NZ617203B2 - Ectoparasitic treatment method and composition - Google Patents
Ectoparasitic treatment method and composition Download PDFInfo
- Publication number
- NZ617203B2 NZ617203B2 NZ617203A NZ61720313A NZ617203B2 NZ 617203 B2 NZ617203 B2 NZ 617203B2 NZ 617203 A NZ617203 A NZ 617203A NZ 61720313 A NZ61720313 A NZ 61720313A NZ 617203 B2 NZ617203 B2 NZ 617203B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- spinosyn
- sheep
- lice
- animal
- spinosad
- Prior art date
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Abstract
The disclosure relates to a method of treating a non-human animal, particularly sheep infested with biting lice of the species Bovicola ovis, wherein the method comprises the step of administering internally to the animal a pharmaceutically effective amount of spinosyn such that the spinosyn reaches multiple areas of a body of the non-human animal, at least in part via the bloodstream such that spinosyn is present systemically within the animal, wherein the spinosyn is spinosad or spinetoram, and wherein the spinosyn is administered in a total dosage of equal to or less than 40 milligrams per kilogram of the animal such that the spinosyn is administered to the animal in the order of two or more 1 to 6 milligrams per kilogram dosages spaced apart by a day or more. multiple areas of a body of the non-human animal, at least in part via the bloodstream such that spinosyn is present systemically within the animal, wherein the spinosyn is spinosad or spinetoram, and wherein the spinosyn is administered in a total dosage of equal to or less than 40 milligrams per kilogram of the animal such that the spinosyn is administered to the animal in the order of two or more 1 to 6 milligrams per kilogram dosages spaced apart by a day or more.
Description
James & Wells ref: 133718/92
ECTOPARASITIC TREATMENT METHOD AND COMPOSITION
TECHNICAL FIELD
This invention relates to an ectoparasitic treatment method and composition.
In particular, the present invention relates to the treatment of biting lice on sheep,
although it should be appreciated that aspects of the present invention can be
extended to related matters.
BACKGROUND ART
Ectoparasites are a significant animal health concern as well as significantly
affecting production and increasing labour and capital costs.
In general, there are many ways to treat ectoparasites, but it is a continual battle to
find new and more effective treatments.
Referring now to a specific problem the inventors seek to address, lice and
blowflies are the two most significant external parasite problems experienced by
sheep in Australia. Both parasite groups cause extensive production losses and
serious animal welfare concerns. Of these two ectoparasite groups only the lice are
obligate and permanent sheep parasites. That is, they are dependent on spending
their entire life cycle on sheep. The most prevalent and most important of the
sheep lice is the biting louse, Bovicola (formerly Damalinia) ovis.
Lice are typically categorised into those that feed directly on the blood of the host,
i.e. sucking lice, and those that feed on the skin surface (e.g. on secretions and
James & Wells ref: 133718/92
skin debris), i.e. biting (or chewing) lice. Three species of sucking louse are known
to occur on sheep but are rarely identified or implicated in production losses or
disease in Australia. These are Linognathus ovillus (the face louse) and
Linognathus pedalis (the foot louse) and Linognathus africanus (O’Callaghan et al.,
1989).
In Australia, lice have been estimated to cost the wool industry more than $120
million per year. Such costs include expenditure on treatment and control of
infestations as well as production losses. Significant reductions in fleece value (e.g.
up to 30%), greasy fleece weight and clean fleece weight have all been
demonstrated in lice-infested flocks (Wilkinson et al., 1982; Niven & Pritchard,
1985; Elliott et al., 1986; Cleland et al., 1989). Lice infestation has also been
shown to detrimentally affect the colour of the fleece, i.e. making it less bright and
more yellow (Kettle and Lukies, 1982), and can result in the downgrading of skins
due to ‘cockle’ (Heath, 1995a).
The impacts on animal welfare and production due to sheep lice (i.e. B. ovis) are a
consequence of the irritation experienced by infested sheep. Primarily, the sheep
show signs of pruritus (itchiness) such as rubbing, biting and scratching and these
behaviours damage the integrity of the fleece (e.g. causing ‘pulled’ or cotted wool).
In some sheep the pruritus can be intense and the irritation can manifest as
changes to the skin, including increased scurf and thickening of the epidermis and
overlying lipid layer (Britt et al. 1986; Heath et al. 1995b). There is variation
between individual sheep susceptibility to lice and this may be linked to an immune
response to infestation (James 1999; James et al. 2002).
B. ovis are recognised as feeding on “skin scurf, lipids, loose stratum corneum
squames and bacteria” (James, Moon & Brown, 1998). Although most lice
(particularly adults) have been observed in the fleece, away from the skin surface,
1 rd
http://www.wool.com/Grow_LiceBoss.htm Accessed on: 3 May 2012.
James & Wells ref: 133718/92
they are quite mobile and are likely to feed on substrates other than just the loose
debris present at that location (Sinclair, Butler & Picton, 1989). The feeding
behaviour of B. ovis at skin level appears to occur only on the surface of the
epidermis and does not bring it into direct contact with the internal tissues or blood
of the host. Observations have determined that B. ovis “does not ingest nucleated
keratinocytes and apparently does not penetrate deeper than the outer layers of
the stratum corneum” (James, Moon & Brown, 1998).
Lice are transmitted between sheep via direct contact. Lice control relies upon
effective chemical treatment of an entire flock and subsequent biosecurity
measures to prevent re-infestation (i.e. exclusion of lice-infested sheep). Due to
the surface-feeding habits of B. ovis, all successful chemical treatments previously
used have involved topical delivery of the lousicidal chemical. The methods used
can be broadly categorised into high-volume application of diluted chemical (i.e. in
water) or low-volume delivery of concentrated chemical formulations.
High-volume application methods used in the past have included plunge dips,
shower dips, jetting races and hand jetting. These methods require prolonged
wetting of the animal or high-pressure jets to ensure adequate penetration or
saturation of the fleece with the chemical solution (Rothwell, 2005). Although they
have often proven to be very reliable some disadvantages of these methods of
application include the capital expenditure on equipment, additional labour
required, exposure of operators to chemical (Anon., 2006), stress to animals,
secondary disease problems (e.g. transmission of infections), in-use maintenance
of adequate chemical concentrations (Levot, 1995) and the safe disposal of left-
over chemical solution (Levot, Lund & Black, 2004; Beynon, 2012).
Low-volume application methods have become very popular due to their
convenience and include pour-on and spray-on formulations. These products are
generally ready-to-use and the operator applies them to individual sheep using a
James & Wells ref: 133718/92
manual or gas-powered applicator. There is inevitably a high concentration of
chemical at the sites of application but its subsequent distribution through the
fleece and over the skin is uneven. Persistent chemical residues from some of
these products have been identified as a potential environmental risk when the
wool is processed at scouring plants (Anon., 2006). Furthermore, the uneven
distribution and persistence of sub-lethal concentrations of chemicals in the fleece
have been implicated in accelerating the development of insecticide resistance
within sheep lice populations (Johnson, Boray & Dawson, 1992; Rothwell, 2005).
Insecticide resistance within sheep lice populations in Australia has become a
significant problem. Reports of synthetic pyrethroid (SP)-based lousicide failures
became frequent in the mid-1980s and resistance to the insect growth regulator
(benzoylphenyl urea) pour-on products emerged around 2003-2004 (Levot &
Sales, 2008). Chemical groups to which sheep lice in Australia are generally
regarded as susceptible include the organophosphates (OPs), macrocyclic
lactones (MLs), neonicotinoids and spinosyns. However, the limited number of
different product formulations containing these chemicals restricts the ability of
sheep producers to choose between different methods of application.
It is evident that an ideal lousicide will:
1) Incorporate an active ingredient to which sheep lice are known to be
susceptible
2) Deliver a high level of lousicidal efficacy
3) Be safe for administration to sheep
4) Rapidly deliver lethal insecticide concentrations to all areas of skin where
the lice reside
) Be convenient for the operator to apply
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6) Minimise operator exposure to the chemical
7) Ensure minimal chemical residues persist in the fleece
8) Not require disposal of used or excess chemical into the environment
It can therefore be seen why there is continued research to find effective ways to
treat ectoparasites – biting ones in particular. An ideal treatment would achieve a
high insect mortality rate (via even exposure of the parasites to lethal chemical
concentrations), have no detrimental effects on the host animal, be cost effective
and not labour intensive, and it would be safe for operators and the environment.
It is an object of the present invention to address the foregoing problems or at least
to provide the public with a useful choice.
All references, including any patents or patent applications cited in this
specification are hereby incorporated by reference. No admission is made that any
reference constitutes prior art. The discussion of the references states what their
authors assert, and the applicants reserve the right to challenge the accuracy and
pertinency of the cited documents. It will be clearly understood that, although a
number of prior art publications are referred to herein, this reference does not
constitute an admission that any of these documents form part of the common
general knowledge in the art, in New Zealand or in any other country.
Throughout this specification, the word "comprise", or variations thereof 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.
Further aspects and advantages of the present invention will become apparent
from the ensuing description which is given by way of example only.
James & Wells ref: 133718/92
DISCLOSURE OF THE INVENTION
According to one aspect of the present invention there is provided a method of
treating an animal infested with biting lice
characterised by the step of
administering internally to the animal a pharmaceutically effective amount of at
least one spinosyn such that the spinosyn is present systemically within the animal.
According to a further aspect of the present invention there is provided a
composition when used for internal administration to an animal to treat biting lice,
the composition including at least one spinosyn in the order of 0.1% to 65 w/v.
According to a further aspect of the present invention there is provided a use of a
composition including a pharmaceutically effective amount of at least one
spinosyn, wherein the use includes administering the composition internally to the
animal such that the spinosyn is present systemically within the animal,
characterised in that the use of the composition is for the treatment or prevention
of biting lice.
According to yet another aspect of the present invention there is provided a
dosage regime to treat biting lice on an animal characterised by the step of
administering at least one spinosyn internally to the animal with a total dosage of
equal to or less than 100 milligrams per kilogram animal.
Throughout the specification, the use of the present invention will be described
mainly in relation to the treatment of biting lice on sheep (Bovicola ovis). It
should be appreciated however that the principles in the present invention
could apply to and be useful for other situations – for example treating
biting insects on other ruminant and camelid species. Many of the
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problems associated with sheep are also present in, for example, cows,
goats, and alpaca, albeit with different species of biting lice. The inventors
expect that the present invention may be applicable, for reasons discussed
herein, to many animals that are prone to, or suffer from, biting lice. Such
animals that are prone to different species of biting and sucking lice are well
documented, for instance as outlined in Livestock Pest Management
(herein incorporated entirely by reference).
The medicament can be administered to the animal by a variety of means.
For example, in one embodiment the medicament may be administered orally, for
example with a drench gun such as that used for other medicaments.
Alternatively, an injectable liquid may be used and delivered via an injector – for
example such as that used to deliver antibiotics.
However other methods may be incorporated, for example solid dose forms (e.g.
tablets, pellets, boluses, implants) or other routes of administration/absorption (e.g.
transcutaneous, transmucosal).
A critical aspect of the invention however is that regardless of the mode of
administration, the spinosyn is present systemically within the animal.
Overview of prior art uses of spinosyn and other lousicides
The first major chemical group that included systemic pesticides used for control of
ectoparasites on animals were the organophosphates (OPs). These systemically-
active chemicals were absorbed by the animal and carried, via the bloodstream, to
the parasite (Khan, 1964; Pitman & Rostas, 1981). During the 1960s there was a
Edward Walker and Julie Stacheki Livestock Pest Management: A Training Manual for Commercial
Pesticide Applicators (Category 1D) (Michigan State University, United States, 1996)
James & Wells ref: 133718/92
significant focus on development of systemic parasiticides for livestock with over
100 new compounds tested during this period (Khan, 1969). The new,
systemically-active compounds significantly influenced the evolution of
ectoparasiticide products for livestock and three major trends were identified by
Drummond (1985):
1) A reduction in the amount of material applied dermally (i.e. from spray or
dip, to pour-on, to spot-on)
2) Increasing use of oral or percutaneously-absorbed chemicals to control
various ectoparasites
3) The development of sustained-release devices to provide prolonged
efficacy
During this period extensive research was conducted into the systemic OP
chemicals for use in livestock species. There was a universal shift from high-
volume to low-volume dermal application methods (e.g. from dip to pour-on
formulations) and the introduction of alternative routes of administration of
systemic ectoparasiticides (i.e. oral or injectable). Despite these developments to
products for other livestock and/or parasite species, no such advances occurred in
the control of sheep lice, which are known to be biting lice not sucking lice. That is,
until introduction of the (non-systemic) SP pour-ons in the early 1980s.
Therefore, for two decades (i.e. from 1958 until registration of the SPs), Australian
sheep producers were reliant upon OP and arsenic-based dips for control of sheep
lice (Levot, 2001). Numerous OPs were available for use on sheep, the most
popular including: diazinon, chlorfenvinphos, coumaphos, fenthionethyl and
carbophenothion (Levot 2001). These chemicals were usually applied by plunge or
shower dipping – a mode of application intended to bring the chemical into contact
with the parasite rather than via systemic absorption (Pitman & Rostas, 1981).
James & Wells ref: 133718/92
Unfortunately, during this period, “the incidence of properties with lice was 25-30%”
and “many treatments were ineffective” (Levot, 2001). In addition, there was
regulatory pressure to quarantine those flocks affected (Levot, 2001).
Within this context there was certainly strong demand for new and effective sheep
lousicide products during the 1960s and 1970s in Australia. Unfortunately none of
the developments in OP control of biting lice on other livestock species, e.g. cattle,
were successful in sheep. For example, a fenthion-based product for sheep
(Tiguvon® Sheep Dip) was available in Australia from the late 1960s. The efficacy
of fenthion as a systemic insecticide for use in cattle was described in 1967 (Cox,
Mullee & Allen, 1967). Despite the subsequent development of fenthion into a
highly-effective systemic spot-on for sucking and biting lice on cattle (Tiguvon®
Spot-On Cattle Lice Insecticide), released in the early 1970s, a low-volume
fenthion-based product was never successfully developed for control of sheep lice.
Coumaphos was another OP with established systemic activity in cattle (Cox,
Mullee & Allen, 1967) that was used extensively for control of sheep lice in
Australia from the 1960s. As for fenthion, neither coumaphos nor any of the other
OP chemicals with recognised systemic activity in other species and/or against
blood-feeding parasites of sheep were developed into systemically-active products
for sheep lice control.
The next major class of parasiticides to be developed with systemic activity were
the MLs. These chemicals have been used extensively for control of internal and
external parasites of sheep and cattle since abamectin was introduced in Australia
in 1985 (Holdsworth, 2005). The term ‘endectocide’ was coined to describe the
MLs because they have been so successful for control of both internal (endo-) and
external (ecto-) parasites.
James & Wells ref: 133718/92
Abamectin, ivermectin, doramectin eprinomectin and moxidectin have all
demonstrated activity against biting lice on cattle, i.e. Bovicola bovis (Titchener et
al, 1994; Clymer et al, 1998; Colwell, 2002; Holste, 1997; Lloyd et al, 2001; Lloyd
et al, 1996). However, due to their skin-surface feeding habits, B. bovis are more
susceptible to the topical formulations of MLs applied on or near the sites of
infestation than those administered by injection (Logan et al, 1993; Cleale, 2004).
Consistent with this observation is the fact that “sucking lice are typically more
susceptible to injectable formulations of macrocyclic lactones than are chewing
lice” (Cleale et al, 2004).
Although the purely systemic route of ML delivery to B. bovis is not ideal, injectable
products based on doramectin and moxidectin carry claims to “aid in the control” of
this parasite in Australia. Products based on all of the MLs (except eprinomectin
and doramectin) have been registered and used extensively since the 1980s for
control of internal parasites of sheep in Australia. Topical formulations, i.e. an
ivermectin jetting concentrate and an abamectin pour-on, have been used for
control of B. ovis on sheep.
However, despite the experience with biting lice in cattle, none of the MLs delivered
via the systemic route have been registered for control of biting lice on sheep.
Likewise, a search of the published literature does not yield evidence of any of the
MLs providing control of these sheep lice when administered via the systemic
route.
Doramectin has shown efficacy against biting lice when administered by injection
to cattle. Based on published literature (Barber et al, 2003), this formulation was
selected as a good candidate to provide sufficient systemic levels to control sheep
lice following injection. Yet, doses up to 3-times that recommended for cattle were
administered to sheep with natural infestations of B. ovis. No efficacy against the
lice populations was observed (data not published).
James & Wells ref: 133718/92
The consensus in published literature is that, despite their activity against other
ectoparasites of sheep, the MLs delivered via the systemic route do not provide
effective control of the biting louse, B. ovis (Coop et al, 2002; Bates, 2004). In
reference to B. ovis, Bates (2012) states clearly: “No ML injection is effective
against chewing lice”.
The reasons for the differences observed in ML activity following systemic
administration for biting lice on cattle and sheep are unclear. Although related, B.
bovis and B. ovis are distinct species of biting lice, which are known to be very
host-specific. This means that each louse species is highly adapted to its particular
host animal species. In other words, B. bovis cannot infest sheep and B. ovis
cannot infest cattle. Given that the lice are host-adapted, there may be differences
in their biology (e.g. preferred skin substrates to feed on, frequency of feeding,
proximity to skin surface, mobility) that make B. bovis on cattle more susceptible to
MLs (and perhaps OPs) delivered via the systemic route.
Theoretically, some chemicals present in the blood stream may be delivered to the
skin surface by diffusion between cells of the skin (intercellular), diffusion through
cells of the skin (intracellular), diffusion into the hair follicles, secretion in sweat,
secretion in sebum or by accumulation inside epidermal cells which gradually move
towards the skin surface (Patzelt et al 2008).
It is not known precisely which of these mechanisms are responsible for the
delivery of ML and OP chemicals to the skin surface of cattle where they can exert
an effect on B. bovis. However, marked differences in the skin layers and
appendages (i.e. hair follicles, sebaceous glands and sweat glands) are known to
occur between different species.
For example, cattle skin may have around 890 follicles/cm whereas a Merino
sheep can have up to 10,000 follicles/cm (Mills & Cross, 2006). The density of
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blood vessels, thickness of the skin, and the rate and composition of the
sebaceous secretions can also differ (Mills & Cross, 2006). It is evident that the
significant structural and physiological differences between the skin of cattle and
sheep could certainly influence the delivery of chemicals to biting lice feeding on
the skin surface.
Also, the different structural and chemical features that exist between compounds
are known to have a considerable and often unpredictable consequence on their
potential to transfer from the bloodstream to the skin surface in humans (Patzelt et
al 2008). The same variability is expected in other mammals and further
compounded by the physiological differences between non-human species.
Therefore, although OPs and MLs have been shown to have a therapeutic effect
against biting lice in cattle when administered systemically, it does not translate
that other actives will be able transfer to such vectors in a similar mode of action.
WO 0111961 and WO 0111962 (Eli Lilly and Company) both describe formulations
containing spinosyn for controlling insects/pests in small ruminants, such as sheep
and goats. The formulations and methods of controlling these insects/pests are
described as being topically applied to a ruminant.
This follows the general understanding that to treat biting lice, such as those seen
on sheep, the spinosyn containing composition was topically applied. This general
consensus is further supported by the review of spinosyns and their use in Kirst et
al .
NZ 516790 describes an oral formulation for controlling an ectoparasite infestation
on a companion animal for a prolonged time, said formulations comprising a
spinosyn component. NZ 516790 follows conventional wisdom in that it describes
Current Topics in Medicinal Chemistry 2002, 2, pages 675-699
James & Wells ref: 133718/92
a method of treatment only to be used for killing sucking lice, which feed from the
blood of the animal.
Pages 7-8 of NZ 516790 provides a good overview on the understanding and
spinosad usage for treating lice:
“Systemic efficacy (ingestion of blood containing spinosad
by the blood feeding parasites, such as fleas) provides
different mode of exposure compared to topically applied
ectoparasitcides where contact with the parasite at the skin
surface is the mode of exposure. The advantages of oral
systemic treatments and killing of parasites from ingestion of
blood, compared to topical applications and contact killing
include:
a) Reduced exposure to the human applicator and
children and objects in the animal’s environment (e.g.
flooring, carpets, furniture),
b) No worry about loss from exposure of the animal to
water (lakes, streams, bathing, etc) or from loss due
to rubbing,
c) No concern about UV exposure and degradation
d) No problems with oxidation from oils on skin, etc; and
e) Assurance that the entire dose is administered
(compared to a topical application where some of the
dose may drip off, rub off and/or maintain in the
dispensing tube immediately after treatment ) . ”
[EMPHASIS ADDED]
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It is clear from this passage that there are many advantages to systemic treatment
opposed to topical treatment for killing lice.
WO 03024223 describes the use of a synergistic combination of spinosad and a
macrocyclic lactone. The trials therein show that systemic use of spinosad is more
effective than contact application. However, opposite the present invention, the
term “systemic” is used in regard to the pest (i.e lice) rather than the host (e.g.
sheep). While the trials did determine that ingestion of sheep epidermis treated
with the composition is effective in killing the lice, it does not teach that systemic
administration to the host is effective at killing the lice.
Given the different structure of the skin between sheep and cattle, and the general
understanding in the art, as discussed above, it would be unexpected that systemic
administration of a spinosyn would provide a therapeutic effect by killing biting lice
such as those on sheep.
It can be summarised that it has been commonly understood and is general
practice to:
- treat biting lice with topically applied spinosyn compositions as the active
agent will be present on the external surfaces which are ingested by the
lice; or
- treat sucking lice with systemically applied spinosyn compositions as the
active agent will be present in the blood.
Definitions
Throughout this specification, the term spinosyn (also known as fermentation
product A83543) should be taken as meaning any compound, a derivative or
analogue thereof, either naturally derived or synthetically derived, generally having
a 5,6,5-tricyclic ring system, fused to a 12-membered macrocyclic lactone, a
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neutral sugar (2N,3N,4N-tri-O-methylrhamnose) and an amino sugar (forosamine).
The meaning of spinosyn is further outlined in NZ 531787, the contents of which
are incorporated herein in its entirety for reference.
The family of natural components of A83543 include a genus taught in EP
0375316 and having the general formula:
wherein R is H or a group selected from
2 4 3 5 6
and R , R , R , R and R are hydrogen or methyl; or an acid addition salt thereof
when R is other than hydrogen.
Spinosyns are known to occur in over 20 natural forms and currently can be
provided in over 200 synthetic forms. Incorporated herein by reference, Kirst et al
and NZ 516790 further outlines the scope and variants of spinosyns. As discussed
in Kirst et al and NZ 516790, one such example is Spinosad which includes a
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racemic mix of two spinosyns, Spinosyn A, the major component and Spinosyn D
(the minor component), an approximate 17:3 ratio.
An example of a more recent spinosyn derivative is ‘spinetoram’ which, when
compared to Spinosad, has been found to be effective against a greater spectrum
of insect pests with an increased potency and duration of efficacy . Spinetoram
includes a major component (3’ethoxy-5,6-dihydro spinosyn J) and a minor
component (3’-ethoxy spinosyn L).
Throughout this specification, the term biting/chewing lice should be taken as
meaning ectoparasites whose mouthparts are adapted for chewing, and eat skin
fragments, skin secretions, feathers, hair and/or wool.
Throughout this specification, the term sucking lice should be taken as meaning
ectoparasites whose mouthparts are adapted for sucking the blood of their host.
Throughout this specification, the term systemic treatment should be taken as
meaning any treatment which is applied internally to an animal and which reaches
different areas of the body primarily through the bloodstream. For example, this
may include oral, parenteral, and anal delivery.
Throughout this specification, the term topical treatment should be taken as
meaning any treatment which is applied onto an external surface of an animal such
as the skin or hair/wool of an animal.
Throughout this specification, the term Bovicola ovis should be taken as meaning a
sheep body louse (plural = lice).
Sparks, T.C., Watson, G.B. and Dripps, J.E. (2010) A6 Addendum: The Spinosyns. In: Insect Control:
Biological and Synthetic Agents, Eds: Gilbert L.I. and Gill, S.S., Academic Press, London
Kirst, H.A. (2010) The spinosyn family of insecticides: realizing the potential of natural products
research, The Journal of Antibiotics, vol. 63, pp 101-111.
James & Wells ref: 133718/92
Preferred embodiments of the present invention
Preferred method of treatment
Preferably the biting lice is the species Bovicola ovis (B.ovis).
As discussed previously, it was very unexpected that spinosyn, when administered
systemically, would have been effective in treating biting lice (B.ovis) in sheep,
especially due to the different characteristics between the skin of sheep and other
animals (e.g. cows).
Preferably the animal is a sheep.
Bovicola ovis is a species of lice specific to sheep, known to be biting lice rather
than sucking lice. With knowledge of the present invention, the inventors
extrapolated that spinosyn may also be effective for systemic treatment of biting
lice present in other animals beyond sheep.
Preferably, the administration route is oral.
For example, it is envisaged that the composition may be provided as a
suspension, tablet, powder, drench or the like.
Alternatively, the administration route is via injection.
Regardless of whether the administration is oral or via injection, the main
advantage of systemic administration is that it helps to ensure the total dosage is
being given to the animal. With topical administration, as per conventional wisdom
with spinosyns used for biting lice, the disadvantage is the dosed medicament may
be licked off by other animals, rubbed off by the animal or possibly be washed
away in rain.
Preferably, the spinosyn is spinosad.
James & Wells ref: 133718/92
As noted above, spinosad is a mixture of spinosyn A and spinosyn D. These two
spinosyns are currently known as very effective types of spinosyn insecticides.
Also, spinosad is beneficial to use as per the present invention, as it is already
used both topically (for biting lice) and systemically (for sucking lice). Therefore, it
is known to be safe to use, has low side effects and has widespread approval
amongst the farming industry.
Of course, it should be recognized that other forms of spinosyn (whether currently
available or developed in future) may be used in the present invention without
departing from the scope thereof. One such preferred example of a spinosyn
derivative, more recently identified as being particularly effective, is spinetoram.
Indeed, it is thought that other members of the spinosyn insecticide class may also
have the physicochemical properties, similar to spinosad, that are required to be
effective via this route.
It is believed by the inventor that contrary to expectations, a systemic introduction
of a spinosyn causes the chemical to be present in vectors that biting lice feed on,
for example skin, skin secretions and associated debris (e.g. dead cells) at
concentrations sufficient to be lousicidal.
It should be appreciated that the present invention can be co-formulated with other
active ingredients, for example anthelmintic treatments, vaccines, vitamins/mineral
supplements and the like. Not only does this offer advantages by having two or
more treatments being delivered in a single dose, but there may also be
complementary effects resulting. For example, the inclusion of vitamins and
minerals may assist the skin recovery of an animal once the biting lice have
disappeared as a result of the insecticide treatment.
James & Wells ref: 133718/92
Preferred composition
It is envisaged that preferred compositions will include spinosyn in the order of 0.1
% to 65 % w/v as.
Preferably, the concentration of spinosyn is 1 % to 35% w/v.
More preferably, the concentration of spinosyn is approximately 9 % w/v.
In preferred formulations, in addition to the active there may be provided dispersing
agents, preservatives, anti-foaming agents and humectants.
Preferably, the composition is prepared as an oral composition. For example, this
may be in the format of a tablet, powder, drench, gel and so forth.
Alternatively, the composition may be in the form of an injectable composition or
sustained release composition such as a bolus or implant, or the like.
Preferred dosage
In the past, Spinosyn previously was administered topically for treatment of biting
lice. One of the advantages identified by the inventors in administering spinosyn
systemically was the lower than expected dose that is required to be
therapeutically effective in ridding the animal of biting lice. After the inventors
arrived at the present invention, the transfer of the Spinosyn from blood to the
external skin surface was still expected to be inefficient and only partial, at best.
Instead, the lower concentrations and dosages used in tudies were for the most
part highly effective at killing biting lice, despite being at levels similar to or even
below those described in NZ 516790 (for killing sucking lice). This was quite
unexpected, and is a considerable advantage, as outlined further below.
James & Wells ref: 133718/92
Trial 1 (see Best Mode section) identified that a daily dosage of about 1620 mg per
sheep was found to be an effective and safe (due to the inherent safety of
spinosyns such as spinosad). However, the inventors were surprised to find that
the dosage could be lowered significantly below 1620 mg per sheep yet still
provide a therapeutic effect.
Therefore, preferably, the daily dosage administered (mg/per sheep) is less than
about 2000 mg/sheep/day.
More preferably, the dosage may be between 100 - 2000 mg/sheep/day.
One significant advantage of these findings is reducing production costs. A further
advantage may be lowering side effects, avoiding a build-up of resistance, and so
forth.
Preferably, the spinosyn is administered at total dosage of equal to or less than
100 milligrams per kilogram of animal.
Although preliminary trials showed no harmful effects were seen when higher total
dosages (e.g. 80 mg per kg) were used, lower dosages also showed acceptable
therapeutic effects.
For instance, after 14 days post treatment (one dosage of 6.75 mg spinosad per kg
animal on day 0), the inventors observed a total depletion of live lice on the sheep.
Although a further 10-fold reduction in dosage (0.675 mg/kg animal) led to only
partial reduction of live lice on the sheep, the inventors still expect that the dosage
may be reduced significantly below 6.75 mg/kg; for example to a total dosage of
about 1-6 mg/kg animal.
The dosage regime may also vary significantly. In preliminary trials, the inventors
identified that either a single or double dosage of 6.75 mg/kg/day (i.e. just on day
James & Wells ref: 133718/92
0, or on both day 0 and day 1) regime was sufficient to eradicate the lice.
However, other regimes may also be suitable, for example depending on the
severity of the condition.
For example, this may include the administration of a number of discrete dosages
over a few days, or alternate embodiments could involve the use of a slow release
device. One such possibility is a sustained release product which releases the
active at low levels over a given period of time, such as 3-7 days.
Naturally, the composition being administered will vary dependent upon the
administration route and whether a single dose will be used or the active is to be
administered over time. Further, as discussed previously, the present invention
can be used with other actives as well.
It can be seen that the present invention has a number of advantages over the
prior art.
Firstly, there is provided an alternate treatment for biting lice which does not have
the intensive labour requirement, capital overheads and potential human health
risks of topical treatments.
Further, by determining a systemic administration route, and an appropriate
dosage level then equal delivery of a sufficiently high dosage to all of the parasites
can be ensured – providing reliable efficacy and avoiding factors that accelerate
the development of insecticide resistance.
Further, minimisation of insecticide residues in the fleece will reduce the risks to
the environment secondary to wool processing.
James & Wells ref: 133718/92
BEST MODES FOR CARRYING OUT THE INVENTION
Preferred compositions are shown in examples 1 to 4 below.
Example 1: Injectable composition
A composition suitable for administration by injection is provided in Table 1.
Ingredient Quantity %w/v
Spinosad 5
NMP 35
Castor oil 14
BHT 0.05
Soyabean oil qs
Table 1
Example 2: Tablet composition
A composition for a 1000 mg tablet, suitable for oral administration is provided in
Table 2.
Ingredient Quantity mg/tablet Quantity %w/w
Spinosad 315 31.5
Monopropylene glycol 55 5.5
Povidone K 30 26 2.6
Dicalcium Phosphate 150 15.0
Microcrystalline Cellulose 150 15.0
Sodium starch glycolate 265 26.5
Aerosil 200 18 1.8
James & Wells ref: 133718/92
Magnesium stearate 21 2.1
Table 2
Example 3: Tablet composition
A further composition for a tablet, suitable for oral administration is provided in
Table 3.
Ingredient Quantity mg/tablet Quantity %w/w
Spinosad 315 31.5
Microcrystalline cellulose 150 15.0
Lactose 285 28.5
Sodium starch glycolate 150 15.0
Povidone K 30 30 3.0
Magnesium stearate 50 5.0
Silicon dioxide, colloidal 20 2.0
Table 3
Example 4: Oral drench composition
A composition suitable for administration as an oral drench is provided in Table 4.
Ingredient Quantity %w/v
Spinosad 9.0
Propylene glycol 12
Tween 80 12
Benzyl alcohol 1.0
Sodium metabisulphite 0.1
PVP K25 2.5
James & Wells ref: 133718/92
Aerosil 200 1.0
Defoamer RD 0.2
Citric acid 1.9
Deionised water q.s.
Table 4
Example 5: Trial 1
In a first trial, a number of lousicide agents were tested to determine their efficacy
for treating biting lice on sheep (B. ovis) when administered systemically. It was
expected as per conventional wisdom that systemic administration would not
present the active compound in vectors which would be consumed by the biting
lice.
Treatment Dose level Dosage regime No. Pre- Day 14 –
Group Sheep treatment – arithmetic
arithmetic mean lice
mean lice per sheep
per sheep
1. Untreated - - 5 316.8 296.2
Once daily for 3
2. Ivermectin 0.2 mg/kg 5 336.6 286.0
days
1620 Once daily for 3
3. Spinosad 5 296.4 0.0
mg/sheep days
Once daily for 3
4. Imidacloprid 5 mg/kg 5 257.6 245.4
days
Table 5
Contrary to expectations, trial 1 illustrated that at 14 days after treatment the live
lice on sheep dropped to zero for the spinosad group (group 3) but appeared
unaffected in the imidacloprid and ivermectin-treatment groups (group 2 and 4).
This supported that spinosad, unlike ivermectin and imidacloprid, unexpectantly
was able to present itself to the biting lice.
James & Wells ref: 133718/92
Example 6: Trial 2
Building on the results seen in trial 1, the results of preliminary trial 2 further
supports the efficacy of systemically administered spinosyn(s) for control and
treatment of biting lice, such as those of sheep (B. ovis). This trial also illustrates
the potential dosage requirements necessary to achieve a required therapeutic
effect.
Five groups of sheep were treated with a range of oral dosages of spinosad as
detailed in Table 6. The average weight of the sheep in the trail was approximately
40 kg. The dosage form used for the trial was the commercially available tablet
Comfortis™, by Elanco™. The tablets used in the trial contained either 270 mg or
1620 mg of spinosad.
The assessment of live lice present on the animals after days 5, 14, 30 and 56 is
provided as a mean for each group in Table 7. Four groups showed 100%
reduction in lice numbers. The lowest dose group showed only a partial and short-
lived reduction in live lice numbers.
Blood plasma levels and fleece concentrations of spinosad were determined for
two of the groups, as shown in Tables 8 and 9. Plasma and fleece concentrations
correlated with the dose administered.
The study again showed, contrary to expectations and what would be expected for
the treatment of biting lice, that systemic administration of spinosad is able to
present itself in at least one vector (e.g. wool) which contains substrates that are
eaten by the biting lice, thereby providing a preventative and/or therapeutic effect.
Daily Dose Daily Dose Total Dose
Administere Administered Dosing Administered No.
Treatment Group
d (approx. Regime (approx. Sheep
(mg/sheep) mg/kg) mg/kg)
1. Spinosad 27 27 Once on Day
0.675* 0.675 5
mg mg/sheep* 0
2. Spinosad 270 270 Once on Day
6.75 6.75 5
mg mg/sheep 0
3. Spinosad 540 270 Once on Day
6.75 13.5 5
mg mg/sheep 0 and Day 1
4. Spinosad 1620 Once on Day
40.5 40.5 5
1620 mg mg/sheep 0
. Spinosad 1620 Once on Day
40.5 81 5
3240 mg mg/sheep 0 and Day 1
James & Wells ref: 133718/92
Table 6: Dosage regime of five treatment groups.
*A single 270 mg spinosad tablet was ground finely and evenly suspended in
approx. 50 mL of water. Each sheep in Group 1 received 5 mL of the suspension.
Treatment Group Total Dose
Mean No. Live Lice per Sheep
Administered
(approx.
Day -5 Day 14 Day 56
mg/kg)
1. Spinosad 27 mg 0.675 269.0 51.2 241.2 446.0
2. Spinosad 270 mg 6.75 337.4 0.0 0.2 0.0
3. Spinosad 270 mg + 270
13.5 261.2 0.0 0.0 0.0
4. Spinosad 1620 mg 40.5 246.2 0.0 0.0 0.0
. Spinosad 1620 mg + 1620
81 212.0 0.0 0.0 0.0
Table 7: Assessment of live lice per sheep over time in five treatment groups
Mean Spinosad Concentration
Total Dose
Administered in Wool (mg/kg)
Treatment Group
(approx.
mg/kg)
Day 14 Day 30
2. Spinosad 270 mg 6.75 0.33 0.20
4. Spinosad 1620 mg 40.5 2.26 0.84
Table 8: Assessment of mean spinosad concentration in wool over time in
treatment groups 2 and 4.
Spinosad Concentration in Composite
Total Dose
Plasma Samples (mg/L)
Administere
Treatment Group
d (approx.
mg/kg)
2 hours 8 hours 24 hours 48 hours
hours
2. Spinosad 270 mg 6.75 0 0.035 0.064 0.076 0.056
4. Spinosad 1620
40.5 0.049 0.17 0.42 0.4 0.18
James & Wells ref: 133718/92
Table 9: Assessment of spinosad concentration in plasma in treatment groups 2
and 4.
Most preferred compositions are given as Examples 7 and 8 below.
Example 7: Spinosad injectable solution 5%w/v
Sl no Ingredients %w/v
1 Spinosad 5
2 Benzyl alcohol 15
Butylated hydroxyltoluene
3 (BHT) 0.05
Glycerine formal stabilised
4 (GFS) qs
Example 8: Spinosad oily suspension 7.5%w/v - Oral
Sl no Ingredients %w/v
1 Spinosad 7.5
2 Cetomacrogol 1000 0.1
3 Hydrogenated castor wax 0.15
4 Sorbitan monooleate (Span 80) 0.1
Aerosil R972 PHARMA 1
6 Methyl paraben 0.075
7 Propyl parabern 0.025
8 Miglyol 812N qs
They were used in the following study outline
Study Outline
Title:
A screening study to evaluate various formulations of Spinosad administered for
control of sheep body lice (Bovicola ovis)
James & Wells ref: 133718/92
Justification:
Release of the APVMA’s preliminary findings from ‘The reconsideration of
approvals of selected sheep ectoparasiticide products and their associated labels’
(2006) highlighted the potential OH&S and environmental concerns associated with
chemical residues in wool. This report proposed to enforce significant changes to
the labels of existing products used for control of lice. A number of products
formerly available for lice control on sheep with long wool would have to be
withdrawn from that use. Development of new products for control of lice on sheep
with long wool is problematic. The levels of chemical required for effective lice
control by backline application to the fleece generally result in wool residue levels
that exceed acceptable limits. Application of products by hand-jet often results in
unacceptable levels of chemical exposure to the operator. Previous studies have
shown lousicide activity when spinosad is administered orally. No signs of toxicity
were seen in any sheep in those studies. This study will determine if spinosad is
effective, safe and will provide a profile of the bioavailability of spinosad in plasma
when administered either as a subcutaneous injection or oral drench.
Animals:
Lousy Merino ewes or wethers, 2-8 years of age, with at least 3 months of wool
growth.
Treatment Groups:
Dose Rate
Treatment Administration
Sheep
Active Vol.
1. Spinosad 7.5% 10 mg/kg 0.13
Oral (By syringe) 4
Oral bw ml/kg
2. Spinosad 7.5% 30 mg/kg 0.40 4
Oral (By syringe)
Oral bw ml/kg
3. Spinosad 5% 5 mg/kg 0.10 Subcutaneous injection 4
Injectable bw ml/kg high on the neck
4. Spinosad 5% 15 mg/kg 0.30 Subcutaneous injection 4
Injectable bw ml/kg high on the neck
James & Wells ref: 133718/92
Details:
Pooled plasma samples to be analysed.
Schedule:
Study Day Activity
Sheep acclimatise to paddock. Sheep drenched (with BZ+LV
-14 to -1
anthelmintic) and vaccinated if required.
Conduct pre-treatment Lice counts.
Allocate to Treatment Groups.
Measure mid-side wool length.
-3 to -1 Group 3&5: Clip jugular veins & injection sites on neck.
Group 3&5: Collect pre-Treatment bloods.
Centrifuge bloods to separate plasma, harvest plasma, split into 2
replicates and store frozen.
Weigh sheep and calculate individual doses.
Treatment.
Include comments on apparent pain on injection.
Group 3&5: Collect bloods at 2, 4 and 8 HAT.
Harvest plasma, split into 2 replicates and store frozen.
Yard observations plus injection site and oral observation comments.
Group 3&5: Collect bloods at 24 HAT.
Centrifuge bloods to separate plasma and store refrigerated.
1 Harvest plasma, split into 2 replicates and store frozen.
Examine injection sites for abnormalities or mouth for ulceration (as
relevant).
Group 3&5: Collect bloods at 48 HAT.
Centrifuge bloods to separate plasma and store refrigerated.
2 Harvest plasma, split into 2 replicates and store frozen.
Examine injection sites for abnormalities or mouth for ulceration (as
relevant).
7-8 Send frozen plasma samples to the laboratory.
7, 28 Conduct lice counts.
56 Complete final study report.
FEC to be conducted as required during the study to maintain health and wellbeing
of sheep
And the highly successful results were
There was a pre-treatment lice burden of 122 lice per sheep averaged over all
groups.
At 7 days post-treatment sheep treated with 10 mg/kg spinosad orally with an oily
suspension had an average of 6 lice per sheep (96% efficacy); sheep treated with
mg/kg spinosad orally had no detectable lice (100% efficacy).
James & Wells ref: 133718/92
At 7 days post-treatment sheep treated with 5 mg/kg spinosad by subcutaneous
injection had an average of 62 lice per sheep (49% efficacy) and sheep treated
with 15 mg/kg spinosad by subcutaneous injection had an average of 45 lice per
sheep (62% 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.
James & Wells ref: 133718/92
Claims (10)
1. A method of treating a non-human animal infested with biting lice characterised by the step of administering internally to the non-human animal a pharmaceutically effective amount of spinosyn such that the spinosyn reaches multiple areas of a body of the non-human animal, at least in part via the bloodstream, wherein the biting lice is the species Bovicola ovis.
2. A method as claimed in claim 1 wherein the administration route is oral.
3. A method as claimed in either claim 1 or claim 2 wherein the spinosyn is spinosad.
4. A method as claimed in any one of claims 1 to 3 wherein the spinosyn is spinetoram.
5. A method as claimed in any one of claims 1 to 4 wherein the spinosyn is administered in a total dosage of equal to or less than 40 milligrams per kilogram of the non-human animal.
6. A method as claimed in any one of claims 1 to 5 wherein the spinosyn is administered over a period of time.
7. A method as claimed in claim 6 wherein the spinosyn is administered in multiple doses.
8. A method as claimed in claim 6 wherein the spinosyn is administered in slow release form.
9. The use of an amount of spinosyn in the order of 0.1% to 65% w/v for the manufacture of a medicament for internal administration to a sheep infested with biting lice.
10. The use of a spinosyn in a dosage regime to treat biting lice on a sheep characterised by the step of administering the spinosyn internally with a dosage equal to or less than 40 milligrams per kilogram of the sheep. James & Wells ref:
Publications (1)
Publication Number | Publication Date |
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NZ617203B2 true NZ617203B2 (en) | 2015-09-01 |
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