Sustained release solid oral bolus

Abstract

A sustained release solid oral bolus that, once ingested, is capable of providing sustained release of a therapeutically effective amount of a non-steroidal anti-inflammatory drug (NSAID), and its use for treating fever, pain and / or inflammation, preferably caused by periparturient disorders, such as mastitis, lameness, endometritis, metritis, or subfertility.

Description

Sustained Release Solid Oral Bolus Related applications

[0001] This application claims priority of Australian Patent Application No.2023900580, filed 6 March 2023, the entire contents of which are incorporated herein by way of reference. Field of the invention

[0002] This invention broadly relates to a sustained release solid oral bolus comprising a non- steroidal anti-inflammatory drug (NSAID), as well as to methods of treatment of animals, particularly cattle. Background of the invention

[0003] Commercially available veterinary dosage forms for cattle containing an NSAID, such as ketoprofen, are often formulated as injectable solutions for intramuscular or intravenous administration. Such dosage forms require administration by a veterinarian or medically trained personnel.

[0004] Long-acting NSAIDs are used to control postpartum systemic inflammation in cattle, which, if not kept under control, can impact milk production and the incidence of metabolic disease, and can increase the chance of diseases such as mastitis and lameness.

[0005] Lameness, due to injury or disease in the foot or leg, is one of the most important welfare problems facing dairy cattle today. Cow lameness is the third most important cause of economic loss behind reproduction and mastitis, and the treatment of this condition with long acting NSAID may offer a greater benefit to farmers. Current NSAID treatment regimens consist mainly of multiple intramuscular or subcutaneous injections which may or may not have a withholding period for milk and meat.

[0006] Detailed description of the invention

[0007] It is an object of one or more embodiments of the present invention to provide a sustained release solid oral bolus that provides controlled release of a therapeutically effective amount of a non-steroidal anti-inflammatory drug (NSAID), or to provide the public with a useful commercial choice.

[0008] The invention therefore broadly relates to a sustained release solid oral bolus that, once ingested, is capable of providing sustained release of a therapeutically effective amount of NSAID, and, in some embodiments, its use for treating disease, fever, pain and / or inflammation, preferably caused by periparturient disorders, such as mastitis, lameness, endometritis, metritis, subfertility or postpartum systemic inflammation.

[0009] According to an aspect of the present invention, there is provided a sustained release solid oral bolus comprising a sustained release matrix formulation, wherein the sustained release matrix formulation comprises a therapeutically effective amount of an NSAID.

[0010] According to an aspect of the present invention, there is provided a sustained release solid oral bolus comprising an NSAID that, once ingested by an animal, is capable of providing sustained release of a therapeutically effective amount of the NSAID, preferably for at least 3 days.

[0011] According to an aspect of the present invention, there is provided a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide an animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0012] According to an aspect of the present invention, there is provided a sustained release solid oral bolus for treating disease, fever, pain and / or inflammation in an animal, said bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0013] According to an aspect of the present invention, there is provided a sustained release solid oral bolus for use or when used for treating disease, fever, pain and / or inflammation in an animal, said bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0014] According to an aspect of the present invention, there is provided use of a sustained release matrix formulation comprising an NSAID in the manufacture of a medicament for treating disease, fever, pain and / or inflammation in an animal, said medicament being in the form of a sustained release solid oral bolus, and said medicament being formulated to provide sustained release of the NSAID from the sustained release matrix formulation, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0015] According to an aspect of the present invention, there is provided a method of treating disease, fever, pain and / or inflammation in an animal, said method comprising the step of administering to the animal a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0016] According to an aspect of the present invention, there is provided use of a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID for treating disease, fever, pain and / or inflammation in an animal, said sustained release matrixformulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0017] According to an aspect of the present invention, there is provided a bolus applicator containing a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID for treating disease, fever, pain and / or inflammation in an animal, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID preferably for at least 3 days following ingestion of the bolus by the animal.

[0018] According to an aspect of the present invention, there is provided a kitset for use or when used in a method of treating disease, fever, pain and / or inflammation in an animal, wherein the kitset comprises: a bolus applicator capable of administering a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID preferably for at least 3 days following ingestion of the bolus by the animal.

[0019] According to an aspect of the present invention, there is provided a process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of:

[0020] (A) mixing at least a waxy material, a therapeutically effective amount of an NSAID, and optionally one or more excipients selected from the group consisting of a densifier, a water-soluble non-ionic surfactant, and a sustained release polymer, to form a drug-containing composition; and subsequently

[0021] (B) shaping the drug-containing composition to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0022] According to an aspect of the present invention, there is provided a process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of:

[0023] (A1) mixing at least a waxy material and one or more ingredients selected from the group consisting of a densifier, a water-soluble non-ionic surfactant, and a sustained release polymer to form a composition;

[0024] (A2) mixing the composition obtained in step (A1) and a therapeutically effective amount of an NSAID to form a drug-containing composition; and

[0025] (B) shaping the drug-containing composition to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0026] According to an aspect of the present invention, there is provided a process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of:

[0027] (A1-1) mixing at least a waxy material and a water-soluble non-ionic surfactant at a temperature which is at least 20°C higher than the melting point of the waxy material to form a composition (1);

[0028] (A1-2) mixing the composition (1) obtained in step (A1-1) with at least a sustained release polymer and a densifier at a temperature which is at least 20°C higher than the melting point of the waxy material to form a composition (2);

[0029] (A2) mixing the composition (2) obtained in step (A1-2) and a therapeutically effective amount of an NSAID at a temperature which is at least 10°C higher than the melting point of the waxy material, and at least 3°C lower than the melting point of the NSAID to form a drug- containing composition; and

[0030] (B) shaping the drug-containing composition obtained in step (A2) to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0031] According to an aspect of the present invention, there is provided (i) a sustained release matrix formulation of a sustained release solid oral bolus or (ii) a sustained release solid oral bolus, which is obtainable by or when obtained by a process of manufacture as described according to an aspect of the present invention.

[0032] Features described below relate to all aspects of the invention described above, context permitting. Features described in respect of boluses / compositions / formulations / medicaments may also relate to methods / uses and vice-versa, context permitting. It is to be understood that the terms ‘bolus’, ‘formulation’, ‘medicament’ and ‘composition’ may be used interchangeably, context permitting.

[0033] The term “oral NSAID bolus” means an NSAID formulated as a single dose, administrable orally to an animal.

[0034] The term “sustained release” means that the NSAID is released from the bolus over an extended period of time, preferably being at least 3 days.

[0035] The term “sustained release” or “extended release” or “modified release”, as used herein, refers to dosage forms which are formulated to modify the release profile and thus make the drug available over an extended period after ingestion, thereby allowing a reduction in dosing frequency compared to a drug presented as a conventional dosage form (e.g., as a solution or an immediate release dosage form).

[0036] The term “bolus”, as used herein, refers to an administration mode where the entire amount of drug, whether in solid or liquid form, is administered at once. For example, a solution of a drug can be administered as a bolus by subcutaneous or intravenous injection, as opposed to, for example, administering the solution by infusion or via the drinking water.

[0037] The term “oral bolus”, as used herein, refers to a veterinary dosage form, which is administered orally to animals (in particular ruminants such as cattle, preferably dairy cows) and adapted to arrive and preferably remain in the reticulorumen, in particular in the reticulum or the rumen, for release of the drug. Oral administration of the oral bolus can be performed, e.g., using a bolus applicator, such as a bolus gun.

[0038] The term “sustained release matrix formulation”, as used herein, means a shaped (or unshaped in some embodiments) solid form of a composition comprising at least one active agent (here an NSAID), and at least one matrix material, such as a waxy material and a sustained release polymer, and optionally further excipients, such as a densifier. The term “sustained release matrix formulation, which comprises a therapeutically effective amount of an NSAID”, as used herein, means that the therapeutically effective amount of the NSAID is embedded (e.g., dispersed) in the matrix formulation.

[0039] The sustained release solid oral bolus or sustained release matrix formulation can comprise one type of NSAID or more than one type of NSAID. Any suitable type of NSAID or NSAIDs can be used. A suitable NSAID includes salicylic acid derivatives, such as salicylic acid, acetylsalicylic acid (aspirin), diflunisal, salicylsalicylate (salsalate), magnesium salicylate, or amides of salicylic acid; acetic acid derivatives, such as indomethacin, diclofenac, lonazolac, bromfenac, tolmetin, etodolac, aceclofenac, or oxametacin; propionic acid derivatives, for example ibuprofen, flurbiprofen, ketoprofen, dexketoprofen (an analgesic), naproxen, tiaprofenic acid, suprofen, fenoprofen, carprofen, fenbufen, ketorolac, oxaprozine, loxoprofen, indoprofen, alminoprofen, or pirprofen; oxicams, for example piroxicam, tenoxicam, meloxicam, or lornoxicam; anthranilic acid derivatives, for example mefenamic acid, flufenamic acid, tolfenamic acid, or meclofenamic acid; coxibs, for example celecoxib, rofecoxib, etoricoxib, valdecoxib, parecoxib, or lumiracoxib; sulfonanilides, for example nimesulide, or compounds such as oxaceprol, or aceclofenac. Another example of an NSAID is flunixin meglumine.

[0040] The term “non-steroidal anti-inflammatory drug” or “NSAID”, as used herein, also includes pharmaceutically active metabolites of the above-mentioned compounds and their prodrug compounds, for example acetamicin or nabumetone.

[0041] In the literature, certain non-acidic, antipyretic analgesics such as paracetamol, metamizole, phenylbutazone or flupirtine, are occasionally also referred to as NSAIDs, although their anti- inflammatory effect is low. For purposes of the present invention, these compounds should also be regarded as NSAIDs in the broader sense.

[0042] The term “non-steroidal anti-inflammatory drug”, as used herein, encompasses the free form of the respective drug (i.e., the free base or free acid form) and pharmaceutically acceptable salts thereof. The free form and the pharmaceutically acceptable salts of the NSAID may be presentin solvent free form, such as in anhydrous form, in solvated form, such as in hydrated form, and as complex, and as mixtures of the foregoing.

[0043] In some embodiments, the NSAID is one or more of ketoprofen, meloxicam, carprofen, ibuprofen, tolfenamic acid, acetylsalicylic acid and flunixin meglumine.

[0044] In some embodiments, the NSAID is a propionic acid derivative. Preferably, the NSAID is ketoprofen.

[0045] The term “ketoprofen”, as used herein, means ketoprofen in free form (i.e., the free acid form of ketoprofen), and pharmaceutically acceptable salts thereof. The free form of ketoprofen and pharmaceutically acceptable salts thereof may be present in solvent free form, such as in anhydrous form, in solvated form, such as in hydrated form, and as complex, and as mixtures of the foregoing. The same meaning applies mutatis mutandis for other specifically mentioned NSAID drugs, such as “propionic acid derivative”, “ibuprofen”, “flurbiprofen”, “naproxen”, etc.

[0046] For purposes of the present invention, whenever after the mention of ketoprofen, the molecular formula C16H14O3is given in parentheses, this means that the free acid form of ketoprofen (2-(3-benzoylphenyl)-propionic acid having a molecular weight of 254.28 g / mol, free of solvents or complexing agents) is referred to.

[0047] Optically active substances (e.g., ketoprofen) can be used in the form of their stereoisomers or as a mixture of stereoisomers, e.g. as pure or enriched enantiomers or as racemates. In certain embodiments, wherein the NSAID is ketoprofen, it is used as the racemate. Racemic ketoprofen can be expressed by formula (I):

[0049] The term "pharmaceutically acceptable salt", as used herein, means a salt of an NSAID, which is safe and effective for topical or systemic use in animals (in particular ruminants) and that possesses the desired biological activity. The counter ion is suitable for the intended use, non-toxic, and it does not interfere with the desired biological action of the compound. Pharmaceutically acceptable salts in the context of the present invention include the salts reviewed in the IUPAC Handbook of Pharmaceutically Acceptable Salts (Wermuth, C.G. and Stahl, P.H., Pharmaceutical Salts: Properties, Selection and Use - A Handbook, Verlag Helvetica Chimica Acta (2002)), the entire contents of which are incorporated herein.

[0050] The pharmaceutically acceptable salts may be acid addition salts and basic salts. Pharmaceutically acceptable acid addition salts are for example the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, glycolic acid, lactic acid, succinic acid, citric acid, myristic acid, formic acid, tartaric acid, maleic acid,methanesulphonic acid, 4-toluenesulphonic acid, benzenesulphonic acid, galacturonic acid, gluconic acid, embonic acid, glutamic acid or aspartic acid. Furthermore, the NSAIDs can be bound to acidic or basic ion exchangers. The pharmaceutically acceptable basic salts include the alkali metal salts, for example the sodium or potassium salts, the alkaline earth metal salts, for example the magnesium or calcium salts, the zinc salts, the silver salts and the guanidinium salts. Furthermore, organic compounds with a basic reaction can be used for salt formation, for example ammonia or mono-, di-, and trialkylamines and their derivatives, for example triethylamine, triethanolamine, 2-aminoethanol, N-methylglucamine (meglumine), cyclic amines, for example morpholine, piperazine, or basic amino acids, in particular arginine, lysine, or their decarboxylation products, for example cholamine. The term “salt” includes solvates, such as hydrates, of the respective salt.

[0051] Any suitable type of animal can be treated. The term “animal” includes livestock, i.e., domesticated animals raised in an agricultural setting to produce labor and commodities such as meat, eggs, milk, fur, leather, and wool. In this connection, e.g., cattle, horses, donkeys, mules, sheep, goats, pigs, buffalo, oxen, llamas and camels are to be named. In some embodiments, the animal is a ruminant. Ruminants are mammals of the suborder Ruminantia and include animals in the families of Giraffidae, Cervidae, Antilocapridae, Ovidae, and Bovidae that chew their cud, with respective examples being giraffes, deer, antelope, sheep, cattle, and camel. In some embodiments, the animal is a bovine (head of cattle), goat, sheep, deer, gazelle, antelope, llama, alpaca, camel, buffalo, or wild bovine. In some embodiments, the animal is a ruminant, such as a head of cattle (“cattle”). The term “cattle”, as used herein, means animals of the genus Bos. In preferred embodiments, the term “cattle” means animals of the species Bos taurus, Bubalus arnee, Bos indicus, and Bos mutus f. grunniens. The term “cattle”, as used herein, includes cows, heifers, uncastrated and castrated males (bulls and oxen), calves, weaners, and yearlings. The term “cow”, as used herein, means an adult female that has had a calf. The term “heifer”, as used herein, means a young female (typically under three years of age) before having had a calf.

[0052] The term “a group of cows”, e.g., in the expression “after single-dose administration to a group of cows”, as used herein, refers to a group of at least two cows, at least three cows, or at least six cows. In certain embodiments, the cows are adult healthy cows. In certain embodiments, the cows are adult healthy lactating dairy cows (e.g., Holstein breed). In certain such embodiments the mean body weight of the cows ranges from 300 to 900 kg, preferably from 400 to 700 kg.

[0053] For purposes of the present invention, where two different pharmacokinetic parameters are specified or related, e.g. where the Cmaxand the Tmaxare indicated, or where a ratio of two parameters is indicated, this means that the respective parameters are measured in the same study in the same group of cows.

[0054] The term “Cmax”, as used herein, denotes the maximum concentration, preferably the maximum plasma concentration or the maximum milk concentration, obtained during a dosing interval. Unless being specifically designated otherwise, it is to be understood that Cmaxrefers to the maximum plasma concentration.

[0055] The term “Tmax”, as used herein, denotes the time point at which the maximum concentration (Cmax, e.g. maximum plasma concentration or the maximum milk concentration) is reached.

[0056] The term “AUC” or “Area Under the Curve” corresponds to the area under the concentration-time curve (e.g. the plasma concentration-time curve or the milk concentration-time curve).

[0057] Mean pharmacokinetic values as indicated herein, such as mean Cmax, mean Tmax, or mean concentration (e.g. mean plasma concentration or mean milk concentration), refer to geometric mean values.

[0058] For purposes of the present invention, the expression “mean plasma concentrations of said NSAID (e.g., ketoprofen) in a time period of from about x hours to about y hours after administration” refers to the respective mean plasma concentrations measured at several time points within the indicated time period, including the endpoints of the indicated time period (i.e., “x hours” and “y hours”) and at least one time point in-between. For example, “mean plasma concentrations of ketoprofen in a time period of from about 3 hours to about 48 hours after administration” refers to the mean plasma concentrations measured, e.g., at 3, 24, and 48 hours after administration, or at 3, 6, 12, 24, and 48 hours after administration, or at 3, 6, 8, 12, 24, 36 and 48 hours after administration.

[0059] Equally, the expression “mean milk concentrations of said NSAID (e.g., ketoprofen) in a time period of from about x hours to about y hours after administration” refers to the respective mean milk concentrations measured at several time points within the indicated time period, including the endpoints of the indicated time period (i.e., “x hours” and “y hours”) and at least one time point in between. For example, “mean milk concentrations of ketoprofen in a time period of from about 3 hours to about 48 hours after administration” refers to the mean milk concentrations measured, e.g., at 3, 24, and 48 hours after administration, or at 3, 6, 12, 24, and 48 hours after administration, or at 3, 6, 8, 12, 24, 36 and 48 hours after administration.

[0060] The term “minimum effective concentration”, as used herein, refers to the lowest plasma concentration that results in the desired pharmacological response or therapeutic effect.

[0061] The term “water soluble”, as used herein, refers to a substance having a water solubility (at 20°C) that is classified according to the USP solubility criteria as “very soluble”, “freely soluble”, or “soluble”.

[0062] The term “(practically) insoluble in water”, as used herein, refers to a substance having a water solubility (at 20°C) that is classified according to the USP solubility criteria as “practically insoluble, or insoluble”.

[0063] For purposes of the present invention, the descriptive terms related to the USP water solubility of a substance are defined as follows: 1 g of a very soluble substance dissolves in less than 1 mL of water, 1 g of a freely soluble substance dissolves in 1 to 10 mL of water, 1 g of a soluble substance dissolves in 10 to 30 mL of water, 1 g of a sparingly soluble substance dissolves in 30 to 100 mL of water, 1 g of a slightly soluble substance dissolves in 100 to 1000 mL of water, 1 g of a very slightly soluble substance dissolves in 1,000 to 10,000 mL of water, and 1 g of a practically insoluble, or insoluble substance dissolves in greater than or equal to 10,000 mL of water. A substance having a solubility corresponding to the threshold value between two solubility classes is considered for the purposes of the present invention to belong to the higher solubility class. For example, if 1 g of a substance dissolves in 30 mL of water, it is considered as a soluble (and not as a sparingly soluble) substance.

[0064] The term “fatty acid”, as used herein, refers to an aliphatic monocarboxylic acid with an aliphatic chain, which is either saturated or unsaturated. In certain embodiments, the aliphatic chain has a number of carbon atoms of from 12 to 36, or from 14 to 28, or from 16 to 22, or from 16 to 18. In certain embodiments, the aliphatic chain is unbranched and / or has an even number of carbon atoms. In certain embodiments the aliphatic chain is saturated.

[0065] The term “fatty alcohol”, as used herein, refers to an aliphatic monohydric (primary) alcohol with an aliphatic chain, which is either saturated or unsaturated. In certain embodiments, the aliphatic chain has a number of carbon atoms of from 12 to 36, or from 14 to 28, or from 16 to 22, or from 16 to 18. In certain embodiments, the aliphatic chain is unbranched and / or has an even number of carbon atoms. In certain embodiments the aliphatic chain is saturated.

[0066] The term “surfactant”, as used herein, refers to an organic substance which has an amphiphilic structure (including a hydrophobic portion and a hydrophilic portion) and can lower the surface tension of the medium (e.g., water) in which it is dissolved, and / or the interfacial tension with other phases. A surfactant is further characterized by the capability to form micelles in aqueous phase, once the critical micellization concentration (CMC) is reached. Reference is made to Remington’s Pharmaceutical Sciences, 18th edition, 1990, Chapter 19, pages 267-271, the contents of which are hereby incorporated in their entirety. In certain embodiments of the present invention, the term “surfactant” refers to a substance, which further has a molecular weight below 5000 g / mol. In certain such embodiments, the term “surfactant” refers to a substance which further has a molecular weight below 2,000 g / mol.

[0067] The term “cylinder”, as used herein, refers to a right circular cylinder with radius “r” and height “h”. The diameter “d” of a cylinder is calculated using the formula d = 2×r.

[0068] The term “a cylinder with rounded ends”, as used herein, means a cylinder wherein one or both ends of the cylinder are hemispherical.

[0069] Active agent

[0070] The sustained release solid oral bolus according to one or more embodiments of the present invention comprises a sustained release matrix formulation, which comprises a therapeutically effective amount of at least one type of NSAID. In certain embodiments, the amount of the NSAID in the sustained release matrix formulation is from about 1 g to about 15 g (inclusive of about 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, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 and 15 g), or from about 1 g to about 10 g (inclusive of about 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 g), or from about 1 g to about 5 g (inclusive of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5 g), or from about 2 g to about 4 g (inclusive of about 2, 2.5, 3, 3.5 and 4 g).

[0071] As previously mentioned, any suitable type of NSAID or NSAIDs can be used. In certain embodiments, the NSAID is a propionic acid derivative. In certain embodiments, the NSAID is selected from ibuprofen, flurbiprofen, ketoprofen, naproxen, tiaprofenic acid, suprofen, fenoprofen, carprofen, fenbufen, ketorolac, oxaprozine, loxoprofen, indoprofen, alminoprofen, pirprofen, or mixtures of the foregoing.

[0072] In certain embodiments, the NSAID is selected from ketoprofen, meloxicam, carprofen, ibuprofen, tolfenamic acid, acetylsalicylic acid and flunixin meglumine, or mixtures of the foregoing.

[0073] In certain preferred embodiments, the NSAID is ketoprofen.

[0074] In certain embodiments, wherein the NSAID is ketoprofen, the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to from about 1 g to about 10 g of ketoprofen (C16H14O3) (inclusive of about 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 g), or from about 1 g to about 8 g of ketoprofen (C16H14O3) (inclusive of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 g), or from about 1 g to about 5 g of ketoprofen (C16H14O3) (inclusive of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5 g), or from about 1 g to about 4 g of ketoprofen (C16H14O3) (inclusive of about 1, 1.5, 2, 2.5, 3, 3.5 and 4 g), or from about 2 g to about 4 g of ketoprofen (C16H14O3) (inclusive of about 2, 2.5, 3, 3.5 and 4 g). In certain embodiments, the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to about 2 g of ketoprofen (C16H14O3), or is equimolar to about 2.5 g of ketoprofen (C16H14O3), or is equimolar to about 3 g of ketoprofen (C16H14O3) or is equimolar to about 3.5 g of ketoprofen (C16H14O3) or is equimolar to about 4 g of ketoprofen (C16H14O3). In certain embodiments, the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to about 3 g of ketoprofen (C16H14O3).

[0075] In certain such embodiments, the NSAID is ketoprofen (C16H14O3).

[0076] In the above-described embodiments, the amount of the NSAID (e.g., ketoprofen) in the sustained release matrix formulation preferably corresponds to the total amount of the NSAID in the sustained release solid oral bolus.

[0077] Plasma levels

[0078] In certain embodiments, the sustained release solid oral bolus, after single-dose administration to a group of animals, preferably a group of cows, provides in said group of animals mean plasma concentrations of said NSAID (e.g., ketoprofen) in a time period of from about 3 hours to about 24 hours after administration, or from about 3 hours to about 48 hours after administration, or from about 3 hours to about 72 hours after administration, or from about 3 hours to about 96 hours after administration, or from about 3 hours to about 120 hours after administration, which correspond at least to the minimum effective concentration of said NSAID. It is particularly preferred that the sustained release solid oral bolus, after single-dose administration to a group of animals such as cows, provides in said group mean plasma concentrations of said NSAID (e.g., ketoprofen) in a time period of from about 3 hours to about 24 hours after administration, or from about 3 hours to about 48 hours after administration, or from about 3 hours to about 72 hours after administration, which correspond at least to the minimum effective concentration of said NSAID. From about 3 hours to about 72 hours after administration is particularly preferred.

[0079] In certain embodiments, the sustained release solid oral bolus, after single-dose administration to a group of animals such as cows, provides in said group a ratio of the mean plasma concentration of said NSAID (e.g., ketoprofen) at 48 hours after administration to the mean plasma concentration of said NSAID at 24 hours after administration of from about 0.2 to about 1.0 (inclusive of about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1.0), or from about 0.3 to about 0.9 (inclusive of about 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 and 0.9), or from about 0.4 to about 0.8 (inclusive of about 0.4, 0.5, 0.6, 0.7 and 0.8), or from about 0.5 to about 0.7 (inclusive of about 0.5, 0.6 and 0.7).

[0080] In certain embodiments, the sustained release solid oral bolus, after single-dose administration to a group of animals such as cows, provides in said group a ratio of the mean plasma concentration of said NSAID (e.g., ketoprofen) at 48 hours after administration to the mean Cmaxof said NSAID of from about 0.1 to about 1.0 (inclusive of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1.0), or from about 0.2 to about 0.8 (inclusive of about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7 and 0.8), or from about 0.3 to about 0.8 (inclusive of about 0.3, 0.4, 0.5, 0.6, 0.7 and 0.8), or from about 0.3 to about 0.5 (inclusive of about 0.3, 0.4 and 0.5).

[0081] In certain embodiments, wherein the NSAID is ketoprofen, the sustained release solid oral bolus, after single-dose administration to a group of animals such as cows, provides in said group mean plasma concentrations of ketoprofen in a time period of from about 3 hours to about 24 hoursafter administration, or from about 3 hours to about 48 hours after administration, or from about 3 hours to about 72 hours after administration, which are at least 50 μg / L, or at least 100 μg / L.

[0082] In certain embodiments, wherein the NSAID is ketoprofen, the sustained release solid oral bolus, after single-dose administration to a group of animals such as cows, provides in said group a mean Cmaxof ketoprofen of about 11,000 μg / L or less, about 5,000 μg / L or less, about 4,000 μg / L or less, about 3,000 μg / L or less, about 2,000 μg / L or less, or about 1,000 μg / L or less, or from about 200 μg / L to about 11,000 μg / L, from about 200 μg / L to about 5,000 μg / L, from about 200 μg / L to about 4,000 μg / L, from about 200 μg / L to about 3,000 μg / L, from about 200 μg / L to about 2,000 μg / L, or from about 200 μg / L to about 1,000 μg / L. In certain such embodiments, the sustained release solid oral bolus, after single-dose administration to said group of cows, further provides in said group a mean Tmaxof from about 5 hours to about 20 hours, from about 5 hours to about 15 hours, from about 6 hours to about 14 hours, or from about 7 hours to about 13 hours after administration.

[0083] Preferably, the group of animals is a group of cows.

[0084] Composition of the sustained release matrix formulation

[0085] The sustained release solid oral bolus comprises a sustained release matrix formulation, wherein the sustained release matrix formulation comprises a therapeutically effective amount of an NSAID as described herein above (e.g., ketoprofen).

[0086] In certain embodiments, the amount of the NSAID (e.g., ketoprofen) in the sustained release matrix formulation is from about 1 wt% to about 15 wt% (inclusive of about 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, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 and 15 wt%), preferably from about 1 wt% to about 5 wt% (inclusive of about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5 wt%), more preferably from about 1 wt% to about 3wt% (inclusive of about 1, 1.5, 2, 2.5 and 3 wt%), most preferably from about 2 wt% to about 3 wt% (inclusive of about 2, 2.5 and 3 wt%) (based on the weight of the sustained release matrix formulation).

[0087] The sustained release matrix formulation can comprise at least one ingredient other than an NSAID. Any suitable amount and type of ingredient can be used. Two of more different types of ingredients can be used. The ingredient can comprise at least one matrix material, excipient and / or adjuvant, for example. Suitable ingredients include, for example, polysorbate 80, triacetin, polyethylene glycol 400 (PEG 400), lactose monohydrate, barium sulphate, glyceryl monostearate, ethyl cellulose, and HPMC.

[0088] The sustained release matrix formulation can comprise at least one matrix material. Any suitable amount and type of matrix material can be used. Two of more different types of matrix materials can be used. For example, the at least one matrix material can comprise a waxy material and / or a sustained release polymer.

[0089] The sustained release matrix formulation can comprise at least one excipient. Any suitable amount and type of excipient can be used. Two of more different types of excipients can be used. For example, the excipient can be a densifier, solvent, filler, diluent, lubricant and / or a water- soluble non-ionic surfactant. For example, the excipient can be a film coating, such as a cosmetic film coating.

[0090] The sustained release matrix formulation can comprise at least one adjuvant. Any suitable amount and type of adjuvant can be used. Two of more different types of adjuvants can be used.

[0091] In certain embodiments, the sustained release matrix formulation comprises a therapeutically effective amount of an NSAID, and a waxy material.

[0092] In certain embodiments, the waxy material is practically insoluble in water. In certain embodiments, the waxy material has a melting point of at least 40 °C, or at least 45 °C, or at least 50 °C. In certain embodiments, the waxy material is a non-ionic surfactant having an HLB value of not more than about 8, or not more than about 6, or not more than about 5. In certain embodiments the HLB value is from about 2 to about 8, or from about 3 to about 6, or from about 3 to about 5.

[0093] In certain embodiments, the waxy material is selected from the group consisting of fatty acids (such as stearic acid or palmitic acid), fatty alcohols (such as cetyl alcohol, stearyl alcohol or cetostearyl alcohol), fatty acid esters, or mixtures of the foregoing.

[0094] In certain embodiments, the waxy material is selected from the group consisting of glyceryl monostearate, glyceryl dibehenate, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, stearic acid, palmitic acid, bees wax, carnauba wax, or mixtures of the foregoing.

[0095] In certain embodiments, the waxy material is a fatty acid ester. In certain such embodiments, the fatty acid ester is selected from esters of a fatty acid with a fatty alcohol, esters of a fatty acid with a polyhydric alcohol (such as ethylene glycol and glycerol), or mixtures of the foregoing.

[0096] In certain embodiments, the waxy material is an ester of a fatty acid with glycerol. In certain embodiments, the waxy material is selected from mono-, and diglycerides of a fatty acid.

[0097] In certain preferred embodiments, the waxy material is glyceryl monostearate. Glyceryl monostearate is available in different grades. The commercial products are mixtures of variable proportions of glyceryl monostearate and glyceryl monopalmitate.

[0098] In certain embodiments, the glyceryl monostearate corresponds to the PhEur 2005 grade “glyceryl monostearate 40-55% Type I” including 40.0-55.0% monoglycerides and wherein the composition of fatty acids used in manufacturing the product contains 40.0-60.0% stearic acid and a sum of stearic acid and palmitic acid of not less than 90.0%. In certain embodiments, the glyceryl monostearate corresponds to the PhEur 2005 grade “glyceryl monostearate 40-55% Type II” including 40.0-55.0% monoglycerides and wherein the composition of fatty acids used inmanufacturing the product contains 60.0-80.0% stearic acid and a sum of stearic acid and palmitic acid of not less than 90.0%. In certain embodiments, the glyceryl monostearate corresponds to the PhEur 2005 grade “glyceryl monostearate 40- 55% Type III” including 40.0-55.0% monoglycerides and wherein the composition of fatty acids used in manufacturing the product contains 90.0-99.0% stearic acid and a sum of stearic acid and palmitic acid of not less than 96.0%. In certain embodiments, the glyceryl monostearate corresponds to the USPNF 23 grade “glyceryl monostearate 90%”, which contains not less than 90.0% of monoglycerides of saturated fatty acids, chiefly glyceryl monostearate and glyceryl monopalmitate. In certain embodiments, the glyceryl monostearate is used as a self-emulsifying grade (glyceryl monostearate SE). In certain such embodiments, the glyceryl monostearate corresponds to the grade Imwitor® 960 K, a self- emulsifiying grade with a minimum of 30% of monoglycerides that complies with the B.P. and having a melting point of 56-61°C.

[0099] In certain embodiments, the amount of the waxy material in the sustained release matrix formulation is at least about 20 wt%, preferably at least about 30 wt%, more preferably at least about 40 wt%, most preferably at least about 45 wt% (based on the weight of the sustained release matrix formulation). In certain embodiments, the amount of the waxy material in the sustained release matrix formulation is from about 20 wt% to about 70 wt% (inclusive of about 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 and 70 wt%), preferably from about 30 wt% to about 60 wt% (inclusive of 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 and 60 wt%), more preferably from about 40 wt% to about 55 wt% (inclusive of about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 wt%), most preferably from about 45 wt% to about 50 wt% (inclusive of about 45, 46, 47, 48, 49 and 50 wt%) (based on the weight of the sustained release matrix formulation).

[0100] In certain embodiments, the sustained release matrix formulation comprises a therapeutically effective amount of an NSAID as described herein, a waxy material as described herein, and a densifier.

[0101] A densifier is a pharmaceutically acceptable material that is included to increase the density of the sustained release matrix formulation and thus the density of the overall sustained release solid oral bolus, preferably to retain the bolus in a rumen of the animal and prevent its regurgitation. Suitable densifiers are known to the skilled person and include metals, for example selected from the group consisting of zinc, iron, manganese, copper, cobalt, barium, or mixtures thereof, as well as metal oxides and metal salts, for example oxides and salts (e.g., sulphates) derived from the aforementioned metals. Suitable densifiers (including preferred shapes and diameters) are described, e.g., in EP 2 193 786 A1 (Agrimin Limited), the contents of which are hereby incorporated by reference.

[0102] In certain embodiments, the densifier is an alkaline earth metal salt, such as an alkaline earth metal sulphate. In certain preferred embodiments, the densifier is barium sulphate.

[0103] In certain embodiments, the amount of the densifier in the sustained release matrix formulation is at least about 25 wt%, preferably at least about 30 wt%, more preferably at least about 35 wt%, most preferably at least about 37 wt% (based on the weight of the sustained release matrix formulation). In certain embodiments, the amount of the densifier in the sustained release matrix formulation is from about 25 wt% to about 75 wt% (inclusive of about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 and 75 wt%), preferably from about 30 wt% to about 60 wt% (inclusive of 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 and 60 wt%), more preferably from about 35 wt% to about 50 wt% (inclusive of about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50 wt%), most preferably from about 37 wt% to about 43 wt% (inclusive of about 37, 38, 39, 40, 41, 42 and 43 wt%) (based on the weight of the sustained release matrix formulation).

[0104] In certain embodiments, the sustained release matrix formulation comprises a therapeutically effective amount of an NSAID, a waxy material, a densifier, and a water-soluble non-ionic surfactant.

[0105] In certain embodiments, the water-soluble non-ionic surfactant exhibits an HLB value of at least about 12, preferably of at least about 14. In certain embodiments, the water-soluble non-ionic surfactant exhibits an HLB value of from about 12 to about 18 (inclusive of about 12, 13, 14, 15, 16, 17 and 18), or from about 14 to about 18 (inclusive of about 14, 15, 16, 17 and 18).

[0106] In certain embodiments, the water-soluble non-ionic surfactant has a molecular weight of not more than about 5,000 g / mol, preferably not more than about 2,000 g / mol or not more than about 1,500 g / mol.

[0107] In certain embodiments, the water-soluble non-ionic surfactant is a polyoxyethylene sorbitan fatty acid ester (polysorbate). In certain such embodiments, the water-soluble non-ionic surfactant is a polyoxyethylene sorbitan fatty acid ester (polysorbate) having an HLB value of at least about 12, preferably of at least about 14, more preferably from about 14 to about 18 (inclusive of about 14, 15, 16, 17 and 18), or from about 14 to about 16 (inclusive of about 14, 15 and 16).

[0108] In certain embodiments the water-soluble non-ionic surfactant is selected from the group consisting of polyoxyethylene 20 sorbitan monolaurate (polysorbate 20), polyoxyethylene 20 sorbitan monopalmitate (polysorbate 40), polyoxyethylene 20 sorbitan monostearate (poly- sorbate 60), polyoxyethylene 20 sorbitan monooleate (polysorbate 80), polyoxyethylene 20 sorbitan monoisostearate (polysorbate 120), or mixtures of the foregoing. In certain preferredembodiments, the water-soluble non-ionic surfactant is polyoxyethylene 20 sorbitan monooleate (polysorbate 80).

[0109] In certain embodiments, the amount of the water-soluble non-ionic surfactant in the sustained release matrix formulation is from about 1 wt% to about 15 wt% (inclusive of about 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, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 and 15 wt%), preferably from about 2 wt% to about 11 wt% (inclusive of about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5 and 11 wt%), more preferably from about 3 wt% to about 7 wt% (inclusive of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5 and 7 wt%), most preferably from about 4 wt% to about 6 wt% (inclusive of about 4, 4.5, 5, 5.5 and 6 wt%), (based on the weight of the sustained release matrix formulation).

[0110] In certain embodiments, the sustained release matrix formulation comprises a therapeutically effective amount of an NSAID, a waxy material, a densifier, optionally a water- soluble non-ionic surfactant, and a sustained release polymer.

[0111] In certain embodiments, the sustained release polymer is a cellulose ether, such as a (hydroxy)alkyl cellulose. In certain embodiments, the sustained release polymer is selected from the group consisting of ethylcellulose, methylcellulose, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), or mixtures of the foregoing.

[0112] In certain preferred embodiments, the sustained release polymer is ethylcellulose. In certain such embodiments, the sustained release polymer is ethylcellulose exhibiting a viscosity of at least about 40 mPa-s, when tested as a 5% w / v solution in a solvent blend of 80% toluene : 20% ethanol (w / w) at 25 °C. In certain preferred embodiments, the sustained release polymer is ethylcellulose exhibiting a viscosity of at least about 80 mPa-s, when tested as a 5% w / v solution in a solvent blend of 80% toluene : 20% ethanol (w / w) at 25 °C. In certain embodiments, the sustained release polymer is ethylcellulose exhibiting a viscosity of from about 80 mPa-s to about 105 mPa-s, when tested as a 5% w / v solution in a solvent blend of 80% toluene : 20% ethanol (w / w) at 25 °C. A corresponding ethylcellulose grade is available from Aqualon (N-100). In certain embodiments, the sustained release polymer is ethylcellulose exhibiting a viscosity of from about 90 mPa-s to about 110 mPa-s, when tested as a 5% w / v solution in a solvent blend of 80% toluene : 20% ethanol (w / w) at 25 °C. Corresponding ethylcellulose grades are available from Dow Chemical (ETHOCELTMStandard 100 Premium and ETHOCELTMStandard 100 FP Premium).

[0113] In certain embodiments, the amount of the sustained release polymer in the sustained release matrix formulation is from about 1 wt% to about 15 wt% (inclusive of about 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, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 and 15 wt%), preferably from about 3 wt% to about 10 wt% (inclusive of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 wt%), more preferably from about 4 wt% to about 8 wt% (inclusive of about 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 wt%), most preferably from about 5 wt% to about 7 wt%(inclusive of about 5, 5.5, 6, 6.5 and 7 wt%), (based on the weight of the sustained release matrix formulation).

[0114] In certain embodiments, the sustained release matrix formulation comprises further adjuvants and excipients, such as solvents, fillers, diluents, and lubricants. Examples of solvents include triacetin or a polyethylene glycol (e.g., PEG400). An example of a diluent is lactose monohydrate. In certain embodiments, the ingredients of the sustained release matrix formulation as described above are selected such that the sustained release matrix formulation is degradable or digestible.

[0115] In certain embodiments, the melting point of the sustained release matrix formulation is at least about 45 °C.

[0116] In certain embodiments, the density of the sustained release matrix formulation is from about 1 g / cm3to about 6 g / cm3(inclusive of about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0), or from about 1.2 g / cm3to about 5 g / cm3(inclusive of about 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 and 5.0), or from about 1.3 to about 4 g / cm3(inclusive of about 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 and 4.0).

[0117] The bolus can be retained in a rumen / reticulum of the animal by means other than a densifier, or in addition to the use of a densifier. In some embodiments, the bolus can comprise a high-density core which helps retain the bolus within the rumen / reticulum of the animal. The high- density core can be released into or disintegrate within the digestive tract of the animal once an outer layer of the sustained release matrix formulation loses its structural integrity. The high- density core can be of any suitable size, shape and composition. For example, the high-density core can comprise a metal core, iron shot or compressed iron filings. In some embodiments, the high-density core can be spherical or cylindrical. In some embodiments, the sustained release solid oral bolus comprises a high-density core enveloped or contained within a sustained release matrix formulation comprising an NSAID.

[0118] In some embodiments, the bolus can be shaped so as to be better retained within the rumen / reticulum of the animal. For example, an external surface of the bolus can comprise one or more projections or wings. These projections or wings can be comprised of the sustained release matrix formulation, or can be separate attachments such as plastic wings.

[0119] Shape and dimensions

[0120] The sustained release solid oral bolus may be of any size and shape suitable for oral administration to animals, such as ruminants, eg. cattle.

[0121] In certain embodiments, the sustained release solid oral bolus exhibits the shape of a sphere, a cylinder, a cylinder with rounded ends, a disc, or an ellipsoid, preferably of a cylinder with rounded ends.

[0122] In some embodiments, the external surface of the bolus can comprise one or more projections or wings.

[0123] In certain embodiments, the sustained release solid oral bolus further has a diameter of from about 10 mm to about 70 mm (inclusive of about 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 and 70 mm), or from about 15 mm to about 60 mm (inclusive of about 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 mm), or from about 20 mm to about 50 mm (inclusive of about 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 and 50 mm), or from about 20 mm to about 40 mm (inclusive of about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 and 40 mm), or from about 25 mm to about 35 mm (inclusive of about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35 mm). In certain such embodiments, the sustained release solid oral bolus has a diameter of about 26 mm, or about 28 mm, or about 30 mm, or about 32 mm, or about 34 mm.

[0124] The size and shape of the sustained release solid oral bolus is substantially determined by the size and shape of the sustained release matrix formulation. For example, in certain embodiments, the sustained release matrix formulation can be present in two or more subunits, for example as two identical subunits. In this case, the size and shape of the sustained release solid oral bolus can be determined by the size, shape, and spatial arrangement of the subunits.

[0125] In certain embodiments, the sustained release matrix formulation has a weight from about 50 to about 300 g (inclusive of about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 and 300 g), or from about 70 to about 280 g (inclusive of about 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270 and 280 g), or about 90 to about 250 g (inclusive of about 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 and 250 g). In certain preferred embodiments, the sustained release matrix formulation has a weight of from about 100 to about 200 g (inclusive of about 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 and 200 g), or from about 110 to about 180 g (inclusive of about 110, 120, 130, 140, 150, 160, 170 and 180 g).

[0126] In certain embodiments, the weight of the sustained release matrix formulation corresponds to at least about 90%, or at least about 95%, or at least about 98%, or to about 100% of the weight of the sustained release solid oral bolus (inclusive of about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100%).

[0127] In certain embodiment, the sustained release matrix formulation is biodegradable.

[0128] In certain embodiments, the sustained release solid oral bolus consists of the sustained release matrix formulation.

[0129] Manufacture of the sustained release solid oral bolus

[0130] The sustained release solid oral bolus according to the present invention can be prepared by methods known in the art, including atmospheric molding, injection molding, extrusion, melt granulation and subsequent compression, or direct compression. Some of these processes of manufacture are described, e.g., in US 4,166,107 A, EP 0236901 B1, and US 5,720,972, the contents of which are hereby incorporated by reference.

[0131] In certain embodiments, the present invention relates to a process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus or (ii) a sustained release solid oral bolus as described herein above, which comprises the steps of:

[0132] (A) mixing or blending at least a waxy material, a therapeutically effective amount of an NSAID, and optionally one or more ingredients selected from the group consisting of a densifier, a water-soluble non-ionic surfactant, and a sustained release polymer, to form a drug-containing composition; and subsequently

[0133] (B) shaping the drug-containing composition to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0134] In certain embodiments, step (A) is performed at a temperature above the melting point of the waxy material. In certain embodiments, the temperature in step (A) is at least 10°C higher than the melting point of the waxy material. In certain embodiments, the temperature in step (A) is at least 10°C higher than the melting point of the waxy material, and at least 3°C lower than the melting point of the NSAID. In certain embodiments, the temperature in step (A) is at least 15°C higher than the melting point of the waxy material, and at least 5°C lower than the melting point of the NSAID. For example, the temperature in step (A) can be from about 65°C to about 90°C, or from about 70°C to about 90°C, or from about 80°C to about 90°C.

[0135] These temperature ranges can, for example, be selected in embodiments, wherein the non- steroidal anti-inflammatory drug is ketoprofen and / or wherein the waxy material is glycerol monostearate.

[0136] In certain such embodiments, step (A) comprises blending at least a waxy material, a therapeutically effective amount of an NSAID, a densifier, optionally a water-soluble non-ionic surfactant, and a sustained release polymer, to form a drug-containing composition.

[0137] Furthermore, in certain embodiments, step (A) can comprise a step of homogenizing the drug-containing composition prior to performing step (B).

[0138] In certain embodiments, the present invention relates to a process of manufacturing a sustained release matrix formulation of (i) a sustained release solid oral bolus or (ii) a sustained release solid oral bolus, which comprises the steps of:

[0139] (A1) mixing or blending at least a waxy material and one or more ingredients selected from the group consisting of a densifier, a water-soluble non-ionic surfactant, and a sustained release polymer to form a composition;

[0140] (A2) blending the composition obtained in step (A1) and a therapeutically effective amount of an NSAID to form a drug-containing composition; and

[0141] (B) shaping the drug-containing composition to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0142] In certain embodiments, step (A1) is performed at a temperature above the melting point of the waxy material. In certain embodiments, the temperature in step (A1) is at least 20°C higher than the melting point of the waxy material. In certain embodiments, the temperature in step (A1) is at least 25°C higher than the melting point of the waxy material. For example, the temperature in step (A1) can be from about 90°C to about 120°C, or from about 95°C to about 115°C, or from about 100°C to about 110°C. These temperature ranges can, for example, be selected in embodiments wherein the waxy material is glycerol monostearate.

[0143] In certain such embodiments, step (A1) comprises blending at least a waxy material, a densifier, optionally a water-soluble non-ionic surfactant, and a sustained release polymer, to form a composition.

[0144] In certain embodiments, step (A2) is performed at a temperature above the melting point of the waxy material. In certain embodiments, the temperature in step (A2) is at least 10°C higher than the melting point of the waxy material. In certain embodiments, the temperature in step (A2) is at least 10°C higher than the melting point of the waxy material, and at least 3°C lower than the melting point of the NSAID. In certain embodiments, the temperature in step (A2) is at least 15°C higher than the melting point of the waxy material, and at least 5°C lower than the melting point of the NSAID. For example, the temperature in step (A2) can be from about 65°C to about 90°C, or from about 70°C to about 90°C, or from about 80°C to about 90°C. These temperature ranges can, for example, be selected in embodiments, wherein the non-steroidal anti-inflammatory drug is ketoprofen and / or wherein the waxy material is glycerol monostearate.

[0145] In certain embodiments, the temperature in step (A2) is lower than the temperature in step (A1), such that an intermediate cooling step may be required to adapt to the temperature to be applied in step (A2) prior to addition of the NSAID.

[0146] In certain embodiments, step (A2) comprises a step of homogenizing the drug-containing composition prior to performing step (B).

[0147] In certain embodiments wherein step (A) or step (A1) and (A2) are performed at a temperature above the melting point of the waxy material, step (B) comprises a step of transferring (e.g., pouring) the (softened or molten) composition into a mold at atmospheric pressure.

[0148] The mold can, for example, be a stainless-steel mold (optionally preheated to a temperature of, e.g., from about 50°C to about 70°C), a silicone mold, an aluminium mold, or a metal alloy mold.

[0149] In certain embodiments wherein step (A) or step (A1) and (A2) are performed at a temperature above the melting point of the waxy material, step (B) comprises a step of injecting the (softened or molten) composition into a mold under pressure.

[0150] In certain embodiments, step (B) is performed at a temperature above the melting point of the waxy material. In certain embodiments, the temperature in step (B) is at least 10°C higher than the melting point of the waxy material. In certain embodiments, the temperature in step (B) is at least 10°C higher than the melting point of the waxy material, and at least 3°C lower than the melting point of the NSAID.

[0151] In certain embodiments, the temperature in step (B) is at least 15°C higher than the melting point of the waxy material, and at least 5°C lower than the melting point of the NSAID. For example, the temperature in step (B) can be from about 65°C to about 90°C, or from about 70°C to about 90°C, or from about 80°C to about 90°C. These temperature ranges can, for example, be selected in embodiments, wherein the non-steroidal anti-inflammatory drug is ketoprofen and / or wherein the waxy material is glycerol monostearate.

[0152] In certain embodiments, wherein step (B) is performed at a temperature above the melting point of the waxy material, step (B) comprises a step of extruding the composition.

[0153] In certain preferred embodiments, the present invention relates to a process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus or (ii) a sustained release solid oral bolus, which comprises the steps of:

[0154] (A1-1) blending at least a waxy material and a water-soluble non-ionic surfactant at a temperature which is at least 20°C higher than the melting point of the waxy material to form a composition (1);

[0155] (A1-2) blending the composition (1) obtained in step (A1-1) with at least a sustained release polymer and a densifier at a temperature which is at least 20°C higher than the melting point of the waxy material to form a composition (2);

[0156] (A2) blending the composition (2) obtained in step (A1-2) and a therapeutically effective amount of an NSAID at a temperature which is at least 10°C higher than the melting point of the waxy material, and at least 3°C lower than the melting point of the NSAID to form a drug- containing composition; and

[0157] (B) shaping the drug-containing composition obtained in step (A2) to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0158] In certain embodiments, the temperature applied in step (A1-1) is from about 90°C to about 120°C, or from about 95°C to about 115°C, or from about 100°C to about 110°C. In certain embodiments, the temperature applied in step (A1-2) is from about 90°C to about 120°C, or from about 95°C to about 115°C, or from about 100°C to about 110°C.

[0159] In certain embodiments, the temperature applied in step (A2) is from about 65°C to about 90°C, or from about 70°C to about 90°C, or from about 80°C to about 90°C. These temperature ranges can, for example, be selected in embodiments wherein the NSAID is ketoprofen and / or wherein the waxy material is glycerol monostearate.

[0160] In certain such embodiments, step (B) comprises a step of transferring (e.g., pouring) the (softened or molten) composition into a mold at atmospheric pressure.

[0161] In certain embodiments, the processes of manufacturing as described above can comprise a further step (C) of coating the sustained release matrix formulation obtained in step (B), preferably with a cosmetic film coating (e.g., an Opadry™ coating).

[0162] The present invention also relates to (i) a sustained release matrix formulation of a sustained release solid oral bolus or (ii) a sustained release solid oral bolus, which is obtainable by a process of manufacture as described herein.

[0163] Preferred sustained release solid oral bolus formulations

[0164] In some embodiments, preferred sustained release solid oral bolus formulations comprise:

[0165] (a) Ketoprofen; Polysorbate 80; Triacetin; Polyethylene glycol 400 (PEG 400); Lactose monohydrate; Barium sulphate; and Glyceryl monostearate;

[0166] (b) Ketoprofen; Polysorbate 80, Barium sulphate; and Glyceryl monostearate;

[0167] (c) Ketoprofen; Polysorbate 80; Ethyl cellulose; Barium sulphate; and Glyceryl monostearate; or

[0168] (d) Ketoprofen; Polysorbate 80; HPMC; Barium sulphate; and Glyceryl monostearate.

[0169] Preferred sustained release solid oral bolus formulations (with approximate %w / w) are shown below.

[0170] Formulation PF26Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 10.16 9.75 Polysorbate 80 7.8 7.49 Triacetin 7.8 7.49 Polyethylene glycol 400 (PEG 400) 7.8 7.49 Lactose monohydrate 5.0 4.80 Barium sulphate 31.2 29.95 Glyceryl monostearate SE 30.24 29.03 Total Weight 100.00 96.00

[0171] Formulation PF30 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 10.05 9.70 Polysorbate 80 10 9.70 Barium sulphate 35 33.95 Glyceryl monostearate SE 44.95 43.60 Total Weight (g) 100.00 97.00

[0172] Formulation PF31 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 10.05 9.70 Polysorbate 80 5 4.85 Ethyl cellulose N-100 Premium 5 4.85 Barium sulphate 35 33.95 Glyceryl monostearate SE 44.95 43.60 Total Weight (g) 100.00 97.00

[0173] Formulation PF32 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 10.71 9.75 Polysorbate 80 5 4.55 HPMC 100 Premium 5 4.55 Barium sulphate 35 31.85 Glyceryl monostearate SE 44.29 40.30Total Weight (g) 100.00 91.00

[0174] Formulation PF 33 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 10.71 9.75 Polysorbate 80 5 4.55 HPMC 100 Premium 5 4.55 Barium sulphate 35 31.85 Glyceryl monostearate SE 44.29 40.30 Total Weight (g) 100.00 91.00

[0175] Formulation PF 34 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 3.81 4.50 Polysorbate 80 5 5.90 Ethyl cellulose- N100 5 5.90 Barium sulphate 39.14 46.19 Glyceryl monostearate SE 47.05 55.52 Total 100 118.00

[0176] Formulation PF30 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 4.65 4.51 Polysorbate 80 10.54 10.22 Barium sulphate 36.9 35.79 Glyceryl monostearate SE 47.91 46.47 Total Weight 100.00 97.00

[0177] Formulation PF34 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 3.81 4.50 Polysorbate 80 5 5.90 Ethyl cellulose 100 5 5.90 Barium sulphate EP 39.14 46.19 Glyceryl monostearate SE 47.05 55.52 Total Weight100 118

[0178] Formulation PF37 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 2.97 3.50 Polysorbate 80 5 5.90 Ethyl cellulose premium N-100 5.5 6.49 Barium sulphate 39.48 46.59 Glyceryl monostearate SE 47.05 55.52 Total Weight 100.00 118.00

[0179] Formulation PF38 Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 2.52 3.0 Polysorbate 80 5.00 6.0 Ethyl cellulose N100 5.50 7.0 Barium sulphate 39.65 47.0 Glyceryl monostearate SE 47.33 56.0 Total Weight 100.00 119

[0180] Veterinary uses and methods of treatment

[0181] In certain embodiments, the present invention is directed to a sustained release solid oral bolus for use in the treatment (reduction) of fever, pain and / or inflammation in an animal, preferably in cattle.

[0182] It is to be understood that according to one or more embodiments of the present invention the animal is preferably livestock, preferably a ruminant, preferably selected from the group consisting of cattle, horses, donkeys, mules, sheep, goats, camels, llamas, and pigs, more preferably selected from the group consisting of cattle, sheep, goats, camels, and llamas, in particular cattle.

[0183] In certain embodiments, the sustained release solid oral bolus as described herein is for use in the treatment of a disease selected from periparturient disorders, lameness, abdominal pain, mastitis, respiratory diseases, osteoarthritis, endometritis, metritis, postpartum systemic inflammation, and wound healing in an animal, preferably in cattle.

[0184] In certain embodiments, the sustained release solid oral bolus is for use in the treatment of lameness associated with pain and / or inflammation in an animal, preferably in cattle.

[0185] In certain embodiments, the sustained release solid oral bolus is for use in the treatment of pain and / or inflammation associated with musculoskeletal disorders and lameness in an animal, preferably in cattle.

[0186] In certain embodiments, the sustained release solid oral bolus is for use in the treatment of fever, pain, and / or inflammation associated with mastitis in an animal, preferably in cattle.

[0187] In certain embodiments, the sustained release solid oral bolus is for use in the treatment of fever, pain, and / or inflammation associated with metritis or endometritis in an animal, preferably in cattle.

[0188] Without being bound to any theory, it is assumed that lameness, musculoskeletal disorders, metritis, and endometritis in cattle are also associated with periparturient disorders.

[0189] In certain embodiments, the cattle are dairy cattle or beef cattle, preferably dairy cattle. In certain embodiments, the cattle are dairy cows (e.g., lactating dairy cows). In certain embodiments the cattle (such as dairy cows) have an approximate body weight of from about 200 kg to about 900 kg, from about 300 kg to about 800 kg, or from about 400 kg to about 700 kg.

[0190] In certain embodiments, the treatment comprises orally administering a sustained release solid oral bolus as described herein to an animal (e.g., cattle) in need thereof once daily, or less frequently.

[0191] In certain embodiments, the treatment comprises orally administering the sustained release solid oral bolus to an animal in need thereof every second day (i.e., on day 1, on day 3, and optionally on day 5, day 7, etc.), or less frequently.

[0192] In certain embodiments, the treatment comprises orally administering the sustained release solid oral bolus to an animal in need thereof every third day (i.e., on day 1 and on day 4, and optionally on day 7, day 10, etc.), or less frequently. In certain embodiments, the treatment comprises orally administering the sustained release solid oral bolus to an animal in need thereof every third day.

[0193] In certain embodiments the treatment comprises orally administering a single dose of a sustained release solid oral bolus to an animal (e.g., dairy cow) in need thereof (i.e., one administration on day 1, and no further administration on subsequent days).

[0194] In certain embodiments, wherein the dosing frequency is less than once daily (e.g., every second day or single dose administration), the indicated doses refer to the dose of ketoprofen per sustained release solid oral bolus.

[0195] In certain of the above embodiments, the NSAID in the sustained release solid oral bolus is ketoprofen. In certain such embodiments, the treatment comprises orally administering the sustained release solid oral bolus to an animal (e.g., cattle) in need thereof at a dose of ketoprofen which is equimolar to from about 1 g to about 10 g of ketoprofen (C16H14O3) once per at least three days (inclusive of about 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 g), or equimolar to from about 2 g to about 7.5 g of ketoprofen (C16H14O3) once per at least three days (inclusive of about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 and 7.5 g), or equimolar to from about 2 g to about 4 g of ketoprofen (C16H14O3) once per at least three days (inclusive of about 2, 2.5, 3, 3.5and 4 g), or equimolar to from about 4 g to about 7.5 g of ketoprofen (C16H14O3) once per at least three days (inclusive of about 4, 4.5, 5, 5.5, 6, 6.5, 7 and 7.5 g), or equimolar to about 2 g of ketoprofen (C16H14O3) once per at least three days, or equimolar to about 3 g of ketoprofen (C16H14O3) once per at least three days, or equimolar to about 3.5 g of ketoprofen (C16H14O3) once per at least three days, or equimolar to about 4 g of ketoprofen (C16H14O3) once per at least three days, or equimolar to about 5 g of ketoprofen (C16H14O3) once per at least three days, or equimolar to about 6 g of ketoprofen (C16H14O3) once per at least three days, or equimolar to about 7.5 g of ketoprofen (C16H14O3) once per at least three days. In this connection, it is to be understood that the term “once per at least three days” preferably denotes a single administration of ketoprofen in a time range of three to six days, more preferably of three to five days, even more preferably of three to four days, and in particular of three days.

[0196] The above-described embodiments directed to a sustained release solid oral bolus for use are also meant to refer to the respective methods of treatment, and to the respective uses of a sustained release solid oral bolus as described herein in the manufacture of a medicament. Thus, in certain embodiments, the present invention is directed to a method of treating fever, pain and / or inflammation in cattle comprising administering to an animal in need thereof a sustained release solid oral bolus as described herein. In certain other embodiments, the present invention is directed to a use of a sustained release solid oral bolus as described herein in the manufacture of a medicament for treating fever, pain and / or inflammation in cattle.

[0197] Preferred embodiments of the invention are defined in the paragraphs below:

[0198] 1. A sustained release solid oral bolus comprising a sustained release matrix formulation, wherein the sustained release matrix formulation comprises a therapeutically effective amount of an NSAID.

[0199] 2. A sustained release solid oral bolus comprising an NSAID that, once ingested by an animal, is capable of providing sustained release of a therapeutically effective amount of the NSAID, preferably for at least 3 days.

[0200] 3. A sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide an animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0201] 4. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the NSAID is selected from one or more of ketoprofen, meloxicam, carprofen, ibuprofen, tolfenamic acid, acetylsalicylic acid and flunixin meglumine, preferably the NSAID is ketoprofen.

[0202] 5. The sustained release solid oral bolus of paragraph 1, 2, 3 or 4, wherein the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to from about 1 g to about 10 g of ketoprofen (C16H14O3), or from about 1 g to about 8 g of ketoprofen (C16H14O3),or from about 1 g to about 5 g of ketoprofen (C16H14O3), or from about 1 g to about 4 g of ketoprofen (C16H14O3), or from about 2 g to about 4 g of ketoprofen (C16H14O3); or wherein the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to about 2 g of ketoprofen (C16H14O3), or is equimolar to about 2.5 g of ketoprofen (C16H14O3), or is equimolar to about 3 g of ketoprofen (C16H14O3), or is equimolar to about 3.5 g of ketoprofen (C16H14O3) ), or is equimolar to about 4 g of ketoprofen (C16H14O3).

[0203] 6. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of said NSAID in a time period of from about 3 hours to about 24 hours after administration, or from about 3 hours to about 48 hours after administration, or from about 3 hours to about 72 hours after administration, or from about 3 hours to about 96 hours after administration, or from about 3 hours to about 120 hours after administration, which correspond at least to the minimum effective concentration of said NSAID; and / or wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group a ratio of the mean plasma concentration of said NSAID at 48 hours after administration to the mean plasma concentration of said NSAID at 24 hours after administration of from about 0.2 to about 1.0, or from about 0.3 to about 0.9, or from about 0.4 to about 0.8, or from about 0.5 to about 0.7; and / or wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group a ratio of the mean plasma concentration of said NSAID at 48 hours after administration to the mean Cmaxof said NSAID of from about 0.1 to about 1.0, or from about 0.2 to about 0.8, or from about 0.3 to about 0.8, or from about 0.3 to about 0.5.

[0204] 7. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the NSAID is ketoprofen, and wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of ketoprofen in a time period of from about 3 hours to about 24 hours after administration, or from about 3 hours to about 48 hours after administration, or from about 3 hours to about 72 hours after administration, which are at least 50 μg / L, or at least 100 μg / L; and / or wherein the NSAID is ketoprofen, and wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group a mean Cmaxof ketoprofen of about 11,000 μg / L or less, about 5,000 μg / L or less, about 4,000 μg / L or less, about 3,000 μg / L or less, about 2,000 μg / L or less, or about 1,000 μg / L or less, or from about 200 μg / L to about 11,000 μg / L, from about 200 μg / L to about 5,000 μg / L, from about 200 μg / L to about 4,000 μg / L, from about 200 μg / L to about 3,000 μg / L, from about 200 μg / L to about 2,000 μg / L, or from about 200 μg / L to about 1,000 μg / L.

[0205] 8. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the amount of the NSAID in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 1 wt% to about 5 wt%, more preferably from about 1 wt% to about 3 wt%, most preferably from about 2 wt% to about 3 wt%, based on the weight of the sustained release matrix formulation.

[0206] 9. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the sustained release matrix formulation further comprises a waxy material, wherein the waxy material is optionally selected from the group consisting of fatty acids, fatty alcohols, fatty acid esters, and mixtures of the foregoing.

[0207] 10. The sustained release solid oral bolus of paragraph 9, wherein the amount of the waxy material in the sustained release matrix formulation is at least about 20 wt%, or from about 20 wt% to about 70 wt%, preferably from about 30 wt% to about 60 wt%, more preferably from about 40 wt% to about 55 wt%, most preferably from about 45 wt% to about 50 wt%, based on the weight of the sustained release matrix formulation.

[0208] 11. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the sustained release matrix formulation further comprises a densifier, wherein the densifier is optionally an alkaline earth metal sulphate.

[0209] 12. The sustained release solid oral bolus of paragraph 11, wherein the amount of the densifier in the sustained release matrix formulation is at least about 25 wt% or from about 25 wt% to about 75 wt%, preferably from about 30 wt% to about 60 wt%, more preferably from about 35 wt% to about 50 wt%, most preferably from about 37 wt% to about 43 wt%, based on the weight of the sustained release matrix formulation.

[0210] 13. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the sustained release matrix formulation further comprises a water-soluble non-ionic surfactant, wherein the water-soluble non-ionic surfactant is optionally a polyoxyethylene sorbitan fatty acid ester and / or optionally exhibits an HLB value of at least about 12.

[0211] 14. The sustained release solid oral bolus of paragraph 13, wherein the amount of the water- soluble non-ionic surfactant in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 2 wt% to about 11 wt%, more preferably from about 3 wt% to about 7 wt%, most preferably from about 4 wt% to about 6 wt%, based on the weight of the sustained release matrix formulation.

[0212] 15. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the sustained release matrix formulation further comprises a sustained release polymer, wherein the sustained release polymer is optionally a cellulose ether.

[0213] 16. The sustained release solid oral bolus of paragraph 15, wherein the amount of the sustained release polymer in the sustained release matrix formulation is from about 1 wt% to about15 wt%, preferably from about 3 wt% to about 10 wt%, more preferably from about 4 wt% to about 8 wt%, most preferably from about 5 wt% to about 7 wt%, based on the weight of the sustained release matrix formulation.

[0214] 17. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the sustained release matrix formulation is degradable; and / or wherein the melting point of the sustained release matrix formulation is at least about 40 °C.

[0215] 18. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the sustained release solid oral bolus exhibits the shape of a sphere, a cylinder, a cylinder with rounded ends, a disc, or an ellipsoid, preferably of a cylinder with rounded ends; and / or wherein the sustained release solid oral bolus has a diameter of from about 10 mm to about 70 mm, or from about 15 mm to about 60 mm, or from about 20 mm to about 50 mm, or from about 20 mm to about 40 mm, or from about 25 mm to about 35 mm; and / or wherein the sustained release matrix formulation has a weight of from about 50 to about 300 g, or from about 70 to about 280 g, or from about 90 g to about 250 g.

[0216] 19. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the sustained release solid oral bolus has a formulation comprising:

[0217] (a) Ketoprofen; Polysorbate 80; Triacetin; Polyethylene glycol 400 (PEG 400); Lactose monohydrate; Barium sulphate; and Glyceryl monostearate;

[0218] (b) Ketoprofen; Polysorbate 80, Barium sulphate; and Glyceryl monostearate;

[0219] (c) Ketoprofen; Polysorbate 80; Ethyl cellulose; Barium sulphate; and Glyceryl monostearate; or

[0220] (d) Ketoprofen; Polysorbate 80; HPMC; Barium sulphate; and Glyceryl monostearate.

[0221] 20. The sustained release solid oral bolus of any one of the preceding paragraphs, wherein the sustained release solid oral bolus has a formulation comprising:

[0222] - Formulation PF26: Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 10.16 9.75 Polysorbate 80 7.8 7.49 Triacetin 7.8 7.49 Polyethylene glycol 400 (PEG 400) 7.8 7.49 Lactose monohydrate 5.0 4.80 Barium sulphate 31.2 29.95 Glyceryl monostearate SE 30.24 29.03 Total Weight 100.00 96.00

[0223] - Formulation PF30:Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 10.05 9.70 Polysorbate 80 10 9.70 Barium sulphate 35 33.95 Glyceryl monostearate SE 44.95 43.60 Total Weight (g) 100.00 97.00

[0224] - Formulation PF31: Ingredients Approximate Approximate Content (%w / w) Mass per bolus (g) Ketoprofen 10.05 9.70 Polysorbate 80 5 4.85 Ethyl cellulose N-100 Premium 5 4.85 Barium sulphate 35 33.95 Glyceryl monostearate SE 44.95 43.60 Total Weight (g) 100.00 97.00

[0225] - Formulation PF32: Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 10.71 9.75 Polysorbate 80 5 4.55 HPMC 100 Premium 5 4.55 Barium sulphate 35 31.85 Glyceryl monostearate SE 44.29 40.30 Total Weight (g) 100.00 91.00

[0226] - Formulation PF 33: Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 10.71 9.75 Polysorbate 80 5 4.55 HPMC 100 Premium 5 4.55 Barium sulphate 35 31.85 Glyceryl monostearate SE 44.29 40.30 Total Weight (g) 100.00 91.00

[0227] - Formulation PF 34:Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 3.81 4.50 Polysorbate 80 5 5.90 Ethyl cellulose- N100 5 5.90 Barium sulphate 39.14 46.19 Glyceryl monostearate SE 47.05 55.52 Total 100 118.00

[0228] - Formulation PF30: Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 4.65 4.51 Polysorbate 80 10.54 10.22 Barium sulphate 36.9 35.79 Glyceryl monostearate SE 47.91 46.47 Total Weight 100.00 97.00

[0229] - Formulation PF34: Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 3.81 4.50 Polysorbate 80 5 5.90 Ethyl cellulose 100 5 5.90 Barium sulphate EP 39.14 46.19 Glyceryl monostearate SE 47.05 55.52 Total Weight100 118

[0230] - Formulation PF37: Ingredients Approximate Approximate Content (%w / w) Mass per bolus (g) Ketoprofen 2.97 3.50 Polysorbate 80 5 5.90 Ethyl cellulose premium N-100 5.5 6.49 Barium sulphate 39.48 46.59 Glyceryl monostearate SE 47.05 55.52 Total Weight 100.00 118.00

[0231] - Formulation PF38:Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 2.52 3.0 Polysorbate 80 5.00 6.0 Ethyl cellulose N100 5.50 7.0 Barium sulphate 39.65 47.0 Glyceryl monostearate SE 47.33 56.0 Total Weight 100.00 119

[0232] 21. A sustained release solid oral bolus for treating disease, fever, pain and / or inflammation in an animal, said bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0233] 22. A sustained release solid oral bolus for use or when used for treating disease, fever, pain and / or inflammation in an animal, said bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0234] 23. Use of a sustained release matrix formulation comprising an NSAID in the manufacture of a medicament for treating disease, fever, pain and / or inflammation in an animal, said medicament being in the form of a sustained release solid oral bolus, and said medicament being formulated to provide sustained release of the NSAID from the sustained release matrix formulation, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0235] 24. A method of treating disease, fever, pain and / or inflammation in an animal, said method comprising the step of administering to the animal a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0236] 25. Use of a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID for treating disease, fever, pain and / or inflammation in an animal, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

[0237] 26. The sustained release solid oral bolus according to the use of paragraph 21 or paragraph 22, or the use according to paragraph 23 or 25, or the method according to paragraph 24, which is for use in the treatment of a disease selected from periparturient disorders, lameness, abdominal pain, mastitis, respiratory diseases, osteoarthritis, endometritis, metritis, postpartum systemicinflammation, and wound healing in an animal, preferably in cattle; and / or which is for use in the treatment of pain and / or inflammation associated with musculoskeletal disorders and lameness in an animal, preferably in cattle; and / or which is for use in the treatment of fever, pain, and / or inflammation associated with mastitis in an animal, preferably in cattle; and / or which is for use in the treatment of fever, pain, and / or inflammation associated with metritis or endometritis in an animal, preferably in cattle, and / or postpartum systemic inflammation, in an animal, preferably in cattle.

[0238] 27. The sustained release solid oral bolus according to the use of paragraph 21 or paragraph 22, or the use according to paragraph 23 or 25, or the method according to paragraph 24, which is for use in treating disease, fever, pain and / or inflammation in an animal caused by periparturient disorders, such as mastitis, lameness, endometritis, metritis, or subfertility, or postpartum systemic inflammation.

[0239] 28. The sustained release solid oral bolus according to the use of paragraph 21, 22, 26 or 27, or the use according to paragraph 23, 25, 26 or 27, or the method according to paragraph 24, 26 or 27, wherein the animals are cattle, preferably wherein the cattle are dairy cattle or beef cattle, preferably dairy cattle.

[0240] 29. The sustained release solid oral bolus according to the use of paragraph 21, 22, 26, 27 or 28, or the use according to paragraph 23, 25, 26, 27 or 28, or the method according to paragraph 24, 26, 27 or 28, wherein the sustained release solid oral bolus is as defined in any one of paragraphs 1 to 20.

[0241] 30. A bolus applicator containing a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID for treating disease, fever, pain and / or inflammation in an animal, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID preferably for at least 3 days following ingestion of the bolus by the animal.

[0242] 31. The bolus applicator according to paragraph 30, wherein said sustained release solid oral bolus is as defined in any one of paragraphs 1 to 20.

[0243] 32. A kitset for use or when used in a method of treating disease, fever, pain and / or inflammation in an animal, wherein the kitset comprises: a bolus applicator capable of administering a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID preferably for at least 3 days following ingestion of the bolus by the animal.

[0244] 33. The kitset according to paragraph 32, wherein said sustained release solid oral bolus is as defined in any one of paragraphs 1 to 20.

[0245] 34. A process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of:

[0246] (A) mixing at least a waxy material, a therapeutically effective amount of an NSAID, and optionally one or more excipients selected from the group consisting of a densifier, a water-soluble non-ionic surfactant, and a sustained release polymer, to form a drug-containing composition; and subsequently

[0247] (B) shaping the drug-containing composition to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0248] 35. A process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of:

[0249] (A1) mixing at least a waxy material and one or more ingredients selected from the group consisting of a densifier, a water-soluble non-ionic surfactant, and a sustained release polymer to form a composition;

[0250] (A2) mixing the composition obtained in step (A1) and a therapeutically effective amount of an NSAID to form a drug-containing composition; and

[0251] (B) shaping the drug-containing composition to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0252] 36. A process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of:

[0253] (A1-1) mixing at least a waxy material and a water-soluble non-ionic surfactant at a temperature which is at least 20°C higher than the melting point of the waxy material to form a composition (1);

[0254] (A1-2) mixing the composition (1) obtained in step (A1-1) with at least a sustained release polymer and a densifier at a temperature which is at least 20°C higher than the melting point of the waxy material to form a composition (2);

[0255] (A2) mixing the composition (2) obtained in step (A1-2) and a therapeutically effective amount of an NSAID at a temperature which is at least 10°C higher than the melting point of the waxy material, and at least 3°C lower than the melting point of the NSAID to form a drug- containing composition; and

[0256] (B) shaping the drug-containing composition obtained in step (A2) to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

[0257] 37. The process of manufacturing according to paragraph 34, 35 or 36, wherein said sustained release solid oral bolus is as defined in any one of paragraphs 1 to 20.

[0258] 38. A (i) sustained release matrix formulation of a sustained release solid oral bolus or a (ii) sustained release solid oral bolus, which is obtainable by or when obtained by the process of manufacture of any one of paragraphs 34 to 37.

[0259] 39. The invention as defined in any one or more of paragraphs 1-38, context permitting, wherein the animal or animals are selected from: livestock; ruminants; or, cattle, horses, donkeys, mules, sheep, goats, camels, llamas, pigs, buffalo, oxen, deer, antelope, bovine, gazelles, alpacas, or wild bovine.

[0260] 40. The invention as defined in any one or more of paragraphs 1-39, context permitting, wherein:

[0261] - the sustained release solid oral bolus is capable of providing or provides sustained release of a therapeutically effective amount of the NSAID for at least 3 days, preferably for about 3 to 5 days;

[0262] - the NSAID is ketoprofen; and

[0263] - after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of ketoprofen in a time period of from about 3 hours to about 72 hours after administration, which are at least 100 μg / L.

[0264] Further preferred embodiments of the invention are defined in the paragraphs below:

[0265] 1. A sustained release solid oral bolus comprising a sustained release matrix formulation, wherein the sustained release matrix formulation comprises a therapeutically effective amount of a non-steroidal anti-inflammatory drug (NSAID).

[0266] 2. The sustained release solid oral bolus according to paragraph 1, wherein the NSAID is selected from one or more of ketoprofen, meloxicam, carprofen, ibuprofen, tolfenamic acid, acetylsalicylic acid and flunixin meglumine, preferably the NSAID is ketoprofen.

[0267] 3. The sustained release solid oral bolus according to paragraph 1 or 2, wherein the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to from about 1 g to about 10 g of ketoprofen (C16H14O3), or from about 1 g to about 8 g of ketoprofen (C16H14O3), or from about 1 g to about 5 g of ketoprofen (C16H14O3), or from about 1 g to about 4 g of ketoprofen (C16H14O3), or from about 2 g to about 4 g of ketoprofen (C16H14O3); or wherein the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to about 2 g of ketoprofen (C16H14O3), or is equimolar to about 2.5 g of ketoprofen (C16H14O3), or is equimolar to about 3 g of ketoprofen (C16H14O3), or is equimolar to about 3.5 g of ketoprofen (C16H14O3) ), or is equimolar to about 4 g of ketoprofen (C16H14O3).

[0268] 4. The sustained release solid oral bolus according to any one of paragraphs 1 to 3, wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of said NSAID in a time period of from about 3 hours to about 24 hours after administration, or from about 3 hours to about 48 hours afteradministration, or from about 3 hours to about 72 hours after administration, or from about 3 hours to about 96 hours after administration, or from about 3 hours to about 120 hours after administration, which correspond at least to the minimum effective concentration of said NSAID; and / or wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group a ratio of the mean plasma concentration of said NSAID at 48 hours after administration to the mean plasma concentration of said NSAID at 24 hours after administration of from about 0.2 to about 1.0, or from about 0.3 to about 0.9, or from about 0.4 to about 0.8, or from about 0.5 to about 0.7; and / or wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group a ratio of the mean plasma concentration of said NSAID at 48 hours after administration to the mean Cmaxof said NSAID of from about 0.1 to about 1.0, or from about 0.2 to about 0.8, or from about 0.3 to about 0.8, or from about 0.3 to about 0.5.

[0269] 5. The sustained release solid oral bolus according to any one of paragraphs 1 to 4, wherein the NSAID is ketoprofen, and wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of ketoprofen in a time period of from about 3 hours to about 24 hours after administration, or from about 3 hours to about 48 hours after administration, or from about 3 hours to about 72 hours after administration, which are at least 50 μg / L, or at least 100 μg / L; and / or wherein the NSAID is ketoprofen, and wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group a mean Cmaxof ketoprofen of about 11,000 μg / L or less, about 5,000 μg / L or less, about 4,000 μg / L or less, about 3,000 μg / L or less, about 2,000 μg / L or less, or about 1,000 μg / L or less, or from about 200 μg / L to about 11,000 μg / L, from about 200 μg / L to about 5,000 μg / L, from about 200 μg / L to about 4,000 μg / L, from about 200 μg / L to about 3,000 μg / L, from about 200 μg / L to about 2,000 μg / L, or from about 200 μg / L to about 1,000 μg / L.

[0270] 6. The sustained release solid oral bolus according to any one of paragraphs 1 to 5, wherein the amount of the NSAID in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 1 wt% to about 5 wt%, more preferably from about 1 wt% to about 3 wt%, most preferably from about 2 wt% to about 3 wt% (based on the weight of the sustained release matrix formulation).

[0271] 7. The sustained release solid oral bolus according to any one of paragraphs 1 to 6, wherein the sustained release matrix formulation further comprises a waxy material, wherein the waxy material is optionally selected from the group consisting of fatty acids, fatty alcohols, fatty acid esters, and mixtures of the foregoing.

[0272] 8. The sustained release solid oral bolus according to paragraph 7, wherein the amount of the waxy material in the sustained release matrix formulation is at least about 20 wt%, or fromabout 20 wt% to about 70 wt%, preferably from about 30 wt% to about 60 wt%, more preferably from about 40 wt% to about 55 wt%, most preferably from about 45 wt% to about 50 wt% (based on the weight of the sustained release matrix formulation).

[0273] 9. The sustained release solid oral bolus according to any one of paragraphs 1 to 8, wherein the sustained release matrix formulation further comprises a densifier, wherein the densifier is optionally an alkaline earth metal sulphate.

[0274] 10. The sustained release solid oral bolus according to paragraph 9, wherein the amount of the densifier in the sustained release matrix formulation is at least about 25 wt% or from about 25 wt% to about 75 wt%, preferably from about 30 wt% to about 60 wt%, more preferably from about 35 wt% to about 50 wt%, most preferably from about 37 wt% to about 43 wt% (based on the weight of the sustained release matrix formulation).

[0275] 11. The sustained release solid oral bolus according to any one of paragraphs 1 to 10, wherein the sustained release matrix formulation further comprises a water-soluble non-ionic surfactant, wherein the water-soluble non-ionic surfactant is optionally a polyoxyethylene sorbitan fatty acid ester and / or optionally exhibits an HLB value of at least about 12.

[0276] 12. The sustained release solid oral bolus according to paragraph 11, wherein the amount of the water-soluble non-ionic surfactant in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 2 wt% to about 11 wt%, more preferably from about 3 wt% to about 7 wt%, most preferably from about 4 wt% to about 6 wt% (based on the weight of the sustained release matrix formulation).

[0277] 13. The sustained release solid oral bolus according to any one of paragraphs 1 to 12, wherein the sustained release matrix formulation further comprises a sustained release polymer, wherein the sustained release polymer is optionally a cellulose ether.

[0278] 14. The sustained release solid oral bolus according to paragraph 13, wherein the amount of the sustained release polymer in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 3 wt% to about 10 wt%, more preferably from about 4 wt% to about 8 wt%, most preferably from about 5 wt% to about 7 wt% (based on the weight of the sustained release matrix formulation).

[0279] 15. The sustained release solid oral bolus according to any one of paragraphs 1 to 14, wherein the sustained release matrix formulation is degradable; and / or wherein the melting point of the sustained release matrix formulation is at least about 40 °C.

[0280] 16. The sustained release solid oral bolus according to any one of paragraphs 1 to 15, wherein the sustained release solid oral bolus exhibits the shape of a sphere, a cylinder, a cylinder with rounded ends, a disc, or an ellipsoid, preferably of a cylinder with rounded ends; and / or wherein the sustained release solid oral bolus has a diameter of from about 10 mm to about 70 mm, or from about 15 mm to about 60 mm, or from about 20 mm to about 50 mm, or from about20 mm to about 40 mm, or from about 25 mm to about 35 mm; and / or wherein the sustained release matrix formulation has a weight of from about 50 to about 300 g, or from about 70 to about 280 g, or from about 90 g to about 250 g.

[0281] 17. A sustained release solid oral bolus as described or substantially as described in any one of the accompanying Examples or having a formulation or features as described or substantially as described in any one of the accompanying Tables, including Table 1.1a, 1.1b, 2.1a, 2.1b, 2.1c, 3.1a, 3.1b, 3.1c, 4.1, 5.1, 6.1 or 7.1.

[0282] 18. A sustained release solid oral bolus according to any one of paragraphs 1 to 17, for use in the treatment of disease, fever, pain and / or inflammation in an animal.

[0283] 19. The sustained release solid oral bolus for use according to paragraph 18, which is for use in the treatment of a disease selected from periparturient disorders, lameness, abdominal pain, mastitis, respiratory diseases, osteoarthritis, endometritis, metritis, postpartum systemic inflammation, and wound healing in an animal, preferably in cattle; and / or which is for use in the treatment of pain and / or inflammation associated with musculoskeletal disorders and lameness in an animal, preferably in cattle; and / or which is for use in the treatment of fever, pain, and / or inflammation associated with mastitis in an animal, preferably in cattle; and / or which is for use in the treatment of fever, pain, and / or inflammation associated with metritis or endometritis in an animal, preferably in cattle, and / or postpartum systemic inflammation, in an animal, preferably in cattle.

[0284] 20. The sustained release solid oral bolus for use according to paragraph 18 or 19, wherein the animals are cattle, preferably wherein the cattle are dairy cattle or beef cattle, preferably dairy cattle.

[0285] 21. The sustained release solid oral bolus for use according to any one of paragraphs 17 to 20, wherein the treatment comprises orally administering a single dose of the sustained release solid oral bolus to an animal in need thereof.

[0286] 22. The invention as defined in any one or more of paragraphs 1-21, context permitting, wherein the animal or animals are selected from: livestock; ruminants; or, cattle, horses, donkeys, mules, sheep, goats, camels, llamas, pigs, buffalo, oxen, deer, antelope, bovine, gazelles, alpacas, or wild bovine.

[0287] 23. The invention as defined in any one or more of paragraphs 1-22, context permitting, wherein:

[0288] - the sustained release solid oral bolus is capable of providing or provides sustained release of a therapeutically effective amount of the NSAID for at least 3 days, preferably for about 3 to 5 days;

[0289] - the NSAID is ketoprofen; and

[0290] - after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of ketoprofen in a time period of from about 3 hours to about 72 hours after administration, which are at least 100 μg / L.

[0291] Further preferred embodiments of the invention are further defined in the paragraphs below:

[0292] 1. A sustained release solid oral bolus comprising an NSAID that, once ingested by an animal, is capable of providing sustained release of a therapeutically effective amount of the NSAID, preferably for at least 3 days.

[0293] 2. The bolus of paragraph 1, wherein the bolus comprises a sustained release matrix formulation comprising a therapeutically effective amount of the NSAID.

[0294] 3. The bolus according to paragraph 1 or 2, wherein the NSAID is selected from one or more of ketoprofen, meloxicam, carprofen, ibuprofen, tolfenamic acid, acetylsalicylic acid and flunixin meglumine, preferably the NSAID is ketoprofen.

[0295] 4. The bolus according to any one of paragraphs 1 to 3, wherein the sustained release matrix formulation comprises a waxy material, wherein the waxy material is optionally selected from the group consisting of fatty acids, fatty alcohols, fatty acid esters, and mixtures of the foregoing.

[0296] 5. The bolus according to paragraph 4, wherein the amount of the waxy material in the sustained release matrix formulation is at least about 20 wt%, or from about 20 wt% to about 70 wt%, preferably from about 30 wt% to about 60 wt%, more preferably from about 40 wt% to about 55 wt%, most preferably from about 45 wt% to about 50 wt% (based on the weight of the sustained release matrix formulation).

[0297] 6. The bolus according to any one of paragraphs 1 to 5, wherein the sustained release matrix formulation further comprises a densifier, wherein the densifier is optionally an alkaline earth metal sulphate.

[0298] 7. The oral bolus according to paragraph 6, wherein the amount of the densifier in the sustained release matrix formulation is at least about 25 wt% or from about 25 wt% to about 75 wt%, preferably from about 30 wt% to about 60 wt%, more preferably from about 35 wt% to about 50 wt%, most preferably from about 37 wt% to about 43 wt% (based on the weight of the sustained release matrix formulation).

[0299] 8. The bolus according to any one of paragraphs 1 to 7, wherein the sustained release matrix formulation further comprises a water-soluble non-ionic surfactant, wherein the water-soluble non- ionic surfactant is optionally a polyoxyethylene sorbitan fatty acid ester and / or optionally exhibits an HLB value of at least about 12.

[0300] 9. The bolus according to paragraph 8, wherein the amount of the water-soluble non-ionic surfactant in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 2 wt% to about 11 wt%, more preferably from about 3 wt% to about 7 wt%,most preferably from about 4 wt% to about 6 wt% (based on the weight of the sustained release matrix formulation).

[0301] 10. The bolus according to any one of paragraphs 1 to 9, wherein the sustained release matrix formulation further comprises a sustained release polymer, wherein the sustained release polymer is optionally a cellulose ether.

[0302] 11. The bolus according to paragraph 10, wherein the amount of the sustained release polymer in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 3 wt% to about 10 wt%, more preferably from about 4 wt% to about 8 wt%, most preferably from about 5 wt% to about 7 wt% (based on the weight of the sustained release matrix formulation).

[0303] 12. The bolus according to any one of paragraphs 1 to 11, wherein the sustained release matrix formulation is degradable; and / or wherein the melting point of the sustained release matrix formulation is at least about 40 °C.

[0304] 13. The bolus according to any one of paragraphs 1 to 12, wherein the bolus exhibits the shape of a sphere, a cylinder, a cylinder with rounded ends, a disc, or an ellipsoid, preferably of a cylinder with rounded ends; and / or wherein the sustained release solid oral bolus has a diameter of from about 10 mm to about 70 mm, or from about 15 mm to about 60 mm, or from about 20 mm to about 50 mm, or from about 20 mm to about 40 mm, or from about 25 mm to about 35 mm; and / or wherein the sustained release matrix formulation has a weight of from about 50 to about 300 g, or from about 70 to about 280 g, or from about 90 g to about 250 g.

[0305] 14. The bolus according to any one of paragraphs 1 to 13, wherein the animal is a ruminant.

[0306] 15. The bolus according to any one of paragraphs 1 to 14, wherein the bolus is formulated to remain and release the NSAID within a reticulorumen of the animal.

[0307] 16. The bolus according to any one of paragraphs 1 to 15, wherein the animal is a head of cattle.

[0308] 17. A sustained release solid oral bolus as described or substantially as described in any one of the accompanying Examples or having a formulation or features as described or substantially as described in any one of the accompanying Tables, including Table 1.1a, 1.1b, 2.1a, 2.1b, 2.1c, 3.1a, 3.1b, 3.1c, 4.1, 5.1, 6.1 or 7.1.

[0309] 18. The bolus according to any one of paragraphs 1 to 17, wherein, once ingested by the animal, is capable of providing sustained release of the therapeutically effective amount of the NSAID for at least 3 days.

[0310] 19. The bolus according to any one of paragraphs 1 to 18, formulated for treating disease, fever, pain and / or inflammation in an animal, preferably caused by periparturient disorders, such as mastitis, lameness, endometritis, metritis, or subfertility.

[0311] 20. The bolus according to any one of paragraphs 1 to 18, for use or when used for treating disease, fever, pain and / or inflammation in an animal, preferably caused by periparturient disorders, such as mastitis, lameness, endometritis, metritis, subfertility, or postpartum systemic inflammation.

[0312] 21. Use of a sustained release matrix formulation comprising an NSAID in the manufacture of a medicament for treating disease, fever, pain and / or inflammation in an animal, preferably caused by periparturient disorders, such as mastitis, lameness, endometritis, metritis, subfertility, or postpartum systemic inflammation, said medicament being in the form of a sustained release solid oral bolus, and said medicament being formulated to provide sustained release of the NSAID from the sustained release matrix formulation, preferably for at least 3 days, following ingestion of the bolus by the animal, wherein said bolus is preferably as defined in any one of paragraphs 1 to 18.

[0313] 22. A method of treating disease, fever, pain and / or inflammation in an animal, preferably caused by periparturient disorders, such as mastitis, lameness, endometritis, metritis, subfertility, or postpartum systemic inflammation, said method comprising the step of administering to the animal the bolus according to any one of paragraphs 1 to 18.

[0314] 23. The invention as defined in any one or more of paragraphs 1-22, context permitting, wherein the animal or animals are selected from: livestock; ruminants; or, cattle, horses, donkeys, mules, sheep, goats, camels, llamas, pigs, buffalo, oxen, deer, antelope, bovine, gazelles, alpacas, or wild bovine.

[0315] 24. The invention as defined in any one or more of paragraphs 1-23, context permitting, wherein:

[0316] - the sustained release solid oral bolus is capable of providing or provides sustained release of a therapeutically effective amount of the NSAID for at least 3 days, preferably for about 3 to 5 days;

[0317] - the NSAID is ketoprofen; and

[0318] - after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of ketoprofen in a time period of from about 3 hours to about 72 hours after administration, which are at least 100 μg / L.

[0319] Having broadly described the invention in its various embodiments, non-limiting examples of preferred embodiments will now be described.

[0320] Brief description of the figures

[0321] Figure 1 depicts the NSAID ketoprofen in vitro release profile from wax boluses (Hot melt) of PF26 different shapes (long and short).

[0322] Figure 2 depicts the ketoprofen plasma concentrations of wax bolus PF26 (long and short shape) per os.

[0323] Figure 3 depicts the ketoprofen in vitro release profile from wax boluses of PF30, PF31 and PF32.

[0324] Figure 4 depicts the ketoprofen plasma concentrations of oral solution vs. wax bolus PF30 per os.

[0325] Figure 5 depicts the ketoprofen in vitro release profile from wax boluses of PF33 and PF34.

[0326] Figure 6 depicts the ketoprofen in vitro release profile from wax boluses of PF30 (4.5 g).

[0327] Figure 7 depicts the ketoprofen in vitro release profile from wax boluses of PF34 (4.5 g).

[0328] Figure 8 depicts the ketoprofen plasma concentrations of wax bolus PF30 (4.5 g) vs. wax bolus PF34 (4.5 g) per os.

[0329] Figure 9 depicts the ketoprofen in vitro release profile from wax boluses PF37.

[0330] Figure 10 depicts the ketoprofen plasma concentrations of wax bolus PF37 per os.

[0331] Figure 11 depicts the ketoprofen plasma concentrations of wax bolus PF38 per os.

[0332] Description of preferred embodiments

[0333] Examples

[0334] It is to be understood that unless otherwise indicated, the milk used for the pharmacokinetic studies is the bucket milk sample, which was collected per milking time from 0 to 24, 48, or 96 hours per cow.

[0335] The studies were designed regarding Guideline EMEA / CVMP / 133 / 99-Final (Guideline for the conduct of pharmacokinetic studies in target animal species) and followed the standards of Good Scientific Practice (DLG, 1998).

[0336] Example 1 (PF26)

[0337] a) Formulation and manufacture

[0338] In Example 1, wax boluses containing ketoprofen (ie. each in the form of a sustained release matrix formulation comprising ketoprofen as the NSAID) were prepared using two different prototype molds (short and long). The formulation details are indicated in Table 1.1a and 1.1b.

[0339] Table 1.1a: Formulation details of PF26Ingredients Content (%w / w) Mass per bolus (g) Active Constituent: Ketoprofen 10.16 9.75 Excipients: Polysorbate 80 7.8 7.49 Triacetin 7.8 7.49 Polyethylene glycol 400 (PEG 400) 7.8 7.49 Lactose monohydrate 5.0 4.80 Barium sulphate 31.2 29.95 Glyceryl monostearate SE 30.24 29.03 Total Weight 100.00 96.00

[0340] Table 1.1b: Two different dimensions of mold (short and long) of PF26 Two different dimensions of mold (short and long) were used to make wax boluses Parameter Short bolus Long bolus Diameter of Bolus ~ 32 mm ~ 28 mm Length of Bolus ~ 96 mm ~ 120 mm Weight ~ 96 g ~ 96 g

[0341] The wax boluses of Example 1 (PF26, short and long) were manufactured as follows:

[0342] Manufacturing Procedure

[0343] In a clean and dry beaker, the required quantities of glyceryl monostearate and polysorbate 80 were weighed out.

[0344] The above mixture was dissolved at around 110°C using heat with intermittent stirring. The required quantity of barium sulphate was added to form a suspension (temperature maintained around 100-110°C).

[0345] The required quantity of ketoprofen (temperature was maintained at around 80-90°C) was added and mixed to form a suspension (temperature was maintained around 80-90°C and homogenous suspension formed at around 80°C).

[0346] While mixing, the above molten mass was slowly poured to a preheated (65°C) stainless- steel mold (i.e. to form the short bolus and the long bolus).

[0347] The mold was tapped on the sides to release the air bubbles. The solidified bolus was removed from the mold on the next day.

[0348] b) In vitro release profile

[0349] The wax boluses of Example 1 (PF26 short and long) were subjected to in vitro dissolutiontesting.

[0350] Dissolution study was performed using Electro lab (India) TDT 08L dissolution apparatus USP apparatus-II (paddle method). For these studies 2 Liters beakers were used employing 1500 mL of dissolution medium (phosphate buffer pH 6.8 with 2% polysorbate 80) at a temperature of 38°C±0.5°C with a paddle speed of 150 RPM maintaining from 3-5 days. The samples were withdrawn at every 24 hours up to 5 days and ketoprofen released was analysed using HPLC. The HPLC method is detailed as below.

[0351] Table 1.1c: Analytical method Parameter Conditions HPLC SystemShimadzu Class VPDetector Diode Array Column Synergy Fusion RP 4 µ 80A 250 x 4.6 mm Column Temperature 25°C Sample Temperature 15°C Mobile PhaseSodium perchlorate buffer* : Acetonitrile60 40 Flow Rate 1.1 mL / min Injection Volume 10 µL

[0352] *Sodium Perchlorate buffer was prepared by dissolving 2.22 g of sodium perchlorate in 800 mL of water. The pH was adjusted to 2.5 with phosphoric acid or 1M NaOH. The buffer was made up to 1 L with water.

[0353] Results

[0354] The in vitro dissolution results are presented in Figure 1 and Table 1.2 below.

[0355] Based on the release profiles, the ketoprofen release from both boluses (short and long) was comparable as can be seen from Figure 1. Approximately 30 % ketoprofen was released over 102 hours from the wax boluses.

[0356] Table 1.2 In vitro dissolution results (short and long) Time (hrs.) % ketoprofen released % ketoprofen released PF26-short (# T2170) PF26-long (# T2169) 24 14.8 15.4 48 21.5 21.0 72 27.6 26.7 96 30.9 27.8 102 31.4 29.5

[0357] c) In vivo release (PK Study)

[0358] The wax boluses of Example 1 (PF26, short and long) were tested in vivo.

[0359] An animal study was conducted to compare wax bolus PF 26 long and short, three non- lactating dairy per group. In this study both formulations were tested in a parallel study design.

[0360] The test items were administered orally using a bolus gun. The bolus gun was inserted via the mouth, cautiously pushed forward above the dorsal prominence of the tongue and the pill was deposited in the pharynx. In this way the swallowing reflex was stimulated.

[0361] Blood sampling was done over a period of 14 days. Pharmacokinetic (PK) results up to 96 hours are depicted in Figure 2 and Table 1.3 below. After 96 hours, the detection limit was reached.

[0362] Table 1.3: Geometric mean PK parameters after a single dose of ketoprofen derived in cattle Example 1 n=3 / group Dairy Cow / single dose / oral PF26-short PF26-long Dose rate Dose rate 9.75 g / cow 9.75 g / cow Parameter Units Geometric Mean Geometric Mean AUClast h*ug / L 201993 175609 AUClast_D h*kg / L 10.72 9.38 Cmax ug / L 9665 10158 Cmax_D kg / L 0.51 0.54 HL_Lambda_z h 4.87 5.01 Lambda_z 1 / h 0.14 0.14 Tmax h 8.00 8.00

[0363] Example 2 (PF30, PF31, PF32)

[0364] a) Formulation and manufacture

[0365] In Example 2, wax boluses containing ketoprofen (9.75 g) were prepared using the long mold used in Example 1. The formulation details are indicated in Tables 2.1a to 2.1c.

[0366] Table 2.1a: Formulation details of PF30 Ingredients Content (%w / w) Mass per bolus (g) Active Constituent: Ketoprofen 10.05 9.70 Excipients: Polysorbate 80 10 9.70Barium sulphate 35 33.95 Glyceryl monostearate SE 44.95 43.60 Total Weight (g) 100.00 97.00

[0367] Table 2.1b: Formulation details of PF31 Ingredients Content (%w / w) Mass per bolus (g) Active Constituent: Ketoprofen 10.05 9.70 Excipients: Polysorbate 80 5 4.85 Ethyl cellulose N-100 Premium 5 4.85 Barium sulphate 35 33.95 Glyceryl monostearate SE 44.95 43.60 Total Weight (g) 100.00 97.00

[0368] Table 2.1c: Formulation details of PF32 Ingredients Content (%w / w) Mass per bolus (g) Active Constituent: Ketoprofen 10.71 9.75 Excipients: Polysorbate 80 5 4.55 HPMC 100 Premium 5 4.55 Barium sulphate 35 31.85 Glyceryl monostearate SE 44.29 40.30 Total Weight (g) 100.00 91.00

[0369] The wax boluses of Example 2 (PF30, PF31, PF32) were manufactured as follows:

[0370] In a glass beaker the required quantity of glyceryl monostearate SE was weighed out and the required quantity of polysorbate 80 was added.

[0371] The mixture was melted at around 100°C using heat with intermittent stirring.

[0372] The required quantity of barium sulphate (temperature maintaining around 90-100°C) was added.

[0373] The required quantity of ethyl cellulose / or HPMC was added at around 90-100°C. The required quantity of ketoprofen was added at around 80°C.

[0374] The mixture was homogenised to a homogenous suspension at around 75°C.

[0375] While mixing the above molten mass was poured to the preheated (65°C) stainless steel mold (i.e. to form the long bolus).

[0376] The mold was tapped on the sides to release the air bubbles. The solidified bolus was removed from the mold on the next day.

[0377] b) In vitro release profile

[0378] The wax boluses of Example 2 (PF30, PF31, PF32) were subjected to in vitro dissolution testing. The dissolution condition used is described in Example 1.

[0379] Results

[0380] The in vitro dissolution results are presented in Figure 3 and Table 2.2 below.

[0381] The release profile of ketoprofen from NSAID wax bolus is shown in the Figure 3.

[0382] Table 2.2: In vitro dissolution results (PF30, PF31, PF32) Time (hrs.) % ketoprofen % ketoprofen % ketoprofen released released released PF30 PF31 PF32 00 0 02412.88 9.69 16.194815.55 14.31 22.747220.31 17.92 26.1396 29.97 27.86 33.59

[0383] c) In vivo release (PK Study)

[0384] The wax bolus of Example 2 (PF30 – 9.75 g) was tested in vivo.

[0385] The test item was administered orally using a bolus gun. The bolus gun was inserted via the mouth, cautiously pushed forward above the dorsal prominence of the tongue and the pill was deposited in the pharynx. In this way the swallowing reflex was stimulated. PK results are presented in Figure 4 and Table 2.3 below.

[0386] A commercially available oral solution (active substance: ketoprofen) was used as reference item. The different formulations were tested in 5 lactating cows per group.

[0387] Table 2.3 Geometric mean PK parameters after a single dose of ketoprofen derived in lactating dairy cows. Due to too few data, no evaluation for oral solution in bucket milk could be performed. Data are derived from quarter milk (collected from one front quarter per sample per time and cow).Example 2 dairy cow n = 5 oral solution Ketoprofen #T2211 (PF30) 3mg / kg / per os (solution)9.75 g / cow / (per os (bolus)plasma Quarter milk plasma milkQuartermilk Parameter Units Geometric Mean AUClast h*ug / L 18431 64.04 120830 325 295 AUClast_D h*kg / L 6.14 0.02 6.50 0.02 0.02 Cmax ug / L 2306 8.53 4092 12.45 11.16 Cmax_D kg / L 0.77 0.00 0.22 0.00 0.00 Example 2 dairy cow n = 5 oral solution Ketoprofen #T2211 (PF30) 3mg / kg / per os (solution)9.75 g / cow / (per os (bolus)plasma Quarter milk plasma milkQuartermilk Parameter Units Geometric Mean HL_Lambda_z h 4.74 6.09 5.28 13.6 18.7 Lambda_z 1 / h 0.15 0.11 0.13 0.05 0.04 Tmax h 1.08 3.96 12.71 13.78 9.97

[0388] This study was a cross-over (2x1) design, research pharmacokinetic study conducted for the investigation of the bioavailability and release pattern after oral dosing of a bolus formulation compared to solution. The test item was orally administered using a bolus gun at a dose rate of 9.75 g / cow. The reference item was orally administered as a solution mixed with drinking water at a dose rate of 3 mg / kg (given as bolus administration).

[0389] Compared to the immediate release oral solution, for the wax bolus PF30 a prolonged release could be observed over a time frame of about 96 h.

[0390] Example 3 (PF33, PF34)

[0391] a) Formulation and manufacture

[0392] In Example 3, wax boluses containing ketoprofen (9.75g - 4.5 g) were prepared using a new mold. The formulation details are indicated in Tables 3.1a and 3.1b. The dimensions of the new mold are summarized in Table 3.1c.

[0393] Table 3.1a: Formulation details of PF 33 with 9.75 g / bolus ketoprofenIngredients Content (%w / w) Mass per bolus (g) Active Constituent: Ketoprofen 10.71 9.75 Excipients: Polysorbate 80 5 4.55 HPMC 100 Premium 5 4.55 Barium sulphate 35 31.85 Glyceryl monostearate SE 44.29 40.30 Total Weight (g) 100.00 91.00

[0394] Table 3.1b: Formulation details of PF 34 with 4.5 g / bolus ketoprofen Ingredients %w / w Mass per bolus (g) Active Constituents: Ketoprofen 3.81 4.50 Excipients: Polysorbate 80 5 5.90 Ethyl cellulose- N100 5 5.90 Barium sulphate 39.14 46.19 Glyceryl monostearate SE 47.05 55.52 Total 100 118.00

[0395] Table 3.1c: Different dimension of mold; *Bolus weight depends on the dimensions and the ingredients added Parameter Diameter of Bolus ~ 31 mm Length of Bolus ~ 117 mm Weight* ~ 97 - 120 g

[0396] The wax boluses of Example 3 (PF33, PF34) were manufactured as follows:

[0397] In a glass beaker the required quantity of glyceryl monostearate SE was weighed out and the required quantity of polysorbate 80 was added.

[0398] The mixture was melted at around 100°C using heat with intermittent stirring.

[0399] The required quantity of barium sulphate (temperature maintaining around 90-100°C) was added.

[0400] The required quantity of ethyl cellulose / or HPMC was added at around 90-100°C. The required quantity of ketoprofen was added at around 80°C.

[0401] The mixture was homogenised to a homogenous suspension at around 75°C.

[0402] While mixing the above molten mass was poured on to the respective preheated (65°C) stainless steel mold.

[0403] The mold was tapped on the sides to release the air bubbles and left at room temperature. The solidified bolus was removed from the mold on the next day.

[0404] b) In vitro release profile

[0405] The wax boluses of Example 3 (PF33, PF34) were subjected to in vitro dissolution testing. The dissolution condition used is described in Example 1.

[0406] The in vitro dissolution results are presented in Figure 5 and Table 3.2 below.

[0407] Table 3.2: In vitro dissolution results (PF33, PF34); n.d. denotes “not determined” Time (hrs.) % ketoprofen released % ketoprofen released PF33 PF34 24 12.74 10.58 48 17.30 15.01 72 n.d. 18.29 96 n.d. 21.78 120 27.66 n.d. 144 n.d. 29.89

[0408] Example 4 (PF30 – 4.5 g ketoprofen)

[0409] a) Formulation and manufacture

[0410] In Example 4, a wax bolus containing ketoprofen (4.5 g) was prepared using the long mold used in Example 1. The formulation details are indicated in Table 4.1.

[0411] Table 4.1: Formulation details of the wax bolus of Example 4. Ingredients Content (%w / w) Mass per bolus (g) Active Constituent: Ketoprofen 4.65 4.51 Excipients: Polysorbate 80 10.54 10.22 Barium sulphate 36.9 35.79 Glyceryl monostearate SE 47.91 46.47 Total Weight 100.00 97.00

[0412] The wax bolus of Example 4 (PF30 – 4.5 g ketoprofen) was manufactured as follows:

[0413] In a glass beaker the required quantity of glyceryl monostearate SE was weighed out and the required quantity of polysorbate 80 was added.

[0414] The mixture was melted at around 100°C using heat with intermittent stirring.

[0415] The required quantity of barium sulphate was added (temperature maintaining around 90- 100°C).

[0416] The required quantity of ketoprofen was added at around 80°C.

[0417] The mixture was homogenised to a homogenous suspension at around 75°C.

[0418] While mixing the above molten mass was poured to the preheated (65°C) stainless steel mold (long).

[0419] The mold was tapped on the sides to release the air bubbles and left at room temperature. The solidified bolus was removed from the mold on the next day.

[0420] b) In vitro release profile

[0421] The wax bolus of Example 4 (PF30 – 4.5 g ketoprofen) was subjected to in vitro dissolution testing. The dissolution condition used is described in Example 1. The in vitro dissolution results are presented in Figure 6 and Table 4.2 below.

[0422] Table 4.2: In vitro dissolution results (PF30 – 4.5 g ketoprofen) Time (hrs.) % ketoprofen released PF30 – 4.5 g 24 18.8 48 26.8 72 33.8 96 39.2 100 39.3 144 50.4

[0423] c) In vivo release (PK Study)

[0424] In vivo results of PF30 (4.5 g) are summarized in section c) of Example 5.

[0425] Example 5 (PF34 – 4.5 g ketoprofen)

[0426] a) Formulation and manufacture

[0427] In Example 5, a wax bolus containing ketoprofen (4.5 g) was prepared using the same mold as used in Example 3. The formulation details are indicated in Table 5.1.

[0428] Table 5.1: Formulation details of the wax bolus PF34Ingredients Content (%w / w) Mass per bolus (g) Active Constituent:Ketoprofen 3.81 4.50 Excipients:Polysorbate 80 5 5.90 Ethyl cellulose 100 5 5.90 Barium sulphate EP 39.14 46.19 Glyceryl monostearate SE 47.05 55.52Total Weight100 118

[0429] The wax bolus of Example 5 (PF34 – 4.5 g ketoprofen) was manufactured as follows:

[0430] In a glass beaker the required quantity of glyceryl monostearate SE was weighed out and the required quantity of polysorbate 80 was added.

[0431] The mixture was melted at around 100°C using heat with intermittent stirring.

[0432] The required quantity of barium sulphate was added (temperature maintaining around 90- 100°C).

[0433] The required quantity of ethyl cellulose at 90-100°C was added with mixing. The required quantity of ketoprofen was added at around 80°C.

[0434] The mixture was homogenised to a homogenous suspension at around 75°C.

[0435] While mixing the above molten mass was poured to the preheated (65°C) stainless mold. The mold was tapped on the sides to release the air bubbles and left at room temperature for solidify.

[0436] The solidified bolus was removed from the mold on the next day.

[0437] b) Release profile

[0438] The wax bolus of Example 5 (PF34 – 4.5 g ketoprofen) was subjected to in vitro dissolution testing. The dissolution condition used is described in Example 1. The in vitro dissolution results are presented in Figure 7 and Table 5.2 below.

[0439] Table 5.2: In vitro dissolution results (PF34 – 4.5 g ketoprofen) Time (hrs.) % ketoprofen released PF34 – 4.5 g ketoprofen 24 15.49 48 23.46 72 29.15 96 32.54144 45.74

[0440] b) In vivo release (PK Study)

[0441] The wax boluses of Example 4 (PF30 – 4.5 g ketoprofen) and Example 5 (PF34 – 4.5 g ketoprofen were tested in vivo in one study. The results are illustrated in Table 5.3 and Figure 8. These two different bolus formulations were tested in a serial study design in four lactating dairy cows per group.

[0442] The test items were administered orally using a bolus gun. The bolus gun was inserted via the mouth, cautiously pushed forward above the dorsal prominence of the tongue and the pill was deposited in the pharynx. In this way the swallowing reflex was stimulated.

[0443] Table 5.3: Geometric mean PK parameters of ketoprofen after a single dose to cows; n.d. denotes “not determined” Lactating dairy cow per os n=4 Period 1 Period 2 Ketoprofen #T2220 (PF30) Ketoprofen #T2221 (PF34) wax bolus / 4.5 g / cow wax bolus / 4.5 g / cow milk plasma milk plasma Parameter Units Geometric Mean AUClast h*µg / L 127.54 48338 121.62 455028 AUClast_D h*kg / L 0.02 6.33 0.02 5.96 Cmax µg / L 7.07 2193 4.42 1353 Cmax_D kg / L 0.00 0.29 0.00 0.18 Lactating dairy cow per os n=4 Period 1 Period 2 Ketoprofen #T2220 (PF30) Ketoprofen #T2221 (PF34) wax bolus / 4.5 g / cow wax bolus / 4.5 g / cow milk plasma milk plasma Parameter Units Geometric Mean HL_Lambda_z H n.d. 4.63 n.d. 7.36 Lambda_z 1 / h n.d. 0.15 n.d. 0.09 Tmax h 14.27 10.84 12.00 12.00

[0444] The wax bolus PF30 of Example 4 showed higher initial plasma and milk concentrations (<24 h) after administration, i.e. higher Cmax and AUC values as compared to wax bolus PF34 of Example 5, whereas the wax bolus of Example 5 showed the preferable prolonged release profile.

[0445] Example 6 (PF37)

[0446] In Example 6, a wax bolus containing ketoprofen (3.5 g) was prepared using the same mold as used in Example 3. The formulation details are indicated in Table 6.1.

[0447] Table 6.1: Formulation details of the wax bolus PF37 Ingredients Content (%w / w) Mass per bolus (g) Active Constituent:Ketoprofen 2.97 3.50 Excipients:Polysorbate 80 5 5.90 Ethyl cellulose premium N-100 5.5 6.49 Barium sulphate 39.48 46.59 Glyceryl monostearate SE 47.05 55.52 Total Weight 100.00 118.00

[0448] The wax bolus of Example 6 (PF37) was manufactured as follows:

[0449] In a glass beaker the required quantity of glyceryl monostearate SE was weighed out and the required quantity of polysorbate 80 was added.

[0450] The mixture was melted at around 100°C using heat with intermittent stirring.

[0451] The required quantity of barium sulphate (temperature maintaining around 90-100°C) was added.

[0452] The required quantity of ethyl cellulose was added at 90-100°C with mixing.

[0453] The required quantity of ketoprofen was added at around 80°C.

[0454] The mixture was homogenised to a homogenous suspension at around 75°C.

[0455] While mixing the above molten mass was poured to a preheated (65°C) stainless steel mold.

[0456] The mold was tapped on the sides to release the air bubbles and left at room temperature. The solidified bolus was removed from the mold on the next day.

[0457] b) In vitro release profile

[0458] The wax bolus of Example 6 (PF37) was subjected to in vitro dissolution testing. Dissolution test as per Example 1. The in vitro dissolution results are presented in Figure 9 and Table 6.2 below.

[0459] Table 6.2: In vitro dissolution results (PF37) Time (hrs.) % ketoprofen released PF37 0 0 5 6.91 24 14.54 48 20.97 120 35.27

[0460] b) In vivo release (PK Study)

[0461] The wax bolus of Example 6 (PF37) was tested in vivo. One bolus formulation was tested in four lactating dairy cows. The results are illustrated in Table 6.3 and Figure 10.

[0462] The test item was administered orally using a bolus gun. The bolus gun was inserted via the mouth, cautiously pushed forward above the dorsal prominence of the tongue and the pill was deposited in the pharynx. In this way the swallowing reflex was stimulated.

[0463] Table 6.3: Geometric mean PK parameters after a single dose derived in cattle; *1: n= 3, since for one cow the acceptance criteria for the Rsq adjusted were not met (<0.8) dairy cow n=4 Long acting Ketoprofen 3.5 g bolus (PF37) per os / wax bolus / 3.5 g / cow milk plasma Parameter Units Geometric Mean AUClast h*ug / L 81.93 32499 AUClast_D h*kg / L 0.01 5.61 Cmax ug / L 2.99 933.2 Cmax_D kg / L 0.0005 0.1611 HL_Lambda_z h 33.68*19.23*1Lambda_z 1 / h 0.02*10.08*1dairy cow n=4 Long acting Ketoprofen 3.5 g bolus (PF37) per os / wax bolus / 3.5 g / cow milk plasma Parameter Units Geometric Mean Tlast h 44.67 87.91 Tmax h 12.00 10.84

[0464] This study was a research pharmacokinetic study conducted for the investigation of the plasma pharmacokinetics after oral dosing of a wax bolus formulation. The test item ketoprofenPF37 was administered orally using a bolus gun at a dose rate of 3.5 g / cow.

[0465] With the wax bolus PF37 of Example 6 a prolonged release over a period of more than 120 h could be shown.

[0466] Example 7 (PF38)

[0467] In Example 7, a wax bolus containing ketoprofen (3.0 g) was prepared using the mold as used in Example 3. The formulation details are indicated in Table 7.1.

[0468] Table 7.1: Formulation details of the wax bolus of PF38 Ingredients Content Mass per bolus (g) (%w / w) Active Constituent: Ketoprofen 2.52 3.0 Excipients: Polysorbate 80 5.00 6.0 Ethyl cellulose N100 5.50 7.0 Barium sulphate 39.65 47.0 Glyceryl monostearate SE 47.33 56.0 Total Weight 100.00 119

[0469] The wax bolus of Example 7 (PF38) was manufactured as follows:

[0470] In a clean, dry glass beaker, glyceryl monostearate and polysorbate 80 were weighed out and heated to 100–110 °C to melt the excipients. The mixture was continuously stirred with a magnetic stirrer bar.

[0471] Once melted, ethyl cellulose and then barium sulphate were added and stirred to form a suspension. The temperature of the matrix was maintained between 100–110 °C.

[0472] The matrix was cooled to 80–90 °C, then the ketoprofen was added and stirred to form a suspension. The temperature of the matrix was maintained between 80–90 °C.

[0473] Once thoroughly mixed by hand, the homogeniser was placed into the matrix for 2 minutes at 20,000 RPM to ensure a homogeneous mixture. The temperature of the matrix was maintained between 80–90 °C.

[0474] While mixing, the molten mixture was slowly poured into a mold, which was placed into the holder, and left to solidify at room temperature. Once solid the bolus was ejected from the mold.

[0475] c) In vivo release (PK Study)

[0476] The wax bolus of Example 7 (PF38) was tested in vivo. An animal study was conducted with lactating cows to see exposure of wax bolus formulation PF38. The results are illustrated in Table 7.2 and Figure 11.

[0477] The test item was administered orally using a bolus gun. The bolus gun was inserted via the mouth, cautiously pushed forward above the dorsal prominence of the tongue and the pill was deposited in the pharynx. In this way the swallowing reflex was stimulated.

[0478] Table 7.2: Geometric mean PK parameters of ketoprofen derived in dairy cows Ketoprofen / dairy cow / Single dose per os / T2230 (PF38, 3 g) / wax bolus / 3 g / cow milk plasma Parameter Units Geometric Mean AUClast h*ug / L 62.80 16303 AUClast_D h*kg / L 0.01 3.05 Cmax ug / L 2.23 557.2 Cmax_D kg / L 0.00042 0.1042 HL_Lambda_z h 114.26 47.38 Lambda_z 1 / h 0.01 0.01 Tlast h 42.76 48.00 Tmax h 12.00 7.56

[0479] With the wax bolus PF38 of Example 7 a prolonged release over a time period of more than 90 h could be shown.

[0480] In the present specification, the word ‘comprising’ and its derivatives including ‘comprises’ and ‘comprise’ include each of the stated integers but does not exclude the inclusion of one or more further integers.

[0481] The terms "about" and "approximately" denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10 %, preferably ±5 %, more preferably ±2 %, and even more preferably ±1 %.

[0482] Reference in this specification to any number range includes all possible numbers / numerical values falling within that range, and further includes all possible subranges falling within that range, context permitting.

[0483] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0484] Reference throughout this specification to ‘one embodiment’ or ‘an embodiment’ means that a particular feature, structure, or characteristic described in connection with the embodimentis included in at least one embodiment of the present invention. Thus, the appearance of the phrases ‘in one embodiment’ or ‘in an embodiment’ in various places 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.

[0485] In compliance with the statute, the invention has been described in language more or less specific to structural or methodical features. It is to be understood that the invention is not limited to specific features shown or described since the means herein described comprises preferred forms of putting the invention into effect. The invention is, therefore, claimed in any of its forms or modifications within the proper scope of the appended claims appropriately interpreted by those skilled in the art.

Claims

Claims 1. A sustained release solid oral bolus comprising a sustained release matrix formulation, wherein the sustained release matrix formulation comprises a therapeutically effective amount of an NSAID.

2. A sustained release solid oral bolus comprising an NSAID that, once ingested by an animal, is capable of providing sustained release of a therapeutically effective amount of the NSAID, preferably for at least 3 days.

3. A sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide an animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

4. The sustained release solid oral bolus of any one of the preceding claims, wherein the NSAID is selected from one or more of ketoprofen, meloxicam, carprofen, ibuprofen, tolfenamic acid, acetylsalicylic acid and flunixin meglumine, preferably the NSAID is ketoprofen.

5. The sustained release solid oral bolus of claim 1, 2, 3 or 4, wherein the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to from about 1 g to about 10 g of ketoprofen (C16H14O3), or from about 1 g to about 8 g of ketoprofen (C16H14O3), or from about 1 g to about 5 g of ketoprofen (C16H14O3), or from about 1 g to about 4 g of ketoprofen (C16H14O3), or from about 2 g to about 4 g of ketoprofen (C16H14O3); or wherein the sustained release matrix formulation comprises an amount of ketoprofen which is equimolar to about 2 g of ketoprofen (C16H14O3), or is equimolar to about 2.5 g of ketoprofen (C16H14O3), or is equimolar to about 3 g of ketoprofen (C16H14O3), or is equimolar to about 3.5 g of ketoprofen (C16H14O3) ), or is equimolar to about 4 g of ketoprofen (C16H14O3).

6. The sustained release solid oral bolus of any one of the preceding claims, wherein after single- dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of said NSAID in a time period of from about 3 hours to about 24 hours after administration, or from about 3 hours to about 48 hours after administration, or from about 3 hours to about 72 hours after administration, or from about 3 hours to about 96 hours after administration, or from about 3 hours to about 120 hours after administration, which correspond at least to the minimum effective concentration of said NSAID; and / or wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group a ratio of the mean plasma concentration of said NSAID at 48 hours after administration to the mean plasma concentration of said NSAID at 24 hours after administration of from about 0.2 to about 1.0, or from about 0.3 to about 0.9, or from about 0.4 to about 0.8, or from about 0.5 to about 0.7; and / or wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus providesin said group a ratio of the mean plasma concentration of said NSAID at 48 hours after administration to the mean Cmaxof said NSAID of from about 0.1 to about 1.0, or from about 0.2 to about 0.8, or from about 0.3 to about 0.8, or from about 0.3 to about 0.

5.

7. The sustained release solid oral bolus of any one of the preceding claims, wherein the NSAID is ketoprofen, and wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group mean plasma concentrations of ketoprofen in a time period of from about 3 hours to about 24 hours after administration, or from about 3 hours to about 48 hours after administration, or from about 3 hours to about 72 hours after administration, which are at least 50 μg / L, or at least 100 μg / L; and / or wherein the NSAID is ketoprofen, and wherein after single-dose administration to a group of animals such as cows, the sustained release solid oral bolus provides in said group a mean Cmaxof ketoprofen of about 11,000 μg / L or less, about 5,000 μg / L or less, about 4,000 μg / L or less, about 3,000 μg / L or less, about 2,000 μg / L or less, or about 1,000 μg / L or less, or from about 200 μg / L to about 11,000 μg / L, from about 200 μg / L to about 5,000 μg / L, from about 200 μg / L to about 4,000 μg / L, from about 200 μg / L to about 3,000 μg / L, from about 200 μg / L to about 2,000 μg / L, or from about 200 μg / L to about 1,000 μg / L.

8. The sustained release solid oral bolus of any one of the preceding claims, wherein the amount of the NSAID in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 1 wt% to about 5 wt%, more preferably from about 1 wt% to about 3 wt%, most preferably from about 2 wt% to about 3 wt%, based on the weight of the sustained release matrix formulation.

9. The sustained release solid oral bolus of any one of the preceding claims, wherein the sustained release matrix formulation further comprises a waxy material, wherein the waxy material is optionally selected from the group consisting of fatty acids, fatty alcohols, fatty acid esters, and mixtures of the foregoing.

10. The sustained release solid oral bolus of claim 9, wherein the amount of the waxy material in the sustained release matrix formulation is at least about 20 wt%, or from about 20 wt% to about 70 wt%, preferably from about 30 wt% to about 60 wt%, more preferably from about 40 wt% to about 55 wt%, most preferably from about 45 wt% to about 50 wt%, based on the weight of the sustained release matrix formulation.

11. The sustained release solid oral bolus of any one of the preceding claims, wherein the sustained release matrix formulation further comprises a densifier, wherein the densifier is optionally an alkaline earth metal sulphate.

12. The sustained release solid oral bolus of claim 11, wherein the amount of the densifier in the sustained release matrix formulation is at least about 25 wt% or from about 25 wt% to about 75 wt%, preferably from about 30 wt% to about 60 wt%, more preferably from about 35 wt% to about50 wt%, most preferably from about 37 wt% to about 43 wt%, based on the weight of the sustained release matrix formulation.

13. The sustained release solid oral bolus of any one of the preceding claims, wherein the sustained release matrix formulation further comprises a water-soluble non-ionic surfactant, wherein the water-soluble non-ionic surfactant is optionally a polyoxyethylene sorbitan fatty acid ester and / or optionally exhibits an HLB value of at least about 12.

14. The sustained release solid oral bolus of claim 13, wherein the amount of the water-soluble non-ionic surfactant in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 2 wt% to about 11 wt%, more preferably from about 3 wt% to about 7 wt%, most preferably from about 4 wt% to about 6 wt%, based on the weight of the sustained release matrix formulation.

15. The sustained release solid oral bolus of any one of the preceding claims, wherein the sustained release matrix formulation further comprises a sustained release polymer, wherein the sustained release polymer is optionally a cellulose ether.

16. The sustained release solid oral bolus of claim 15, wherein the amount of the sustained release polymer in the sustained release matrix formulation is from about 1 wt% to about 15 wt%, preferably from about 3 wt% to about 10 wt%, more preferably from about 4 wt% to about 8 wt%, most preferably from about 5 wt% to about 7 wt%, based on the weight of the sustained release matrix formulation.

17. The sustained release solid oral bolus of any one of the preceding claims, wherein the sustained release matrix formulation is degradable; and / or wherein the melting point of the sustained release matrix formulation is at least about 40 °C.

18. The sustained release solid oral bolus of any one of the preceding claims, wherein the sustained release solid oral bolus exhibits the shape of a sphere, a cylinder, a cylinder with rounded ends, a disc, or an ellipsoid, preferably of a cylinder with rounded ends; and / or wherein the sustained release solid oral bolus has a diameter of from about 10 mm to about 70 mm, or from about 15 mm to about 60 mm, or from about 20 mm to about 50 mm, or from about 20 mm to about 40 mm, or from about 25 mm to about 35 mm; and / or wherein the sustained release matrix formulation has a weight of from about 50 to about 300 g, or from about 70 to about 280 g, or from about 90 g to about 250 g.

19. The sustained release solid oral bolus of any one of the preceding claims, wherein the sustained release solid oral bolus has a formulation comprising: (a) Ketoprofen; Polysorbate 80; Triacetin; Polyethylene glycol 400 (PEG 400); Lactose monohydrate; Barium sulphate; and Glyceryl monostearate; (b) Ketoprofen; Polysorbate 80, Barium sulphate; and Glyceryl monostearate; (c) Ketoprofen; Polysorbate 80; Ethyl cellulose; Barium sulphate; and Glyceryl monostearate; or(d) Ketoprofen; Polysorbate 80; HPMC; Barium sulphate; and Glyceryl monostearate.

20. The sustained release solid oral bolus of any one of the preceding claims, wherein the sustained release solid oral bolus has a formulation comprising: - Formulation PF26: Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 10.16 9.75 Polysorbate 80 7.8 7.49 Triacetin 7.8 7.49 Polyethylene glycol 400 (PEG 400) 7.8 7.49 Lactose monohydrate 5.0 4.80 Barium sulphate 31.2 29.95 Glyceryl monostearate SE 30.24 29.03 Total Weight 100.00 96.00 - Formulation PF30: Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 10.05 9.70 Polysorbate 80 10 9.70 Barium sulphate 35 33.95 Glyceryl monostearate SE 44.95 43.60 Total Weight (g) 100.00 97.00 - Formulation PF31: Ingredients Approximate Approximate Content (%w / w) Mass / bolus (g) Ketoprofen 10.05 9.70 Polysorbate 80 5 4.85 Ethyl cellulose N-100 Premium 5 4.85 Barium sulphate 35 33.95 Glyceryl monostearate SE 44.95 43.60 Total Weight (g) 100.00 97.00 - Formulation PF32: Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 10.71 9.75 Polysorbate 80 5 4.55 HPMC 100 Premium 5 4.55Barium sulphate 35 31.85 Glyceryl monostearate SE 44.29 40.30 Total Weight (g) 100.00 91.00 - Formulation PF 33: Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 10.71 9.75 Polysorbate 80 5 4.55 HPMC 100 Premium 5 4.55 Barium sulphate 35 31.85 Glyceryl monostearate SE 44.29 40.30 Total Weight (g) 100.00 91.00 - Formulation PF 34: Ingredients Approximate Approximate Content (%w / w) Mass per bolus (g) Ketoprofen 3.81 4.50 Polysorbate 80 5 5.90 Ethyl cellulose- N100 5 5.90 Barium sulphate 39.14 46.19 Glyceryl monostearate SE 47.05 55.52 Total 100 118.00 - Formulation PF30: Ingredients Approximate Approximate Content (%w / w) Mass per bolus (g) Ketoprofen 4.65 4.51 Polysorbate 80 10.54 10.22 Barium sulphate 36.9 35.79 Glyceryl monostearate SE 47.91 46.47 Total Weight 100.00 97.00 - Formulation PF34: Ingredients Approximate Approximate Content (%w / w) Mass per bolus (g) Ketoprofen 3.81 4.50 Polysorbate 80 5 5.90 Ethyl cellulose 100 5 5.90 Barium sulphate EP 39.14 46.19Glyceryl monostearate SE 47.05 55.52 Total Weight100 118- Formulation PF37: Ingredients Approximate Approximate Content (%w / w) Mass per bolus (g) Ketoprofen 2.97 3.50 Polysorbate 80 5 5.90 Ethyl cellulose premium N-100 5.5 6.49 Barium sulphate 39.48 46.59 Glyceryl monostearate SE 47.05 55.52 Total Weight 100.00 118.00 - Formulation PF38: Ingredients Approximate Approximate Mass Content (%w / w) per bolus (g) Ketoprofen 2.52 3.0 Polysorbate 80 5.00 6.0 Ethyl cellulose N100 5.50 7.0 Barium sulphate 39.65 47.0 Glyceryl monostearate SE 47.33 56.0 Total Weight 100.00 119 21. A sustained release solid oral bolus for treating disease, fever, pain and / or inflammation in an animal, said bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

22. A sustained release solid oral bolus for use or when used for treating disease, fever, pain and / or inflammation in an animal, said bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

23. Use of a sustained release matrix formulation comprising an NSAID in the manufacture of a medicament for treating disease, fever, pain and / or inflammation in an animal, said medicament being in the form of a sustained release solid oral bolus, and said medicament being formulated to provide sustained release of the NSAID from the sustained release matrix formulation, preferably for at least 3 days, following ingestion of the bolus by the animal.

24. A method of treating disease, fever, pain and / or inflammation in an animal, said method comprising the step of administering to the animal a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

25. Use of a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID for treating disease, fever, pain and / or inflammation in an animal, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID, preferably for at least 3 days, following ingestion of the bolus by the animal.

26. The sustained release solid oral bolus according to the use of claim 21 or claim 22, or the use according to claim 23 or 25, or the method according to claim 24, which is for use in the treatment of a disease selected from periparturient disorders, lameness, abdominal pain, mastitis, respiratory diseases, osteoarthritis, endometritis, metritis, postpartum systemic inflammation, and wound healing in an animal, preferably in cattle; and / or which is for use in the treatment of pain and / or inflammation associated with musculoskeletal disorders and lameness in an animal, preferably in cattle; and / or which is for use in the treatment of fever, pain, and / or inflammation associated with mastitis in an animal, preferably in cattle; and / or which is for use in the treatment of fever, pain, and / or inflammation associated with metritis or endometritis in an animal, preferably in cattle, and / or postpartum systemic inflammation, in an animal, preferably in cattle.

27. The sustained release solid oral bolus according to the use of claim 21 or claim 22, or the use according to claim 23 or 25, or the method according to claim 24, which is for use in treating disease, fever, pain and / or inflammation in an animal caused by periparturient disorders, such as mastitis, lameness, endometritis, metritis, or subfertility, or postpartum systemic inflammation.

28. The sustained release solid oral bolus according to the use of claim 21, 22, 26 or 27, or the use according to claim 23, 25, 26 or 27, or the method according to claim 24, 26 or 27, wherein the animals are cattle, preferably wherein the cattle are dairy cattle or beef cattle, preferably dairy cattle.

29. The sustained release solid oral bolus according to the use of claim 21, 22, 26, 27 or 28, or the use according to claim 23, 25, 26, 27 or 28, or the method according to claim 24, 26, 27 or 28, wherein the sustained release solid oral bolus is as defined in any one of claims 1 to 20.

30. The sustained release solid oral bolus according to the use of claim 21, 22, 26, 27, 28 or 29, or the use according to claim 23, 25, 26, 27, 28 or 29, or the method according to claim 24, 26, 27, 28 or 29, wherein the animal or animals are selected from: livestock; ruminants; or, cattle, horses, donkeys, mules, sheep, goats, camels, llamas, pigs, buffalo, oxen, deer, antelope, bovine, gazelles, alpacas, or wild bovine.

31. A bolus applicator containing a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID for treating disease, fever, pain and / or inflammation in an animal, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID preferably for at least 3 days following ingestion of the bolus by the animal.

32. The bolus applicator according to claim 31, wherein said sustained release solid oral bolus is as defined in any one of claims 1 to 20.

33. A kitset for use or when used in a method of treating disease, fever, pain and / or inflammation in an animal, wherein the kitset comprises: a bolus applicator capable of administering a sustained release solid oral bolus comprising a sustained release matrix formulation comprising an NSAID, said sustained release matrix formulation being formulated to provide the animal with sustained release of the NSAID preferably for at least 3 days following ingestion of the bolus by the animal.

34. The kitset according to claim 33, wherein said sustained release solid oral bolus is as defined in any one of claims 1 to 20.

35. A process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of: (A) mixing at least a waxy material, a therapeutically effective amount of an NSAID, and optionally one or more excipients selected from the group consisting of a densifier, a water-soluble non-ionic surfactant, and a sustained release polymer, to form a drug-containing composition; and subsequently (B) shaping the drug-containing composition to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

36. A process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of: (A1) mixing at least a waxy material and one or more ingredients selected from the group consisting of a densifier, a water-soluble non-ionic surfactant, and a sustained release polymer to form a composition; (A2) mixing the composition obtained in step (A1) and a therapeutically effective amount of an NSAID to form a drug-containing composition; and (B) shaping the drug-containing composition to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

37. A process of manufacturing (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus, which comprises the steps of: (A1-1) mixing at least a waxy material and a water-soluble non-ionic surfactant at a temperature which is at least 20°C higher than the melting point of the waxy material to form a composition (1);(A1-2) mixing the composition (1) obtained in step (A1-1) with at least a sustained release polymer and a densifier at a temperature which is at least 20°C higher than the melting point of the waxy material to form a composition (2); (A2) mixing the composition (2) obtained in step (A1-2) and a therapeutically effective amount of an NSAID at a temperature which is at least 10°C higher than the melting point of the waxy material, and at least 3°C lower than the melting point of the NSAID to form a drug- containing composition; and (B) shaping the drug-containing composition obtained in step (A2) to form (i) a sustained release matrix formulation of a sustained release solid oral bolus, or (ii) a sustained release solid oral bolus.

38. The process of manufacturing according to claim 35, 36 or 37, wherein said sustained release solid oral bolus is as defined in any one of claims 1 to 20.

39. A (i) sustained release matrix formulation of a sustained release solid oral bolus or a (ii) sustained release solid oral bolus, which is obtainable by or when obtained by the process of manufacture of any one of claims 35 to 38.

40. The sustained release solid oral bolus of any one of claims 1 to 3, wherein the sustained release solid oral bolus is capable of providing or provides sustained release of a therapeutically effective amount of the NSAID for at least 3 days, and the NSAID is ketoprofen.

41. The sustained release solid oral bolus according to the use of claim 21, 22, 26, 27, 28 or 29, or the use according to claim 23, 25, 26, 27, 28 or 29, or the method according to claim 24, 26, 27, 28 or 29, wherein the sustained release solid oral bolus is capable of providing or provides sustained release of a therapeutically effective amount of the NSAID for at least 3 days, or for about 3 to about 5 days, and the NSAID is ketoprofen.

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