AU2005297340A1

AU2005297340A1 - Anti-inflammatory preparation

Info

Publication number: AU2005297340A1
Application number: AU2005297340A
Authority: AU
Inventors: Alan Richard Bell; Geoffrey Noel O'connor
Original assignee: Parnell Laboratories Aust Pty Ltd
Current assignee: Parnell Laboratories Aust Pty Ltd
Priority date: 2004-10-21
Filing date: 2005-10-21
Publication date: 2006-04-27

Description

WO 2006/042381 PCT/AU2005/001650 Anti-inflammatory Preparation Technical Field The present invention relates to preparations comprising an anti-inflammatory drug for oral administration. 5 Background of the Invention Carprofen is a non-steroidal anti-inflammatory drug and is used as an analgesic and anti-inflammatory agent, primarily in the treatment of osteoarthritis in animals. Until recently it has only been available as a tablet, as a palatable chewable dosage form, or as an injection. 10 Osteoarthritis is a chronic condition requiring daily treatment to relieve the associated pain. Due to the frequency of administration, a dosage form that is readily administered and is well accepted by the animal is desirable. A disadvantage with the use of Carprofen tablets is that regular administration of Carprofen in tablet form may be difficult in some animals or for some owners. A disadvantage with many oral is preparations of Carprofen is that Carprofen is bitter to human taste and can cause a burning sensation in the throat on swallowing. Although animals may have different taste sensations, it is reasonable to assume that, if the Carprofen formulation is unpleasant and can be tasted even when mixed with food, the animal may reject the food and therefore fail to receive medication. 20 Additionally, solutions of Carprofen may require additives such as antioxidants and/or antimicrobials in order to improve their shelf life. Such additives may increase the cost of the preparation. There is therefore a need for a product comprising an anti-inflammatory drug such as Carprofen that is well received by the animal by inclusion in their food. Such a product 25 would provide significant administration advantages for owners and their pets. Object of the Invention It is the object of the present invention to overcome or substantially ameliorate at least one of the above disadvantages. It is a further object to at least partially satisfy the above need. 30 Summary of the Invention In a first aspect of the invention there is provided an anti-inflammatory preparation which is acceptable to a subject to which it is administered orally comprising: - an anti-inflammatory substance; and - an orally acceptable liquid carrier. 35 At least a portion of the anti-inflammatory substance may be not dissolved in the liquid carrier. A non-irritating portion of the anti-inflammatory substance may be WO 2006/042381 PCT/AU2005/001650 2 dissolved in the liquid carrier. The quantum of a non-irritating portion of the anti inflammatory substance may depend on the nature of the anti-inflammatory substance. The quantum of a non-irritating portion of the anti-inflammatory substance may depend on the nature of the anti-inflammatory substance in combination with the liquid carrier. 5 The anti-inflammatory substance may be sparingly soluble or insoluble in the liquid carrier. The anti-inflammatory preparation may be a pharmaceutical preparation or a veterinary preparation. The veterinary preparation may be suitable for administration to a dog or to a cat or to some other domestic pet. 10 The anti-inflammatory substance may be one which, when dissolved in a liquid in a therapeutically effective amount and consumed by the subject, is unacceptable, unpalatable, irritating (for example irritating to at least a portion of the throat), unpleasant and/or offensive and/or causes burning of the throat. The anti-inflammatory substance in combination with a liquid substance in which an irritating portion of the anti is inflammatory substance is dissolved may be unacceptable, unpalatable, irritating (for example irritating to at least a portion of the throat), unpleasant and/or offensive to the subject, and/or cause burning of the throat of the subject, when taken orally. The anti inflammatory substance in combination with a liquid substance in which the major portion of the anti-inflammatory substance is dissolved may be unacceptable, unpalatable, 20 irritating (for example irritating to at least a portion of the throat), unpleasant and/or offensive to the subject, and/or cause burning of the throat of the subject, when taken orally. The major portion may be greater than 50%, 60%, 70%, 80% or 90%. The major portion may be about 50%, 60%, 70%, 80/o, 90%, 95% or 100% (i.e. the minor portion, which is in suspension, may be less than about 50, 40, 30, 20, 10 or 5% or the total 25 amount of anti-inflammatory substance). The major portion may be 100%. The amount of preparation consumed by the subject may be a therapeutically effective amount. The amount of preparation consumed by the subject may be sufficient that a therapeutically effective amount of the anti-inflammatory substance is consumed by the subject. The subject may be an animal or human subject. The anti-inflammatory substance may be a 30 non-steroidal anti-inflammatory substance (NSAID), or may be a combination of different NSAIDs or a combination of one or more NSAIDs with one or more non-NSAID anti inflammatory substances. It may be a non-narcotic substance. It may have antipyretic and/or analgesic activity. It may be, or comprise, Carprofen (6-chloro-alpha-methyl-9H carbazole-2-acetic acid). It may be present in the preparation at between about 1 and WO 2006/042381 PCT/AU2005/001650 3 100mg/ml. The amount of the anti-inflammatory substance in the preparation may be a therapeutically, clinically and/or veterinarily effective amount. The anti-inflammatory substance may be not dissolved in the liquid carrier, and may be suspended in the liquid carrier. The amount of the anti-inflammatory substance in solution may be less than about 5 50%w/w of the total amount of anti-inflammatory substance present and may be less than about 0.5%w/v of the preparation. The anti-inflammatory substance may have a particle size such that it does not settle rapidly when suspended in the liquid carrier. The liquid carrier may be a liquid at 25'C, may be clinically and/or veterinarily acceptable, may be non-toxic and/or not unpalatable and/or non-irritating to a subject to 10 which the preparation is administered and may be capable of masking the taste of, and/or reducing irritation due to, the anti-inflammatory substance. It may be palatable to the subject. The liquid carrier may completely or partially mask the taste of, and/or may completely or partially reduce irritation due to, the anti-inflammatory substance. The irritation may be a burning sensation or some other irritation. Where the liquid carrier 15 partially masks the taste of, and/or partially reduces irritation due to, the anti inflammatory substance the preparation may nevertheless be palatable. Where the liquid carrier completely masks the taste of, and/or completely reduces irritation due to, the anti inflammatory substance the preparation may be palatable. The flavour of the preparation may be acceptable to the subject. The preparation may be a flavour acceptable 20 preparation. The preparation may cause some burning sensation of the throat of the subject on oral administration. The burning sensation may be acceptable to the subject. The preparation may have a pleasant taste to the subject. It may not have an unpleasant taste to the subject. The liquid carrier may be for example glycerol, a polyglycitol syrup or a maltitol syrup or a mixture of any two or more of these. The liquid carrier may 25 perform the function of a stabilizer, an antioxidant, a preservative and/or an antimicrobial agent. The liquid carrier may comprise a single liquid or it may comprise a mixture of liquids. The liquid carrier may be capable of masking the taste of the anti-inflammatory substance. The liquid carrier may not promote microbial growth. The liquid carrier may have no added water. The liquid carrier may have sufficiently little water that it does not 30 promote microbial growth. The anti-inflammatory preparation may have no added stabilizer, antioxidant, preservative or antimicrobial agent other than the liquid carrier, and may have no intentionally added water. The preparation may have no additionally added stabilizer, antioxidant, preservative or antimicrobial agent. The preparation may not contain an WO 2006/042381 PCT/AU2005/001650 4 additional stabilizer for stabilizing the suspension. In the preparation of the invention the liquid carrier may mask the taste of the anti-inflammatory substance. The preparation may be suitable for on-food administration to an animal, i.e. the preparation may be combined with food which the animal subsequently consumes. The preparation may be non 5 irritating and/or not unpalatable and/or may provide reduced burning sensation and/or may provide reduced irritation to the subject to which it is administered orally. The reduced burning sensation and/or the reduced irritation may be reduced relative to the sensation and/or irritation caused by consuming a preparation having the same level of the same anti-inflammatory substance completely dissolved in an orally acceptable liquid 10 carrier, or may be reduced relative to the sensation and/or irritation caused by consuming the same quantity of the anti-inflammatory substance as is present in the anti inflammatory preparation, but with no liquid carrier. In an embodiment, there is provided an anti-inflammatory preparation which is acceptable to a subject to which it is administered orally comprising: 15 - an anti-inflammatory substance; and - an orally acceptable liquid carrier; the amount of the anti-inflammatory substance dissolved in the liquid carrier being less than about 0.5%w/v of the preparation at 25'C. The amount of the anti-inflammatory substance in the preparation may be a therapeutically, clinically and/or veterinarily 20 effective amount. In another embodiment there is provided an anti-inflammatory preparation which is acceptable to a subject to which it is administered orally comprising: - an anti-inflammatory substance; and - an orally acceptable liquid carrier, 25 wherein the solubility of the anti-inflammatory substance in the liquid carrier is selected from the group consisting of sparingly soluble and insoluble, and wherein the liquid carrier masks the taste of the anti-inflammatory substance. In another embodiment, there is provided an anti-inflammatory preparation which is acceptable to a subject to which it is administered orally consisting of: 30 - an anti-inflammatory substance; and - an orally acceptable liquid carrier. The anti-inflammatory substance may be sparingly soluble or insoluble in the liquid carrier. The anti-inflammatory preparation may have no other intentionally added components other than the anti-inflammatory substance and the liquid carrier.

WO 2006/042381 PCT/AU2005/001650 5 In a further embodiment, there is provided an anti-inflammatory preparation which is acceptable to a subject to which it is administered orally comprising: - between about 5 and about 50mg/ml Carprofen; and - glycerol; 5 wherein the concentration of Carprofen dissolved in the glycerol is less than about 4mg/ml at 25"C. The amount of Carprofen dissolved in the glycerol may be less than about 50% of the total amount of Carprofen. The preparation may consist only of Carprofen and glycerol, and may have no other intentionally added components. It may have no intentionally added water. 10 In a particular embodiment, there is provided an anti-inflammatory preparation which is acceptable to a subject to which it is administered orally consisting of: - about 30mg/ml Carprofen; and - glycerol; wherein the amount of Carprofen dissolved in the glycerol is about 3mg/ml or less at 15 25 0 C. In another particular embodiment, there is provided an anti-inflammatory preparation which is acceptable to a subject to which it is administered orally consisting of: - about 10mg/ml Carprofen; and 20 - glycerol; wherein the amount of Carprofen dissolved in the glycerol is about 3mg/ml or less at 25 0 C. There is also provided a unit dosage of the preparation according to the first aspect wherein the anti-inflammatory substance is present in a therapeutically effective amount. 25 The unit dosage may be contained, packaged or otherwise stored in an ampoule, vial or other container. In a second aspect of the invention there is provided a process for making an anti inflammatory preparation comprising the step of combining an anti-inflammatory substance with an orally acceptable liquid carrier, wherein the carrier is such that the anti 30 inflammatory preparation is acceptable to a subject to which it is administered orally. In an embodiment there is provided a process for making an anti-inflammatory preparation comprising the step of combining an anti-inflammatory substance with an orally acceptable liquid carrier, wherein the carrier is such that the preparation is acceptable to a subject to which it is administered orally and wherein the solubility of the WO 2006/042381 PCT/AU2005/001650 6 anti-inflammatory substance in the liquid carrier is selected from the group consisting of sparingly soluble and insoluble and wherein the liquid carrier masks the taste of the anti inflammatory substance. The process may be such that no materials are intentionally added to the anti 5 inflammatory preparation other than the anti-inflammatory substance and the liquid carrier. The process may be such that no stabilizer, preservative, anti-microbial or anti oxidant is added to the anti-inflammatory preparation other than the liquid carrier. The combining may be such that the anti-inflammatory preparation has an amount of the anti inflammatory substance in solution less than about 0.5%w/v of the preparation at 25 0 C. 10 The combining may be such that the amount of anti-inflammatory substance dissolved in the liquid carrier is less than about 50% of the total amount of anti-inflammatory substance at 25"C. The combining may comprise adding one or both of the anti inflammatory substance and the liquid carrier in one step, or in two or more steps. The combining may comprise one or more of stirring, shaking, mixing, agitating, churning, 15 sparging, sonication, ultrasonication or some other method of combining, and may use a mixer, a stirrer, an agitator, a chum, a sparge, a sonicator, an ultrasonicator, a colloid mill or some other equipment. The process may comprise making a concentrate comprising the anti-inflammatory substance and the liquid carrier, and combining the concentrate with an additional amount of the liquid carrier to form the anti-inflammatory preparation. 20 The concentrate may be a paste, a milled mixture or some other type of concentrate, and may comprise at least a portion of the anti-inflammatory substance that is not dissolved in the liquid carrier. The process may additionally comprise the step of reducing the particle size of the anti-inflammatory substance before combining the concentrate with an additional amount of the liquid carrier. 25 In an embodiment the process comprises combining Carprofen with glycerol, wherein no materials are intentionally added other than Carprofen and glycerol, and wherein, after the combining, the concentration of Carprofen dissolved in the glycerol is less than about 4mg/ml at 25 0 C. The total amount of Carprofen may be between about 5 and 50mg/ml of glycerol, and the amount of the Carprofen dissolved in the glycerol may 30 be less than about 50% of the total amount of Carprofen at 25 0 C. In another embodiment the process comprises the steps of: 1. adding a portion of liquid carrier to a mixing vessel, WO 2006/042381 PCT/AU2005/001650 7 2. combining a portion of the liquid carrier and a portion of anti-inflammatory substance to form a mixture and passing the mixture through a colloid mill to form a milled mixture, 3. repeating step 2 until all of the anti-inflammatory substance has been passed 5 through the colloid mill, 4. adding the milled mixtures to the mixing vessel, 5. adding an additional amount of the liquid carrier to the mixing vessel, and 6. mixing the contents of the mixing vessel to form a uniform suspension. Step 2 may be conducted such that the temperature of the mixture does not exceed 10 about 75'C, or does not exceed 70, 65, 60, 55 or 50'C. Step 5 may comprise rinsing the colloid mill, and/or vessels in which the anti-inflammatory substance has come in contact, with the liquid carrier. In yet another embodiment the process comprises the steps of: forming a paste comprising an anti-inflammatory substance and an orally acceptable is liquid carrier, wherein the carrier is such that the preparation is acceptable to a subject to which it is administered orally; and diluting the paste with an additional amount of the liquid carrier. After the step of diluting the paste may be mixed with the additional amount of the liquid carrier. The step of mixing may form a suspension of the anti-inflammatory 20 substance in the liquid carrier. In the present invention there is also provided an anti-inflammatory preparation when made by the process of the second aspect of the invention. In a third aspect of the invention there is provided a food preparation for administering an anti-inflammatory substance to a subject comprising a food and an anti 25 inflammatory preparation according to the invention, wherein the anti-inflammatory preparation comprises the anti-inflammatory substance. The anti-inflammatory preparation may be according to the first aspect of the invention, or may be niade by the process of the second, aspect of the invention. The food may be incapable of dissolving the anti-inflammatory substance. The food may be incapable of dissolving sufficient of 30 the anti-inflammatory substance that the resulting food preparation is unpalatable to the subject, or irritating or provides a burning sensation when consumed by the subject. The food may be a non-oil-based food. The food may contain less than about 5 wt% oil, or less than about 4, 3, 2 or 1 wt% oil. The food may be non-alkaline food. The pH of the food may be less than about 9, or less than about 8.5, 8, 7.5 or 7. The food may be a food WO 2006/042381 PCT/AU2005/001650 8 for the subject. It may be, or may be derived from, a canned pet food, for example a canned dog food or canned cat food. It may be palatable to the subject. The food preparation may be palatable, or not unpalatable, to the subject. The food preparation may have a pleasant taste to the subject. It may have a sweet taste. The food preparation may 5 be not irritating or provide a burning sensation to the subject when the subject consumes the food. At least a portion of the anti-inflammatory substance may be not dissolved in the liquid carrier. The anti-inflammatory substance may be sparingly soluble or insoluble in the liquid carrier. The ratio of the food to the anti-inflammatory preparation (or to the anti-inflammatory substance) may be such that, when the subject consumes a quantity 10 (i.e. weight or volume) of the food preparation equivalent to the quantity of the food normally consumed by the subject in a single meal, the amount of the anti-inflammatory substance consumed is a therapeutically, clinically or veterinarily effective dose. The ratio may be such that, when the subject consumes a quantity (i.e. weight or volume) of the food preparation equivalent to the quantity of the food normally consumed by the subject 15 in a single meal, the amount of the liquid carrier consumed is a non-toxic amount. This ratio may depend on the nature of the subject, the nature of the anti-inflammatory substance and/or on the concentration of the anti-inflammatory substance in the anti inflammatory preparation. The ratio may be for example between about 1000:1 and about 10:1 on a w/w or v/v basis, or between about 1000:1 and 50:1, 1000:1 and 100:1, 1000:1 20 and 500:1, 500:1 and 10:1, 100:1 and 10:1, 50:1 and 10:1, 500:1 and 50:1, 500:1 and 100:1, 100:1 and 50:1 or 200:1 and 50:1, and may be about 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 50:1, 40:1, 30:1, 25:1, 20:1, 15:1 or 10:1 w/w or v/v, or may be some other ratio. The anti-inflammatory preparation may be distributed homogeneously or inhomogeneously within the food 25 preparation. In a fourth aspect of the invention there is provided a process for making a food preparation for administering an anti-inflammatory substance to a subject, said process comprising combining an anti-inflammatory preparation according to the invention and a food, wherein the anti-inflammatory preparation comprises the anti-inflammatory 30 substance. The food may be incapable of dissolving the anti-inflammatory substance. The food may be incapable of dissolving sufficient of the anti-inflammatory substance that the resulting food preparation is unpalatable to the subject, or irritating or provides a burning sensation when consumed by the subject. In making the food preparation, if the food comprises a fat, the process may not involve heating the food sufficiently to cause the fat WO 2006/042381 PCT/AU2005/001650 9 to melt and to dissolve the anti-inflammatory substance. The food may be a non-oil-based food. The food may contain less than about 5 wt% oil, or less than about 4, 3, 2 or 1 wt% oil. The food may be non-alkaline food. The pH of the food may be less than about 9, or less than about 8.5, 8, 7.5 or 7. The combination may be in a ratio of food to anti 5 inflammatory preparation such that, when the subject consumes a quantity (i.e. weight or volume) of the food preparation equivalent to the quantity of the food normally consumed by the subject in a single meal, the amount of the anti-inflammatory substance consumed is a therapeutically, clinically or veterinarily effective dose. The combining may comprise one or more of stirring, mixing, blending, homogenizing, mashing or some other process 10 suitable for distributing the anti-inflammatory preparation in the food, or it may comprise pouring the anti-inflammatory preparation on, or otherwise applying the anti inflammatory preparation to, the food. The combining may be conducted immediately or shortly before the subject consumes the food preparation, or it may be made some time before the subject consumes the food preparation. In the latter case, following the 15 combining, the food preparation may be packaged, for example tinned, canned or bagged, thereby allowing it to be stored for a time, for example for sufficient time for distribution to retail outlets etc. The time may depend on the nature of the food, and may be for example up to 5 years, or up to 4, 3, 2, or 1 year, or up to 11, 10, 9, 8, 7 or 6 months. Before being packaged, the food preparation may be dried, in order to inhibit 20 deterioration. There is also provided a food preparation for administering an anti-inflammatory substance to a subject, said food preparation being made by the process of the fourth aspect of the invention. There is further provided a method for administering an anti inflammatory substance to a subject comprising allowing the subject to consume a food 25 preparation according to the third aspect of the invention, or a food preparation made by the process of the fourth aspect of the invention. In a fifth aspect of the invention there is provided a method for administering an anti-inflammatory substance to a subject comprising the steps of: - combining an anti-inflammatory preparation comprising the anti-inflammatory 30 substance and an orally acceptable liquid carrier with food for the subject; and - allowing the subject to consume the food; wherein the anti-inflammatory preparation is acceptable to the subject. In an embodiment there is provided a method for administering an anti inflammatory substance to a subject comprising the steps of: WO 2006/042381 PCT/AU2005/001650 10 - combining an anti-inflammatory preparation comprising an anti-inflammatory substance and an orally acceptable liquid carrier with food for the subject; and - allowing the subject to consume the food; wherein the solubility of the anti-inflammatory substance in the liquid carrier is selected 5 from the group consisting of sparingly soluble and insoluble and wherein the preparation is acceptable to the subject and wherein the liquid carrier masks the taste of the anti inflammatory substance. The combining may be conducted immediately prior to the subject consuming the food, or may be about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 minutes, or more than 10 60 minutes, before the subject consumes the food. The anti-inflammatory preparation may be an anti-inflammatory preparation according to the first aspect of the invention, and may be an anti-inflammatory preparation made by the process of the second aspect of the invention. The step of combining may comprise one or more of adding or applying the anti-inflammatory preparation to the food, pouring the anti-inflammatory preparation on 15 the food, and mixing or stirring the anti-inflammatory preparation with the food. The food may be a non-oil-base food. The food may be non-alkaline food. The pH of the food may be less than about 9, or less than about 8.5, 8, 7.5 or 7. The anti-inflammatory preparation may be non-irritating and/or not unpalatable and/or may provide reduced irritation and/or burning sensation to the subject. The subject may be for example a cat, a dog or some 20 other domestic pet. The method may therefore be a method for administering an anti inflammatory substance to a cat, or to a dog, or to some other domestic pet. In an embodiment the step of combining may comprise combining an anti inflammatory preparation having no intentionally added components other than the anti inflammatory substance and the liquid carrier with the food. 25 In another embodiment there is provided a method for administering an anti inflammatory substance to a subject comprising the steps of: - combining an anti-inflammatory preparation consisting of Carprofen and glycerol with food for the subject, wherein the amount of Carprofen is between about 5 and 50mg/1 in the preparation, the concentration of Carprofen dissolved 30 in the glycerol is less than about 4mg/ml at 25'C, and less than about 50% of the Carprofen is dissolved in the glycerol; and - allowing the subject to consume the food. In a sixth aspect of the invention there is provided a method for treating or alleviating the symptoms of a condition for which a non-steroidal anti-inflammatory drug WO 2006/042381 PCT/AU2005/001650 11 is indicated, comprising orally administering to an animal or human subject in need thereof a therapeutically effective amount of an anti-inflammatory preparation according to the first aspect of the invention, or of an anti-inflammatory preparation when made by the second aspect of the invention. The administration may be according to the third 5 aspect of the invention or it may be by direct administration, for example by a dropper, a syringe or some other means. The condition may be a musculoskeletal disease such as osteoarthritis. The method of the sixth aspect may alternatively or additionally comprise allowing the subject to consume a therapeutically, clinically or' veterinarily effective amount of a food preparation according to the third aspect of the invention or of a food 10 preparation made by the fourth aspect of the invention. In an embodiment there is provided a method for treating or alleviating the symptoms of a condition for which a non-steroidal anti-inflammatory drug is indicated, comprising orally administering to an animal or human subject in need thereof a therapeutically effective amount of an anti-inflammatory preparation comprising: is - an anti-inflammatory substance; and - an orally acceptable liquid carrier, wherein the solubility of the anti-inflammatory substance in the liquid carrier is selected from the group consisting of sparingly soluble and insoluble and wherein the liquid carrier masks the taste of the anti-inflammatory substance. 20 There is also provided an anti-inflammatory preparation or a food preparation according to the invention when used for treating or alleviating the symptoms of a condition for which a non-steroidal anti-inflammatory drug is indicated. There is also provided the use of anti-inflammatory substance for the manufacture of an anti-inflammatory preparation according to the present invention. 25 The anti-inflammatory preparation may be a taste masked anti-inflammatory preparation. Brief Description of the Drawings A preferred form of the present invention will now be described by way of example with reference to the accompanying drawing wherein: 30 Figure 1 shows a particle size distribution of an anti-inflammatory preparation according to the present invention, when 1 drop of the preparation is diluted in 8ml MQ (Milli-Q) water; Figure 2 shows a particle size distribution of the same anti-inflammatory preparation as used for Figure 1, when 2 drops of the preparation are diluted in 8ml MQ water; and WO 2006/042381 PCT/AU2005/001650 12 Figure 3 shows a particle size distribution of the same anti-inflammatory preparation as used for Figure 1, when 4 drops of the preparation are diluted in 8ml MQ water. Detailed Description of the Preferred Embodiments In the present specification, the term "consisting of' is taken to mean that no other 5 components other than those specified have been intentionally added whereas the term "comprising" allows for the possibility of other components being intentionally added. It will be understood by one skilled in the art that many commercially available materials, such as those in the preparations of the present invention, contain minor impurities, and that these may be present in the preparations of the present invention. For example it is 10 known that polyols, for example glycerol, may contain minor amounts of water, and/or minor impurities remaining from their manufacture, and it will be understood that these may be present in the preparations of the present invention, even when not added intentionally. An anti-inflammatory preparations according to the present invention may provide is an anti-inflammatory substance in a stable, palatable, single vehicle, containing no other added substances, for on-food administration to a subject to provide anti-inflammatory and/or analgesic activity. The administration may be used for the treatment, or alleviation of symptoms, of musculoskeletal disease such as osteoarthritis. The preparation may be for relieving inflammation or pain. The preparation may be for relieving inflammation or 20 pain associated with osteoarthritis. It may be for control of postoperative pain. The postoperative pain may be pain associated with soft tissue and/or orthopaedic surgery in an animal or human subject. A suitable anti-inflammatory substance for use in the present invention is Carprofen. Carprofen is a common name for 6-chloro-alpha-methyl-9H-carbazole-2 25 acetic acid. The empirical formula of Carprofen is CisH 1 2 ClN0 2 and its molecular weight 273.72. Carprofen is a white, crystalline compound. It is freely soluble in ethanol, but practically insoluble in water at 25'C. It is sparingly soluble in glycerol. Other anti inflammatory substances may be used in the present invention. The anti-inflammatory substance may be a COX-2 inhibitor. It may be a propionic acid derivative. Other 30 examples of suitable anti-inflammatory substances include ibuprofen, naproxen, ketoprofen, sulindac, diflunisal, ketorolac, piroxicam, meclofenamate, benzydamine, diclofenac, etodolac, fenbufen, mefenamic, nabumetone, phenylbutazone, tolmetin, sodium naproxen, aspirin, alminoprofen, benzoxaprofen, bucloxic acid, fenoprofen, fluprofen, flurbiprofen, indoprofen, miroprofen, oxaprozin, pirprofen, pranoprofen, WO 2006/042381 PCT/AU2005/001650 13 suprofen, taprofenic acid, tioxaprofen, Firocoxib, Celecoxib, Meloxicam and indomethacin. The anti-inflammatory substance may be a mixture of any two or more of the above. The anti-inflammatory substance when dissolved in solution or by itself or when not taste masked may be unpalatable or provide a burning sensation or be irritating 5 to a subject to which it is administered. The anti-inflammatory substance in the anti inflammatory preparation of the invention may not be adsorbed on a substrate and in particular may not be adsorbed on a particulate substrate, or on particles. A suitable liquid carrier for use in the present invention is not unpalatable to an animal or human subject to which the preparation is to be administered, is largely non-irritating to 10 the throat of the subject, and may have low or very low oral toxicity towards the subject. The solubility of the anti-inflammatory substance in the liquid carrier may be low, very low or zero. It may have an oral LD50 for rats, or for the subject to which the anti inflammatory preparation is to be administered, of greater than about 5000 mg/kg of body weight, or greater than about 6000, 7000, 8000, 9000, 10000, 11000, 12000, 13000, 15 14000 or 15000 mg/kg of body weight and may have an oral LD50 for rats, or for the subject to which the anti-inflammatory preparation is to be administered, of about 5000, 6000, 7000, 8000, 9000, 10000, 11000, 12000, 13000, 14000 or 150000 mg/kg of body weight. It may be a liquid wherein the solubility of the anti-inflammatory substance is less than about 5mg/ml, or less than about 4, 3, 2 or lmg/ml at 25 0 C, and may be about 0.5, 1, 20 2, 3, 4, or 5 mg/ml at 25'C. The liquid carrier may be palatable to animals and/or to humans and may be capable of masking the taste of the anti-inflammatory substance dissolved therein and/or suspended therein. It may be a polar liquid. It may be sweet tasting. It may have a sweetness index of at least about 0.5 (relative to sucrose) or at least about 0.6, 0.7, 0.8, 0.9 or 1, and may have a sweetness index of about 0.5, 0.55, 0.6, 0.65, 25 0.7, 0.75, 0.8, 0.85, 0.9, 0.95 or 1 or greater than 1. It may be of similar or greater sweetness than glycerol. It may be or comprise for example a polyol, a polyether polyol or a polyether, for example glycerol, glycerine, triethylene glycol, propylene glycol, diethylene glycol monoethyl ether, 1,3-butylene glycol, a polyglycitol syrup or a maltitol syrup, or some other suitable compound or it may be a mixture of any two or more of 30 these. If the liquid carrier is a mixture of two or more of the above, each of the liquids may be present in the mixture at between about 1 and about 99%w/w. w/v or v/v, provided that the total of the percentages of the liquids is 100%. Crodamol GTCC (caprylic/captric triglyceride) may also be used. The preparation may comprise a sweetener, such as fructose, dextrose, maltose, arabinose, sorbitol, maple syrup, corn WO 2006/042381 PCT/AU2005/001650 14 syrup, molasses, honey, fondant, aspartame, glycine, saccharin, acesufame K, polydextrose, sucralose, alitame, propylene glycol, erythritol, pentaerythritol, mannitol, xylitol, polymeric polyols (such as the polyol glycerols represented by triglycerol, tetraglycerol, hexaglycerol, decaglycerol, pentaglycerol and the like, including isomeric 5 forms) or isomalt or a mixture of any two or more of these. The preparation may comprise a sugar, saccharide or polyhydric alcohol. It may comprise a mono-, di- or oligosaccharide. The liquid carrier may be a solution of a sweetener in a solvent, whereby the solvent is a solvent for the sweetener, and whereby the anti-inflammatory substance is insoluble or sparingly soluble in a solution formed by dissolving the sweetener in the 10 solvent. Additionally or alternatively, the sweetener may be in suspension in the liquid carrier, or may be partially in suspension and partially in solution in the liquid carrier. The amount of the sweetener in the liquid carrier (either in solution or in suspension) may be sufficient to mask the taste of the anti-inflammatory substance. The amount of the sweeter may depend on the nature of the sweetener (e.g. its sweetness index, solubility etc.), and is the nature of the anti-inflammatory substance, and may be readily determined by one skilled in the art. A suitable liquid carrier may comprise for example the sweetener composition described in US 4,686,107, which comprises "a solution of from about 92 to about 98 wt. % glycerol, from about 0.5 to about 3.0 wt. % glycine, and from about 1.5 to about 5.0 wt. % gum arabic". 20 Earlier liquid preparations of Carprofen have provided Carprofen in solution. The present inventors hypothesise that Carprofen in solution in a therapeutically effective amount can provide an unpleasant sensation, irritation or burning sensation on impacting on the throat of an animal or human subject to a greater degree than if the Carprofen were in suspension and undissolved. The anti-inflammatory preparation of the present 25 invention may be a palatable formulation which is suitable for oral consumption by an animal subject or by a human subject. The taste of the anti-inflammatory substance may be masked, and may be masked by the liquid carrier. They further hypothesise that Carprofen in solution is less stable than as a solid. Consequently in preparations in which Carprofen is in solution, it may be necessary to 30 add stabilizers, for example antioxidants, in order to achieve an acceptable shelf life of the preparation. The inventors have found that a preparation having Carprofen in suspension causes low irritation on oral administration to an animal or human subject, and the Carprofen in such a preparation is sufficiently stable to provide an acceptable shelf life for the preparation. An anti-inflammatory preparation of Carprofen with no added WO 2006/042381 PCT/AU2005/001650 15 water does not provide a suitable environment for microbial growth. An anti inflammatory preparation according to the invention may have less than about 5% water, or less than about 4, 3, 2, 1, 0.5, 0.2 or 0.1% water (w/w, w/v or v/v), and may have about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5% water. It may 5 have a sufficiently low concentration of water that microbial growth is inhibited or eliminated in a sealed container having the preparation therein for at least about 6 months, or at least about 9, 12, 15, 18, 21 or 24 months (for example for about 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 or 36 months). Thus the anti-inflammatory preparations of the present invention may be formulated with no added water and without addition of an anti 10 microbial agent or preservative. This may provide benefits including one or more of: reduced cost, long shelf life, ease of oral administration, reduced toxicity, greater simplicity (and hence possibly lower cost) of manufacture and reduced possibility of interactions between components of the anti-inflammatory preparation. Thus the liquid carrier of the present invention may be one in which the anti is inflammatory substance is insoluble or sparingly soluble, which is capable of masking the taste of the anti-inflammatory substance, and which does not promote microbial growth. The liquid carrier may have no water deliberately added to it. It may be dried. It may have a water content of less than about 5%, or less than about 4, 3, 2, 1, 0.5, 0.2 or 0.1% (w/w, w/v or v/v), and may have about 0.1, 0.2, 0.3, 0.4, 0.5,'0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 20 3.5, 4, 4.5 or 5% water. It may have a sufficiently low concentration of water that microbial growth is inhibited or eliminated in a sealed container having the liquid carrier therein for at least about 6 months, or at least about 9, 12, 15, 18, 21 or 24 months. The liquid carrier may comprise a colouring agent, e.g. a dye or a colourant. The anti inflammatory substance in the preparation may be stable for at least about 6 months, or at 25 least about 9, 12, 15, 18, 21 or 24 months (for example for about 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 or 36 months), where "stable" is defined by the concentration of the anti inflammatory substance remaining within about 10% (or about 8, 6, 12 or 15%) of its original concentration in the preparation. The anti-inflammatory preparations of the present invention may be sterilisable, and 30 may be sterilized, e.g. by autoclaving, UHT treatment or other suitable process. The anti inflammatory preparations of the present invention may be terminally sterilized. The standard method of sterilization, comprises raising of the temperature of the preparation to 121.degree. C. for 15 minutes in an autoclave.

WO 2006/042381 PCT/AU2005/001650 16 In anti-inflammatory preparations having Carprofen in suspension, such as the preparations of the present invention, the Carprofen may settle over time. The anti inflammatory substance in the present invention may be in suspension in the liquid carrier. Over time the anti-inflammatory substance may settle out of the liquid carrier of 5 may rise in the liquid carrier, depending on the relative densities of the liquid carrier and the anti-inflammatory substance. However the inventors have found that Carprofen in the anti-inflammatory preparations of the present invention may be readily resuspended, and may remain in suspension for a sufficient period of time to allow administration to a subject. The suspension may be stable for sufficient time to enable a substantially 10 homogeneous portion, or a representative portion, of the anti-inflammatory preparation to be administered in an acceptable period after agitating the preparation. Where the anti inflammatory substance has settled out or risen in the preparation, it may be suspended in the liquid carrier by shaking, stirring, swirling or otherwise agitating the preparation. In settling or rising, the anti-inflammatory substance may not form a cake which is not is readily resuspended in the liquid carrier. The anti-inflammatory preparation may not comprise a suspending agent, and may not comprise a dispersing agent or dispersant. The anti-inflammatory substance may be suspended in the anti-inflammatory preparation, and may not be encapsulated or microencapsulated. The anti-inflammatory preparation may not contain surfactant and may not contain surfactant micelles. It may 20 not be an emulsion or a microemulsion. The particles of the anti-inflammatory substance may have no coating or surface modifying agent on the surface thereof, and may have no surface modification. They may have no material other than the liquid carrier on the surface thereof. The particles of the anti-inflammatory substance may not agglomerate in the suspension. The suspension may be a smooth suspension. The suspension may be a 25 stable suspension. The anti-inflammatory substance may be, in the form of particles of a size whereby a uniform suspension is fomed when the particles are mixed with the liquid carrier. The suspension may be stable. A definition of a "suspension" from http://www.thefreedictionary.coml/suspension is: "[a] system in which microscopically visible particles are dispersed throughout a less dense liquid or gas from which they are 30 easily filtered but not easily settled because of system viscocity [sic] or molecular interactions." The anti-inflammatory preparation of the present invention is thus a two phase system. The anti-inflammatory preparation of the present invention is acceptable to a subject to which it is administered orally. That is, it is sufficiently non-irritant, palatable, WO 2006/042381 PCT/AU2005/001650 17 inoffensive and/or causes sufficiently little burning sensation in the throat that the subject to which it is administered in a therapeutically, clinically or veterinarily effective amount in combination with food for the subject will not reject the food due to the presence of the preparation. 5 The anti-inflammatory substance may be present in the anti-inflammatory preparation in between about 1 and about 100mg/ml, or between about 1 and 50 or 1 and 30 or 1 and 10 or 10 and 100 or 50 and 100 or 10 and 50 or 5 and 50 or 5 and 20 or 5 and 15 or 8 and 12 or 20 and 50 or 20 and 40 or 25 and 35 or 28 and 32 or 5 and 35 or 10 and 30mg/ml, and may be present at about 1, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 26, 10 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100mg/ml. Of the anti-inflammatory present, less than about 50% may be in solution at 25 0 C or at about 5, 10, 15, 20, 25, 30 or 35'C, or less than about 45, 40, 35, 30, 25, 20, 15 or 10% may be in solution at 25'C or at about 5, 10, 15, 20, 25, 30 or 35 0 C, or about 5, 10, 15, 20, 25, 30, 35, 50, 45 or 50% may be in solution at 25C or at about 5, 10, 15, 20, 15 25, 30 or 35 0 C. The amount of anti-inflammatory substance in solution, or the solubility of the anti-inflammatory substance in the liquid carrier, may depend on the nature of the liquid carrier, on the temperature, and on the nature of the anti-inflammatory substance, and may, for example at about 5, 10, 15, 20, 25, 30 or 35'C, be less than about 5mg/ml, or less than about 4, 3, 2 or 1mg/ml, and may be about 0.5, 1, 2, 3, 4, or 5 mg/ml. The 20 solubility of the anti-inflammatory substance in the liquid carrier may be sufficiently low that the amount of the anti-inflammatory substance in solution is not sufficient to render the anti-inflammatory preparation unpalatable or unacceptable to a subject to which it is administered orally. The solubility may be sufficiently low that the amount of the anti inflammatory substance in solution is not sufficient to cause irritation or burning of the 25 throat to the subject when administered orally. The amount of the anti-inflammatory substance in solution in the anti-inflammatory preparation, and/or the solubility of the anti-inflammatory substance in the liquid carrier, may be sufficiently low that the taste and/or irritation of the anti-inflammatory substance does not overcome the taste masking due to the liquid carrier and/or the sweetener to an extent that the anti-inflammatory 30 substance is unpalatable or orally unacceptable to the subject. This level of solubility may be termed "sparingly soluble". The anti-inflammatory substance may under certain circumstances be in the form of large particles and/or crystals. In order that the anti inflammatory substance stays in suspension for an acceptable time, the anti-inflammatory substance may have a mean particle size less than about 1mm, or less than about 0.5, 0.4, WO 2006/042381 PCT/AU2005/001650 18 0.3, 0.2, 0.1, 0.05, 0.01, 0.005 0.004, 0.003, 0.002 or 0.001mm. It may have a mean particle size between about 0.3 and about 300 microns, or between about 0.5 and 300, 0.5 and 250, 1 and 250, 10 and 250, 100 and 250, 50 and 300, 0.5 and 100, 0.5 and about 50 microns, or between about 0.5 and 20, or between about 0.5 and 10, 0.5 and 5, 0.5 and 4, 5 0.5 and 3, 0.5 and 2.5, 1 and 10, 1 and 5, 1 and 3, 1 and 2.5, 1 and 4 microns or 1 and 2.8. It may have a mean particle size about 0.0003, 0.0005, 0.001, 0.0015, 0.002, 0.0025, 0.003, 0.0035, 0.004, 0.0045, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.025, 0.02, 0.025, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4 or 0.5mm. The mean particle size may be a number average, weight average or Z-average particle size, or may be a peak particle size. Particle 10 size distributions measured on an anti-inflammatory preparation according to the invention (Tergive 30) are shown in Figs. 1 to 3. Tergive 30 is an anti-inflammatory preparation according to the present invention comprising Carprofen (about 3% w/v) and glycerol. In Figs. 1 to 3, different distributions are shown for different dilutions of the preparation in water. As may be seen, the particle size distributions varies slightly with is dilution in water, from 2094nm Z-average (1 drop preparation per 8ml water: Fig. 1) to 2178nm Z-average (2 drops preparation per 8ml water: Fig. 2) to 2711 nm Z-average (4 drops preparation per 8ml water: Fig. 3). The differences in Z-average particle size may be due to some agglomeration as the concentration is increased. The anti-inflammatory substance may be suspended or resuspended in the liquid carrier by stirring, shaking, 20 mixing, agitating, churning, sparging, sonication, ultrasonication or some other method. Once the anti-inflammatory substance is homogeneously suspended in the liquid carrier, it may take greater than about 15 minutes to settle, or more than about 30 or 45 minutes, or more than about 1, 2, 3, 4, 5, 6, 12, 18 or 24 hours to settle, and may take about 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes, or about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 25 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours to settle. In this context the anti-inflammatory substance may be considered to have settled if the amount of suspended substance in the upper half of the volume of the preparation is less than about 80% of the amount of suspended substance in the lower half of the volume of the anti inflammatory preparation, or less than about 75, 70, 65, 60, 55 or 50% of the amount of 30 suspended substance in the lower half of the volume of the preparation. Thus the anti inflammatory preparation may be a stable suspension. The viscosity of the carrier liquid may be sufficient to maintain the anti-inflammatory substance in suspension for the abovementioned time, and may depend on the density and particle size of the anti inflammatory agent. The viscosity at 25'C may greater than about 2mPa.s, or greater than WO 2006/042381 PCT/AU2005/001650 19 about l0OmPa.s, or greater than about 200mPa.s, or greater than about 500, 750, 1000, 1250 or 1500mPa.s, and may be between about 2 and 200 mPa.s, 2 and 100, 2 and 50, 2 and 20, 50 and 200, 50 and 500, 50 and 1000, 200 and 1000 or 500 and 1500mPa.s, or between about 500 and 1000 or between about 1000 and 1500 or between about 750 and 5 1250 or between about 800 and 10OOmPa.s, and may be about 2, 5, 10, 20, 30, 40, 50, 100,150,200,250,300, 350,400,450,500,550,600,650,700,750,800,850,900,950, 1000, 1100, 1200, 1300, 1400 or 1500mPa.s. Suitable liquid carriers for the present invention include glycerol (about 650mPa.s), propylene glycol (about 56mPa.s), diethylene glycol monoethyl ether (about 4mPa.s) and triethylene glycol (about 40mPa.s). 10 The liquid carrier may comprise a viscosity modifier, for example a thickener. A suitable viscosity modifier may be for example gum arabic, starch, guar gum, agar agar, a food grade polymeric substance or some other type of viscosity modifier, or may be a mixture of viscosity modifiers. The concentration of the thickener in the liquid carrier may be sufficient that the viscosity of the liquid carrier is as described above. is The ratio between the density of the anti-inflammatory substance and the liquid carrier may be such that the anti-inflammatory substance stays in suspension for an acceptable time, as described above. The density of the liquid carrier at 25'C may be between about 0.9 and 1.5 grams/cm 3 or between about 1 and about 1.5, or may be less than 0.9 or greater than 1.5. The density may be between about 0.9 and 1, 0.9 and 1.1, 0.9 20 and 1.3, 1 and 1.4, 1 and 1.3, 1 and 1.2, 1.1 and 1.5, 1.2 and 1.5, 1.3 and 1.5, 1.1 and 1.4, 1.1 and 1.3, 1.2 and 1.3 or 1.23 and 1.27, and may be about 0.9, 0.95, 1, 1.05, 1.1, 1.15, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.35, 1.4, 1.45 or 1.5. Suitable liquid carriers include glycerol, which has a density of 1.26, triethylene glycol (density 1.125), propylene glycol (density 1.036) and diethylene glycol monoethyl ether (density 25 0.999). The density of the anti-inflammatory compound may be between about 1.0 and about 1.6, or may be between about 1.0 and 1.5, 1.0 and 1.45, 1.0 and 1.4, 1.0 and 1.3, 1.0 and 1.2, 1.0 and 1.1, 1.2 and 1.6, 1.4 and 1.6, 1.3 and 1.6, 1.1.25 and 1.6, 1.2 and 1.6, 1.35 and 1.6, 1.3 and 1.6, 1.3 and 1.5, 1.3 and 1.4, 1.35 and 1.45 or 1.34 and 1.4, and may be about 1, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.38, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, , or 30 may be greater than 1.6 or less than 1. The ratio of the density of the liquid carrier to the density of the anti-inflammatory substance may be about 0.8:1 and about 1:0.8, or between about 0.8:1 and 1:1, 0.9:1 and 1:1, 0.95:1 and 1:1, 1:1 and 1:0.95, 1:1 and 1:0.9, 1:1 and 1:0.8, 0.9:1 and 1:0.9, 1:0.95 and 1:0.85 or 0.95:1 and 0.85:1, and maybe about 0.8:1, 0.85:1, 0.9:1, 0.91:1, 0.92:1, 0.93:1, 0.94:1, 0.95:1, 0.96:1, 0.97:1, 0.98:1, 0.99:1, WO 2006/042381 PCT/AU2005/001650 20 1:1, 1:0.99, 1:0.98, 1:0.97, 1:0.96, 1:0.95, 1:0.94, 1:0.93, 1:0.92, 1:0.91, 1:0.9, 1:0.85 or 1:0.8. The density of the anti-inflammatory preparation at 25'C may be between about 1 and about 1.5, or may be less than 1 or greater than 1.5. The density may be between about 1 and 1.4, 1 and 1.3, 1 and 1.2, 1.1 and 1.5, 1.2 and 1.5, 1.3 and 1.5, 1.1 and 1.4, 1.1 5 and 1.3, 1.2 and 1.3 or 1.23 and 1.27, and may be about 1, 1.05, 1.1, 1.15, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.35, 1.4, 1.45 or 1.5. The amount of anti-inflammatory substance in suspension may be between 0.5 and 10 grams per 100 ml, 1 and 10 grams per 100 ml, 2 and 10 grams per 100 ml, 2.5 and 10 grams per 100 ml, 0.5 and 8 grams per 100 ml, 0.5 and 7 grams per 100 ml, 0.5 and 6 10 grams per 100 ml, 0.5 and 5 grams per 100 ml, 0.5 and 4 grams per 100 ml, 0.5 and 3 grams per 100 ml, 0.5 and 6 grams per 100 ml, 0.5 and 5 grams per 100 ml or 0.5 and 4 grams per 100 ml. The amount of anti-inflammatory substance in suspension may be less than 0.5 grams per 100 ml or may be about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 2, 2.3, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.8, 4, 4.3, 4.5, 4.8, 5, 15 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 grams per 100 ml or more. The preparations of the present invention may have a shelf life of at least about 12 months when stored at or below 30'C. The shelf life may be at least about 6, 7, 8, 9, 10, 11, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 42, or 48 months, and may be about 6, 9, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 42 or 48 months or may be greater 20 than about 48 months. In this context a product is taken to have exceeded its shelf life when it contains less than about 90%, or greater than about 110%, of the amount of the original anti-inflammatory substance i.e. the concentration of anti-inflammatory substance is less than about 90%, or greater than about 110%, of the original value. Values greater than 100% may be due to loss of the liquid carrier. After 24 months, the 25 anti-inflammatory preparation may have between about 90 and about 110% of the original concentration of anti-inflammatory substance, and may have between about 90 and 100, 100 and 110, 90 and 95, 95 and 100, 100 and 105, 105 and 110, 95 and 105 or 93 and 98%, or about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109 or 110% of the original concentration of anti-inflammatory substance. 30 The pH of the anti-inflammatory preparation may be between about 3 and about 7, between about 3 and about 6, between about 3 and about 5, between about 3 and about 4.5, or between about 3.5 and 4.5, 4 and 4.5, 3 and 4, 3 and 3.5 or 3.5 and 4, and may be about 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5 or 4.6.

WO 2006/042381 PCT/AU2005/001650 21 The anti-inflammatory preparations of the presentation may be made by combining an anti-inflammatory substance with an orally acceptable liquid carrier. The orally acceptable liquid carrier may be acceptable as a food additive. The orally acceptable liquid carrier may be food grade. The process may comprise making a concentrate 5 comprising the anti-inflammatory substance and the liquid carrier, and thereafter combining the concentrate with an additional amount of the liquid carrier so as to form a suspension. The step of combining may comprise adding the liquid carrier to the concentrate and mixing so as to form a suspension. The mixing may comprise one or more of agitating, stirring, swirling, shaking, sonicating, ultrasonicating or some other 10 form of mixing. The concentrate may be a paste. The concentrate may have a ratio of anti-inflammatory substance to liquid carrier of between about 2:1 and 1:10, or between about 2:1 and 1:5, 2:1 and 1:2, 2:1 and 1:1, 1:1 and 1:10, 1:2 and 1:10, 1:5 and 1:10, 1:1 and 1:5 or 1:1 and 1:2, or the ratio may be about 2:1. 3:2, 1:1, 2:3, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10 on a w/w or w/v basis. The ratio of the amount of the concentrate to 1s the additional amount of the liquid carrier may be between about 1:1 and 1:100, or between about 1:1 and 1:20, 1:1 and 1:10, 1:1 and 1:5, 1:1 and 1:2, 1:1.5 and 1:2.5, 1:1.8 and 1:2.2, 1:10 and 1:100, 1:50 and 1:100, 1:2 and 1:20 or 1:5 and 1:10, and may be about 1:1, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:3, 1:4, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 or 1:100, by weight, 20 weight/volume or volume. The process may be such that the final concentration of anti inflammatory to liquid carrier is between about 1 and about 100 mg/ml, or between about 5 and about 50mg/ml. The process may comprise a step of reducing the particle size of the anti-inflammatory substance. This step may be performed before, after or concurrently with combining the anti-inflammatory substance with the liquid carrier. Reducing the 25 particle size may comprise grinding, pulverizing, pounding, comminution, milling, crushing, abrading, granulating, sonication, ultrasonication or some other process, or may comprise a combination of any two or more of these. The preparations of the present invention may be used to treat, or alleviate the symptoms, of musculoskeletal disease such as osteoarthritis in an animal or human 30 subject. The subject may be a vertebrate, and the vertebrate may be a mammal, a marsupial or a reptile. The mammal may be a primate or non-human primate or other non-human mammal. The mammal may be selected from the group consisting of human, non-human primate, equine, murine, bovine, leporine, ovine, caprine, feline and canine. The mammal may be selected from a human, horse, cattle, cow, bull, ox, buffalo, sheep, WO 2006/042381 PCT/AU2005/001650 22 dog, cat, goat, llama, rat, mouse, rodent, rabbit, ape, monkey and a camel, for example. An anti-inflammatory preparation according to the invention may be administered to the subject by combining it with food for the subject or it may be administered directly, for example by a dropper, a syringe or some other means. The other means may comprise for s example presenting the preparation to the subject for the subject to drink. The anti inflammatory preparation of the invention may be combined with food for the subject to make a food preparation comprising the anti-inflammatory substance. This may be done shortly before presentation to the subject, for example on an as needed basis, or it may be done some time before presentation, and may then be packaged and may be distributed 10 commercially. Thus the present invention envisages the preparation and/or use of a commercial product in the form of an optionally packaged food preparation according to the invention. The anti-inflammatory preparation of the present invention may be administered to the subject such that the anti-inflammatory substance is delivered at between about 1 and 15 about 50mg/kg body weight, or between about 1 and 40, 1 and 30, 1 and 20, 1 and 10, 1 and 5, 2 and 5, 5 and 10, 5 and 50, 10 and 50, 20 and 50 or 5 and 20mg/kg body weight, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 or 50mg/kg body weight, or some other suitable dosage. For example a usable dose for administration of Carprofen (or of a preparation according to the invention comprising Carprofen) to a dog 20 may be about 2mg/lb of body weight, or about 4mg/kg of body weight, of the Carprofen. The dosage rate may depend on the condition being treated, and may be once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 36 or 48 hours or more. The anti-inflammatory preparation may be administered to the subject in a dose volume of between about 1 and about 200ml, or between about 1 and 100, 1 and 100, 1 and 50, 1 and 20, 1 and 10, 1 and 25 5, 5 and 200, 10 and 200, 50 and 200, 100 and 200, 5 and 100, 10 and 100, 50 and 100, 5 and 50, 10 and 50 or 5 and 20ml, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110. 120, 130, 140, 150, 160, 170, 180, 190 or 200ml, or some other appropriate dose volume, e.g. 300, 400 or 500ml or more than 500ml. The dose volume may depend on the nature of the subject and the condition being 30 treated. Many anti-inflammatory substances, such as Carprofen, are bitter and can cause a burning sensation in the throat on swallowing. Although animals may have different taste sensations to humans, it is reasonable to assume that if a preparation is unpleasant and can be tasted even when mixed with food, there is a risk that the animal may reject the food WO 2006/042381 PCT/AU2005/001650 23 and therefore fail to receive medication. The selection of an appropriate liquid carrier may improve acceptability to the animal and thereby alleviate this risk. Glycerol is an acceptable liquid carrier for anti-inflammatory preparations comprising Carprofen according to the present invention for the following reasons: - The majority of Carprofen remains undissolved and in suspension in glycerol, thereby imparting less taste sensation. - Glycerol is water soluble and mixes well with food. - Glycerol masks the taste sensation of Carprofen by providing a pleasant sweetness. 10 - The viscosity of glycerol is such that the Carprofen remains in a uniform suspension for sufficient period for uniform dose administration. - The absence of water from the formulation makes the product microbiologically stable without the addition of antimicrobial agents. Advantages of the anti-inflammatory preparations of the present invention include: 15 - A clinically therapeutic dose of anti-inflammatory substance may be supplied in a vehicle (liquid carrier) that provides low taste impact and mixes readily with food. - A single vehicle may be used to minimise the inclusion of foreign substances in the diet. 20 - The preparation may be stable for at least 24 months at 30'C. Examples All example formulations were taste tested by human volunteers. Example 1 Carprofen lg 25 Macrogol 400 (polyethylene glycol) to 1 OOmL Slowly soluble. Evaluation: Very sickening flavour and noticeable burning of throat. Example 2 Carprofen lg 30 Crodamol GTCC to 1 OOmL Solution with a slight haze following ultrasonication for 1Ominutes. Evaluation: Slight fishy taste on tongue and slight burning of throat. Example 3 Carprofen 3g WO 2006/042381 PCT/AU2005/001650 24 Crodamol GTCC to 1OOmL Cream suspension following ultrasonication for 15 minutes. Evaluation: Fish flavour and burning of throat. Not pleasant. Example 4 5 Carprofen 1g Glycerol to 1 OOmL Cream suspension following ultrasonication. Evaluation: Flavour acceptable although some burning of throat. Example 5 1o Carprofen 3g Glycerol to 1 OOmL Cream suspension following ultrasonication. Evaluation: Flavour acceptable, some burning of throat. Example 6 is Carprofen 3g Glycerol to 1 OOmL Cream suspension resulted after making a paste with a small quantity of Glycerol and working with spoon then diluting the paste with remaining Glycerol. Evaluation: Flavour acceptable although some burning of throat. 20 Example 7 Carprofen 3g Glycerol to 1OOmL Method of Manufacture 1. Add half the Glycerol to the mixing vessel. 25 2. Add the portions of the remaining Glycerol and portions of the Carprofen to the hopper of a colloid mill (Fryma Colloid Mill, Model MZ-80/A, tooth mill). 3. Pass the mixture through the mill at a setting that ensures a good dispersion without excessive heating of the product (i.e. maintaining the temperature of the product below 60'C). 30 4. Collect the milled materials in a pail. 5. Repeat previous step until all the Carprofen has been milled. 6. Rinse the mill into a pail with some of the remaining Glycerol. 7. Add the contents of the pail(s) to the mixing vessel. 8. Rinse the pails with remaining Glycerol.

WO 2006/042381 PCT/AU2005/001650 25 9. Add remaining Glycerol to the mixing vessel to the specified volume. 10. Mix until a uniform suspension is obtained. Stability Carprofen Oral Suspension 10mg/mL Batch 835052 5 (1OL batch; 12.5kg glycerol) Storage Conditions: 30 0 C Date Tested: 28-May-02 3-Jun-04 18-June-05 Attribute & Method Specification Initial 24 Months 36 Months Reference Appearance Homogenous white complies complies complies to off white suspension pH report 3.91 3.36 3.63 Carprofen Release: 95.0 to 95.5% 93.0% 92.2% 105.0%LC Expiry: 90 to <10% 110%LC Total Aerobic Count <10 NA NA Microbial BP/EP 2001 Complies NA NA Challenge(PET) (100mL container) NA: not applicable. Test protocol specifies testing for these parameters at 0 and 36 months. Carprofen Oral Suspension 10mg/mL Batch 834052 10 (1OL batch; 12.52kg glycerol) Storage Conditions: 30 0 C Date Tested: 28-May-02 3-Jun-04 18-Jun-05 Attribute & Method Specification Initial 24 Months 36 Months Reference Homogenous white Appearance to off white complies complies complies suspension_ WO 2006/042381 PCT/AU2005/001650 26 pH report 3.82 3.52 3.63 Release: 95.0 to Carprofen 99.0% 95.7% 92.1% 105.0%LC Expiry: 90 to <10% 110%LC Total Aerobic Count <10 NA NA Microbial Challenge(PET) BP/EP 2001 Complies NA NA (100mL container) Carprofen Oral Suspension 30mg/mL Batch 832052 (1OL batch; 12.3 1kg glycerol) Storage Conditions: 30 0 C Date Tested: 28-May-02 3-Jun-04 18-Jun-05 Attribute & Method Specification Initial 24 Months 36 Months Reference Homogenous white Appearance to off white complies complies complies suspension pH report 3.76 3.95 3.64 Release: 95.0 to Carprofen 97.5% 95.6% 96.7% 105.0%LC Expiry: 90 to <10% 110%LC Total Aerobic Count <10 NA NA Microbial Challenge(PET) BP/EP 2001 Complies NA NA (100mL container) 5 WO 2006/042381 PCT/AU2005/001650 27 Carprofen Oral Suspension 30mg/mL Batch 833052 (1OL batch; 12.3kg glycerol) Storage Conditions: 30 0 C Date Tested: 28-May-02 3-Jun-04 18-Jun-05 Attribute & Method Specification Initial 24 Months 36 Months Reference Homogenous white Appearance to off white complies complies complies suspension pH report 3.80 3.58 3.64 Release: 95.0 to Carprofen 95.9% 96.1% 97.1% 105.0%LC Expiry: 90 to <10% 110%LC Total Aerobic Count <10 NA NA Microbial Challenge(PET) BP/EP 2001 Complies NA NA (100mL container)

Claims

1. An anti-inflammatory preparation which is acceptable to a subject to which it is administered orally comprising: - an anti-inflammatory substance; and 5 - an orally acceptable liquid carrier, wherein the solubility of the anti-inflammatory substance in the liquid carrier is selected from the group consisting of sparingly soluble and insoluble.

2. The anti-inflammatory preparation of claim 1 wherein the liquid carrier masks the taste of the anti-inflammatory substance. 10

3. The anti-inflammatory preparation of claim 1 wherein the liquid carrier is glycerol.

4. The anti-inflammatory preparation of claim 1 wherein the anti-inflammatory substance is a non-steroidal anti-inflammatory substance.

5. The anti-inflammatory preparation of claim 1 wherein the anti-inflammatory is substance is Carprofen (6-chloro-alpha-methyl-9H-carbazole-2-acetic acid).

6. The anti-inflammatory preparation of claim 1 wherein the anti-inflammatory substance is present in the anti-inflammatory preparation at between about 1 and 100mg/ml.

7. The anti-inflammatory preparation of claim 1 wherein the anti-inflammatory 20 substance is present in the anti-inflammatory preparation in an amount selected from the group consisting of a therapeutically, a clinically and a veterinarily effective amount.

8. The anti-inflammatory preparation of claim 1 wherein the anti-inflammatory substance is suspended in the liquid carrier.

9. The anti-inflammatory preparation of claim I wherein the amount of the anti 25 inflammatory substance in solution is less than about 50%w/w of the total amount of anti inflammatory substance present at 25'C.

10. The anti-inflammatory preparation of claim 1 wherein the amount of the anti inflammatory substance in solution is less than about 0.5%w/v of the preparation at 25C.

11 The anti-inflammatory preparation of claim 1 wherein the amount of the anti 30 inflammatory substance is between about 5 and about 50mg/ml and the concentration of the anti-inflammatory dissolved in the liquid carrier is less than about 4mg/ml at 25"C

12. The anti-inflammatory preparation of claim 1 wherein the anti-inflammatory substance has a particle size such that it does not settle rapidly when suspended in the liquid carrier. WO 2006/042381 PCT/AU2005/001650 29

13. The anti-inflammatory preparation of claim 1 wherein the liquid carrier is selected from the group consisting of non-toxic, not unpalatable and non-irritating to the subject to which the preparation is administered.

14. The anti-inflammatory preparation of claim 1 wherein the liquid carrier is 5 capable of reducing irritation due to the anti-inflammatory substance.

15. The anti-inflammatory preparation of claim 1 wherein the liquid carrier is selected from the group consisting of glycerol, triethylene glycol, propylene glycol, diethylene glycol monoethyl ether, a polyglycitol syrup and a maltitol syrup.

16. The anti-inflammatory preparation of claim 1 wherein the liquid carrier is 10 performs at least one function selected from the group consisting of the functions of a stabilizer, an antioxidant, a preservative and an antimicrobial agent.

17. The anti-inflammatory preparation of claim 1 wherein the anti-inflammatory preparation has no added stabilizer, antioxidant, preservative or antimicrobial agent other than the liquid carrier. 15

18. The anti-inflammatory preparation of claim 1 consisting of: - about 1Omg/ml Carprofen or about 3Omg/ml Carprofen; and - glycerol; wherein the amount of Carprofen dissolved in the glycerol is about 3mg/ml or less at 25 0 C. 20

19. A process for making an anti-inflammatory preparation comprising the step of combining an anti-inflammatory substance with an orally acceptable liquid carrier, wherein the carrier is such that the preparation is acceptable to a subject to which it is administered orally and wherein the solubility of the anti-inflammatory substance in the liquid carrier is selected from the group consisting of sparingly soluble and insoluble. 25

20. The process of claim 19 wherein the liquid carrier masks the taste of the anti inflammatory substance.

21. The process of claim 19 wherein no stabilizer, preservative, anti-microbial or anti-oxidant is added to the anti-inflammatory preparation other than the liquid carrier.

22. The process of claim 19 which does not comprise a step of adding water. 30

23. The process of claim 19 wherein the anti-inflammatory preparation has an amount of the anti-inflammatory substance in solution less than about 0.5%w/v of the preparation at 25C. WO 2006/042381 PCT/AU2005/001650 30

24. The process of claim 19 wherein the amount of anti-inflammatory substance dissolved in the liquid carrier is less than about 50% of the total amount of anti inflammatory substance at 25 0 C.

25. The process of claim 19 comprising making a concentrate comprising the 5 anti-inflammatory substance and the liquid carrier, and combining the concentrate with an additional amount of the liquid carrier.

26. The process of claim 25 additionally comprising the step of reducing the particle size of the anti-inflammatory substance before combining the concentrate with an additional amount of the liquid carrier. 10

27. A food preparation for administering an anti-inflammatory substance to a subject comprising a food and an anti-inflammatory preparation according to claim 1, wherein the anti-inflammatory preparation comprises the anti-inflammatory substance.

28. The food preparation of claim 27 wherein the liquid carrier masks the taste of the anti-inflammatory substance. is

29. A process for making a food preparation for administering an anti inflammatory substance to a subject, said process comprising combining an anti inflammatory preparation according to claim 1 and a food, wherein the anti-inflammatory preparation comprises the anti-inflammatory substance.

30. The process of claim 29 wherein the liquid carrier masks the taste of the anti 20 inflammatory substance.

31. A method for administering an anti-inflammatory substance to a subject comprising the steps of: - combining an anti-inflammatory preparation comprising an anti-inflammatory substance and an orally acceptable liquid carrier with food for the subject; and 25 - allowing the subject to consume the food; wherein the solubility of the anti-inflammatory substance in the liquid carrier is selected from the group consisting of sparingly soluble and insoluble and wherein the preparation is acceptable to the subject.

32. The method of claim 31 wherein the liquid carrier masks the taste of the anti 30 inflammatory substance.

33. A method for administering an anti-inflammatory substance to a subject comprising allowing the subject to consume a food preparation comprising a food and an anti-inflammatory preparation according to claim 1, wherein the anti-inflammatory preparation comprises the anti-inflammatory substance. WO 2006/042381 PCT/AU2005/001650 31

34. A method for treating or alleviating the symptoms of a condition for which a non-steroidal anti-inflammatory drug is indicated, comprising orally administering to an animal or human subject in need thereof a therapeutically effective amount of an anti inflammatory preparation comprising: 5 - an anti-inflammatory substance; and - an orally acceptable liquid carrier, wherein the solubility of the anti-inflammatory substance in the liquid carrier is selected from the group consisting of sparingly soluble and insoluble.

35. The method of claim 34 wherein the liquid carrier masks the taste of the anti 10 inflammatory substance.

36. The method of claim 34 wherein the condition is a musculoskeletal disease.