NZ329247A - Anthelmintic compositions containing solubilised benzimidazoles such as oxfendazole and a carrier including a pyrrolidone - Google Patents

Abstract

The clear composition contains at least one benzimidazole in solubilised form in a pharmacologically acceptable carrier system including a pyrrolidine such as N-methyl-pyrrolidone or N-octyl-pyrrolidone useful as an anthelmintic. The solubilised form is where the benzimidazole is maintained in a true solution or micellar arrangement.

Description

1 PATENTS FORM NO. 5 Fee No. 4: $260.00 PATENTS ACT 1953 COMPLETE SPECIFICATION After Provisional No: 329247 Dated: 20 November 1997 JamflB & Wells Ref: 13835/4 LW IMPROVEMENTS IN AND RELATING TO ANTHELMINTIC COMPOSITIONS I/WE Bomac Laboratories Limited, a New Zealand company of Cnr.

Wiri Station Road and Hobill Avenue, Manukau City, Auckland, New Zealand hereby declare the invention for which I/We pray that a patent may be granted to me/us, and the method by which it is to be performed to be particularly described in and by the following statement: 2 RELATING TO ANTHELMINTIC Technical Field The present invention is directed to compositions incorporating 5 solubilised benzimidazoles. These compositions are typically used as anthelmintics for veterinary applications.

BACKGROUND ART The group of compounds known as benzimidazoles are commonly used as anthelmintics in predominantly veterinary applications. Their use 10 has been summarised in earlier NZ patent application No. 260018 by the applicants, while the class of compound is described in: The Synthesis and Chemistry of Certain Anthelmintic Benzimidazoles (1990), L. B. Townsend and D. S. Wise, Parasitology Today 6(4):107-112; The Metabolism of Benzimidazole Anthelmintics (1990), D. W. Gottschall, V. J. Theodorides, and R. Wang, Parasitology Today 6(4): 115-124; Anthelmintics - A Review (1984), T. Barragiy, NZ Vet J 32:161-164.

While the effectiveness of benzimidazoles are known, they are 20 extremely insoluble in water which severely limits their administration - parenteral rates of administration, other than by mouth, are generally precluded. This represents a significant problem as pour-on drenches, relying on transdermal migration of the active component, represent one of the most common methods of 25 administration to cattle.

IMPROVEMENTS IN & COMPOSITIONS 3 The prior art has accepted the insoluble nature of benzimidazoles per se, and has reacted by attempting to formulate workable compositions, with a useful shelf-life, in which the active benzimidazole component is present in a finely suspended form. These form a group of drenches commonly referred to as the Vhite drench' family, and are typically administered orally - a less user-friendly method of administration with farmers.

Each of NZ patent specification No. 186378, Australian patent specification No. 10277/92, and United Kingdom patent specification 10 Nos. 1,527,584 and 1,498,816 describe compositions in which benzimidazoles are present in a finely suspended form - the typical fluid media comprising oils, emulsifiers, and solvents used in the preparation of the composition.

The applicants invention of NZ patent specification No. 260018 is a 16 more recent development of the invention, comprising an effective transdermal composition with included benzimidazole (preferably oxfendazole) suspended in a transdermal vehicle.

However despite such workable benzimidazole suspensions being available, there are a number of inherent disadvantages. For instance, 20 a primary problem with suspended systems is maintaining the components in a homogenous suspension for useful periods of time. This can even affect the manufacturing phase, introducing difficulties in ensuring that a homogenous product is packaged. This necessitates costly equipment and exhaustive control systems.

These problems extend through to use of the product, with equal care and preparation being required by the user to ensure the correct dose is administered to the animal. 4 Further problems affecting much of the art is that the white drenches are typically limited to oral administration, a more time-consuming and difficult method of administration. This results in a reluctance by the end user for such products, due to the effort required and risk of 5 injury to the operator by unco-operative animals.

Further, the efficacy of transdermal migration of suspended benzimidazole compositions of the type described in Australian patent specification No. 10277/92 may be reduced when compared to a system where the active component is soluble in a transdermal solvent. 10 Accordingly, higher proportions of benzimidazole in a composition may need to be considered to compensate for any loss in efficacy. If transdermal transport is slow or delayed, environmental conditions may potentially reduce the effective amount of active components delivered to the animal's system - again influencing dosage 15 considerations. For instance, faster absorption results in higher blood levels and greater worm kill.

Also associated with difficulties in transdermal migration are time frames. Quite clearly, an active component dissolved in an effective transdermal solvent will cross this boundary more rapidly and in 20 higher proportions than a non-solubilised form. This can represent a useful advantage in the field.

A further problem involves equipment. A common problem associated with suspensions and non-solubilised drenches is clogging of the applicator gun. This can be relatively frequent, and halts dosing until 26 the problem is rectified. When an applicator gun is only partially clogged, incomplete dosing of each animal may also occur.

I 5 P However the most observable problem, and the most difficult to counter, is public perception of the white drench family of products, i.e. problems with settling and non-homogeneity, and additional effort required for their preparation for use, and administration.

The consequence of perception is that the consumer now expects, and prefer a clear composition able to be used straight from the container.

Another prior art document, NZ patent specification No, 235647, describes non-aqueous micellar solutions of a number of various anthelmintic compounds, including benzimidazole carbamates. The preferred embodiments of the invention solubilise, in micellar form, the active component in a co-solvent system comprising both a polyethoxylated oil or fat (the preference being a polyethoxylated castor oil) and at least one member of a group including dimethyl sulphoxide, n-methyl pyrrolidone, tetraglycol, and propylene glycol.

The present invention includes one of these components - n-methyl pyrrolidone - in a number of preferred embodiments. Early investigations by the applicants, as an extension of their work note that while n-methyl pyrrolidone is an effective solvent for benzimidazoles, trials based on at least the oxfendazole/n-methyl pyrrolidone system show that n-methyl pyrrolidone solubilised systems are unstable. This instability may exhibit itself within a few hours, which severely limits their usefulness.

The present invention investigates different solvent systems than the co-solvent arrangement proposed by Crooks.

It is an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice. 6 Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only.

Disclosure of I .tt'jaiCmW According to one aspect of the present invention there is provided benzimidazoles, in a solubilised form, for use in administration to animals.

According to a further aspect of the present invention there is provided a method for the preparation of a composition comprising a 10 benzimidazole in a solubilised form, said method comprising; the dissolution of a benzimidazole in at least one member of the group of pharmaceutically acceptable solvents, optionally including excipients, and optionally including co-solvents compatible with the remaining components.

The group of pharmaceutically acceptable solvents include those regarded as pharmacologically acceptable, when the composition is used in the intended manner on the intended type of animal.

According to another aspect of the present invention there is provided a method of the preparation of a composition comprising a 20 benzimidazole in a solubilised form, substantially as described above, in which the chosen pharmaceutically acceptable solvent(s) comprise polar solvents such as pyrrolidones, and preferably n-alkyl pyrrolidones such as n-methyl pyrrolidone.

According to yet a further aspect of the present invention there is provided a composition comprising a benzimidazole in a solubilised form. k 7 P According to another aspect of the present invention there is provided a composition, substantially as described above, in which the benzimidazole is a carbamate benzimidazole, such as oxfendazole.

According to a further aspect of the present invention there is provided 5 a composition, including an effective amount of at least one benzimidazole compound, which is substantially clear.

According to yet a further aspect of the present invention there is provided the use of a composition comprising a benzimidazole in a solubilised form.

According to yet a further aspect of the present invention there is provided the use of a pyrrolidone as a solvent for benzimidazoles in veterinary and pharmaceutical compositions containing same.

According to another aspect of the present invention there is provided the use, as a solvent for benzimidazoles, at least one member of the 15 group of preferred solvents comprising: pyrrolidones, n-alkyl pyrrolidone, n-methyl pyrrolidone, n-octyl pyrrolidone and gamma-butyrolactone.

According to yet a further aspect of the present invention there is provided a multi-component system for preparing a solubilised 20 carbamate benzimidazole containing composition, said system comprising two or more component compositions which when mixed prior to use yield the desired resulting composition.

The term 'benzimidazole' when used herein shall mean, unless specifically stated otherwise, compounds falling within the general 25 class of compounds known as benzimidazoles, as well as prodrugs and derivatives thereof. 8 || The term 'carbamate benzimidazole' when used herein shall mean, unless specifically stated otherwise, compounds falling within the subclass of benzimidazole compounds known as carbamate benzimidazoles, as well as prodrugs and derivatives thereof.

Reference may be made to: The Synthesis and Chemistry of Certain Anthelmintic Benzimidazoles (1990), L. B. Townsend and D. S. Wise, Parasitology Today 6(4):107-112; The Metabolism of Benzimidazole Anthelmintics (1990), D. W. 10 Gottschall, V. J. Theodorides, and R. Wang, Parasitology Today 6(4):115-124; Anthelmintics - A Review (1984), T. Barragry, NZ Vet J 32:161-164.

The term oxfendazole when used herein shall mean, unless specifically stated otherwise, oxfendazole as well as its pharmaceutically useful 15 derivatives. This also applies to other specifically mentioned active components - i.e. their prodrugs and derivatives are included. Reference is also made to: "The Benzimidazole Anthelmintic Agents - A Review"; (1990), McKellar & Scott, Jnl Veterinary Pharmacology & Therapeutics 18, pp 20 223-247.

In the broadest sense the present invention is directed to compositions, and methods for the preparation of same, which include one or more benzimidazole compounds in a solubilised form. The main envisaged application of these compositions is for administration to animals and 25 accordingly it is desirable that the compositions also be pharmacologically acceptable. 9 Physical and Pharmacological Attributes It is envisaged that the scope of the present invention will include compositions which may be administered by common routes, including orally, parenterally, etc., as well as topically.

Typically tux embodiment of the present invention comprises a benzimidazole solubilised in a pharmacologically acceptable carrier. Pharmacologically acceptable is used in the context of the method of intended application, as well as considering the nature of the animal to which the composition is to be administered.

For instance, there are a number of known solvents for benzimidazole compounds. However, in many cases these solvents are not acceptable for use in a pharmaceutical composition. By way of example, dimethylsulphoxide (DMSO) is an effective solvent but produces an unacceptable degree of skin irritation in most animals when applied 15 dermally. Accordingly, a fluid system based solely on DMSO as a solvent would not be considered pharmacologically acceptable for this reason, though compositions containing lesser amounts of this component (so as not to cause an unacceptable degree of unwanted side effects) may be considered for topical use.

There are a number of desirable properties for a composition according to the present invention, and these will influence the components and method of manufacture. For instance, it is desirable that a composition according to the present invention is stable. In this context stability relates primarily to decomposition and/or separation 25 over time. Precipitation of components, and reactions affecting activity are examples of stability failure.

Preferably, desired physical characteristics of the resulting composition should be maintained for a reasonable period of time. Typically this period of time comprises what is considered to be a useful shelf life for the product. This is preferably at least three 5 months and ideally at least twelve months from the date of manufacture, under normal storage conditions - e.g. at a temperature less than 30°C, and protected from direct sunlight.

A desired physical characteristic of various embodiments of the present invention is clarity. Preferably a clear composition exhibits no 10 turbidity, milkiness, or evidence of non-dissolved particles. This solution should be transparent, rather than translucent or opaque, but may be coloured. As optional components may be included without affecting the performance of a composition, the attribute of clarity is in relation to the benzimidazole component(s) and the associated 15 solvent/carrier system i.e. other optional components excluded when evaluating clarity.

In some situations the stable life of the usable composition may be relatively short. However other attributes or advantages associated with such embodiments may compensate for a short life span. It is 20 proposed to address such situations through the use of a multi component system in which separate components may be pre-mixed prior to use. Desirably these separate component compositions will individually be stable and have a relatively long shelf life (preferably in excess of three months, and desirably at least twelve months). As 25 for the non-multi component compositions, the shelf life shall be taken to mean normal expected storage conditions, at temperatures not exceeding 30°C and not being exposed to direct sunlight. 'i Compositions of the Invention At the broadest level, compositions according to the present invention include one or more active components in a compatible solvent system.

The main active component in compositions according to the present 5 inventions are benzimidazole compounds. Embodiments of the present invention will include one or more of these compounds as an active component. Preferred uses of these compositions are as anthelmintics.

A preferred benzimidazole compound is oxfendazole.

Other active components may be included. For anthelmintic 10 compositions these will typically include other parasiticides, with preferred choices being (but not restricted to) members of the group: Levamisole, and Ivermectin. Other choices include members of the following classes of compound: avermectins, nitrophenolics, milbemycins, imidazothiazoles, benzoenedisulphonamides, 15 pyrazinoisoquinolines, salicylanilides, tetrahydropyrimidines, and organophosphatee.

Compositions according to the present invention may have more than one mode of action and address other afflictions. Accordingly other active components appropriate to user requirements may be included.

However, consideration should be given to ensure that these additional components do not interfere with or adversely affect, desired physical attributes - including attributes such as clarity, solubilisation of other components and/or stability - to an unacceptable degree. Where complications are observed or anticipated, multi-component systems 25 may be employed in which components exhibiting reduced long term compatibility are kept separately until use. The components of the 12 system may be mixed prior to use, and used within their window of stability.

As an extension of this concept, a system having a base formulation (comprising a solubilised benzimidazole) may be adopted, with optional 5 other component formulations being added prior to use as requirements dictate. The user may have a selection of options available, each addressing a problem or task, and which can be chosen to enhance the main formulation.

The solvent and carrier system is the next major component of the 10 various embodiments of the present invention. The main requirement is that the chosen fluid component or components should be able to solubilise the included benzimidazole components, and desirably any other components. By the term solubilise is meant that these components are not in a suspended form typical of prior art 15 suspensions. Accordingly, the term solubilise in the context of benzimidazole compounds, will mean that these components are maintained as a true solution, or as a micellar arrangement. Typically, compositions filling these criteria will exhibit the characteristic of being substantially clear.

That the chosen solvent/carrier system needs to be pharmacologically acceptable has been previously mentioned. A further desirable characteristic is the suitability of the fluid components for the task. For instance, in dermally applied compositions, it is useful if the chosen carrier/solvent system includes at least one dermal carrier able 25 to assist in transporting the active component through the skin, and are the preference. 13 Preferred solvents for use in compositions according to the present inventions are typically polar and include pyrrolidoneB. Preferred pyrrolidones are n-alkyl pyrrolidones. Particularly preferred pyrrolidones include n-methyl pyrrolidone, and also n-octyl 5 pyrrolidone, though this latter solvent is more preferred as a co-solvent than primary solvent.

Co-solvents may be optionally included in various embodiments of the present invention. These may include additional solvents suitable as a primary solvent. They may also include other compounds which would 10 be considered less effective as a primary solvent. In preferred embodiments of the present invention, preferred co-solvents are pyrrolidones, with one preferred pyrrolidone for use with n-methyl pyrrolidone being 2-pyrrolidone. Another preferred solvent is gamma-butyrolactone.

Other optional components forming part of the fluid portion include excipients of various types. These may include stabilisers, preservatives, permeability enhancers, and spreadability enhancers as well as other excipients normally used in compositions of this type. Some examples of various excipients which may be used include: 20 parabens (and in particular alkyl parabens such as methyl paraben and propyl paraben) as preservatives; vegetable oils (such as canola oil) as permeability and spreadability enhancers; as well as benzyl and aryl alcohols; and polyvinyl povidones.

Other excipients may include substances which enhance transport of 25 active components into the biological system to which they are applied. For dermally applied compositions, this will normally comprise transdermal enhancers. However, n-methyl pyrrolidone appears relatively effective for promoting the transport of benzimidazoles ^ 14 through the dermal layer and may be adequate without the need for other transdermal enhancers.

Methods of preparing compositions A number of methods for preparing compositions according to the 5 present invention are envisaged. The main objective is to ensure that the components are incorporated into a composition which possesses the desired physical and pharmacological attributes. Generally this will require some consideration of the selected components as well as their proportions.

It is envisaged that different embodiments of the invention will employ different combinations of prescribed components. This may affect how the preferred method is implemented, or indeed alternative methods, and may require some experimentation to optimise both the method of production and the resulting product. However, it is envisaged that 15 such experimentation would be well within the ability of a skilled addressee of the art given the teachings herein.

In a preferred general method, the least soluble active component or components are initially solubilised in the primary solvent. Typically this will comprise the benzimidazole components which, in the case of 20 more than one being present, may be dissolved individually or together. Preferably the least soluble component is dissolved in the primary solvent first.

Due to the relative insolubility of benzimidazole compounds, it is envisaged that the solution will only be achieved after heating of the 25 solvent and some stirring or agitation of the mixture. It is envisaged that in most cases heating the solvent within the range 40°C • 80°C will be sufficient. Heating to higher temperatures may be considered, though this may exceed the boiling point of the solvent and thus pressurised mixing systems may need to be considered. Possible decomposition, or unwanted reactions, of the components will need to be considered if higher temperatures are employed.

Other techniques, apparent to those skilled in the art, may also be employed to assist the dissolution of the relatively insoluble components. This includes using a higher proportion of primary solvent than is required for the final product, and then reducing the solution to the required concentration by solvent removal (e.g. 10 evaporation).

Other active components, including non-benzimidazoles, may be incorporated into the solution next. It is possible to add these components earlier, though this is a departure from the preferred route.

If a high proportion of benzimidazole components are already present, and possible precipitation is a concern, it may be desirable to add other fluid components before other non-fluid active components. As a variation, other active components may be solubilised in other fluid components which are subsequently added to the primary solvent 20 solution.

It should also be considered that in some embodiments, a proportion of the main active components may also be divided out and introduced into other fluid components such as co-solvents, before addition into the main primary solvent. It is also possible that the total amount of 25 primary solvent may be split and different components introduced into each before their combination. 16 Continuing along the preferred general route where we have a primary solvent mixture containing dissolved active components, desired excipients Eire typically added next. The nature of these components have been previously described. However, when embodiments are 5 being prepared where it is considered that the addition of excipients may precipitate already dissolved active components, the excipients responsible for such problems may be introduced to the co-solvent (when present), or a proportion of primary solvent, first. This portion will then be introduced, along with any other included components, 10 into the primary solvent mixture.

The final step in the general method comprises the addition of any co-solvent into the primary solvent mixture. This normally represents the last step in the method, after which the resulting composition is prepared for packaging.

Typically some mixing or agitation of the components is required during the various steps of the method to ensure thorough mining. It is also envisaged that the elevated temperature may need to be maintained to assist in mixing and incorporation of components. However, the temperature need not be maintained at the same level 20 throughout, and some minimal trial and experimentation will undoubtedly optimise conditions for a particular embodiment of a composition being prepared.

The result should be a composition exhibiting the desired physical characteristics. Ideally this should be that the components are 25 maintained substantially homogeneously within the composition, and remain that way until use. Typically homogeneity is achieved through solubilisation of the components resulting in a true solution or a stable micellar arrangement. 17 It is envisaged that modifications and additions may be made to the general method, as would be apparent to a skilled addressee of the art given the teaching herein. It is also envisaged that the same general procedures may be employed for the production of multi component 5 systems which are intended to be combined prior to use.

Brief Description of Drawings Further aspects of the present invention will become apparent from the following description which is given by way of example only and with reference to the accompanying drawings in which: Figure 1 is a flow chart of a preferred method for performing the invention; Best modes for Carrying out the invention Example 1 This example comprises a general method of preparation for preferred 15 embodiments of the present invention. The steps are also summarised in Figure 1.

Step 1: A primary solvent is selected. This should ideally be a polar solvent, and preferably be of high polarity. It is also desirable that it be pharmacologically acceptable for the intended use. 20 As an example, a preferred solvent is N-methyl pyrrolidone.

Step 2: The solvent is heated, typically to a temperature of 40-80°C. The chosen temperature may vary from this preferred range and will depend upon the chosen solvent, the active component(s), and the conditions required to effect dissolution. 18 In most cases, it is anticipated that the temperature will not exceed 100°C.

The active component(s) is then added, the mixture being agitated until dissolved. The result should be a clear liquid.

The normally chosen active component(s) comprise benzimidazole compounds (and their prodrugs and derivatives). Preferred active components comprise in particular oxfendazole and its pharmaceutically acceptable derivatives.

Optionally, other non-benzimidazole active components may be included. For anthelmintic type compositions this may include avermectins, nitrophenolics, milbemycins, imidazothiazoles, tetrahydropyrimidines, organophosphates, salicylanilides, benzoenedisulphonamides, and pyrazinoisoquinolines. Other compounds may be considered, especially for when addressing other afflictions than helminth parasites.

Step 3; The elevated temperature of the mixture is maintained while one or more excipients are added. This includes stabilisers, spreadability enhancers, and dermal permeability enhancers. While optional in cruder embodiments of the invention, they are included in preferred embodiments. Preferred excipients include vegetable oils, N-octyl pyrrolidone, and polyvinyl povidones.

Preservatives, such as benzyl alcohol, may also be included.

The quantities are selected such that the result after mixing is a clear liquid. 19 Step 4: The elevated temperature of the mixture is maintained for the optional, but preferred, step of including one or more co-solvents. The chosen co-solvent should also be pharmacologically acceptable (with respect to the intended use) 5 as should the selected excipients if present.

The co-solvent should also be compatible with the other components present in the formulation. A preferred co-solvent for use with the present invention is 2-pyrrolidone, though other solvents may be considered - these are likely to be polar solvents, though need not be restricted to this category.

The co-solvent, as well as excipients present, may be used to dilute any adverse effects of the chosen primary solvent (or indeed an excipient if represents a problem) to pharmacologically acceptable levels.

Step 5: Any other optional components, such as colourings etc., which have not already been included may be now added. The prepared composition is then cooled, and any further steps such as packaging performed. The resulting composition should be clear, and substantially free of any turbidity.

Example 2 A preferred embodiment of the present invention is prepared as follows.

N-methyl pyrrolidone is selected as the primary solvent. The quantity selected is between 45 - 55%, by weight, of the total weight of the final composition. This is heated, with stirring, to around 60°C. ♦ 20 The chosen active component is oxfendazole. The selected amount is ±1%, by weight, of the total weight of the resulting composition. This is added to the heated primary solvent while being stirred.

After total dissolution of the active component, the following excipients 5 are included. This comprises methyl paraben — 0.2 ± 0.1% as a preservative; propyl paraben — 0.1 ± 0.05% as a preservative; and canola oil — 2.0 % ± 0.5% as a permeability and spreadability enhancer.

The composition thus far should be stirred until clear.

At this stage the co-solvent and stabiliser is added. The preferred co-solvent is 2-pyrrolidone and the quantity is such to make the composition up to 100% (by weight). Stirring should be continued until all components are homogeneously distributed and the resulting solution is clear.

Typically the composition is brown in colouration, and should have stable dosage form. Based on available data, this appears to equate to a shelf life exceeding three months.

Example 3 A generalised formulation follows the methods of Examples 1 and 2. 20 However, while Example 2 was optimised for dermal application, some situations may require varying amounts of active, and other, components. The following formulation represents a broader range of embodiments considered to fall within the scope of the present invention: m 21 Preferred formulation (to a total of 100% bv weight) Oxfendazole 0.1 -17% N-methyl pyrrolidone 0.5 - 99% Preservative(s) 0.02 - 6.0% Vegetable oil 0.2 -10% 2-pyrrolidone 0.9 - 99.4% Example 4 The following represents further compositions according to the present invention, which includes more than one active component. The 10 method of manufacture may follow the preferred method of Example 1, though other methods of combining the components may also be considered.

Example 4a To the formulations of Examples 2 and 3 are included from 2 - 15% of 15 levamisole, or a derivative thereof. The preferred amount is from 2.5-10%. When present within this range, a preferred amount of oxfendazole is 2.5 ± 5.0%.

Example 4b A preferred example according to Example 4a comprises the following 20 composition: Formulation (to a total of 100% bv weight) Oxfendazole 2.5 - 5.0% Levamisole HC1 2.5 - 5% Benzyl Alcohol 0.02 - 5% v/V N-octyl pyrrolidone 0.2 -10% v/v 22 Sesame seed oil 0.2 -10% v/v Citric acid 0.1 - 5% 2-pyrrolidone De-ionised Water 2 - 25% v/v - 20% v/v N-methyl pyrrolidone to the total of 100% N-octyl pyrrolidone functions at least partially as a dermal permeability enhancer.

Example 4c Initial tests indicate that formulations including other components such as levamisole may be temperamental in terms of both stability and maintaining the effectiveness of levamisole (generally requiring an acidic pH (2.5 - 4.0) to maintain its activity). As a variation to Example 4b, a two component system may be used in which the levamisole, and/or any other active components, are separate from the main composition.

Such a multi component composition will be combined immediately prior to use. In such instances, relatively short lifetimes before decomposition or loss of clarity of the solution, may be acceptable with the user mixing only enough composition before use to complete the intended job. This arrangement allows other components to be kept under different conditions more suitable for their long term stability, and also avoids unwanted reactions which may occur between components over time. 23 Example 5 Reductions in worm egg count following treatment has been found to be a useful measure of worm kill (efficacy) of an anthelmintic.

In trial AgVet/BOMAC Trial No. 97 05 01, fifteen 12-2 year old Limousin cattle with high Faecal Egg Counts were divided into three treatment groups of five animals per group and treated with either: 1. a clear solution of oxfendazole (Tables 1 and 2), or 2. untreated as control animals (Table 3).

Oxfendazole is the benzimidazole, and the only substance in the pour-on formulation to have anthelmintic activity.

As shown in Table 1, the group receiving the clear solution containing Oxfendazole has Faecal Egg Count reductions between 4 to 14 days after treatment varying from 100 - 92% compared with pre-treatment egg counts. These egg counts were lower than those of the untreated control group which exhibited a significant increase in the fecal egg count. This implies the action was due to the Oxfendazole component alone. This is consistent with a highly effective anthelmintic action. Good weight gain increases averaging 0.75kg/day were also observed.

Title: Comparative Faecal Egg Count Reduction and Weight Gain in Cattle following treatment with Transdermal Oxfendazole pour on.

AgVet Consultants Ltd / BOMAC Trial 97-07-01.

Table 1 Pour oil Oxfendazole Solution Tag FEC FEC FEC FEC FEC FEC Group Treatment Treat 18/9 19/9 /9 26/9 22/10 Day 1 Day 2 Day 3 Day 4 Day 10 Day 36 W24 2 OXF 1000 0 0 N/T 0 0 R21 2 lmL/5Kg. 400 100 0 N/T 0 0 W20 2 250 100 0 N/T 0 0 R38 2 150 150 0 N/T 100 550 W16 2 50 50 0 N/T 0 50 Y86 2 (50) 0 0 N/T 50 0 Total 1900 400 0 150 600 Mean 316 66.6 0 100 Efficacy 79% 100% 92% NT = Not Tested.

Pour on Oxfendazole Solution Tag Group Treatment Volume Weight 18/09 Weight 22/10 Gain (kg) W24 2 OXF Clear. 48 238 241 3 R21 2 lmL/5Kg. 40 200 210 W20 2 60 300 374 74 R38 2 39 195 210 W16 2 50 250 252 2 Y86 2 47 236 286 50 Total 154 Mean Efficacy 0.75kfi/day Table 3 Untreated Controls.

Tag FEC FEC FEC FEC FEC FEC Group Treatment Treat 18/9 19/9 /9 26/9 22/10 Day 1 Day 2 Day 3 Day 4 Day 10 Day 36 G16 Untreated 50 150 0 250 200 200 G19 Control. 50 0 200 250 50 200 MY45 50 150 350 750 350 1400 OR34 100 250 100 700 200 300 W2 50 150 50 100 50 100 Y87 50 0 0 50 0 150 Total 350 700 700 2100 850 2350 Mean 58 117 117 350 142 392 Efficacy Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims.

Claims (27)

WHAT WE CLAIM IS: 32 9247

1. A benzimidazole containing composition, said composition including at least one benzimidazole in a solubilised (as herein defined) form in pharmacologically acceptable carrier system including a pyrrolidone; the resulting composition being characterised by being substantially clear.

2. A composition as claimed in claim 1 in which a benzimidazole is a carbamate benzimidazole.

3. A composition as claimed in any one of the preceding claims in which a benzimidazole is oxfendazole.

4. A composition as claimed in any one of the preceding claims which is substantially stable with respect to precipitation or changes affecting clarity.

5. A composition as claimed in any one of the preceding claims which is substantially stable with respect to chemical changes or reactions of and/or among included components.

6. A composition as claimed in either claims 4 or claim 5 in which the stability of the composition is maintained for a period in excess of 1 month, and preferably 3 months at temperatures of up to 35 °C.

7. A composition as claimed in any one of preceding claims in which the pyrrolidone is N-methyl pyrrolidone, or N-octyl pyrrolidone.

8. A composition as claimed in any one of preceding claims in which the composition is formulated for transdermal application.

9. A composition as claimed in any one of preceding claims in which the included components are such that the resulting composition is substantially free of adverse skin effects when applied transdermally. Intellectual Property Office of NZ 16 JUN 2000 26 RECEIVED 32924 7

A composition as claimed in any one of preceding claims which is suitable for veterinary use.

A composition as claimed in any one of preceding claims formulated for use as an anthelmintic other than in a human.

12. A composition as claimed in any one of preceding claims in which the composition includes more than one carbamate benzimidazole and in which the other carbamate benzimidazole(s) is/are also soluble in the chosen carrier system, such that the resulting composition is substantially clear.

13. A composition as claimed in any one of preceding claims which includes at least one other additional active component selected from the group comprising: anthelmintics, and parasiticidal agents.

14. A composition as claimed in claim 13 in which other chosen active components are also soluble in the chosen carrier system, and the resulting composition is substantially clear.

15. The veterinary use of a substantially clear composition including a carbamate benzimidazole in a solubilised (as herein defined) form in a pharmacologically acceptable carrier system including a pyrrolidone.

16. The use of claim 15 in which the composition is a composition as claimed in any one of claims 1 through 14.

17. The use of claim 15 in which the composition is pharmacologically acceptable in terms of the method of administration.

18. The use of claim 18 in which the composition includes oxfendazole in a pharmacologically acceptable carrier. Intellectual Property Office of NZ V 16 JUN 2000 RECEIVED 0 10. 11.

19. The use of any one of claims 15 through 18 in which the composition is administered to cattle.

20. The use of any one of claims 15 through 18 in which the composition is applied transdermally.

21. The use of any one of claims 15 through 18 in which the composition is applied as a pour-on drench.

22. The use of any one of claims 15 through 18 in which the composition is used as an anthelmintic.

23. A method for the preparation of a veterinary composition comprising a carbamate benzimidazole in a solubilised (as herein defined) form, said method comprising: the dissolution of a carbamate benzimidazole in at least one pyrrolidone, to yield a substantially clear composition, the composition optionally also including excipients, and optionally including co-solvents compatible with the remaining components.

24. A method as claimed in claim 23 in which there is present a pyrrolidone of sufficient polarity to solubilise an effective amount of carbamate benzimidazole.

25. A method as claimed in claim 24 in which the pyrrolidone is an N-alkyl pyrrolidone.

26. A method as claimed in claim 25 in which an N-alkyl pyrrolidone is N-methyl pyrrolidone, or N-octyl pyrrolidones.

27. A method as claimed in any one of claims 23 through 26 in which solubilisation of added carbamate benzimidazole is performed at an elevated temperature of 40°C or greater. H JUL 2000 28 RECEIVED 28 29, 30 31. 32, 33. 34. 35. 36 37 38 32924 A method as claimed in claim 27 in which solubilisation is performed at a temperature not exceeding 100°C, and preferably not exceeding 80°C. A method as claimed in either claim 27 or claim 28 in which excipients are included while the solvent and carbamate benzimidazole mixture is at an elevated temperature. A method as claimed in claim 29 in which an excipient is selected from a group comprising stabilisers, dermal permeability enhancers, preservatives, and/or spreadability enhancers. A method as claimed in claim 30 in which an excipient is selected from a group including vegetable oils, pyrrolidones, benzyl and aryl alcohols, and polyvinyl povidones. A method as claimed in claim 31 in which the pyrrolidone is N-octyl pyrrolidone. A method as claimed in either claim 27 or claim 28 in which co-solvents are added to the reaction mixture while maintained at an elevated temperature. A method as claimed in claim 33 in which a said co-solventincludes pyrrolidones. A method as claimed in claim 34 in which an included pyrrolidone is 2-pyrrolidone. A composition produced according to a method as claimed in any one of claims 23 through 35. The composition of any one of claims 1 through 22 when prepared according to a method as claimed in any one of claims 23 through 35. A veterinary composition comprising from 0.1 - 17.0% oxfendazole in a solubilised form, the composition characterised by being substantially clear and including at least one pyrrolidone as a carrier. Intellectual Property Office of NZ 29 16 JUN 2000 RECEIVED 4" ^ 39 The composition of claim 38 which also includes levamisole. 40 The composition of either claim 38 or claim 39 which includes oxfendazole within the range of 0.1 - 2.5% 41 The composition of any one of claims 38 through 40 which includes at least one of n-octyl pyrrolidone, and 2-pyrrolidone. 42 A composition, substantially as described herein with reference to the contained examples. 43 A method of producing a substantially clear solubilised benzimidazole composition, substantially as described herein with reference to the contained examples. 44 The use of a substantially clear solubilised benzimidazole composition, substantially as described herein with reference to the contained examples. Bomac Laboratories Limited 30 Intellectual Propertv Office of NZ 16 JUN 2000 RECEIVED END