WO2023108206A1 - Solid dosage forms for aquaculture - Google Patents

Abstract

A taste masked ingestible solid dosage form that is suspensible in water is disclosed. The solid dosage form comprises a core element containing at least one therapeutically active substance, at least one taste masking substance, and an outer coating comprising an aquatic animal attractant. An aquatic animal parasite controlling composition is also disclosed.

Description

SOLID DOSAGE FORMS FOR AQUACULTURE

PRIORITY DOCUMENT

[0001] The present application claims priority from Australian Provisional Patent Application

No. 2021904036 titled “SOLID DOSAGE FORMS FOR AQUACULTURE” and filed on

13 December 2021, the content of which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The present disclosure relates to solid dosage forms for delivering therapeutic agents to animals. In a particular form the present disclosure relates to solid dosage forms for delivering therapeutic agents to aquatic animals in aquaculture settings.

BACKGROUND

[0003] One of the fastest growing sectors in animal farming is the farming of aquatic organisms such as fish, crustaceans, molluscs and aquatic plants (i.e. aquaculture). Some of the aquatic species which are commonly farmed include salmon, tilapia, trout, kingfish, oysters, clams, and shrimp. It has been estimated that about one half of the world supply of fish and shellfish processed for human consumption is now produced by aquaculture.

[0004] Current aquaculture practices can often involve large numbers of animals raised in limited space. Farmed aquatic animals typically require large amounts of food and medicine to keep the animals healthy. For example, infestations by trematodes and monogenean parasites, including the blood flukes Cardicola forsteri and Cardicola orientalis, the polyopisthocotylean gill fluke Zeuxapta seriolae and the monopisthocotylean skin flukes Benedenia seriolae and Neobenedenia girellae are common in commercial aquatic animal farming operations throughout the world and need to be treated. Without treatment, trematode and monogenean parasite infestations can lead to anaemia, loss of appetite, poor growth, secondary bacterial infections and mortality. Consequently, trematodes and monogenean parasites have been identified as significant risks to the sustainability and profitability of commercial aquatic animal farming operations.

[0005] Current practice for treatment of parasitic infestations in commercial aquatic animal farming operations is generally based on the use of chemical treatments. For example, in many fish farming operations, infestations are chemically treated by immersion bath treatments such as routine bathing in hydrogen peroxide. Immersion bath treatments, however, are labour intensive, logistically challenging, expensive and cause considerable stress to fish and mortality if not correctly implemented. In-feed treatment has also been used instead of immersion bath treatments. In-feed treatment permits simultaneous medication of all cages on a site and minimises cross infestation that may occur during the several days necessary to apply immersion bath treatments to all cages on a site. However, in-feed treatment can be hampered by incompatibility of active therapeutic ingredients with the usual feeds, palatability issues and selective or low consumption of the active therapeutic ingredients by animals.

[0006] For example, praziquantel (PZQ) is a broad-spectrum anthelmintic drug that has been used therapeutically in animals and humans for many years and has also been shown to be active against a wide range of monogenean parasites in a number of fish species (Schmahl & Mehlhorn 1985, Buchmann 1987, Schmahl & Taraschewski 1987, Thoney 1990, Santamarina et al. 1991). However, PZQ bath treatments are expensive and result in the discharge of large quantities of PZQ into the environment.

There have been varying reports on the efficacy of in-feed PZQ treatments in aquaculture. PZQ is known to be very bitter (Meyer et al. 2009), leading to appetite suppression and diet rejection (Hirazawa et al. 2004; Williams et al. 2007).

[0007] Thus, whilst PZQ has great potential as a cost effective and easily administered treatment against monogenean parasites, its widespread use in commercial aquatic animal farming has yet to be realised. There is, therefore, a need for improved PZQ formulations for aquaculture applications. Alternatively, or in addition, there is a need for PZQ formulations for aquaculture applications that overcome one or more of the problems associated with the use of known PZQ formulations. Alternatively, or in addition, there is a need for PZQ formulations for aquaculture applications that provide a useful alternative to known PZQ formulations.

SUMMARY

[0008] According to a first aspect of the present disclosure, there is provided a taste masked ingestible solid dosage form that is suspensible in water, the solid dosage form comprising: a core element containing at least one therapeutically active substance; at least one taste masking substance; and an outer coating comprising an aquatic animal attractant.

[0009] According to a second aspect of the present disclosure, there is provided an aquatic animal parasite controlling composition comprising an ingestible solid dosage form comprising: a core element containing at least one therapeutically active substance; at least one taste masking substance; and an outer coating comprising an aquatic animal attractant. [0010] According to a third aspect of the present disclosure, there is provided a method for treating or preventing parasite infection in aquatic animals, the method comprising adding the ingestible solid dosage form of the first aspect to a water body that contains the aquatic animals such that the ingestible solid dosage form is suspended in water at a depth that is suitable for it to be consumed by the aquatic animals to be treated.

[0011] According to a fourth aspect of the present disclosure, there is provided a method of preparing a taste masked ingestible solid dosage form that is suspensible in water at a depth that is suitable for it to be consumed by aquatic animals in the water, the method comprising: forming a core element containing at least one therapeutically active substance and at least one taste masking substance; and coating the core element to form an outer coating comprising an aquatic animal attractant.

[0012] According to a fifth aspect of the present disclosure, there is provided a method of preparing a taste masked ingestible solid dosage form that is suspensible in water at a depth that is suitable for it to be consumed by aquatic animals in the water, the method comprising: forming a core element containing at least one therapeutically active substance; and coating the core element to form an outer coating comprising at least one taste masking substance and an aquatic animal attractant.

BRIEF DESCRIPTION OF THE FIGURES

[0013] The present disclosure will be described with reference to the accompanying figures. In the figures:

[0014] Figure 1 is a schematic representation of one embodiment of a solid dosage form of the present disclosure having a taste masking substance in the core element; and

[0015] Figure 2 is a schematic representation of a further embodiment of a solid dosage form of the present disclosure having a taste masking substance coated on the core element.

DESCRIPTION OF EMBODIMENTS

[0016] Disclosed herein and shown schematically in Figures 1 and 2 is an ingestible solid dosage form 10 that can be used to administer one or more therapeutically active substances to aquatic animals. The ingestible solid dosage form 10 is suspensible in water. The solid dosage form 10 comprises a core element 12 comprising at least one therapeutically active substance. The solid dosage form 10 also comprises at least one taste masking substance. The solid dosage form 10 further comprises an outer coating 14 comprising an aquatic animal attractant.

[0017] In different embodiments, the at least one taste masking substance may be present in the core element 12, in a coating on the core element 12 and/or in the outer coating 14 comprising the aquatic animal attractant.

[0018] The ingestible solid dosage form 10 can take any suitable form. However, for delivery of at least one therapeutically active substance to aquatic animals, such as fish, the solid dosage form 10 needs to have certain characteristics. Firstly, the solid dosage form 10 needs to be suspensible in water at a depth that is suitable for it to be consumed by aquatic animals. In some cases, the depth may be just below the surface of the water. In that case, the density, weight and shape of the solid dosage form 10 should be selected to provide that property. Secondly, the solid dosage form 10 needs to remain intact (ie. not dissolve) for a suitable time period so that it can be consumed by the aquatic animals. Thirdly, the solid dosage form 10 must be palatable to the aquatic animals. Fourthly, the solid dosage form 10 must be formulated to administer the therapeutically active substance to the animal after it has been ingested.

[0019] The ingestible solid dosage form 10 described herein is the result of extensive research that has been carried out by and on behalf of the applicant to develop a solid dosage form 10 that is ingested by aquatic animals and gives rise to the desired therapeutic benefit.

[0020] It is contemplated that the ingestible solid dosage form 10 can be used to administer or deliver any therapeutically active substance to aquatic animals including fish, crustaceans, and molluscs. It will also be evident from the description herein that the ingestible solid dosage form 10 is particularly suitable for use as a fish parasite controlling composition. The fish may be any fish that is commonly farmed such as, but not limited to, salmon, tuna, kingfish, trout, perch, flatfish, flounder, herring, puffer, carp, eel, tilapia, barramundi (Asian seabass), sea bass, sea bream, mulloway/jewfish, snapper, trevally, groper, and catfish. The fish may be a salt water or fresh water fish.

[0021] In certain specific embodiments, the ingestible solid dosage form 10 is used to administer or deliver a therapeutically active substance to fish of the species Seriola, such as Seriola lalandi (yellowtail kingfish). A number of Seriola species are being commercially cultured in Australia, Japan, New Zealand, the Americas and Europe.

[0022] The ingestible solid dosage form 10 is used to administer one or more therapeutically active substance. The therapeutically active substance can be any substance that provides a therapeutic benefit to an aquatic animal in need of treatment or disease prevention. For example, the therapeutically active substance may be an antiparasitic agent, such as an anthelmintic agent. Suitable antiparasitic agents include, but are not limited to, praziquantel and fenbendazole. As another example, the therapeutically active substance may be an antibiotic. Suitable antibiotics include, but are not limited to, chloramphenicol, oxytetracycline, kanamycin, nifurprazine, oxolinic acid, flumequine, and ciproflaxin. Other suitable therapeutically active substances include, but are not limited to, antibacterial agents, antiviral agents, antifungal agents, antiprotozoan agents, antimetazoan preparations, probiotics, immunostimulants, vaccines, bacterins, hormones, growth stimulants, anaesthetics, and bioremediators.

[0023] Although not limited to any particular application, the ingestible solid dosage form 10 is particularly suitable for administering poorly palatable therapeutically active substances to aquatic animals. Thus, the therapeutically active ingredient can be any poorly palatable therapeutically active substance that is of use in aquaculture including, but not limited to, praziquantel (PZQ) or an antiparasitic derivative thereof. As discussed, praziquantel (4H-pyrazino[2,l-a]isoquinolin-4-one, 2- (cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-) has previously been used in the treatment of fluke (i.e. trematode or monogenean parasite) infections in fish. However, the bitter taste results in palatability issues which may then result in poor delivery and therapeutic outcomes in fish populations.

[0024] The therapeutically active substance may be an antiparasitic agent that can be used to treat trematode, monogenean or other parasite infections by oral administration. The monogenean parasite infection may be infection by Zeuxapta seriolae (polyopisthocotylean gill fluke), Benedenia seriolae (monopisthocotylean skin fluke), Neobenedenia girellae (monopisthocotylean skin fluke), Paradeontacylix grandispinus, Paradeontacylix kampachi, and Cardicola sp. Other parasite infections that may be treated include coccidian and myxosporideans (kudoa).

[0025] The therapeutically active substance may be used to treat bacterial diseases such as photobacteria and epitheliocystis which is a skin and gill disease caused by pathogenic intracellular bacteria.

[0026] The therapeutically active substance could be a combination of two or more therapeutically active substances, such as a combination of PZQ and one or more additional therapeutically active substance. The two or more therapeutically active substances may act synergistically. By way of non- limiting example, cimetidine (1-cyano-2-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl) methylsulfanyl] ethyl] guanidine is a histamine H2 receptor antagonist. An increase in PZQ levels in plasma of mammals when cimetidine is simultaneously administered has been reported. Thus, it may be advantageous to co- administer PZQ and cimetidine. Other fish parasite-controlling therapeutically active substances that could be used are salicylanilide-based drugs such as oxyclozanide, rafoxanide, or closantel as well as oxytetracycline to control bacterial diseases and fenbendazole. [0027] The amount of therapeutically active substance in the core element 12 (and, therefore, the unit dose) will depend on a number of factors including the nature of the therapeutically active substance, the water temperature, the type of aquatic animal being treated, the size or weight of the aquatic animal being treated, the dissolution time of the solid dosage form 10 in the water, etc. Water temperature and animal size are important factors as both govern their feed rate. For example, small fish eat more than big fish on a %BW basis and fish will eat more at elevated water temperatures. The parasite being targeted also dictates the unit dose. Blood fluke can be treated at 15 mg/kg BW whilst skin fluke take 150 mg/kg BW. The dosage rates can readily be determined by the skilled person. When praziquantel is used to treat parasitic infestations in fish, the amount of praziquantel in the core element 12 (and, consequently also in the solid dosage form 10) may be from about 1 mg to about 100 mg, such as from about 6 mg to about 20 mg, such as about 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg. In certain specific embodiments, the amount of praziquantel in the core element 12 (and, consequently also in the solid dosage form 10) is from about 15 mg to about 18 mg, such as 15 mg, 15.5 mg or 17.5 mg. For fish, the effective overall dose of praziquantel may be from about 10 mg/kg BW to about 200 mg/kg BW. The effective overall dose of praziquantel will be determined by the parasite being treated and, for example, may be about 15 mg/kg BW or about 20 mg/kg BW to treat for blood fluke, about 70mg/kg BW to treat for gill fluke and about 150 mg/kg BW to treat for skin fluke.

[0028] The one or more therapeutically active substance is contained in the core element 12. The core element 12 may be a tablet, a pellet, an extruded particle, a granule or a drug layered bead. In certain embodiments, the core element 12 is a tablet.

[0029] The core element 12 may include up to 100% by weight of the one or more therapeutically active substance. However, the core element 12 will typically comprise the therapeutically active substance dispersed in a matrix. The matrix may comprise one or more pharmaceutically acceptable excipient. The excipients can be any material which is inert in the sense that it substantially does not have any therapeutic and/or prophylactic effect per se. Such an excipient may be added with the purpose of making it possible to obtain a solid dosage form 10 having acceptable technical properties.

[0030] Examples of suitable excipients for use in the solid dosage form 10 include fillers, diluents, disintegrants, binders, lubricants, acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, colouring agents, complexing agents, emulsifying and/or solubilizing agents, flavours, humectants, wetting agents, pH-adjusting agents, stabilizing agents, wetting agents, surface-active agents, suspending agents, absorption enhancing agents, agents for modified release etc. or mixtures thereof. [0031] Examples of suitable fillers, diluents and/or binders include lactose (e.g. spray-dried lactose, a- lactose, P-lactose, Tabletose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcelluiose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g. the 4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen etc. Specific examples of diluents are e.g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc.

[0032] Specific examples of disintegrants are e.g. alginic acid or alginates, microcrystalline cellulose (MCG), hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e.g. Primogel® and Explotab®) etc.

[0033] Specific examples of binders are e.g. acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.

[0034] Specific examples of glidants and lubricants are stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silicon dioxide, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.

[0035] Other additives in the solid dosage form may be antioxidants like e.g. ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives, etc. [0036] The one or more excipient may be present in the core element 12 in an amount of from about 0.1% w/w to about 95% w/w such as, e.g., from about 10% w/w to about 70% w/w, from about 20% w/wto about 60% w/w or from about 30% w/w to about 50% w/w.

[0037] The core element 12 may be of any suitable size. However, it will be appreciated that the core element 12 forms a major part of the solid dosage form 10 ie. in addition to the taste masking coating (if present as a coating) and the animal attractant coating and, therefore the size of the core element 12 is a significant contributor to the overall size of the solid dosage form 10. In certain embodiments, it may be preferable for the solid dosage form 10 to be similar in size to typical feeds that are provided to the aquatic animals to be heated. By way of non-limiting example, fish feeds for yellowtail kingfish may be in the form of % mm, 6 mm and 9 mm diameter pellets and it may be preferable for the solid dosage form 10 described herein to be about the same size.

[0038] The process of tabletting may be conducted by any means available to the skilled addressee. Preferably, the tablet is formed by direct compression. The hardness of the tablets may be in the range of from about 5 kgf to about 20 kgf, for example from about 10 kgf to about 15 kgf, such as about 10 kgf, about 11 kgf, about 12 kgf, about 13 kgf, about 14 kgf or about 15 kgf.

[0039] The taste masking substance acts to reduce the impact of the bitter taste of a therapeutically active substance like PZQ and, therefore, make the solid dosage form 10 more palatable to an aquatic animal such as fish. The taste masking substance may encapsulate the therapeutically active substance sufficiently to retain taste masking for a period long enough to avoid or minimise any taste whilst providing a dissolution profile fast enough to categorise the solid dosage form 10 as immediate release.

[0040] The taste masking substance may be incorporated within the core element 12 and/or it may be coated on the core element 12. When it is coated on the core element 12, the taste masking substance may be present in a separate coating layer from the outer coating layer 14 (e.g. see Figure 2) or it may be incorporated in the outer coating layer 14. The taste masking substance could also be present in each of the core element 14 and any coating layer(s).

[0041] In some embodiments, the taste masking substance is incorporated within the core element 12.

In these embodiments, the taste masking substance may be a lipid or polymer barrier system.

[0042] A suitable polymer barrier system for taste masking comprises a lipid based formulation such as paraffins, waxes (e.g. carnauba wax), beeswax, hydrogenated oil, molten stearyl stearate, higher fatty acids, higher fatty acid esters, glycerin fatty acid esters, polyglycerol fatty acid esters, and/or poly propylene glycols. In certain of these embodiments, the taste masking substance is selected from the group consisting of glyceryl distearate and glyceryl monostearate, or a mixture of each. One suitable glyceryl distearate is commercially available under the trade name Precirol® ATO 5. One suitable glyceryl monostearate is commercially available under the trade name Geleol™ Mono and Diglycerides NF. The ratio of taste masking substance(s) to therapeutically active substance(s) in these embodiments may be from about 0.2:1 to about 100:1, such as about 1:1 to about 50:1 and preferably from about 5:1 to about 20:1. In certain specific embodiments, the ratio of taste masking substance(s) to therapeutically active substance(s) is 2:1.

[0043] A suitable polymer barrier system for taste masking comprises one or more methacrylate polymer, such as a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. One particularly suitable polymer is a Eudragit® E PO which is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. Eudragit® E PO is insoluble in the mouth, but soluble in the stomach. Munster et al. reported solid lipid extrusion combined with Eudragit® E PO and praziquantel achieved a promising taste masking. Other suitable lipid or polymer barrier systems that could be used include magnesium aluminium silicate or gelatine.

[0044] In some embodiments, the taste masking substance is coated on the core element 12. The coating is preferably a substantially continuous coating on the core element 12. By “substantially continuous coating” we mean a coating which retains a smooth and continuous appearance when magnified 1000 times under a scanning electron microscope and wherein no holes or breakage of the coating is evident so as to reduce taste masking.

[0045] In these embodiments, the taste masking substance may be a polymeric material. The polymeric material may include cellulosic materials and polymers, such as alkylcelluloses. One suitable alkylcellulosic polymer is ethylcellulose, although other cellulose and/or alkylcellulose polymers may be readily employed, singly or in combination. The taste masking substance may be a water insoluble polymer of ethyl cellulose.

[0046] The coating may be formed by applying a coating formulation comprising an aqueous dispersion of ethylcellulose to the core element. One suitable aqueous dispersion of ethylcellulose is commercially available as Surelease® (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). Another commercially available aqueous dispersion of ethylcellulose is Aquacoat (EMC Corp., Philadelphia, Pennsylvania, U.S.A.). One particularly suitable aqueous dispersion of ethylcellulose is Surelease® E-7- 19040 (SE).

[0047] The taste masking substance could be a combination of polymeric materials such as ethyl cellulose and hydroxypropylmethylcellulose. For example, the coating composition may comprise a Surelease® composition and an Opadry composition. Suitable hydroxypropylmethylcellulose compositions include Opadry OY-29020 clear (00) (Colorcon, Inc., West Point, Pennsylvania, U.S.A.). The ethyl cellulose and hydroxypropylmethylcellulose may be present in the coating composition at ratios of from about 95:5 to about 70:30 such as 85:15 or 80:20. Ethyl cellulose and hydroxypropylmethylcellulose work together to create a release profile with a slight delay in the initial release, while maintaining the criteria for an immediate release dosage form.

[0048] The coating may be formed on the core element 12 by applying the coating composition using any suitable method know to the skilled person, such as spray coating, fluidised bed coating, rotor coating or high shear coating. In certain embodiments, the coating is applied by fluidised bed coating.

[0049] Optionally, a solvent may be used in the preparation of the coating of the composition. The solvent may be such that it constitutes a good solvent for the coating material but it is substantially a non- solvent or poor solvent for the therapeutically active substance and excipients in the core element 12. The solvent may be selected from alcohols such as methanol, ethanol, halogenated hydrocarbons such as dichloromethane (methylene chloride), hydrocarbons such as cyclohexane, and mixtures thereof.

[0050] The core element 12 may be coated with the taste masking coating composition to weight gains of at least 20%, at least 30%, at least 40%, or at least 50% such as 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% or 50%. In certain embodiments, the core element 12 is coated with the taste masking coating composition to weight gains of 30% to 40%. This level of coating effectively provides taste masking characteristics.

[0051] Core elements 12 containing the therapeutically active substance and the lipid or polymer barrier taste masking substance and/or core elements 12 containing the therapeutically active substance and coated with the taste masking substance are coated with an aquatic animal attractant coating. Alternatively, core elements 12 containing the therapeutically active substance are coated with an aquatic animal attractant coating that also contains the taste masking substance.

[0052] The aquatic animal attractant coating comprises an aquatic animal attractant composition. The aquatic animal attractant composition can comprise any material that is capable of acting as an attractant to the aquatic animal of interest, such as fish for example. The composition will depend on the aquatic animal that is to be treated. In the case of fish, the aquatic animal attractant composition may comprise fishmeal. Fishmeal is made from fish, fish trimmings, bones and offal which are then dried and ground. The fishmeal is preferably in the form of powder. Fishmeal is available commercially and any commercial or non-commercial fish meal can be used. Commercial fishmeal that can be used include

Peruvian or Chilean fishmeal (Prime or Super Prime). In certain embodiments, the aquatic animal attractant composition comprises Peruvian fishmeal (Super Prime). [0053] Other aquatic animal attractant compositions that could be used include nucleotide compositions that are known to attract fish, betaine, and hydrosylates, such as chicken hydrosylate. Betaine is a known palatant and fish attractant that improves feed intake, and also has functional properties in supporting osmoregulation. Hydrolysates are also good attractants and for example chicken, krill, squid and fish hydrolysates can be used in aquatic animal attractant compositions.

[0054] The aquatic animal attractant composition may also comprise one or more additives. Suitable additives include functional additives such as vitamins, minerals, amino acids, proteins, antibiotics, protein hydrolysates, and peptides. Other suitable additives include colouring agents, preservatives, antioxidants, stabilising agents, and osmoregulation agents.

[0055] In certain embodiments, the aquatic animal attractant composition comprises Peruvian fishmeal (Super Prime), betaine and chicken hydrolysate.

[0056] The amount of fishmeal in the aquatic animal attractant composition may be from about 50% w/w to 100% w/w, such as 50% w/w, 51% w/w, 52% w/w, 53% w/w, 54% w/w, 55% w/w, 56% w/w,

57% w/w, 58% w/w, 59% w/w, 60% w/w, 61% w/w, 62% w/w, 63% w/w, 64% w/w, 65% w/w, 66% w/w, 67% w/w, 68% w/w, 69% w/w, 70% w/w, 71% w/w, 72% w/w, 73% w/w, 74% w/w, 75% w/w,

76% w/w, 77% w/w, 78% w/w, 79% w/w, 80% w/w, 81% w/w, 82% w/w, 83% w/w, 84% w/w, 85% w/w, 86% w/w, 87% w/w, 88% w/w, 89% w/w, 90% w/w, 91% w/w, 92% w/w, 93% w/w, 94% w/w,

95% w/w, 96% w/w, 97% w/w, 98% w/w, 99% w/w or 100% w/w. In certain embodiments, the amount of fishmeal in the aquatic animal attractant composition is 100% w/w. In certain other embodiments, the amount of fishmeal in the aquatic animal attractant composition is 96% w/w and the composition also comprises 2% w/w betaine and 2% w/w chicken hydrolysate. In certain other embodiments, the amount of fishmeal in the aquatic animal attractant composition is 71% w/w and the composition also comprises 1.5% w/w betaine and 1.5% w/w chicken hydrolysate.

[0057] Optionally, the outer coating 14 further comprises a colouring agent, such as a black colouring agent. Suitable black colouring agents include black colour OPADRY® II. A colouring agent may be used to colour the solid dosage form 10 so that it is a similar colour to the feed used for the aquatic animals. For example, some commercial fish feeds are dark or black in colour and the use of the black colouring agent in the aquatic animal attractant coating then provides a solid dosage form 10 that is not distinguishable in colour from the feed. Also, a black colouring agent may reduce reflections from the solid dosage form 10. The amount of colouring agent in the aquatic animal attractant coating may be from about 0.5% w/w to about 50% w/w, such as about 20% w/w to 30% w/w. In certain embodiments, the aquatic animal attractant composition comprises 71% w/w fishmeal, 1.5% w/w betaine, 1.5% w/w chicken hydrosylate, 26% w/w black colouring agent. [0058] The aquatic animal attractant coating may be formed on the coated or non-coated core element by applying the aquatic animal attractant composition using any suitable method known to the skilled person, such as spray coating, fluidised bed coating, rotor coating or high shear coating. In certain embodiments, the coating is applied by fluidised bed coating.

[0059] A solvent may be used in the preparation of the aquatic animal attractant composition. The solvent may be such that it constitutes a good solvent for the coating material. The solvent may be selected from water, alcohols such as methanol, ethanol, halogenated hydrocarbons such as dichloromethane (methylene chloride), hydrocarbons such as cyclohexane, and mixtures thereof. In certain embodiments, the solvent is a mixture of ethanol and water.

[0060] The core elements may be coated with the aquatic animal attractant composition to weight gains of at least 5%, at least 10% or at least 20%, such as 5%, 6%, 7 %, 8%, 9%, 10%, 11%, 12%, 13%, 14%,

15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In certain embodiments, the core elements are coated with the taste masking coating composition to weight gains of 10% to 20%, such as 10% or 20%.

[0061 ] Preferably, the sedimentation rate of the solid dosage form should be similar to the sedimentation rate of the feed that is used for the aquatic animals being treated.

[0062] The present invention also provides a method of preparing a taste masked ingestible solid dosage form 10 that is suspensible in water at a depth that is suitable for it to be consumed by aquatic animals in the water, the method comprising: forming a taste masked core element 12 containing at least one therapeutically active substance and at least one taste masking substance; and coating the taste masked core element 12 to form an outer coating 14 comprising an aquatic animal attractant.

[0063] In certain embodiments, the taste masked core element 12 is formed by compressing a core element precursor composition comprising the at least one therapeutically active substance and the at least one taste masking substance under conditions to form the core element 12. The core element precursor composition may further comprise one or more excipients. The at least one taste masking substance may be a polymer barrier composition or a lipid barrier composition.

[0064] In certain other embodiments, the taste masked core element 12 is formed by compressing a core element precursor composition comprising the at least one therapeutically active substance and, optionally, one or more excipients to form a non taste -masked core element 12 and then coating the non taste-masked core element 12 with the at least one taste masking substance to form the taste masked core element 12. The non taste-masked core element 12 may be coated with a taste masking coating composition comprising the at least one taste masking substance and solvent and then removing substantially all of the solvent to form a taste masking coating. The solvent may be removed by drying at a process temperature of from approximately 30°C to 50°C, such as 30°C, 31 °C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41 °C, 42°C, 43 °C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C or 50°C.

[0065] The taste masked core element 12 can be coated with an aquatic animal attractant coating composition comprising an animal attractant and a solvent under conditions to form the outer coating 14 comprising an aquatic animal attractant. The aquatic animal attractant coating 14 may comprise fishmeal as the aquatic animal attractant. The aquatic animal attractant coating 14 may further comprise a black colouring agent. The taste masked core element 12 may be coated with an aquatic animal attractant coating composition comprising the aquatic animal attractant and a solvent and then removing substantially all of the solvent to form the aquatic animal attractant coating 14. The solvent may be removed by drying at a process temperature of from approximately 30°C to 50°C, such as 30°C, 31 °C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C,

48°C, 49°C or 50°C.

EXAMPLES

[0066] The present disclosure will now be described with reference to the accompanying examples. It should be understood, however that the following examples are illustrative only and should not be taken in any way as a restriction on the generality of the disclosure as specified above.

[0067] Example 1 - Praziquantel tablet formulation with lipid barrier taste masking

[0068] Praziquantel was incorporated with lipid barriers for taste masking before being formed into a tablet, which was coated with fish attractant.

[0069] Glyceryl distearate (e.g. Precirol® ATO 5) and glyceryl monostearate (e.g. Geleol™ Mono and Diglycerides NF) were used as lipid barrier systems for taste masking and the formulations in Table 1 were prepared. [0070] Table 1: Formulations

[0071] The 10 formulations shown in Table 1 were prepared by the following process:

1. The lipid according to the formulation was weighed and placed it into a glass bottle;

2. The glass bottle containing the formulation was put on a hotplate heated at 85 °C until all of the lipid had melted;

3. The temperature of the hotplate was cooled to 70°C to 75°C;

4. The drug was added to the lipid and mixed thoroughly (for about 30 minutes);

5. The drug/lipid mixture was cooled to room temperature; and

6. The resultant material was ground in a mortar and passed through a 425 pm sieve for tableting.

[0072] A 300 mg tablet was then formulated using the ingredient shown in Table 2. [0073] Table 2: Tablet formulation with the drug in the lipid system

[0074] A tablet having a hardness = 26.5 kgf and a dissolution time (DT) of >10 minutes was then formed in a commercial tablet punch. After 1 minute in a pH 1.2 buffer solution, about 5% of the tablet disintegrated and remained suspended in the buffer solution.

[0075] The sedimentation rate of the tablet in seawater was then tested. 250 ml of seawater was placed into a 250 ml measuring cylinder. The water height was 251 mm. % mm, 6 mm and 9 mm diameter commercial fish feeds were put into the cylinder, respectively. When the feed reached the bottom of the cylinder, the time was recorded as a sedimentation rate. The average sedimentation rate under these conditions for the 9 mm pellet was 3.57 seconds, for the 6 mm pellet it was 7.14 seconds and the for % mm pellet it was 2.86 seconds.

[0076] Example 2 - Praziquantel tablet formulation with taste masking coating

[0077] Praziquantel was mixed with excipients and formed into a tablet, which was coated with a taste masking coating as the first coating layer, then coated with fish attractant as the final layer.

[0078] Tablet (150 ~ 200 mg) formulation development with pure drug powder as shown in Table 3, [0079] Table 3: Tablet formulation development PQ00TP002

[0080] Since the taste masking coating needs 30% weight gain, the tablet PQ00TP002 was designed as

168.25 mg per tablet so that, after coating, it will be about 190 ± 10 mg per tablet.

[0081] Table 4: Sedimentation rate in seawater

[0082] The sedimentation rate in seawater of PQ00TP002 was close to Fish Feed 1 (i.e. extruded, sinking pellets).

[0083] To determine disintegration time (DT), a tablet was put into 10 ml of a pH 1.2 buffer solution at room temperature, the bottle containing the tablet was gently shaken and when the whole tablet disintegrated, that time was recorded. [0084] Table 5: Disintegration time (DT) test of PQ00TP002 in pH 1.2 buffer solution

[0085] According to the above tests, the formulation PQ00TP002 with 190 ± 10 mg per tablet was selected for the further coating process. The coating process was performed with a Caleva mini coater spray dryer for the laboratory.

[0086] Coating formulations consisting of Surelease E-7- 19040 (SE) and Opadry OY-29020 clear (OO) at ratios of 85:15 and 80:20 were prepared by dispersing the Opadry in deionized water and then adding to Surelease to obtain a coating solution. The final solids content in the coating solution was 12% including solids in Surelease and Opadry powder. Surelease contains 25% solids.

[0087] According to the case studies from Colcorcon, 30% weight gain of coating formulation can achieve taste masking and keep immediate release profiles.

[0088] SE and 00 at ratios of 85:15

[0089] Table 6: Taste masking coating formulation CF 1

[0090] Table 7: Parameters for the coating process of taste masking coating

[0091] The batch size of the tablet coating is 20 g (PQ00TP002), therefore, 50 ml above coating formulation (CF 1) can be applied and achieved 30% WG, which is 6 g weight gain of the coating layer.

[0092] Some tablets stuck together during the coating process, therefore, the parameters of the coating process need to be further optimised.

[0093] SE and OO at ratios of 80:20

[0094] According to the evaluation results, 150 mg to 160 mg per tablet of PQ00TP002 could not achieve a good hardness for further process, so PQ00TP003 was designed with 180 mg per tablet. The weight of a 9 mm tablet is usually about 200 mg to 300 mg. When the weight is less than 200 mg, it is a challenge to achieve a tablet with the required hardness.

[0095] Considering 30% weight gain for taste masking coating, 20% weight gain for fish attractant coating. With a 180 mg tablet, after coating, the final tablet weight will be around 230mg to 250 mg. At the current stage, we used 250 mg as the final tablet weight to calculate the dosage which is 150 mg drug in 6 g tablets.

[0096] 6 g / 0.25 g per tablet = 24 tablets

[0097] 150 mg / 24 tablets = 6.25 mg per tablet [0098] Table 8: Tablet formulation development PQ00TP003

[0099] Table 9: Taste masking coating formulation CF 2

[0100] Table 10: Parameters for coating process of taste masking coating

[0101] 20 g tablets of PQ00TP003 were coated with SE: OO = 80:20, 50 ml of above coating formulation (CF 2) can be applied and achieved 30% WG, which is 6 g of weight gain for coating layer. [0102] Polymer barrier system

[0103] Eudragit® E PO is a functional polymer that can mask taste without delaying drug release. It is insoluble in the mouth, but soluble in the stomach. Eudragit® E PO also combines a smooth texture and appearance with a pleasant mouthfeel and improved swallowability. Munster reported solid lipid extrusion combined with Eudragit® E PO and praziquantel achieved a promising taste masking.

[0104] Polymer film-coating

[0105] Praziquantel will be formed into tablets with the required size and drug loading rate, and then coated with Surelease® and Opadry® in a fluid bed dryer.

[0106] For taste masking applications, Surelease and Opadry® work together to create a release profile with a slight delay in the initial release, while maintaining the criteria for an immediate release dosage form. This combination has been proven to provide effective taste masking of marketed products.

[0107] Tablet formulation development

[0108] ¾ mm, 6 mm and 9 mm diameter feeds are used on the farm. 9 mm tablets were formed. For a

1 kg fish, a tablet formulation with 150 mg drug in 6 g of tablets (diameter: 9 mm) was formulated. For a 3 kg fish, a tablet formulation with 450 mg drug in 12 g tablets (diameter: 9 mm) was formulated. We will start with tablets for 1 kg fish, i.e. 20 tablets containing 150 mg drug in 6 g tablets.

[0109] Formulation evaluation

[01 10] The developed product will be evaluated for quality control and performance in vitro, including:

Assay;

Content uniformity;

Tablet weight variation;

Tablet hardness;

• Disintegration time in seawater and a series of buffered systems based on fish stomach conditions;

Tablet friability;

• Dissolution profiles using an appropriate method (no drug will be released in sea water and mouth, but immediately release the drug in the stomach);

Colour, surface and internal texture and overall appearance; • Sedimentation Rate: the tablet’s sedimentation velocity in the seawater needs to be similar to the fish feed;

• Stability test.

[0111] Formulation dissolution test design

[0112] Release profile in seawater. The seawater is collected from the beach, a developed tablet is placed into 25 ml of seawater at room temperature; after 1 minute, 3 minutes and 6 minutes, a 0.5 ml or 1 ml sample is collected and filtered with a 0.45 pm filter, then HPLC is employed for assay.

[0113] Release profile in the stomach (simulated gastric fluid)

[0114] The simulated gastric fluid is prepared with 37% HC1 to achieve pH 1.2 or 1.5. However, different fish have a big difference in pH value in the stomach; values ranging from 0.9 pH to 7.0 pH have been reported (Seyedehsara Masoomi Dezfooli et al., W. Linn Montgomery, Getachew, T).

[0115] Dissolution conditions

[0116] Dissolution medium: buffer systems at different pH values. Volume: 200 ml to 500 ml;

Apparatus: SOTAX dissolution tester with baskets at 100 rpm; Time points: 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours and 4 hours. Temperature: 37°C ± 0.5°C; Sample volume: 1 ml;

Replacement: 1 ml of dissolution medium.

[0117] Example 3 - PQ00TP004 coated with taste masking layer and fish attractant layer

[0118] To prepare 500 tablets, each ingredient in Table 11 was weighed, mixed and sieved through a 250 μm sieve.

[0119] Table 11: Tablet formulation PQ00TP004

[0120] 20 g tablets of PQ00TP004 are coated with SE:OO = 80:20; the below coating formulation can be applied and achieve 40% WG.

[0121] Table 12: Coating formulation for 20 g tablets (Product code: PQ00TP004-CF 2)

[0122] Table 13: Parameters for the coating process of taste masking coating

[0123] 50.180 g Superprime fishmeal (FM) was milled by an electric spice grinder and sieved with a

150 pm sieve, 16.176 g was less than 150 pm which is 32.24% of Superprime fishmeal.

[0124] 20 g of PQ00TP004 coated with taste masking formulation (CF 2), was then used for fish attractant coating.

[0125] Table 14: Fish attractant coating formulation- PQ00TP004-CF2-FA4

[0126] Measure ethanol firstly, then add Opardry and HPMC until they are suspended uniformly; add water until Opardry and HPMC dissolve; add FM and stir the suspension for the coating process. The final coated tablets were very uniform. [0127] Table 15: Parameters for the coating process of fish attractant coating

[0128] Example 4 - Fish attractant (PBC) coating process

[0129] A fish attractant (PBC) formulation containing the following ingredients was used:

Peruvian Fish Meal - 96% (The Peruvian FM is the Superprime FM)

Betaine - 2%

Chicken Hydrolysate - 2%

[0130] Table 16: Fish attractant coating formulation- PQ00TP004-CF2-FA5

[0131] Measure ethanol firstly, then add Opardry and HPMC until they are suspended uniformly; add water until Opadry and HPMC dissolve; add FM, Betaine and chicken hydrolysate; stir the suspension for the coating process. 20 g of PQ00TP004 was firstly coated with taste masking formulation (CF 2), then used for fish attractant (PBC, FA5) coating.

[0132] Table 17: Parameters for the coating process of fish attractant coating

[0133] Example 5 - Dissolution tests for two layers (taste masking and fish attractant) coated tablets

[0134] Release profile in seawater; Seawater was collected from the beach, a coated tablet was placed into 25 ml of seawater; after 6 minutes, a 1 ml sample is collected and filtered with a 0.45 pm filter, then HPLC was employed for assay.

[0135] Dissolution conditions:

• Dissolution medium: seawater

• Volume: 25 ml

• Apparatus: 70 ml container on the bench

• Time points: 6 minutes

• Temperature: 21°C ± 0.5°C, room temperature

• Sample volume: 1 ml

• Replacement: 1 ml of seawater

[0136] Release profile in the stomach (simulated gastric fluid)

[0137] Dissolution conditions

• Dissolution medium: pH 1.5

• Volume: 500 ml

• Apparatus: SOTAX dissolution tester with basket at 100 rpm

• Time points: 1 hour, 2 hours, 3 hours, and 4 hours

• Temperature: 37°C ± 0.5°C

• Sample volume: 1 ml

• Replacement: 1 ml of dissolution medium

[0138] HPLC conditions

[0139] Table 18: The drug release rate with taste masking and fish attractant coating

[0140] Table 19: The drug release rate with taste masking coating

[0141] The results in Tables 18 and 19 demonstrate that the drug was released slower after the second coating layer of the fish attractant formulations. One tested tablet of PQ00TP004-CF2-FA4 showed 7.32% drug released within 6 minutes in seawater that could be the result of the uniformity of the coating process; however, this “failed” tablet did not show a faster release rate after 6 minutes, compared with other tablets. This 7.32% drug might be the contamination of the analysis process.

[0142] Example 6 - In-vivo trials

[0143] Three batches of the tablets (100 of each) listed below were used for fish trials.

[0144] Tablet 1 contained Praziquantel 15 mg per tablet (PQ00TP004-CF2-FA4 with taste masking coating (WG 40%) and Fishmeal Superprime coating (WG 6%).

[0145] Tablet 2 contained Praziquantel 15 mg per tablet (PQ00TP004-CF2-FA4) with taste masking coating (WG 40%) and Fishmeal Superprime coating (WG 10%). The tablet weight was 188.5 mg before coating, about 230 mg after coating.

[0146] Tablet 3 contained Praziquantel 15 mg per tablet (PQ00TP004-CF2-FA5) with taste masking coating (WG 40%) and fish attractant coating (WG 10%) with a combination of Peruvian FM (96%), Betaine (2%), Chicken Hydrolysate (2%). [0147] Fish trials were successful with the above three batches of tablets.

[0148] Example 7 - Coloured tablets

[0149] Following the trials, it was decided to increase the thickness of the tablet, modify the coating colour to match the feed and have a 10% WG for fish attractant layer coating.

[0150] The following tablet formulations were developed:

[0151] Table 20: Tablet formulation development PQ00TP009

[0152] The successfully formed tablet had a weight of 550 mg with 15.975 mg drug per tablet; hardness was 13.45 kgf, DT was 2 minutes in a pH 1.5 buffer solution and thickness was 6 mm.

[0153] 20 g tablets of PQ00TP009 (550 mg/tablet) were then coated with SE:OO = 80:20; the below taste masking coating formulation to achieve 40% WG. [0154] Table 21: Coating formulation for 20 g tablets (Product code: PQ00TP009-CF 2)

[0155] The coating was applied using the following parameters:

[0156] Table 22: Parameters for the coating process of taste masking coating

[0157] The weight of each tablet (PQ00TP009, 550 mg/tablet) after the taste masking coating was 594 mg. The thickness was 7 mm. Sinking time: in the RO water, the distance was 52 cm, the coated tablet took about 3 seconds; the fish feed (9x9 mm) took 4-6 seconds.

[0158] A fish attractant coating containing black colour coating (OPADRY® II (85F57711 BLACK)) was then added.

[0159] Opadry II 85 series is typically used at 20% solids in water. Typical weight gain on tablets is

3%.

[0160] A fish attractant (PBC) formulation containing the following ingredients was used.

[0161] The coating formulation was as follows: [0162] Table 23: Fish attractant coating formulation PQ00TP009-CF2-FA6

[0163] Opadry OY-29020, HPMC K100M, FM, Betaine, and Black colour OPADRY® II were weighed into a container and the container was shaken to mix them. Ethanol was added, followed by adding water under stirring. The Chicken Hydrolysate was then added and the suspension was stirred for 0.5 hour before the coating process, the parameters of which are set out below.

[0164] Table 24: Parameters for the coating process of fish attractant coating

[0165] Tablet weight after the fish attractant coating was 623 mg. The thickness was 7 mm. Sinking time: in the RO water, the distance was 52 cm, the coated tablet needs about 4 seconds; 9x9 mm fish feed needs 4-6 seconds. DT was 22 minutes to 28 minutes. [0166] Example 8 - Coloured tablets

[0167] The following tablet formulations were developed:

[0168] Table 25: Tablet formulation development PQ00TP010

[0169] The formed tablet had a weight of 550 mg, DT was 2 minutes to 3 minutes in a pH 1.2 buffer solution and thickness was 6 mm.

[0170] 20 g tablets of PQ00TP010 are coated with SE:OO = 80:20; the below coating formulation can be applied and achieve 40% WG.

[0171] Table 26: Taste masking coating formulation for 20 g tablets (Product code: PQ00TP010-CF 2)

[0172] The coating was applied using the following parameters:

[0173] Table 27: Parameters for the coating process of taste masking coating

[0174] A fish attractant coating containing black colour coating (OPADRY® II (85F57711 BLACK)) was then added.

[0175] A fish attractant (PBC) formulation containing the following ingredients was used.

• Peruvian Fish Meal (FM) - 96% (The Peruvian FM is the Superprime FM)

• Betaine - 2%

• Chicken Hydrolysate - 2%

[0176] The coating formulation was as follows:

[0177] Table 28: Fish attractant coating formulation PQ00TP010-CF2-FA7

[0178] Opadry OY-29020, HPMC K100M, FM, Betaine, and Black colour OPADRY® II were weighed into a container and the container was shaken to mix them. Ethanol was added, followed by adding water under stirring. The Chicken Hydrolysate was then added and the suspension was stirred for 0.5 hour before the coating process, the parameters of which are set out below.

[0179] Table 29: Parameters for the coating process of fish attractant coating

[0180] Tablet weight after the fish attractant coating was 630 mg to 667 mg. The thickness was 7 mm.

Sinking time: in the RO water, the distance was 52 cm; the coated tablet (667 mg) needs about 3.5 seconds. DT was 30 minutes to 42 minutes.

[0181] A comparison of the fish feed and the developed tablet is shown in Table 30.

[0182] Table 30: Comparison with the fish feed and the developed tablet

[0183] Example 9 - Tablets with a single layer taste masking and attractant coating

[0184] Tablet preparation

[0185] The following tablet formulations were developed: [0186] Table 31: Tablet formulation PQ00TP010

[0187] Tablets were prepared as follows:

1) Praziquantel was sieved with a 250 pm sieve and the powders that passed through the sieve were collected for the tablet preparation;

2) All the excipients listed in Table 31 were weighed, mixed in a container and passed through a 250 pm sieve;

3) 7.75 g of praziquantel was weighed and mixed with about 8 g of the excipients mixture from step 2;

4) The mixture of step 3 was mixed with about 15 g of excipients mixture from step 2;

5) The mixture of step 3 was mixed with about 30 g of excipients mixture from step 2;

6) The process of step 5 was continued with adding 60 g of excipients mixture, 120 g of excipients mixture until all the excipients mixture from step 2 were mixed with praziquantel.

[0188] The final mixture was placed into a plastic container and the container was shaken for 0.5 hour.

The mixture was then pressed in a tablet press to produce 550 mg tablets with 9 mm diameter and 6 mm thickness. [0189] The tablet weights are shown in Table 32.

[0190] Table 32: Tablet weight variation

[0191] Fish attractant (FM) coating process 1

[0192] A fish attractant formulation containing the following ingredients was used.

[0193] The coating formulation was as follows:

[0194] Table 32: Fish attractant coating formulation (Product code: PQ00TP010-FA8)

[0195] Based on the formulation in Table 32, Opadry OY-29020, HPMC K100M, FM, and Black colour OPADRY® II were weighed into a container and the container was shaken to mix them. The required amount of ethanol was measured and added it into the container with the mixture and all the materials were mixed. The required amount of water was measured and added it to the container with the mixture and the suspension was stirred.

[0196] The fish attractant coating solution was stirred during the whole coating process. The coating process parameters are set out below.

[0197] Table 33: Parameters for the coating process of fish attractant coating

[0198] Coated tablet evaluation

[0199] The coated tablet weights are shown in Table 34.

[0200] Table 34: Coated tablet weight

[0201] The thickness of the tablet was 7 cm to 7.5 cm.

[0202] The DT of the coated tablet in water was 3.5 minutes. This DT can be extended using a thicker fish attractant coating.

[0203] The sink time of the coated tablet in seawater was about 3.5 seconds to 4 seconds for 52 cm.

[0204] Fish attractant (FM) coating process 2

[0205] Coating formulation and process

[0206] A second fish attractant formulation containing the following ingredients was used.

[0207] The coating formulation was as follows:

[0208] Table 35: Fish attractant coating formulation (Product code: PQ00TP010-FA9)

[0209] Based on the formulation in Table 35, Opadry OY-29020, HPMC K100M, FM, and Black colour OPADRY® II were weighed into a container and the container was shaken to mix them. The required amount of ethanol was measured and added it into the container with the mixture and all the materials were mixed. The required amount of water was measured and added to the container with the mixture and the suspension was stirred.

[0210] The fish attractant coating solution was stirred during the whole coating process. The coating process parameters are set out below.

[0211] Table 36: Parameters for the coating process of fish attractant coating

[0212] Coated tablet evaluation

[0213] The DT in seawater at room temperature was 8 minutes to 9 minutes.

[0214] The sinking times of the tablets with the single layer coating (Product code: PQ00TP010-FA9) are shown in Table 37.

[0215] Table 37 - Sinking times in RO water

[0216] Conclusion

[0217] Increasing the coating weight gain of the current coating formulation (FA 9) can achieve a longer disintegration time if it is required. [0218] The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement of any form of suggestion that such prior art forms part of the common general knowledge. It will be appreciated by those skilled in the art that the invention is not restricted in its use to the particular application described. Neither is the present invention restricted in its preferred embodiment with regard to the particular elements and/or features described or depicted herein.

[0219] In some cases, a single embodiment may, for succinctness and/or to assist in understanding the scope of the disclosure, combine multiple features. It is to be understood that in such a case, these multiple features may be provided separately (in separate embodiments), or in any other suitable combination. Alternatively, where separate features are described in separate embodiments, these separate features may be combined into a single embodiment unless otherwise stated or implied. This also applies to the claims which can be recombined in any combination. That is a claim may be amended to include a feature defined in any other claim. Further a phrase referring to “at least one of’ a list of items refers to any combination of those items, including single members. As an example, “at least one of: a, b, or c” is intended to cover: a, b, c, a-b, a-c, b-c, and a-b-c

[0220] It will be appreciated that the invention is not limited to the embodiment or embodiments disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the scope of the invention as set forth and defined by the following claims.

[0221] Throughout the specification and the claims that follow, unless the context requires otherwise, the words “comprise” and “include” and variations such as “comprising” and “including” will be understood to imply the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers.

REFERENCES

[0222] Buchmann K (1987) The effects of praziquantel on the monogenean gill parasite Pseudodactylogyrus bini. Acta Vet Scand 28: 447-450.

[0223] Getachew, T., Stomach pH, feeding rhythm and ingestion rate in Oreochromis niloticus L. (Pisces: Cichlidae) in Lake Awasa, Ethiopia. Hydrobiologia, 1989. 174(43-48).

[0224] Hirazawa N, Mitsuboshi T, Hirata T, Shirasu K (2004) Susceptibility of spotted halibut Verasper variegatus (Pleuronectidae) to infection by the monogenean Neobenedenia girellae (Capsalidae) and oral therapy trials using praziquantel. Aquaculture 238: 83-95.

[0225] Manjeet B.Pimparade, et al., Development of taste masked caffeine citrate formulations utilizing hot melt extrusion technology and in vitro invivo evaluations. International Journal of Pharmaceutics, 2015. 487 p. 167-176.

[0226] Meyer T, Sekljic H, Fuchs S, Bothe H, Schollmeyer D, Miculka C (2009) Taste, a new incentive to switch to (R)-praziquantel in schistosomiasis treatment. PLoS Negl Trop Dis 3: e357.

[0227] Munster, M., et al., Multiparticulate system combining taste masking and immediate release properties for the aversive compound praziquantel. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2017. 109: p. 446-454.

[0228] Santamarina MT, Tojo J, Ubeira FM, Quinteiro P, Sanmartin ML (1991) Anthelmintic treatment against Gyrodactylus sp. infecting rainbow trout Oncorhynchus mykiss. Dis Aquat Org 10: 39-43.

[0229] Schmahl G, Mehlhorn H (1985) Treatment of fish parasites. I. Praziquantel effective against Monogenea (Dactylogyrus vastator, Dactylogyrus extensus, Diplozoon paradoxum).Z Parasitenkd 71 : 727-737.

[0230] Schmahl G, Taraschewski H (1987) Treatment of fish parasites. II. Effects of Praziquantel, Niclosamide, Levamisole-HCl, and Metrifonate on Monogenea (Gyrodactylus aculeati, Diplozoon paradoxum). Parasitol Res 73: 341-351.

[0231] Seyedehsara Masoomi Dezfooli, N.G.-M., Andrea Alfaro, Ali Seyfoddin, Encapsulation for delivering bioactives in aquaculture. Reviews in Aquaculture, 2018: p. 1-30. [0232] Thoney DA (1990) The effects of trichlorfon, praziquantel and copper sulphate on various stages of the Monogenean Benedeniella posterocolpa, a skin parasite of the cownose ray, Rhinoptera bonasus (Mitchill). J Fish Dis 13: 385-389.

[0233] Williams RE, Ernst I, Chambers CB, Whittington ID (2007) Efficacy of orally administered praziquantel against Zeuxapta seriolae and Benedenia seriolae (Monogenea) in yellowtail kingfish Seriola lalandi. Dis Aquat Org 77: 199-205.

[0234] W. Linn Montgomery, P.E.P., Gut anatomy and pH in a Red Sea surgeonfish, Acanth urus nigrofuscus. Marine ecology, 1988. 4: p. 7-13.

Claims

1. A taste masked ingestible solid dosage form that is suspensible in water, the solid dosage form comprising: a core element containing at least one therapeutically active substance; at least one taste masking substance; and an outer coating comprising an aquatic animal attractant.

2. The solid dosage form of claim 1 , wherein the therapeutically active substance is praziquantel or an antiparasitic derivative thereof.

3. The solid dosage form of claim 2, wherein the amount of praziquantel in the core element is from about 6 mg to about 20 mg.

4. The solid dosage form of any one of claims 1 to 3, wherein the taste masking substance is incorporated within the core element.

5. The solid dosage form of claim 4, wherein the taste masking substance is a lipid based formulation.

6. The solid dosage form of claim 5, wherein the lipid based formulation comprises a taste masking substance selected from the group consisting of glyceryl distearate and glyceryl monostearate, or a mixture of each.

7. The solid dosage form of claim 4, wherein the taste masking substance is a polymer based formulation.

8. The solid dosage form of claim 7, wherein the lipid based formulation comprises a taste masking substance is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.

9. The solid dosage form of any one of claims 1 to 3, wherein the taste masking substance is coated on the core element.

10. The solid dosage form of claim 9, wherein the taste masking substance is in the outer coating.

11. The solid dosage form of any one of claims 9 to 10, wherein the taste masking substance is an alkylcellulose.

12. The solid dosage form of claim 11, wherein the taste masking substance is ethylcellulose.

13. The solid dosage form of any one of claims 11 to 12, wherein the taste masking substance further comprises hydroxypropylmethylcellulose.

14. The solid dosage form of any one of claims 12 to 13, wherein the ethyl cellulose and hydroxypropylmethylcellulose are present in the coating composition at a ratio of from about 95:5 to about 70:30.

15. The solid dosage form of any one of claims 9 to 14, wherein the core elements are coated with the taste masking coating composition to weight gains of 30% to 40%.

16. The solid dosage form of any one of claims 1 to 15, wherein the aquatic animal attractant comprises fishmeal.

17. The solid dosage form of claim 16, wherein the aquatic animal attractant further comprises betaine and chicken hydrolysate.

18. The solid dosage form of any one of claims 1 to 17, wherein the outer coating further comprises a colouring agent.

19. The solid dosage form of claim 18, wherein the colouring agent is black colour OPADRY® II.

20. A method for treating or preventing parasite infection in aquatic animals, the method comprising adding the taste masked ingestible solid dosage form of any one of claims 2 to 19 to a water body that contains the aquatic animals such that the taste masked ingestible solid dosage form is suspended in water at a depth that is suitable for it to be consumed by the aquatic animals to be treated.

21. A method of preparing a taste masked ingestible solid dosage form that is suspensible in water at a depth that is suitable for it to be consumed by aquatic animals in the water, the method comprising: forming a core element containing at least one therapeutically active substance and at least one taste masking substance; and coating the core element to form an outer coating comprising an aquatic animal attractant.

22. A method of preparing a taste masked ingestible solid dosage form that is suspensible in water at a depth that is suitable for it to be consumed by aquatic animals in the water, the method comprising: forming a core element containing at least one therapeutically active substance; and coating the core element to form an outer coating comprising at least one taste masking substance and an aquatic animal attractant.