AU2007100254A4 - Improved parasiticide paste - Google Patents

Description

AUSTRALIA

Patents Act 1990 Jurox Pty Ltd COMPLETE SPECIFICATION INNOVATION PATENT Invention Title.

Improved parasiticide paste The following statement is a full description of this invention including the best method of performing it known to us:- Improved Parasiticide Paste Technical Field The present invention relates to an improved oral paste formulation for the treatment of parasites in animals. In particular it relates to a highly concentrated oral paste formulation for the treatment of internal parasites in animals.

Background Art Macrolide anthelmintic compounds are known in the art for treating endo- and ecto-parasite infections in warm-blooded animals. Compounds that are included in this class of compounds include the avermectins and milbemycin series of compounds.

These compounds are potent antiparasitic agents effective against a wide range of internal and external parasites. In addition to treating parasitic insects such as flies, they are used to treat endoparasites such as round worm infections. Their popularity has increased due to their dual activity and because of the increasing resistance to other traditional anthelmintics such as levamisole. A disadvantage of the macrolide anthelmintics is the fact that in their solid form they are poorly absorbed by the animal.

To be bio-available, therefore, they need to be administered as a solution. It is therefore customary practice to formulate these compounds by dissolving them in a solvent before administration.

Avermectins and milbemyins are, however, ineffective against cestodes, such as tape worm, which are also common parasites in warm blooded animals. A compound that is often used to treat cestode and trematode infections is praziquantel. Praziquantel is known to have a very bitter taste making it generally unpalatable in high concentrations. Accordingly, in the past praziquantel has been used in oral formulations in low concentrations so as to be more palatable. The disadvantage of a low concentration formulation is that a greater volume dose is required.

It is known in the art to administer formulations which contain a combination of two or more anthelmintics, which possess different activity, in order to obtain a composition with a broad spectrum of activity. These formulations may be in the form of solutions, suspensions, pastes, oral drenches or pour-on formulations.

The present inventors have noted that there are few oral paste or gel formulations containing a combination of two or more anthelmetics on the market for treating internal parasites and that the formulations that are available have one or more of the following disadvantages: a low active ingredient:excipient ingredient ratio making the formulation difficult to administer due to the large volume of the formulation required to deliver the required dose; unpalatability due to too high a FBR Ref 132100 3 concentration of an unpalatable active such as praziquantel; instability, for example arising from the inability of a formulation to tolerate extreme temperatures, thereby resulting in the formulation solidifying, separating or becoming too runny.

There is clearly a need for an improved oral paste formulation for treating internal parasites in warm blooded animals.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Disclosure of the Invention The present inventors have found an improved oral paste formulation for treating parasites, comprising a high concentration of the active praziquantel and one or more macrocyclic lactones and a specific combination of excipients, that is easy to use, stable and palatable.

In a first aspect, the present invention is directed to a stable oral paste formulation for treating parasites, the formulation comprising: a) about 10 35% w/w praziquantel; b) about 0.5 5.0% w/w of one or more macrocyclic lactones; c) about 1 8% w/w of one or more solubilising agents for solubilising the one or macrocyclic lactones; d) about 1 10% w/w of one or more surfactants; e) about 10 50% w/w of one or more saccharides; and f) optionally about 2-15% w/w/ of one or more humectants.

In a second aspect, the present invention is directed to a stable oral paste formulation for treating parasites, the formulation consisting essentially of: a) about 10 35% w/w praziquantel; b) about 0.5 5.0% w/w of one or more macrocyclic lactones; c) about 1 8% w/w of one or more solubilising agents for solubilising the one or macrocyclic lactones; d) about 1 10% w/w of one or more surfactants; e) about 10 50% w/w of one or more saccharides; and f) optionally about 2-15% w/w/ of one or more humectants; In a third aspect, the present invention is directed to a method of controlling and/or treating an infestation of parasites in an animal, comprising orally administering FBR Ref 132100 to the animal an effective amount of the stable oral paste formulation for treating parasites according to the first or second aspect of the invention.

In a fourth aspect, there is provided a method for preparing a stable oral paste formulation according to the first or second aspect of the invention, the method comprising the steps of: a) dissolving the one or more macrocyclic lactones in the one or more solubilising agents; b) optionally combining the one or more humectants with the one or more macrocyclic lactones before or after step a); c) combining the one or more surfactants with the one or more macrocyclic lactones before or after step a) and/or before or after step b); d) combining the praziquantel with the one or more macrocyclic lactones before or after step a) and/or before or after step b) and/or before or after step c); e) combining the one or more saccharides with the praziquantel before or after step d); f) mixing the one or more macrocyclic lactones, one or more solubilising agents, one or more humectants, one or more surfactants, praziquantel and one or more saccharides until a uniform paste forms.

The oral paste formulation of the present invention contains at least the two active ingredients praziquantel and (ii) one or more macrocyclic lactones and excipients in the form of one or more solubilising agents, one or more surfactants one or more saccharides and optionally one or more humectants, such that the ratio of active:excipient is high. The high concentration of the actives allows a lower volume dose to be administered to the animal being treated. Administration of a low dose volume of formulation to an animal is regarded as being more desirable and much quicker and easier to use than having to administer to an animal a higher dose volume of a formulation having a lower concentration of praziquantel. Accordingly, due to the low dose volume of the paste formulation of the present invention required to deliver a specified dose of praziquantel and one or more macrocyclic lactones to the animal, the formulation of the present invention provides the user with the advantage that they will no longer be required to carry a large bulky quantity of product when a large amount of treatment is required.

The present inventors have surprisingly found that the oral paste formulation of the present invention is palatable despite the high concentration of praziquantel, and have attributed this to the unique combination of actives and excipients in the formulation. Further, the present inventors have surprisingly found that unlike other FBR Ref 132100 prior art oral paste formulations, the oral paste formulation of the present invention does not require traditional thickeners (such as, Veegum, cellulose polymers, gelatin, polyacrylic acids and the like) to achieve a paste-like consistency nor does it require anti-oxidants in order to exhibit stability. The present inventors have found that the oral formulation of the present invention is surprisingly stable upon storage in extreme temperature ranges from hot through to cold. Unlike prior art paste formulations that contain praziquantel, the paste formulation of the present invention does not solidify, separate or thin upon storage in a range of temperatures.

The formulation of the present invention comprises about 10 35% w/w praziquantel. Preferably, the composition comprises about 20-35%w/w praziquantel, more preferably about 20-30%w/w.

The one or more macrocyclic lactones may be selected from one or more of the avermectins, such as abamectin, ivermectin, doremectin, selamectin, emamectin and eprinomectin and/or one or more of the milbemycins such as moxidectin. The preferred macrocyclic lactones are abamectin and ivermectin. The most preferred is ivermectin.

The one or more macrocyclic lactones are included in the formulation in an amount of about 0.5 5.0% w/w. Preferably, the concentration used is in the range of about 1.5 5.0% w/w, more preferably about 1.5 2.5% w/w.

As the macrocyclic lactones are pH sensitive the composition is at a pH of below 7.

The preferred ratio of praziquantel to the one or more macrocyclic lactones in the oral paste composition of the present invention is preferably about 1:20, more preferably about 1:12.

The one or more solubilising agents may be any agent capable of solubilising the one or more macrocyclic lactones. Preferably, the one or more solubilising agents is selected from one or more of the following: an alkyl alcohol, more preferably a C2- C8 alkyl alcohol; a phenyl-substituted alkyl alcohol, more preferably a phenylsubstitued C1-C8 alkyl alcohol; a cyclic ether, preferably a 5- or 6- membered cyclic ether, substituted with an alkyl ether alcohol, an alkyl alcohol or an alcohol group; an alkyl substituted pyrrolidone. Even more preferably the one or more solubilising agent is selected from one or more of the following: benzyl alcohol, glycerol formal, tetraglycol, N-methyl pyrrolidone (NMP) and mixtures thereof. Most preferably, the solubilising agent is benzyl alcohol.

FBR Ref 132100 6 The one or more solubilising agents are included in the formulation in an i amount of about 1 8% w/w. Preferably, the concentration is in the range of about 2 6 w/w, more preferably about 2-3 %w/w.

C One or more surfactants are included in the composition of the invention. The surfactant may be selected from non-ionic, anionic, cationic or amphoteric. Preferably a non-ionic surfactant is used. Non-ionic surfactants may be selected from the group NI consisting of C8-C10 alkylphenol ethoxylates, C9-C17 alcohol ethoxylates, C8-C20 alkyl amine ethoxylates, castor oil ethoxylates, lanolin alcohol ethoxylates, sorbitan fatty acid ester ethoxylates, sorbitan fatty acid esters and mixtures thereof.

The C8-C10 alkylphenol ethoxylates preferably contain from 2 to 100 moles of CN ethylene oxide and may be selected from but not limited to the commercially available products identified as Teric N9, Teric N20 and Teric N100. The C9-C17 alcohol ethoxylates preferably contain from 2 to 25 moles of ethylene oxide and may be selected from but not limited to the commercially available products identified as Teric 9A2 and Teric 16A16. The C8-C20 alkyl amine ethoxylates preferably contain from to 20 moles of ethylene oxide and may be selected from but not limited to the commercially available products identified as Teric 13M15 and Teric 18M20. The castor oil ethoxylates preferably contain from 5 to 60 moles of ethylene oxide and may be selected from but not limited to the commercially available products identified as Cremophor EL, Acconon CA-5 and Teric 380. The lanolin alcohol ethoxylates preferably contain from 5 to 40 moles of ethylene oxide and may be selected form but not limited to the commercially available products identified as Polycol 5 and Polycol The sorbitan fatty acid ester ethoxylates preferably contain 4 to 20 moles of ethylene oxide and may be selected from but not limited to Polysorbate 20, Polysorbate 60 and Polysorbate 80. The sorbitan fatty acid esters preferably have a chain length of C18-C60 and more preferably have an HLB of 2-9 and may be selected from but not limited to sorbitan monoisostearate, sorbitan monostearate, Hodag SML and Span The one or more surfactants are included in the composition in an amount of about 1.0 10%w/w. Preferably, the concentration used is in the range of about 5.0 8%w/w, most preferably about 4%w/w.

One or more saccharides are included in the formulation of the present invention and are preferably selected from glucose, sucrose, fructose (such as high fructose corn syrup), dextrose, mannitol, sorbitol and mixtures thereof. Preferably, the one or more saccharides is in aqueous solution. Preferably, the one or more saccharides is a concentrated glucose solution, preferably a glucose solution (more preferably a aqueous solution), a concentrated sucrose solution (more preferably 75% aqueous FBR Ref 132100 solution) and/or a sorbitol solution such as Sorbitol 70%. Throughout the specification, reference to the term "syrup" may be used to refer to a concentrated saccharide solution, such as a highly concentrated glucose or sucrose solution containing about water or a sorbitol solution, such as Sorbitol The one or more saccharides are included in the formulation in an amount of from about 10 50% w/w, preferably 20-30%w/w.

Optionally, one or more humectants may be used in the formulation of the invention. The one or more humectants may be selected from any humectant known in the art. Preferably, the humectant is a liquid selected from the group consisting of propylene glycol, glycerine, polyethylene glycols and mixtures thereof. Most preferably, the humectant is propylene glycol. The one or more humectants may be present in the composition in an amount of about 2-15% w/w, preferably about 5-10% w/w.

The formulation of the invention may additionally comprise one or more preservatives, flavours, sweetener aids and colouring agents that are commonly used in the art.

The one or more preservatives may be selected from known preservatives in the art, including but not limited to parabens, phenols, sorbic acid and its salts, quaternary ammonium compounds, benzoic acid and its salts and benzyl alcohol. Preferably the one or more preservatives includes benzyl alcohol. It will be appreciated that the one or more preservatives, such as benzyl alcohol, may have multiple functions, such as functioning as a solubilising agent and as a preservative.

The one or more preservatives may be included in the formulation in an amount of about 0.1 w/w 5.0% w/w, more preferably 1.5 2.5% w/w.

In a preferred embodiment according to the first aspect of the invention there is provided a stable oral paste formulation for treating parasites, the formulation comprising: a) about 20 35% w/w praziquantel; b) about 1.5 5.0% w/w of one or more macrocyclic lactones selected from the group consisting of abamectin, ivermectin, doremectin, selamectin, emamectin, eprinomectin and moxidectin and mixtures thereof; c) about 2 6% w/w of one or more solubilising agents selected from the group consisting of benzyl alcohol, glycerol formal, tetraglycol, N-methyl pyrrolidone (NMP) and mixtures thereof; d) about 5 8% w/w of one or more anionic surfactants selected from the group consisting of castor oil ethoxylates, lanolin alcohol ethoxylates, sorbitan fatty acid ester FBR Ref 132100 8 ethoxylates containing from 4 to 20 moles of ethylene oxide and C8-C10 alkylphenol ethoxylates containing from 2 to 100 moles of ethylene oxide and mixtures thereof; e) about 20 30% w/w of one or more saccharides selected from the group consisting of concentrated glucose solutions (more preferably a 75 aqueous solution), sucrose solutions and sorbitol solutions and mixtures thereof; f) optionally about 5-10% w/w of one or more humectants selected from the group consisting of propylene glycol, glycerine, polyethylene glycols and mixtures thereof.

In a preferred embodiment according to the second aspect of the invention there 0 10 is provided a stable oral paste formulation for treating parasites, the formulation CN consisting essentially of: a) about 20 35% w/w praziquantel; b) about 1.5 5.0% w/w of one or more macrocyclic lactones selected from the group consisting of abamectin, ivermectin, doremectin, selamectin, emamectin, eprinomectin and moxidectin and mixtures thereof; c) about 2 6% w/w of one or more solubilising agents selected from the group consisting of benzyl alcohol, glycerol formal, tetraglycol, N-methyl pyrrolidone (NMP) and mixtures thereof; d) about 5 8% w/w of one or more anionic surfactants selected from the group consisting of castor oil ethoxylates, lanolin alcohol ethoxylates, sorbitan fatty acid ester ethoxylates containing from 4 to 20 moles of ethylene oxide and C8-C10 alkylphenol ethoxylates containing from 2 to 100 moles of ethylene oxide and mixtures thereof; e) about 20 30% w/w of one or more saccharides selected from the group consisting of glucose solutions (preferably 75% aqueous solution), sucrose solutions and sorbitol solutions and mixtures thereof; f) optionally about 5-10% w/w of one or more humectants selected from the group consisting of propylene glycol, glycerine, polyethylene glycols and mixtures thereof.

In a preferred embodiment according to the fourth aspect of the invention, there is provided a method for preparing a stable oral paste formulation according to the first or second aspect of the invention, the method comprising the steps of: a) dissolving the one or more macrocyclic lactones in a mixture of the one or more solubilising agents, the one or more surfactants and optionally the one or more humectants; b) combining a) with a mixture of praziquantel and the one or more saccharides; c) mixing to form a uniform paste.

FBR Ref 132100 The present inventors have surprisingly found that the composition of the invention does not require the presence of an antioxidant. Prior art composition require the inclusion of an antioxidant to prevent the oxidation and therefore degradation of compounds such as macrocyclic lactones. Without being bound by theory, the present inventors believe that an antioxidant may be unnecessary in the composition of the present invention due to the presence of the saccharide. They believe that the saccharide has a high affinity for the macrocyclic lactone, making the macrocyclic lactone less available to water and therefore less likely to degrade. Further, the present inventors have surprisingly found that the formulation of the present invention does not require the presence of structural thickeners to form a paste as is required in the prior art formulations. Without being bound by theory, the present inventors believe that the paste structure is built only on the unique combination of actives and excipients.

The composition of the present invention is used orally to treat an animal with a parasite infection and/or act as a prophylactic in an animal with a parasite infection, preferably an internal parasite infection. The paste formulation may be administered in any way that gets the required dose of actives into the animals mouth. Usually, it is convenient to squeeze the paste directly into the animals mouth.

Whilst compositions made according to the invention will find the greatest application in treating horses, they are also useful in treating parasite infestations in sheep, cattle, deer, buffalo and goats.

Throughout this specification the word "consisting essentially of' or variations thereof will be understood to be open-ended but to exclude elements or ingredients that would materially affect the properties/characteristics of the invention described and claimed herein.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

With regard to the method of treating parasites according to the third aspect of the invention, it will be understood that an "effective amount of the formulation for treating parasites" means that the amount of the formulation that is orally administered to the animal must be effective in treating, by way of killing the parasites and resulting in expulsion of the parasite from the animal. The present inventors have found that "an effective amount of the formulation for treating the parasites" may be achieved using a dose calculated on the weight of the animal. Preferably, about 5.4 mg of one or more FBR Ref 132100 macrocyclic lactone and about 250 mg of praziquantel is administered per 100 kg of animal.

As used herein the term "stable" means chemical stability of the active ingredients, praziquantel and the one or more macrocyclic lactones, and physical stability of the formulation over at least a 3 month period, preferably 6 months, when stored at about 30°C/60% relative humidity. By "chemical stability", it is intended to mean that the concentration of the active ingredients, praziquantel and the one or more macrocyclic lactones, remains within about ±10%w/w of the stated concentration of the active ingredients and that the pH of the composition remains below pH 7. By "physical stability", it is intended to mean that the appearance of the formulation is paste-like and the viscosity of the formulation is consistent with that of a paste.

The availability of ingredients is shown in the below Tables.

Table 1- Availability of active ingredients Ingredient Available from Praziquantel Pacific Resource Abamectin Pacific Resource Ivermectin, Pacific Resource Doremectin, Husan Selamectin Husan Emamectin Husan Eprinomectin Husan Moxidectin Husan Table 2 Availability of preferred solubilising agents Ingredient Available from benzyl alcohol Tiger Chemicals glycerol formal Shanghai Chemicals tetraglycol Shanghai Chemicals N-methyl pyrrolidone (NMP) Shanghai Chemicals FBR Ref 132100 Table 3 Availability of preferred surfactants Ingredient Available from Teric N9, Teric N20, Teric N100, Teric 9A2, Teric 16A16, Teric 13M15, Teric 18M20 and Teric 380 ICI Cremophor EL BASF Corporation Acconon CA-5 Karlshamns USA Inc Polycol 5 and Polycol 40 CRODA Polysorbate 20 (trade name Tween Polysorbate 60 (trade name Tween 60) and Polysorbate 80 (trade name Tween 80) ICI Hodag SML Calgene Span 25. ICI Table 4 Availability of preferred saccharides Ingredient Available from aqueous glucose solution Pacific Resource aqueous sucrose solution Pacific Resource Sorbitol 70% Pacific Resource Table 5 Availability of preferred humectants Ingredient Available from propylene glycol Pacific Resource glycerine Pacific Resource polyethylene glycol Pacific Resource FBR Ref 132100 Modes for Carrying out the Invention In order to better understand the nature of this invention, a number of examples will now be described.

Example 1: Ingredient: Quantity: Supplier: Praziquantel 625g Pacific Resource Ivermectin 52g Pacific Resource Benzyl alcohol 80g Tiger Chemicals Polysorbate 80 100g Tiger Chemicals Glucose syrup To 2500g Pacific Resource Example 2: Ingredient: Quantity: Supplier: Praziquantel 625g Pacific Resource Ivermectin 52g Pacific Resource Benzyl alcohol 70g Tiger Chemicals Polysorbate 80 100g Tiger Chemicals Sorbitol 70% To 2500g Pacific Resource 0 In Examples 1 and 2, the compositions were prepared by dissolving the ivermectin in a mixture of benzyl alcohol and Polysorbate 80, combining the mixture with praziquantel and glucose syrup or Sorbitol 70% followed by high speed mixing until a uniform paste has formed.

FBR Ref 132100 Example 3: Ingredient: Quantity: Supplier: Praziquantel 625g Pacific Resource Ivermectin 52g Pacific Resource Benzyl alcohol 70g Tiger Chemicals Polysorbate 80 100g Tiger Chemicals Sorbitol 70% 1000g Pacific Resource Propylene glycol 150g Pacific Resource Glucose syrup To 2500g Pacific Resource In Example 3, the composition was prepared by dissolving the ivermectin in a mixture of benzyl alcohol, propylene glycol and Polysorbate 80, combining the mixture with praziquantel, glucose syrup and Sorbitol 70% followed by high speed mixing until a uniform paste has formed.

Stability Studies A formulation according to Example 1 was subject to stability studies. A sample of the formulation according to Example 1 was kept at a) 30 0 C/60% relative humidity (RH) and b) 40°C/60% RH for 6 months. The appearance of the formulation, the content of actives and viscosity was assessed every 3 months for the oral paste formulation of the present invention. Table 6 shows the results from the stability study at 30oC/60 RH and Table 7 shows the stability study at 40 0 C/60% RH.

Table 6: Time: Parameter: Initial 3 Months 6 Months Appearance: White paste White paste White paste Active Content Assay: Praziquantel 23.10 24.65 23.90 Ivermectin 1.79 1.81 1.84 Viscosity 87500 89500 89500 FBR Ref 132100 Table 7: Time: Parameter: Initial 3 Months 6 Months Appearance: White paste White paste White paste Active Content Assay: Praziquantel 23.10 23.92 23.29 Ivermectin 1.79 1.73 1.72 Viscosity 87500 93600 90500 It can be seen that the formulation according to Example 1 was stable for the 6 month period in relation to appearance, the active content and viscosity at both 30°C/60% RH and 40°C/60% RH. More specifically, for the 6 month period the formulation of the invention maintained its appearance as a white paste and the viscosity of a paste. Further, the concentration of the actives, praziquantel and ivermectin, was constant over the 6 month period.

0 The steps, features, integers, compositions and/or compounds disclosed herein or indicated in the specification of this application individually or collectively, and any and all combinations of two or more of said steps or features.

FBR Ref 132100

Claims (4)

1. A stable oral paste formulation for treating parasites comprising: a) about 10 35% w/w praziquantel; b) about 0.5 5.0% w/w of one or more macrocyclic lactones; c) about 1 8% w/w of one or more solubilising agents for solubilising the one or more macrocyclic lactones; d) about 1 10% w/w of one or more surfactants; e) about 10 50% w/w of one or more saccharides; and f) optionally about 2-15% w/w/ of one or more humectants.

2. The stable oral paste formulation according to claim 1 comprising: a) about 20 35% w/w praziquantel; b) about 1.5 5.0% w/w of one or more macrocyclic lactones; c) about 2 6% w/w of one or more solubilising agents for solubilising the one or more macrocyclic lactones; d) about 5 8% w/w of one or more surfactants; e) about 20 30% w/w of one or more saccharides; and f) optionally about 5-10% w/w/ of one or more humectants.

3. The oral paste formulation according to claim 1 or 2 wherein the: b) one or more macrocyclic lactones is selected from the group consisting of abamectin, ivermectin, doremectin, selamectin, emamectin, eprinomectin and moxidectin and mixtures thereof; c) one or more solubilising agents is selected from the group consisting of C2- C8 alkyl alcohol; phenyl-substituted C1-C8 alkyl alcohol; 5- or 6- membered cyclic ether substituted with an alkyl ether alcohol, an alkyl alcohol or an alcohol group; an alkyl substituted pyrrolidone; and mixtures thereof; d) one or more surfactants is selected from the group consisting of castor oil ethoxylates; lanolin alcohol ethoxylates; sorbitan fatty acid ester ethoxylates containing from 4 to 20 moles of ethylene oxide; C8-C10 alkylphenol ethoxylates containing from 2 to 100 moles of ethylene oxide and mixtures thereof; e) one or more saccharides is selected from the group consisting of aqueous glucose solution; aqueous sucrose solution; aqueous sorbitol solution and mixtures thereof; f) one or more humectants is selected from the group consisting of propylene glycol, glycerine, polyethylene glycols and mixtures thereof.

4. A stable oral paste formulation for treating parasites consisting essentially of: a) about 20 35% w/w praziquantel; FBR Ref 132100 b) about 1.5 5.0% w/w of one or more macrocyclic lactones selected from the group consisting of abamectin, ivermectin, doremectin, selamectin, emamectin, eprinomectin and moxidectin and mixtures thereof; c) about 2 6% w/w of one or more solubilising agents selected from the group consisting of C2-C8 alkyl alcohol; phenyl-substituted C1-C8 alkyl alcohol; 5- or 6- membered cyclic ether substituted with an alkyl ether alcohol, an alkyl alcohol or an alcohol group; an alkyl substituted pyrrolidone; and mixtures thereof; d) about 5 8% w/w of one or more anionic surfactants selected from the group consisting of castor oil ethoxylates, lanolin alcohol ethoxylates, sorbitan fatty acid ester ethoxylates containing from 4 to 20 moles of ethylene oxide and C8-C10 alkylphenol ethoxylates containing from 2 to 100 moles of ethylene oxide; e) about 20 30% w/w of one or more saccharides selected from the group consisting of aqueous glucose solution, aqueous sucrose solution, aqueous sorbitol solution and mixtures thereof; f) optionally about 5-10% w/w of one or more humectants selected from the group consisting of propylene glycol, glycerine, polyethylene glycols and mixtures thereof. The stable oral paste formulation according to any one of claims 1-4 wherein the c) one or more solubilising agents is selected from the group consisting of benzyl alcohol, glycerol formal, tetraglycol, N-methyl pyrrolidone (NMP) and mixtures thereof. Dated this 29th day of March 2007 Jurox Pty Ltd Patent Attorneys for the Applicant: F B RICE CO FBR Ref 132100