WO 2005/039568 PCT/NZ2004/000267
MULTIPLE ACTIVE AGENTS SUCH AS ANTHELNINTZCS SUSTAINED RELEASE DELIVERY
TECHNICAL FIELD
This Invention relates to a process for the administration of active agents to animals.
In particular, this Invention relates to a process for administering an antheiminic preparation combining two or more anthelmintics to an animal to reduce the level of parasitic Infestation and In a manner designed to achieve Increased efficacy against resistant worms.
BACKGROUND ART
Parasites are a major production-lmiting factor In tivestock grazing systems throughout the world. The size of the Issue can be gauged by the global market for parasiticides which is approximately US $3 billon annually of which nearly US $2 billion goes to production animate (sheep, cattle, poultry and pigs). The cattle market alone is nearly US $900M per annum.
The size of the market for parasiticides also reflects the fact that throughout the world most production systems rely heavly on the use of anthelmintic drugs to control Infections in Bvestock. However, In some countries this dependence on the use of anthelmlntics Is now threatened by the development of resistance amongst parasite populations.
Countries such as South Africa, Australia and parts of South America already have serious resistance problems in parasites of sheep and goats. New Zealand. Great Britain and France also have significant and developing problems. In Australia, for example, almost every sheep farm has resistance to

WO 2005/039568 PCT/NZ2004/000267
at least one 'action-family" of antheimtntic. Survey results Indicate that on more than 90% of Australian sheep farms at least 2 action-families (the benzimidazolo and Levamisole groups) are less than fully effective due to resistance. Furthermore, the last 2-3 years has seen a rapid Increase in the prevalence of resistance to the 3rd action-family. the macrocyclic lactone (ML) group.
By comparison, New Zealand has resistance on about 60% of sheep farms, but most sta have effective use of at least 2 action-families. The problem does, however, continue to worsen and recent years have seen confirmation of ML resistance In sheep flocks. In addition, New Zealand has an unquantifted but significant problem with ML resistance in parasites of cattle.
In response to the threat posed by anthelminitic resistance, there has been substantial research into the factors associated with its development and means of preventing or delaying ft.
Genetic theory, reinforced by a number of modelling studies (Tabashnk & Croft, 1982, Environmental Entomology 11, 1134-1137.; Barnes et al 1995. Panstology Today 11, 56-63; Leathwick & Sutherland 2002. Proceedings of the 32nd Seminar, The Society of Sheep and Boef Cattle Veterinarians, NZ. Veterinary Association, 116-127.) shows that the efficacy of an anthelmintic against resistant worms, in particular the heterozygotes (i.e.. worms carrying one resistant and one susceptible alleie or gene) can have a substantial effect on the rate at which resistance develops.
When resistant genes are rare In the population, mating probabilites determine
that they nearly always occur in the heterozygote form. Hence if the
antheimntic kills all or most hetorozygotes then it will be very difficult for
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WO 2005/039568 PCT/NZ2004/000267
resistance to build up in the population. If, however, the onthelmintic does not kill the heterozygote worms, they will build up in the population, and interbreeding will produce even more resistant homozygotes. In essence, the efficacy of any anthelmintic product against resistant worms is a key factor In delaying the development of severe, production-limiting resistance.
It was shown as earty as 1978 (Prichard et al. 1978. Veterinary Parasttology 4, 309-315.) that extending tho period over which worms are exposed to benzimidazole drenches Increases their efficacy. A number of subsequent studies have confirmed that not onfy can efficacy be increased by this approach but also that the dally dose required to do this can be lower than that required for a single dose (Le Jambre et al. 1981. Research In Veterinary Science, 31, 289-294; Songster et al. 1991. Research In Veterinary Scienco 51. 258-263). The same principle has been shown to apply to the ML class of antnelmlntics, but not to Lovamisole.
Repetitive dosing of extensively-grazed animals with anthelmlntics is not practicable. A controBod release device, which would permit extended drug exposure with only a single administration, is therefore required.
Some controBod rolease devices for anthelmlntics are presently on the market The controlled release capsules (CRCs) made by CapTec release between 1/5th and 1/10th the normal therapeutic dose (depending on animal liveweight) of either albendazolo or tvermectin for 100 days.
Currently-available oral products provide albendazole at doses of approximately 3.8 to 5 mg/kg and the macrocydlic lactones at approximately 0.2 mg/kg. Doses given by current CRCs are much Jower, being of the order of 0.5 - 1.0
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WO 2005/039568 PCT/NZ2004/000267
mg/kg/day for albendazole and 0.02 - 0.04 mg/kg/day for the macrocyclic lactones.
Although Le Jambre et al.1981 (Rosearch in Vetorinary Science, 31, 289-294) showed Increased efficacy by releasing a benzimidazole at low doses in a short duration CRC the commercilly available albendazole CRCs appear to show no better efficacy against established drug-eusoptible Ostertagia (<95%) than would be expected from a slngle oral dose at 5 mg/kg (Anderson et at 1988. Australian Advances in Veterinary Science, 60-61).
Similar studies In NZ suggest that efficacy against some worm species is no belter than a single dose (Extender 100™ Technical manual). Banger, 1993 {Proceedings 23rd Seminar, Sheep and Beof Cattle Society, Now Zealand Veterinary Association. 129-136) claims that while the efficacy of the CRC against resistant worms is variable, It is superior to that of a single oral drench. However, other studies do not support this view (Macchi et al. 2001. New Zealand Veterinary Journal 49, 48-53.; Leathwick, et al 2001. Now Zealand Veterinary Journal, 50(2): 70-76.). Thus it remains undear whether the 100 day albendazole capsule (Extender™) does in fact confer increased efficacy against established resistant worms.
Further, tho efficacy of the 100 day lvermectin CRC (Maxinlser™) against resistant adult worms has been shown to be no better than the standard single oral doso of Ivermectin (Sutherland et al, 2002. Veterinary Parasitology, 109: 91-99).
Thus, despite having known for 25 years that extending the duration of worm exposure to some actives can substantially Increase efficacy there has never been a product produced which fully capitalises on this knowledge. Further, the
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WO 2005/039568 PCT/NZ2004/000267
only product on the market for sheep and cattle (NZ & Australia at least) lasts for 100 days, resulting in long withholding periods for tho ivermectin variant
Furthermore, the prolonged deflvery of small doses of antheimintic may actually select for resistance In the worm population (Dobson R.J., La Jambre LF. & GDI J.H. 1996. Management of anthelmintic resistance: inheritance of resistance and selection with persistent drugs. International Journal for Parosittology. 26: 903-1000).
A second and independent method of increasing efficacy against resistant worms b to combine different action-famlies into a single product Tho underlying principle of this approach is that resistant worms able to survtve exposure to one active will be killed by the second (and/or third) active in the mbc The exception is if a single worm carries simultaneously genes for resistance to both drugs. However, if the incidence of resistance is low In a population, the chances of a worm carrying both sets of genes are also very tow.
Until recently the only commercialty-availabe anthelmintic products which combined actives against the same parasite species were oral combinations of benzimidazoie and levamisole. Substantial formulation problems were Inherent in combining tho MLs with either of the other two action famllies- MLs are soluble in oil and require a noutral pH whereas Levamisole is water soluble and requires an add environment Benzimdazole actives are Insoluble but can be formulated as a stable suspension In water.
This problem has recently been solved with the release of two triple combination
products - Triton (described In WO 00/74469, developed by CapTec (a
subsidiary of Nufarm) and marketed by Merial) and Erase MC (a mix before use
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WO 2005/039568 PCT/NZ2004/000267
product developed by Coopers). The latter Is also available in an ivermectln + Levamteote variant
All of these products are liquids designed to be dosed orally. The Triton product utilises a suspoemuison formulation while Erase comes as two liquids which require mbdng before use.
However, because those products are administered as a single oral dose and the active agents are usually absorbed and eliminated according to first order kinetic principles, the effective dose rates are onty maintained for a short period of time. This short residence time, as outlined previously, results in sub-optima) efficacy against resistant worms.
The threats posed by the developing drug resistance as described above are not restricted to the use of anthetmintic drugs in controlling parasitic Infestations in livestock, the development of resistance to drugs used to control a range of animal bacterial and viral Infectious diseases having been well documented.
All references, Including any patents or patent applications ctted in this specification aro hereby incorporated by reference. No admission is made that any reference constitutes prior art The discussion of the references states what their authors assort, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be dearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of those documents form part of the common general knowledge In the art. In New Zealand or in any other country.
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PCT/NZ2004/000267 Received 17 JUNE 2005
Isted components ft directly references, but also other non-epeced componants or elements. This rationale will also be used when the teern 'oomprieed or 'oomprtetoo' to used tn reteflon to one or more steps In a method
or process.
It is an object of the present invention to address the forthgoing problem or at
least to provide this public with a useful choice.
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 INVENTION
According to one aspect of the present invention, there is provided a method of reducing parasites
in animals characterised by the step of:

introducing to the animal a single delivery device containing two or more active agents selected from at
least two types of anthe lmintic compounds of differing chemical groups;
wherein the delivery device is an intra-ruminal bolus configured to release an effective amount
of active agents each day for a period of between 3 and 14 days.
preferably, the two or more anthelmintic compounds have different actives.
preferably, the active agents are released at a substantially continuos rate.
preferably the treatment will be formulated to effect a reduction in the parasite burden of an animal,
and for ease of reference will be referred to as such throughout the specification.
However, this should not be viewed as limiting, for the treatment may alternatively involve
the administration of a number of

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PCT/NZ2004/000267 Received 17 June 2005

different animal remedies.
for example, it is anticipated that the present invention could be used for treating an animal
with an antifungal treatment, particularly when attempting to achieve increased efficacy in the
treatment of bacterial and viral infectious
diseases. Such treatments may be especially useful in the treatment of animal infections or
animal parasites
which have developed resistance standard drug treatments.
It is also anticlpated that the present invention may find use in other animal treatments, such as
the delivery of mineral
and/or nutritional supplements, or so forth.
The term "animal" should be taken to encompass any ruminant animal in need of a reduction
of parasites. the present invention is particularly suited to production animals, including but not
limited to sheep, goats, cattle deer and pigs.
For ease of reference throughout the present specification, the present invention will be
described with
reference to sheep, though this should no be seen as a limitation.
The term "parasite" should be taken to include endoparasites such as heiminths, nematodes,
cestodes,
termatodes and combinations thereof;
in addition to ectoparasites such as licks,lice, flies,fleas and combinations thereof.
The term "anthelmintic" should be taken to mean compounds exhibiting activites selected
from : nematocidal, flukicidal, trematocidal, cestocidal and/or ectoparasiticidal activites and
combinations thereof.

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The term "effective amount" should be taken to mean the level of anthelmintics
necessary to effect a reduction in the level of parasites present in an animal,
including a general increase in efficacy against resistant parasites, whilst minimising
the undue selection of resistance to anthelmintics and the risk of toxicity to the animal.
In preferred embodiments of the present invention the anthelmintics used may be a macrocyclic
lactone such as
adamectin and a benzimidazole such as albendazole.
However, once again this should not be seen as limiting and other anthelmintics could be
used such as
organophosphates, salicylanilide/substituted
phenols, tetramisoles or pyrimidine agents. Derivatives and variations of these compounds,
and their
specific anti-parasitic
action are well known in the art and would be known to a skilled addressee.
In preferred embodiments the daily dose may be ase close to the normal therapeutic (oral) dose
as possible,
while minimising toxicity risks.
therefore, for a given weight range of target animal, it is preferable to target the full dose to
lower end of that range.
Preferably, the daily dose delivered is substantially in the order of 3.0-5.0 mg/kg/day of
albendazole and substantialty 0.1-0.2
mg/kg/day of abamectin.
For example, for adult sheep in the range 50-80 kg it is preferable to deliver approximately
5 mg/kg of albendazole and
approximately 0.2 mg/kg of abamectin
to the 50 kg animal, which equates to approximately 3.125 mg/kg of albendazole and approximately
0.125 mg/kg of abamectin to the 80 kg animal.
It should be appreciated these dosages are given by way example only, and

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PCT/NZ2004/000267 Received 17 JUNE 2005
Should not be viewed as limiting. It is anticipated that the dose rates will vary
WITH DIFFERENT ANTHELMINTICS AND PARASITE RESISTANCE.
IT IS ANTICIPATED THAT DAILY DELIVERY OF THE ACTIVE AGENTS OVER A PERIOD OF THREE
days will be the minimum required to cause an increase in efficacy over standared
anthelmintic compositions.
In time period is also a balance between ensuring sufficient duration of exposure
to
ensure a significant increase in efficacy against resistant worms, whilst minimising
the
duration of exposure to avoid undue selection for resistance and the risks of toxicity
of
the anthelmintics to the animal.
It is anticipated that daily delivery of the active agents over a period of between
3 and 5
days will be the minimum required to ensure a substantial increase in efficacy over
traditional anthelmintic preparations.
Most preferably, the active agents are released each day for a period of between
6 and
8 days.
Standard drenching programmes based on periods of weeks are easy to remember and
calculate, making the final product user friendly. Further,
such a time period allows for some variation in the delivery rates, whilst
maintaining the
efficacy of the treatment.
These are generally four forms of anthelmintic compositions currently available on
the market, a single dose oral liquid drench, a single dose pour-on (dermal)
liquid ; a single dose liquid injection and sustained controlled release devices.
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which release a low level of anthelmintics from a solid matrix tablet encased in a
plastic vehicle over an extended period of time (approxmately 100 days).
Oral drenches deliver a one-off high dose of anthelmintic which kills approximately
>95 % of susceptible nematodes and provides the animal with a short
period of time with a low worm burden.
pour-on and injectable formulations release the drug in responsr to concentration gradients.
this leads to a high initial concentration of drug within the animal, which subsequently declines.
such formulations are no more efficacious than oral formulations and have the disadvantage that
the persistent declining concentrations of drug favour the disadvantage that hte persistent declining
concentrations of drug favour the development of resistent (leathwick and sutherland 2002
proceedings of the 32 ND seminar, the society of sheep and beef cattle veterinarians, n.z,
vaterinary association, 115-127).
Thus none of these formulations have been shown to have the potential to increase efficacy
against resistant worms and/or slow the development of resistance.
it has previously been shown that repeated oral dosing (daily for five days) or continuous
intraruminal infusion for a period of five days can increase the efficacy of albendazole treatment.
however, repetitive dosing of extensively-grazed animals with anthelmintics is not practicable.
in large animals such as cattle and deer, oral drugs are also extremerly difficult to administer,
meaning the high majority of farmers use pour-on drenches.
as the only combination products on the market are orals, thee are very limited options
for the use of combination products in these animals.
the available alternative to repetitive dosing is the provision of controlled

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release device. A number of studies have shown that efficacy against parasites
can be increased by the provision of antheiminitics over an extended period of time,
whilest requring a lower daily level of dose hat
require for a single dose.
Some controlled release devices (CRCs) are currently available that release between
1/5'' and 1/10'' the normal therapeutic dose (depending on animal
liveweight) of either albendazole or ivermectin for 100 days. These devices act
principally as prophylactocs,maintaining parasites at low levels by preventin principally as
prophylactics, maintaining
parasites at low levels by preventing reinfection. However, such devices typically result in
long withholding
periods. Resent studies also do not support the view of increased efficency of these devices
over
standard oral doses. Furthermore, the prolonged delivery of small doses of anthelmintics
may actually
select for resistance in the worm population.
Conventional controlled release device are made from plastic and/ or metal components
which
remain in the animal's rumen.
obviously there is a limit to the number of expired devices that can remain in an animal
without
consequencec for the animal, and thus there is therefore
a limit to how many CRCs can be given to an animal. Further, the component residues pose
problems
in freezing works when the offal is processed.
A second method of increasing efficacy against resistant worms is to combine different action
families into a single product. the principle behind this approach
is that worms resistant to one active will be killed by the second active. However, until
recently the only
commercially available anthelmintic products which used actives in combination against
the same
parasite species were
oral combinations of benzimidazole and levamisole. As the anthelmintic classes have differing
conditions of solubility and pH,
it was difficult to formulate
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PCT/NZ2004/000267 Received 17 JUNE 2005
stable compositions of other actives.
If the anthelmintic composition does not kill resistant worms the numbers of such will
build up in the population.
Therefore, the efficacy of any anthelmintic product against resistant worms is a key
feature
in delaying the development
of severe, production-limiting resistance.
In order to maximise the worm exposure to the anthelmintics, the applicants have
developed a method
of dosing animals which they have termed " maximum intergral dose" and which
combines
high doses, extended duration and the combination of two or more anthelmintics
into a single
product, with the aim of
achieving extremely high efficacy against parasites, including those resistant to
normal doses of single actives.
The intergral in mathematics is used to "find the area enclosed by a given curve" in
this case the ares under
the curve of worm exposure to anthelmintics.
To provide the maximum intergal dose, the present invention may preferably utilise a
controlled release device that
delivers the equivalent of a high oral dose every day over a period of between 3 and
14 days, long enough to provide
extremely high efficacy against parasites, but not long enough to build up resistance in
the worm population.
The essence of the current invention is to produce a product which delivers enhanced
efficacy against most resistant worm
genotypes and therefore can be used to delay the emergence of resistance to the
constitutent actives.
As described above, high dose levels of one or more anthelmintics have previously
only been delivered to animals as a single dose, due to the practical difficulties in
repetitive dosing
of extensively-grazed animals. Therefore, the

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development of a method for delivering a maximum integral dose from a single
elivery device
has a number of significant advantages.
In preferred embodiments, the maximum intergal dose will be delivered from a
controlled release device which releases its payload over a period of between 3
and 14 days, which is
retained in the rumen of an animal by virtue of its density,
and which can release multiple anthelmintic actives at a constant, high rate.
By providing a dose rate that is sufficiently high for each active to ensure increased
efficacy of each against parasites resisatant to that class of drug, it is anticipated that
the combination of extended duration with multiple actives will provide a very high
efficacy product which will substantially
delay the development of resistance.
By way of example, the inventors envisage a three active delivery device containing
abamectin,
albendazole and tricalbendazole. The first and second actives are nematocidal, while the
latter two are flukicides. Such a composition
would thus provide two double combinations in a single product containing three actives.
A major impediment to others developing short-acting controlled released devices has thus
been the requirement for toatal degradation of the
delivery mechanism. The delivery mechanism of the present invention may preferably be
an intraruminal bolous which remains in place due
to this density and which degrades completely, leaving no residue in the animal.
A number of intraruminal boluses are knoen in the art which could be adapted for use in
the present invention, such as those described in
WO 95/19763 and WO 01/87273.
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PCT/NZ2004/000267 Received 17 June 2005
In some embodiments, two active agents may be incorporated into the core of an intraruminal
bolus, with a third
active agent in the form of a tablet added to one end of the bolus. In this manner a triple
combination of active
agents can be delivered- the first as a result of the degradation of the tablet to give an
initial dose, followed by the second and third active agents in comination released from
the bolus over a period of between 3 and 14 days as descrived above.
Advantage of the present Inventon Include:
1. High efficacy even In the face of moderate levels of resistance
2. Ratardation of th e further development of resistance
3. Complete degradation of the device , leaving no residue inthe animal
4. Combination of otherwise incompatible actives in a solid matrix
5. Although a slow release device, it will not be sufficently long-acting to pose a
serious
risk to developing resistance (as with the 100 day CRCs), or require a long with holding
period.

6. Although a slow release device, it will deliver doses at or near the same rate as
standard oral
anthelmintics, significantly higher than other slow release devices, providing greater
efficacy.
7. Ability to be used with large animal over 100 kg, due to the ease of use resulting
in a viable method of delivering combination products to cattle and deer.
It is thus anticipated that the delivery method may provide increased efficacy

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PCT/NZ2004/000267 Received 17 June 2005
against parasites not normally killed effectively by a single oral dose.
Oral albendazole has a label claim for efficacy apperrs variable and less than desirable (Coles
& Staford 2001,
Veterinary Record 148: 723-724.) As in the case of nematadose,
extended exposer of flukes to albendazole substantially increases efficacy
(Kwan et al. 1988. Journal of Controlled Realease 8:31-38).

Delivery of albendazole through the methode of the present invention is
anticipated to substatially increase efficicacy against adult flukes. Further, while
single dose albendazole appears to be ineffective against immature flukes, the
latter may succumb to the longer-term administration of albendazole provided
by the present invention.
The present invention further provides a composition, delivery means and
methode of manufacture thereof, for delivering an effective amount of two or
more active agents to animals over a period of between 3 and 14 days.
BRIEFF 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 shows a typical dose/efficacy profile of a single dose of oral
antheinminitics;

Figure 2 Shows a typical dose/ efficacy profile of a typical slow release
device, and

Figure 3 Shows a dose/efficacy profile of one preferred embodiment, of the

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PCT/NZ2004/000267 Received 17 June 2005
present invention

BEST MODES FOR CARRYING OUT THE INVENTION

Figure 1 shows typical dose/ efficacy profile of a single, high dose of an pral
antheimintic. The oral dose removes greater than 95% of susceptible parasites
and provides the animal with a period of time with a low parasite burden,
However , this is followed by rapid re-infection.

Figure 2 shows a typical dose/efficacy profile of a current slow release devices.
These devices a typical dose/efficacy profile of a current slow release devices.
These devices deliver a low levels of a single antheiminitic over a long period of
time (10 days). It acts as a prophylactic, maintaing parasites at low level.
This limits re-infection for about 100 days. Efficacy is similar to that provided by
a single oral dose as shown by Figure 1, but can require a long withholding
periods after use.

Figure 3 shows a dose/efficacy profole of one preferred embodiment of the
present invention. Parasites are removed at a very high efficacy, with some
delayd onset of re-infection and delayed resistance. The extended short
duration of exposure (between 3 and 14 days) requires only a short withholding
period after use.

Proof of concept trials

Two aspects of the present invention which increase efficacy include A) the
concept of extended duration and B) the combining of multiple actives; both
independently contribute to increasing efficacy.

A) Extended duration.

Proof of concept for increasing efficacy with extended duration was

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PCT/NZ2004/000267 Received 17 June 2005
demonstrated in two different ways i) trials were conducted using repeated oral
dosing to achive extended duration thereby simulating a controlled release
device and ii) Trials were conducted using prototype boluses releasing either
albendazolie or abamectin, hereafter referred to as the "Magnum" boles.
Results are given below;



these results showed that against a range of resistant parasites extending the
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duration of worm exposure to drug was always as good and often far superior to
administering a single oral dose. In addition the varying dose rate as high as possible,
specification.

ii) Trials 3 & 4 - rotype magnum boluses releasing albenzazole in sheep and abamectin in cattle to achive extended duration of expoure.

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B) Combining activites.
Efficacy data for combining Benzimidazole and Levamisole actives against
resistant parasites is reasonably common. Furher, there is considereable
evidence that these actives wirk independently and so it can be expected their
comblned efficacies will work in an additive manner (Anderson et al. 1991.
Australian Veternity Journal 68, 133-136). Hence the expected efficiency of
combining two or more actives can be calculated and compared with the
measured value.

e.g Farm 4 from Anderson et al, 1991
Efficacy of Levamlsole 88%
Efficacy of albendazole 73%
Efficacy of Levamisole + albendazole 95%
Efficacy expected based on additive effects 97%

Data on combining the benzimidazole and macrocyclic lactone classes of
actives (as is propsed in this specification) is harder to find, some does
exist for goiats.
e.g Data from pomroyet al, 1992 (New Zealand Vaterniary Journal 40,76-78)
Efficacy of ivermectin 27%%
Efficacy of oxfendazole 82%%
Efficacy of ivermectin + oxfendazole 97%
Efficacy expected based on additive effects 87%

This concept has again been for the present invention by constructing
and testing for efficacy a Magnum bolus releasing 2 actives simultaneously. A
prototype sheep bolus designed to release 5 mg/kg of albendazole and 0.18

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mg/kg abamectin in a 50 kg sheep was tested against two species of multiple
drench resistant parasites. Trial lambs ranged in weight from 48-55.5 kg

the result show a substantial increase in efficacy of the Magnum bolus over a
combination of the same actives administered as two single oral doses. This
suppots the anticipated synergy which is the foundation of the present
invention, i.e extended delivery of each active gives increased efficacy, but by
combining multiple actives an even greater step up in efficacy is achieved against resistant worms.
This can also been seen in the comparison with
moxidentic which although only a single active is recognised as the potent
single active product on the market.
C)Efficacy against flukes (Fasciola hepatica)
To test the efficacy of prolonged exposure to albendazole against liver fluke a trial was conducted
using an albendazole only bolus in sheep. Sheep from a commercial farm with a previous history of fluke infections
were screened by faecal egg count to identify animals carrying fluke infections.
These animals were than randomly allocated to one of two treatment groups on
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PCT/NZ2004/000267 Received 17 June 2005
the basis of these egg counts and one group was administered a magnum
.bolus
releasing 5 mg/kg in a 50 kg animal. Twenty days after treatment all animals
were
slaughtered and livers recovered for fluke counts. Mean numbers of flukes
recovered were 12.8 and 2.0 from the control and treated groups
respectively, equating to an 84 % reduction as a result of treatment.
Thus treatment with the Magnum bolus containing albendazole has resulted
in a measureable efficency
against liver flukes.
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.
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Amended Sheet IPBA/AU

WHAT WE CLA1M IS:
1 A method of reducing parasites in animals characterised by the step of :
Introducing to the animal a single delivery device containing two or more
active agents selected from at least two types of anthelmintic compounds of differing
chemical groups ;
Wherein the delivery device is an intra-ruminal bolus configured to release an effective
amount of active agents each day for a
period of between 3 and 14 days.

2 A methd as claimed in claim 1 wherein the said two or more anthelmintic compounds have
different activities.
3 A methd as claimed in claim 1 or claim 2 wherein the active agents are released at a
substantially continuous rate.
4 A composition as claimed in any one of the above claims wherein the said two or
more active agents effect a reduction in the parasite burden of the animal
5 A method as claimed in any one of the above claims wherein the said two or more active agents affect
a reduction in the number of resistant
parasites in the animal.

6 A method as claimed in any one of the above claims wherein said anthelmintic compounds are
selected from those exhibiting activities selected from the group
including: nematocidal, flukicidal, trematocidal, cestocidal, ectoparasiticidal activites and
combinations thereof.

23
AMENDED SHEET

11 A composition as claimed in claim 10 wherein the ben/imida/olc is albenda/ole
1 2. A composition as claimed in claim 11 wherein the albenda/ole is delivered at a dosage of substantially 3 0-5 0 mg Vg day
13 A composition as claimed in any one of the above claims wherein said anthelminic compounds
include trealbendazole
14 A composition as claimed in am one of the above claims wherein the animal is a sheep
15 A composition as claimed in any one of the above claims wherein active agents arc released each
day for a period of between 5 and 10 days
16 A composition as claimed in any one of the above claims wherein active agents arc released each
day for a period of between 6 and S days
17 A composition as claimed in any one of the above claims wherein the parasite is an cndoparasitc
selected from the group including helminths, ncniatodes, ecstodes, irematodes, and combinations
thereof
18 A composition as claimed in any one of claims 1 to 16 wherein the parasite is an ectoparasite
selected from the group including ticks, lice, flics, fleas, and combinations thereof
19) A composition as claimed in any of the above claims wherein the delivery device is a controlled release device
20) A composition as claimed in any one of the above claims wherein the delivery device delivers a maximum integral dose
21 The use of two or more anthelmintic compounds of differing chemical groups in the manufacture of a delivery device as claimed in claim 21
22 A composition intended to be used as a medicament for the purpose of reducing parasites in animals
substantially as described herein with reference to and as illustrated by the accompanying description and examples
24 AMENDED PAGE