sustained release of the prostaglandin such that the terminal half-life of the prostaglandin plasma concentration versus time curve is about 3.5 hours or more.

[0301] A composition, method, use or kit as defined in any preceding paragraph (if the context permits), wherein the composition or medicament comprises or consists of Formulation 1, 1A or 1B as described herein or substantially as described herein, Formulation 2, 2A or 2B as described herein or substantially as described herein, Formulation 3, 3A or B as described herein or substantially as described herein, Formulation 4, 4A or 4B as described herein or substantially as described herein, a formulation as described in Table 4 or substantially as described in Table 4, a formulation as described in Table 5 or substantially as described in Table 5, a formulation as described in Table 7 or substantially as described in Table 7, a formulation as described in Table 8 or substantially as described in Table 8, a formulation as described in Table 11 or substantially as described in Table 11, or a composition, formulation or medicament described elsewhere in this specification.

[0302] "Substantially as described" or similar phrases mean that the formulation can vary from that shown and still perform the desired function. The difference can be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% or more of the value shown.

[0303] Having broadly described the present invention in its various embodiments, non-limiting examples of preferred embodiments will now be described. BRIEF DESCRIPTION OF THE DRAWINGS

[0305] Figure 1shows a rotating diffusion cell apparatus used to test the release characteristics of the composition;

[0306] Figure 2 The release characteristics of cloprostenol from a sesame oil suspension and a cloprostenol solution are shown;

[0307] Figure 3 Shows Ovuprost TM , the release characteristics of cloprostenol aqueous solution and cloprostenol oily suspension;

[0308] Figure 4 The release characteristics of cloprostenol from a sesame oil emulsion are shown;

[0309] Figure 5 shows the release characteristics of SAIB compositions of cloprostenol using ethanol; and

[0310] Figure 6 Shown are the release characteristics of SAIB compositions of cloprostenol using Transcutol instead of ethanol.

[0311] Preferred embodiments

[0312] Example 1

[0313] Ovuprost TM Pharmacokinetic studies

[0314] Ovuprost was administered to 15-month-old dairy cows. TM A preliminary study of the commercially available product Ovuprost TM Contains cloprostenol as the sodium salt, premixed with citrate buffered saline solution at a concentration of 0.25 g / L of cloprostenol as the sodium salt.

[0315] Intramuscular injection with 2 ml of Ovuprost TM Heifers weighing 230-300 kg (average -260 kg) were treated. Serum samples were analyzed for cloprostenol by LCMS. The limit of quantification (LOQ) was 0.05 ng / ml, and the limit of detection (LOD) was 0.025 ng / ml. The plasma concentrations of cloprostenol at the sampling time points are shown in Table 1.

[0316] Table 1: Cloprostenol levels (ng / ml) and time to maximum concentration (Tmax) and maximum concentration (Cmax)

[0317]

[0318]

[0319] At time points between 15 and 45 minutes after administration, the maximum concentrations ranged from approximately 0.94 to 3.66 μg / L (mean=1.93, SD=1.0, n=6).

[0320] Example 2

[0321] Release research equipment

[0322] Release studies were performed in rotating diffusion cells, e.g. Figure 1 As shown in Figure 2, the diffusion cell is mounted in a standard USP dissolution test basket, a glass cylindrical container with a hemispherical base and a 1000 ml capacity. The basket is placed in a water bath maintained at 37°C ± 0.5°C. The diffusion cell comprises a cylindrical body forming an internal chamber with a volume of approximately 3.5 ml. At the top of the body is a plug connected to the spindle. A tube passing through the plug provides a sampling port. A perforated gasket is located at the bottom of the internal chamber. A magnetic stir bar is located on top of the perforated gasket. A porous membrane beneath the perforated gasket provides an outlet for the diffusion cell. During use, the diffusion cell is rotated by the spindle. A fixed magnet below the test basket prevents the stir bar from rotating.

[0323] For each release study, a 0.5 g sample of the composition and 0.5 g of water were drawn into a diffusion cell, which was then immersed in 400 ml of release medium (water at 37°C) to a standard depth of 2 mm. The composition was separated from the release medium by a porous membrane, which in all release studies was a cellulose acetate membrane (0.2 μm pore size, 70% porosity, Advantec C020A047A). The diffusion cell was rotated at 50 rpm. The contents of the diffusion cell were mixed by rotating the diffusion cell relative to a fixed stirring rod within the cell. At predetermined times, 0.5 ml of release medium was removed (and replaced) to analyze cloprostenol by HPLC.

[0324] Example 3

[0325] Water-insoluble salts of cloprostenol

[0326] The salt of water-insoluble cloprostenol has been studied as a mode of long-term release of cloprostenol after administration. The cloprostenol sodium solution was titrated with calcium chloride, zinc chloride or zinc acetate solution. The mixture obtained was vortexed, left to stand overnight, and the precipitation that may be produced due to the formation of insoluble salts was observed then. The sample with visible precipitate was centrifuged at 15000rpm for 5min, and the supernatant was taken out then and analyzed for cloprostenol by the HPLC of process verification.

[0327] When calcium (eg, calcium chloride) was used, the mixture remained visibly clear, indicating that the solubility product of cloprostenol calcium was not exceeded and that cloprostenol calcium had good solubility.

[0328] When zinc (eg zinc chloride) was used as the counter cation, precipitation was immediately observed in all samples, which was probably due to the formation of cloprostenol zinc. The best yield of precipitation was relatively low, and the supernatant still contained approximately 74% of cloprostenol.

[0329] Table 2: Titration of cloprostenol sodium with zinc chloride solution

[0330]

[0331] Zinc acetate was then used to avoid problems that could be caused by the more acidic zinc chloride. Precipitation was seen in all samples. The highest precipitation yield was achieved when the supernatant still contained approximately 50% cloprostenol.

[0332] Table 3: Titration of cloprostenol with zinc acetate solution

[0333]

[0334] It is hypothesized that multiple equilibria of different complexes exist in solution after the addition of the zinc salt. Literature on the precipitation of bile salts with divalent cations reports that salt formation can take weeks to reach equilibrium (Hofmann and Mysels 1992). Given the similarities in the physicochemical properties of bile acids and cloprostenol, the formation of the cloprostenol-zinc complex is likely slow, and the different recoveries of cloprostenol from solution shown in the table are a result of the various equilibria.

[0335] Example 4

[0336] Cloprostenol sodium oily suspension

[0337] Compositions of cloprostenol sodium suspended in an oily vehicle / carrier were investigated. The two vehicles / carriers tested were sesame oil and Miglyol 812 (caprylic / capric triglyceride).

[0338] Table 4: Suspension formulations of cloprostenol in oily vehicles / carriers

[0339]

[0340] For each suspension composition, 20 g batches of ingredients were weighed and then mixed using a high-speed homogenizer (ULTRA-TURRAX, IKA T 25B) Mixing at 24000 rpm for 3 min. Each composition was placed in a glass bottle, stored under ambient conditions, and observed daily for seven consecutive days for physical stability. The release of cloprostenol was evaluated at least one day after preparation.

[0341] To assess physical stability, the compositions were visually inspected for lumps and adhesion to the glass container.TM ) to bring the volume to 50 ml and analyze the cloprostenol content. The resulting mixture was treated in an ultrasonic bath for 30 min and centrifuged at 14,000 rpm (Eppendorf centrifuge, 5417C) for 30 min. An aliquot of the clarified supernatant was diluted with ethanol (1:9) and then analyzed for cloprostenol components using HPLC.

[0342] A composition of cloprostenol sodium suspended in Miglyol 812 showed cloprostenol clumping and particles adhering to the walls of the glass container. Vigorous shaking was required to redisperse the cloprostenol particles. This sticking problem was not improved even after increasing the concentration of Span 80 (sorbitan monooleate). When Tween 80 (polysorbate 80) was included, the particles adhered to the bottom of the container and could not be redispersed upon shaking.

[0343] Cloprostenol sodium suspended in sesame oil did not clump or adhere to the glass container, and this composition was selected for further testing.

[0344] The release properties of the sesame oil composition were evaluated using the equipment and methods described in Example 1. An aqueous solution of cloprostenol sodium in water (1 mg / ml) was used as a control to evaluate the effect of the porous membrane on release. For each release study, 0.5 g of the composition sample and 0.5 g of water were drawn into the diffusion cell, which was then immersed in 400 ml of 37° C. water (as the release medium) to a depth of 2 mm. At predetermined times, 0.5 ml of the release medium was removed (and replaced) to analyze the cloprostenol by HPLC.

[0345] First, the release of cloprostenol from sesame oil suspension and the release of cloprostenol from aqueous solution were tested using a diffusion cell rotating at 200 rpm. Figure 2 The release of cloprostenol from sesame oil suspension was significantly slower than that from aqueous solution. Figure 2 The results presented here include two tests on the release of cloprostenol from sesame oil, both samples being taken from the same batch of composition.

[0346] Using the same equipment, sesame oil suspension, 1 mg / ml cloprostenol aqueous solution and commercial product Ovuprost TM Release studies were performed. In these release studies, the diffusion cell was rotated at 50 rpm. The results are shown in Figure 3 Slower rotation speeds result in faster release rates. Relatively fast rotation speeds (such as 200 rpm) may cause the formulation to centrifuge onto the walls of the diffusion cell, resulting in a slower release rate. A slower speed of 50 rpm is preferred because it is more likely to simulate intramuscular conditions.

[0347] Although not shown, approximately 60% of the cloprostenol was released from the oily suspension at 24 h, compared to 100% of the cloprostenol released from the solution at 4 h and 100% of the cloprostenol released from the Ovuprost at 1-1.5 h. TM 100% of the cloprostenol was released. The release from the two batches of sesame oil suspension compared favorably.

[0348] Aqueous solution and Ovuprost TM The different release rates may be due to the different concentrations (aqueous solution 1 mg / ml; Ovuprost TM 0.5 mg / ml) and pH level (pH ~8 in aqueous solution; Ovuprost TM pH~5).

[0349] Example 5

[0350] Cloprostenol water-in-oil emulsion

[0351] The use of a water-in-oil (W / O) emulsion of cloprostenol sodium as a sustained-release composition for cloprostenol has been investigated. The water solubility of cloprostenol sodium is greater than 10 mg / ml and is estimated to be approximately 35 mg / ml. In aqueous solution, the micelle concentration of cloprostenol sodium is approximately 5-10 mg / ml. The minimum amount of water required to dissolve a 3 mg dose of cloprostenol (as the sodium salt) is approximately 0.1 ml. Therefore, a target volume of 2 ml of W / O emulsion requires a minimum proportion of approximately 5% water to incorporate a 3 mg dose of cloprostenol.

[0352] The selection of emulsifiers and their concentrations was guided by standard HLB theory and calculations. The composition details are shown in Table 5.

[0353] Table 5: Water-in-oil cloprostenol composition

[0354]

[0355] Emulsions were prepared in 10 ml and 60 ml batch sizes. Sesame oil was mixed with Span 80 in a beaker by shaking for 15 min. Cloprostenol sodium was dissolved in water and then mixed with Span 80. The aqueous phase was added to the oil phase and then 100 ml of water was added using a high-speed homogenizer (ULTRA-TURRAX, IKA). T 25B) was mixed at 19000 / min for 5 min (for 10 ml batches) and 15 min (for 60 ml batches) with a duty cycle of 2 minutes on and 1 minute off. All compositions formed white foamy liquids after homogenization.

[0356] By adding enough purified water (Milli-Q TM) to bring the volume to 50 ml for analysis of cloprostenol content. The resulting mixture was treated in an ultrasonic bath for 30 min and centrifuged at 14,000 rpm (Eppendorf centrifuge, 5417C) for 30 min. An aliquot of the clarified supernatant was diluted with ethanol (1:9) and analyzed for cloprostenol content using HPLC.

[0357] The emulsions were characterized by conductivity and dye / microscopy to determine whether they were w / o or o / w emulsions and to assess droplet size. Only the sesame oil emulsion showed spherical blue droplets with no conductivity, indicating that a water-in-oil emulsion had formed. The droplets had a diameter of approximately 50 μm.

[0358] Physical stability was screened by applying pressure to the emulsions by centrifugation and observing them for creaming and breaking. The formulations were then stored under ambient conditions and observed for one week. The sesame oil emulsion did not cream even after a week of storage, while the other emulsions separated into oil and water phases after 24 hours.

[0359] Release studies were performed in a rotary diffusion cell using the same conditions as for the oily suspension composition of Example 4. In addition, a mass balance assessment was performed as follows. After the last sampling time, the diffusion cell was disassembled and washed with 100 ml of water. The resulting mixture was treated in an ultrasonic bath for 30 min and then centrifuged at 14,000 rpm (Eppendorf centrifuge, 5417C) for 30 min. The supernatant was analyzed for cloprostenol content as above.

[0360] Release studies have shown that 50-60% of the drug is released after 24 hours in both small and large batches, e.g. Figure 4 Percent release data are presented as mean ± SD, from two studies conducted on two individually prepared 15 ml batches and two studies conducted on a single 60 ml batch.

[0361] With aqueous solution of cloprostenol and Ovuprost TM The release rate from the o / w composition was slower than the release rate from the o / w composition. To determine whether any cloprostenol was lost during the release study, the cloprostenol remaining in the rotary diffusion cell was recovered and analyzed to check the mass balance. As shown in Table 6, the mass fraction (i.e., the mass released plus the mass remaining in the diffusion cell) was close to 100%.

[0362] Table 6: Mass balance assessment

[0363] Lotion Total drug content (%) n 15ml≠1 109±2 2 15ml≠2 109±3 2 60ml 100±2 4

[0364] It was demonstrated that the sesame oil water-in-oil emulsion was physically and chemically stable and provided sustained release of cloprostenol.

[0365] Example 6

[0366] Sucrose acetate isobutyrate composition

[0367] The use of sucrose acetate isobutyrate (SAIB) in situ gelling composition of cloprostenol sodium as a sustained-release composition of cloprostenol was studied.

[0368] Three water-miscible or partially water-miscible solvents, ethanol, triacetin, and Transcutol TM (diethylene glycol monoethyl ether), SAIB preparation was prepared.

[0369] Prepare composition as follows: SAIB (sucrose acetate isobutyrate) of required amount is weighed into glass container, and add 0.3ml cloprostenol solution (10mg / ml, as the cloprostenol of sodium salt in ethanol or Transcutol (diethylene glycol monoethyl ether)). The mixture is heated 30min at 50 ℃, then mixed with oscillator to produce homogeneous solution. Use selected complete / partial water miscible solvent that final weight is adjusted to 2g. The final composition comprises the cloprostenol (as sodium salt) of 1.5mg / g. In a kind of preparation, also comprise sodium chloride.

[0370] Table 7: SAIB formulations using three fully / partially water-miscible organic solvents

[0371]

[0372] Manually extract every kind of SAIB preparation by 21 gauge needles, and then inject to observe the degree of difficulty of injection and the ability of preparation by needle.Except the preparation that is included in 90% SAIB in ethanol, all SAIB preparations show acceptable injectability.The preparation with acceptable injectability has been carried out in vitro release test.

[0373] The chemical stability of cloprostenol was tested in ethanol and Transcutol. A cloprostenol solution (1 mg / ml) was prepared in each solvent and stored at 40°C for 4 days. The solution was then removed and injected into an HPLC run for cloprostenol quantitative analysis, and the chromatogram was examined for the formation of new (degradation) peaks. The cloprostenol solutions in ethanol and Transcutol were stable at 40°C over the 4 days of the test. The drug contents in ethanol and Transcutol were measured to be 101% and 102%, respectively. No degradation peaks were observed in the chromatograms.

[0374] Initially, the release rate of the SAIB composition was studied using the rotary diffusion cell described in Example 1; however, no drug was detected even after 8 hours of study, possibly due to clogging of the porous membrane pores by the viscous gel formed in situ. Therefore, the release study of the SAIB composition was performed using a standard USPII dissolution apparatus.

[0375] The release rate of cloprostenol from ethanol formulations is as follows Figure 5 As shown. The composition comprising 80% SAIB releases very slowly, releasing only 5% of cloprostenol in 6 hours. The composition comprising 50% SAIB causes about 90% of cloprostenol to release suddenly in 30 minutes. For all remaining preparations, sudden release occurs initially and then presents a stable state. In the composition comprising 15% triacetin, the initial burst amount is much lower. The preparation comprising 40% SAIB in ethanol does not form a gel when injecting a dissolution medium. On the contrary, SAIB can precipitate when injected, and therefore the samples collected during the release study of this composition are not analyzed.

[0376] Compositions including NaCl were prepared to investigate whether the presence of a water-miscible salt in the gel would enhance the release of cloprostenol after the initial burst. However, the composition containing NaCl agglomerated and was not investigated further.

[0377] As an alternative to ethanol, Transcutol (diethylene glycol monoethyl ether; 2-(2-ethoxyethoxy)ethanol) was selected due to its water miscibility and its ability to dissolve SAIB to produce an injectable solution. The release characteristics of the Transcutol composition are as follows Figure 6 As shown. Compositions containing only 60% SAIB in Transcutol showed an 80% burst release. Increasing SAIB to 80% prevented the burst release. By varying the percentage of SAIB and using Transcutol alone or using Transcutol and triacetin, intermediate release characteristics were achieved. Unlike ethanol-based compositions, Transcutol compositions (except 70% SAIB in Transcutol and triacetin) showed continuous sustained release after the initial burst release.

[0378] The SAIB-based cloprostenol composition was confirmed to be stable and capable of providing sustained release of cloprostenol.

[0379] Example 7

[0380] Pharmacokinetic studies

[0381] Use castrated bulls to carry out pharmacokinetic study to evaluate the performance of three types of sustained-release cloprostenol compositions.The compositions evaluated are oily suspension, water-in-oil emulsion and SAIB in situ gel.The content of the test composition is detailed in Table 8.The animals in the study are Holstein castrated bulls.The animals are divided into four groups, three animals in each group.The test composition is administered to the animals in each of the three groups, and Ovuprost is administered to the animals in the fourth group. TM As a control.

[0382] The test composition was administered by intramuscular injection in a volume of 5 ml (7.5 mg of cloprostenol as sodium salt). This was higher than the expected required dose of approximately 2 ml (3 mg of cloprostenol). TM The control was administered as an intramuscular injection in a volume of 2 ml (0.5 mg of cloprostenol as sodium salt).

[0383] Table 8: Test compositions used for pharmacokinetic studies

[0384]

[0385] Table 9 shows preliminary data on the levels of cloprostenol in the plasma of each animal studied at 4 hours and 8 hours after treatment.

[0386] Table 9: Cloprostenol concentrations in plasma

[0387]

[0388]

[0389] The results are analyzed and shown in Table 10. Dose correction was obtained for each time point by dividing the mean plasma concentration by the dose of cloprostenol administered.

[0390] At the 4-hour time point, dose-corrected plasma concentrations of cloprostenol were higher with SAIB and suspension formulations than with Ovuprost TM The emulsion formulations showed significantly lower dose-corrected results than the control.

[0391] The Composition / Control ratio is determined by dividing the dose-adjusted value of the test composition by the dose-adjusted value of the control at the selected time point.

[0392] Table 10: Cloprostenol concentrations in plasma of the test composition and the control

[0393]

[0394] Preliminary data indicate that SAIB and suspension formulations provide sustained administration of cloprostenol. The emulsion compositions tested did not exhibit sustained release of cloprostenol, possibly because they released the active substance too quickly upon administration, or the active substance was trapped at the injection site.

[0395] Once all samples have been analyzed, the area under the curve (AUC) and relative bioavailability of the composition are determined.

[0396] Example 8

[0397] Sustained-release cloprostenol compositions for use in reproductive protocols

[0398] Based on the findings in the earlier examples, Table 11 below summarizes sustained release compositions formulated for use in reproductive protocols.

[0399] Table 11: Sustained-release cloprostenol compositions for reproductive protocols

[0400]

[0401]

[0402] Aspects of the present invention have been described by way of example only, and it will be appreciated that modifications and additions may be made thereto without departing from the scope as defined in the appended claims.

[0403] All references cited in this specification (including any patents or patent applications) are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicant reserves the right to challenge the accuracy and relevance of the cited documents. It will be appreciated that although a number of prior art publications are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art in New Zealand or any other country.

[0404] Throughout this specification, the word "comprise" or variations such as "include" or "comprising" should be understood to imply the inclusion of a stated element, integer or step, or collection of elements, integers or steps, but not the exclusion of any other element, integer or step, or collection of elements, integers or steps.

[0405] The terms "about" and "approximately" represent an interval of accuracy that one skilled in the art will understand still ensures the technical effect of the feature in question. The term generally indicates a deviation of ±10%, preferably ±5%, more preferably ±2%, and even more preferably ±1% from the numerical value indicated.

[0406] Reference to any numerical range in this specification includes all possible numbers / values ​​falling within that range and further includes all possible sub-ranges falling within that range (if the context permits). The symbol "..." indicates that all relevant numbers / values ​​should be included even if not shown.

[0407] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more combinations.

[0408] In accordance with the statute, the present invention has been described using language that is more or less specific to structural or methodological features. It should be understood that the present invention is not limited to the specific features shown or described, as the means herein described comprise preferred forms of carrying out the invention. Accordingly, the present invention is claimed in any form or modification within the proper scope of the appended claims as appropriately interpreted by one skilled in the art.

Claims

1. An injectable sustained-release composition comprising a prostaglandin, which is formulated to release the prostaglandin in a sustained manner.

2. The composition of claim 1, wherein the prostaglandin is selected from the group consisting of prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), prostaglandin F 2α (PGF 2α / PGF2α), prostacyclin (PGI2) and thromboxane (TXA2).

3. The composition of claim 2, wherein the prostaglandin is PGF2α, preferably cloprostenol or dinoprost.

4. The composition of claim 3, wherein the PGF2α is the synthetic analog cloprostenol.

5. The composition of claim 4, wherein the cloprostenol is a cloprostenol salt, preferably cloprostenol sodium, preferably anhydrous cloprostenol sodium.

6. The composition of any one of claims 1 to 5, wherein the composition comprises approximately 0.0001% w / v to 10% w / v prostaglandins, 0.0001% w / v to 10% w / v PGF2α, 0.05% to 0.5% w / v prostaglandins, or 0.05% to 0.5% w / v PGF2α.

7. The composition of any one of claims 1 to 6, wherein the composition is in the form of a liquid, solution, suspension, dispersion, emulsion or gel.

8. The composition of claim 7, wherein the composition is in the form of an injectable gel capable of rapidly gelling at the injection site to provide sustained release of the prostaglandin.

9. The composition of claim 8, wherein the composition comprises at least one gelling agent and at least one water-miscible or partially water-miscible solvent or solvent system.

10. The composition of claim 9, wherein the at least one gelling agent comprises sucrose acetate isobutyrate (SAIB).

11. The composition of claim 10, wherein the composition comprises about 70% to about 80% w / v SAIB.

12. The composition of claim 11, wherein the composition comprises about 70% or about 80% w / v SAIB.

13. The composition of claim 9, 10, 11 or 12, wherein the at least one solvent or solvent system comprises one or more of diethylene glycol monoethyl ether (Transcutol), triacetin, and ethanol.

14. The composition of claim 9, 10, 11, 12, or 13, wherein the composition comprises from about 15% to about 30% w / v of at least one solvent or solvent system.

15. The composition of claim 7, wherein the composition is in the form of an injectable suspension capable of providing sustained release of the prostaglandin.

16. The composition of claim 15, wherein the composition comprises a suspension of a prostaglandin such as PGF2a or a cloprostenol ester in at least one oily vehicle.

17. The composition of claim 16, wherein the at least one oily vehicle comprises sesame oil, medium chain triglycerides, capric acid, caprylic acid, propane-1,2,3-triol (Miglyol 812), propane-1,2-diol (Miglyol 840), cottonseed oil, soybean oil, peanut oil, corn oil, or triacetin.

18. The composition of claim 17, wherein the at least one oily vehicle comprises sesame oil.

19. A composition as claimed in claim 16, 17 or 18, wherein the composition comprises at least one surfactant, detergent or emulsifier, preferably from about 0.01% to 10% w / v.

20. The composition of claim 19, wherein the at least one surfactant, detergent, or emulsifier comprises a polysorbate.

21. The composition of claim 21, wherein the polysorbate comprises sorbitan monooleate or sorbitan oleate.

22. The composition of any one of claims 1 to 21, wherein the composition comprises about 0.05% to 0.5% w / v of a prostaglandin, such as PGF2α, such as cloprostenol, preferably about 0.15% w / v of cloprostenol as a sodium salt.

23. The composition of claim 1 comprising a formulation selected from the group consisting of: Preparation 1 Prostaglandins, PGF2α, cloprostenol, or dinoprost 0.05% to 0.5% w / v; SAIB 80% w / v; and Solvent, such as Transcutol q.s., or Formulation 1A Prostaglandin or PGF2α, preferably cloprostenol 0.15% w / v (as sodium salt); SAIB 80% w / v; and Solvent, such as Transcutol q.s., or Formulation 1B Cloprostenol 0.15% w / v (as sodium salt); SAIB 80% w / v; and Transcutol appropriate amount, or Preparation 2 Formulation 2A Formulation 2B Preparation 3 Prostaglandins, PGF2α, cloprostenol, or dinoprost 0.05% to 0.5% w / v; SAIB 70% w / v; and A suitable amount of solvent, such as ethanol, or Formulation 3A Prostaglandin or PGF2α, preferably cloprostenol 0.15% w / v (as sodium salt); SAIB 70% w / v; and A suitable amount of solvent, such as ethanol, or Formulation 3B Cloprostenol 0.15% w / v (as sodium salt); SAIB 70% w / v; and Ethanol, or Preparation 4 Prostaglandins, PGF2α, cloprostenol, or dinoprost 0.05% to 0.5% w / v; an emulsifier or detergent, such as Span 80 0.05% w / v; and Oil, such as sesame oil, or Formulation 4A Prostaglandin or PGF2α, preferably cloprostenol 0.15% w / v (as sodium salt); an emulsifier or detergent, such as Span 80 0.05% w / v; and Oil, such as sesame oil, or Formulation 4B Cloprostenol 0.15% w / v (as sodium salt); Span 80 0.05% w / v; and Appropriate amount of sesame oil.

24. A sustained release composition as defined in any one of claims 1 to 23, formulated for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; or for use in a reproductive breeding program.

25. Use of a sustained release composition as defined in any one of claims 1 to 23 in the preparation of a medicament for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in an animal herd; synchronizing ovulation in an animal herd; or for use in a breeding program.

26. A sustained release composition as defined in any one of claims 1 to 23 for use in, or when used in, a method for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; or for use in a reproductive breeding program.

27. A method of: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; or synchronizing ovulation in a herd of animals; wherein the method comprises administering to the animal a sustained release composition as defined in any one of claims 1 to 23.

28. Use of a sustained release composition as defined in any one of claims 1 to 23 for inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in an animal herd; synchronizing ovulation in an animal herd; or for use in a breeding program.

29. A kit for: inducing luteolysis of a functional corpus luteum in an animal; improving fertility in an animal; improving conception rates in a herd of animals; synchronizing ovulation in a herd of animals; propagating a breeding program; or controlling estrus in an animal, wherein the kit comprises a sustained release composition as defined in any one of claims 1 to 23.

30. A kit for use in a method of controlling estrus in an animal, wherein the kit comprises a sustained release composition as defined in any one of claims 1 to 23.

31. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27 or the use of claim 28, wherein the animal or herd of animals is a domesticated livestock or farm animal, preferably a sheep, horse, goat, pig or dog.

32. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27, or the use of claim 28, wherein the sustained release composition is formulated to provide or will provide a bioactive concentration of the prostaglandin, preferably cloprostenol, for at least about 8 hours after administration, or for at least about 12 hours after administration.

33. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27, or the use of claim 28, wherein the sustained release composition is capable of providing or will provide a prostaglandin, preferably cloprostenol, in a sustained release manner such that the terminal half-life of the prostaglandin plasma concentration versus time curve is about 3.5 hours or longer.

34. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27, or the use of claim 28, wherein about 0.5 to about 10 μg of a prostaglandin, preferably cloprostenol, per kilogram of animal body weight is administered, more preferably about 2.5 to about 10 μg per kilogram of animal body weight, and even more preferably about 3.3 μg per kilogram of animal body weight.

35. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27, or the use of claim 28, wherein an absolute dose of the composition is administered regardless of the weight of the animal, preferably from about 10 μg to about 10 mg, or from about 50 μg to about 5.0 mg, or from about 2.0 mg to about 3.0 mg.

36. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27, or the use of claim 28, wherein the amount of the composition administered is in the range of about 0.5 to about 10 ml.

37. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27, or the use of claim 28, wherein the biologically active plasma concentration of the prostaglandin, preferably cloprostenol or dinoprost, provided by chronic administration is at least about 0.1 ng / ml, or between about 0.1-1.2 ng / ml, more preferably about 0.4-1.2 ng / ml.

38. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27, or the use of claim 28, wherein the reproduction and breeding program further comprises timed administration of GnRH and / or timed administration of progesterone.

39. The composition of claim 38, the use of claim 38, or the method of claim 38, wherein for the reproductive breeding program, each animal is administered a first dose of GnRH and, after about five days, is followed by chronic administration of a prostaglandin, preferably cloprostenol, using the sustained release composition.

40. The composition of claim 39, the use of claim 39, or the method of claim 39, wherein the second GnRH injection is administered 3 days after the prostaglandin.

41. The composition of claim 39, the use of claim 39, or the method of claim 39, wherein the progesterone is administered before the first GnRH injection.

42. The composition of claim 39, the use of claim 39, or the method of claim 39, wherein the progesterone is administered before the first GnRH injection.

43. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27 or the use of claim 28 for luteolysis of a functional corpus luteum in a cow, mare or sow.

44. The composition of claim 24, the use of claim 25, the composition of claim 26, the method of claim 27, or the use of claim 28: - for fixed-time artificial insemination programs in cows with normal estrous cycles, at an approximate dose of 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg per kilogram of animal body weight; or at an approximate dose of 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg per kilogram of animal body weight; or - for the treatment of anestrus in cows, an approximate dose of 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg per kilogram of animal body weight; or an approximate dose of 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg per kilogram of animal body weight; or - a fixed-time artificial insemination program for heifers; or - For synchronous delivery of heifers, the approximate dose is 2,000 to 3,000 μg per animal, preferably in about 2 ml, or about 3.3 to 5 μg per kilogram of animal body weight; or the approximate dose is 2,000 μg per animal, preferably in about 2 ml, or about 3.3 μg per kilogram of animal body weight.

45. A treatment regimen selected from the following: Each of the formulations described herein contains the following ingredients, and all ingredient percentages are approximate: Preparation 1 Prostaglandins, PGF2α, cloprostenol, or dinoprost 0.05% to 0.5% w / v; SAIB 80% w / v; and Solvent, such as Transcutol, Formulation 1A Prostaglandin or PGF2α, preferably cloprostenol 0.15% w / v (as sodium salt); SAIB 80% w / v; and Solvent, such as Transcutol, Formulation 1B Cloprostenol 0.15% w / v (as sodium salt); SAIB 80% w / v; and Transcutol appropriate amount, Preparation 2 Formulation 2A Formulation 2B Preparation 3 Prostaglandins, PGF2α, cloprostenol, or dinoprost 0.05% to 0.5% w / v; SAIB 70% w / v; and A suitable amount of solvent, such as ethanol, Formulation 3A Prostaglandin or PGF2α, preferably cloprostenol 0.15% w / v (as sodium salt); SAIB 70% w / v; and A suitable amount of solvent, such as ethanol, Formulation 3B Cloprostenol 0.15% w / v (as sodium salt); SAIB 70% w / v; and Ethanol in appropriate amount, Preparation 4 Prostaglandins, PGF2α, cloprostenol, or dinoprost 0.05% to 0.5% w / v; an emulsifier or detergent, such as Span 80 0.05% w / v; and Oil, such as sesame oil, Formulation 4A Prostaglandin or PGF2α, preferably cloprostenol 0.15% w / v (as sodium salt); an emulsifier or detergent, such as Span 80 0.05% w / v; and Oil, such as sesame oil, and Formulation 4B Cloprostenol 0.15% w / v (as sodium salt); Span 80 0.05% w / v; and Appropriate amount of sesame oil.

46. ​​A method for preparing a sustained release composition as defined in any one of claims 1 to 23, said method comprising the steps of: A therapeutic amount of a prostaglandin is mixed with a carrier capable of providing sustained release of the prostaglandin such that the terminal half-life of the prostaglandin plasma concentration versus time curve is about 3.5 hours or longer.

Images