WO 2006/127487 PCT/US2006/019513
USEFUL HIGH LOAD CONCENTRATE COMPOSITIONS FOR CONTROL OF
ECTO-AND ENDO-PARASITES
BACKGROUND OF THE INVENTION
Arthropod ectoparasites commonly infecting warm-blooded animals include
ticks, mites, lice, fleas, blowfly, the ectoparasite Lucilia sp. of sheep, biting insects
including keds {Melophagus ovinus) and migrating dipterous larvae such as
Hypoderma sp.and Dermataobia in cattle, Gastrophilus in horses and Cuterebra sp.
in rodents.
Helminthiasis is a widespread disease found in many animals and is
responsible for significant economic losses throughout the world. Among the
helminths most frequently encountered are the group of worms referred to as
nematodes. The nematodes are found in the gastrointestinal tract, heart, lungs,
blood vessels and other body tissues of animals and are a primary cause of anemia,
weight loss and malnutrition in the infected animals. They do serious damage to the
walls and tissue of the organs in which they reside and, if left untreated, may result in
death to the infected animals.
The nematodes most commonly found to be the infecting agents of ruminants
include Haemonchus and Ostertagia generally found in the abomasum; Cooperia,
Trichostrongylus and Nematodirus generally found in the intestinal tract, and
Dictyocaulus found in the lungs. In non-ruminant animals, important nematodes
include Toxocara and Ancylostoma in the intestine and Dirofilaria in the heart of dogs
and cats; Ascaridae in the intestine of swine; and large and small strongyles in
equines.
Arthropod ectoparasites commonly infecting warm-blooded animals include
ticks, mites, lice, fleas, blowfly, the ectoparasite Lucilia sp. of sheep, biting insects
and migrating dipterous larvae such as Hypoderma sp. in cattle, Gastrophilus in
horses and Cuterebra sp. in rodents.
Anti-parasitic macrolide compounds such as LL-F28249α-λ compounds, 23-
oxo or 23-imino derivatives of LL-F28249α-λ, compounds, including, but not limited
to, moxidectin, milbemycin compounds, including but not limited to milbemycin
oxime, avermectin compounds, including, but not limited to abamectin, ivermectin,
and mixtures thereof, are useful for the prevention and control of helminthiasis and

WO 2006/127487 PCT/US2006/019513
infection by acarids and arthropod endo- and ectoparasites in warm-blooded
animals.
Metaflumizone is useful for the prevention and control of infestation by
ectoparasites in warm-blooded animals. Topical administration of this active is a
preferred method for administering this compound.
To provide useful protection against both endoparasitic infections and
ectoparasitic infection or infestation in warm-blooded animals it is desirable to use
formulations having a relatively high loading of active agent, but such formulations
must be stable, both with respect to the physical formulation, and also, with respect
to the chemical stability of the actives. Metaflumizone is one of several useful
insecticidal agents which have found particular application for the control of fleas and
ticks on animals, particularly companion animals such as dogs, cats and horses. It
is particularly advantageous in that it can provide 4-6 weeks of protection from fleas
and ticks in companion animals, but it would be potentially useful for many other
species if suitable formulations could be developed. Nonetheless, formulation of
metaflumizone is made difficult by its insolubility in many solvents, and its instability
in the presence of primary alcohols.
It is the object of the present invention to provide a method for preventing,
controlling or treating helminth, acarid or arthropod endo- or ectoparasitic infection or
infestation in warm-blooded animals which method comprises topically administering
to the warm-blooded animals an anthelmintically, acaricidally or arthropod endo- or
ectoparasiticidally effective amount of a nonaqueous composition which comprises
about 0.1 to 10% w/v of a substantially water-insoluble anti-parasitic macroiide
compound, about 5% to about 40% of metaflumizone; about 0% to about 15% of a
bridging or penetrating agent; about 2 to 8% of a surfactant, and about 50 to 80%
w/v of a pharmaceutically acceptable water-miscible or water immiscible solvent or
solvent system as the carrier.
It is also an object of the present invention to provide a versatile composition
for topical administration which comprises a relatively high loading of metaflumizone
in combination with an anti-parasitic macroiide compound, and which will provide
protection from ecto- and endo-parasitic infestation. Most advantageously, the
formulation can function as a concentrate, which with simple modifications, can be
extended to use for a wide variety of other animals. Thus, the concentrated
formulation can be utilized as a small volume spot-on formulation, for instance, for
protection of companion animals, while further dilutions can be utilized as
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conventional pour-on products for farm animals, with still further dilutions utilizable
for sprays and application to the feed.
It is also an object of the present invention to provide a method for preventing
or treating acarid or arthropod ectoparasitic infestation in warm-blooded animals,
using the compositions of the invention.
It is another object of this invention to reduce or control the proliferation of
such insects in warm-blooded animals for prolonged periods of time by a topically
applied active, with the formulation being mild and gentle enough to avoid adverse
skin reactions upon administration, yet with the ability to be retained in the animal's
skin and/or coat over the time needed for protection.
These and other objects of the present invention will become more apparent
from the description thereof set forth below and the appended claims.
SUMMARY OF THE INVENTION
The present invention provides high-load concentrate compositions for topical
administration which comprise on a weight to volume basis:
about 0.1 to about 10% of substantially water-insoluble anti-parasitic
macrolide compound, especially, moxidectin:
about 5% to about 40% of metaflumizone;
about 0% to about 15% of a bridging or penetrating agent;
about 2 to about 8% of a surfactant and
about 50% to about 80% of a carrier solvent.
The present invention further provides a method for preventing or treating
ectoparasitic and endoparasitic infection or infestation in a warm-blooded animal
which method comprises topically administering to the animal an acaricidally or
arthropod ectoparasiticidaily effective amount of the composition of this invention.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, the high load concentrate
compositions comprise a substantially water-insoluble anti-parasitic macrolide
compound, especially, moxidectin, metaflumizone; an optional bridging agent or
penetration enhancer, a surfactant, and a carrier solvent. The invention also
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provides a method for preventing or treating acarid or arthropod ectoparasitic
infection or infestation in warm-blooded animals by topical application of the
aforesaid formulations.
Preferred high load concentrate compositions of this invention comprise on a
weight to volume basis:
About 0.1 to about 10% of a substantially water-insoluble anti-parasitic
macrolide compound, especially, moxidectin
about 5% to about 40% of metaflumizone;
about 0% to about 15% of a bridging or penetrating agent;
about 2 to about 8% of a surfactant and
about 50% to about 80% of a carrier solvent.
While not wishing to be bound by any particular theory, it is believed that the
compositions of the present invention have the requisite stability by virtue of physical
and or chemical interactions between the surfactant and the metaflumizone. The
exact nature of the interactions is unknown, but apparently the surfactant stabilizes
the metaflumizone in solution so as to ensure that the resultant formulation retains
the desired physical characteristics over time, without loss of potency of the active.
Further, the formulation is sufficiently viscous to be retained upon the animal's skin,
hair, and be released over the desired period of time.
Uniquely, it has been found these high load concentrate compositions can be
further utilized to prepare more dilute compositions for application in various other
manners, i.e., for use as a pour-on for large animals, as a spray for large animals or
for outdoor use, and as a water-dilutable formulation for addition to the feed and/or
water supply of animals under treatment. This has the dual advantage of providing a
concentrated formulation that can be shipped to the end-user for dilution and use, or
to an intermediate formulator to prepare the compositions. The high loading of
metaflumizone in the formulation thus provides a small volume of formulation to use
as a "spot-on" formulation, for instance, for companion animals, especially felines.
The concentrate can then be diluted by an appropriate organic solvent for use as a
pour-on or in a spray, or with water, to provide the feed/water additive.
Metaflumizone is described in U.S. Patent No. 5,543,573, and U. S. Published
Application 2004-0122075A1, both incorporated herein by reference
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Chemically, metaflumizone is known as (E Z)-2-[2-(4-cyanophenyl)-1-[3-
(trifluoromethyl)phenyl]ethylidene]-A/-[4-(trifluoromethoxy)phenyl]
hyd razinecarboxamide.
The substantially water-insoluble anti-parasitic macrolide compounds useful
for the compositions of the present invention are well-know in the art, and are
described in detail in, for instance, "Macrocyclic Lactones in Antiparasitic Therapy,"
edited by J. Vercruysse and R. S. Rew, CABI Publishing, London, 2002. Such
macrolide compounds are subclassed into avermectins and milbemycins, with
avermectins being glycosylated milbemycins. Highly preferred, due to its persistency
of activity, and its environmental friendliness, is the milbemycin moxidectin, sold in
various forms for administration under the Cydectin® tradename.
Bridging agents or penetrating agents or enhancers suitable for use in the
compositions of this invention include, but are not limited to, alkyl methyl sulfoxides
(such as dimethyl sulfoxide, decylmethyl sulfoxide and tetradecylmethyl sulfoxide);
pyrrolidones (such as 2-pyrrolidone, N-methyl-2-pyrrolidone and N-(2-hydroxyethyl)
pyrrolidone); laurocapram; and miscellaneous solvents such as acetone, dimethyl
acetamide, dimethyl formamide, tetrahydrofurfuryl alcohol, cineole, N,N-diethyl-3-
methylbenzamide (DEET), isopropyl myristate (IPM) and dimethyl isosorbide. Other
bridging agents include amphiphiles such as L-amino acids, and fatty acids.
Additional bridging agents are disclosed in Remington: The Science and Practice of
Pharmacy, 19th Edition (1995) on page 1583. Typically, the penetrating agent is used
at a level of about 10% w/v of the formulation where the end use is for a topical
application, but this may vary, especially when the end use of the composition is for
oral administration.
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The surfactant utilized in the present invention may be a single surfactant, or
a mixture of two or more surfactants, again, in part dependent upon whether the end
use of the composition is topical or oral. The surfactant should be non-irritating, and
non-toxic. Preferred are non-ionic, low foaming surfactants, such as the alcohol
alkoxylate surfactants, with those such as nonylphenol ethoxylate (sold under the
tradename Surfonic N-95), and alcohol alkoxylates (sold under the tradename
Synperonic® NCA by Uniqema), and the polyethoxylated caster oil surfactants (also
known as macrogolglycerol ricinoleate, and sold under the Cremaphore® EL
tradename by BASF) being especially suitable. Also useful are ionic surfactants
such as sodium lauryl sulfate and dioctyl sodium sulfosuccinate.
Typically, the surfactant is utilized at a level of about 2 to about 8% w/v of the
composition, but this may vary somewhat depending upon the end use of the
composition. In the case where the end use of the concentrate is as a spray
formulation, or as a water-dispersible feed /water additive, it may be desirable to add
a further surfactant to ensure that the diluted formulation will be a unitary phase.
This ensures that the spray will not block the spray nozzle, and that the active will be
dispersed equally throughout the diluted product. In such cases, the additional
surfactant may be added to the concentrate formulation, or added to the end use
formulation with the diluting solvent. Particularly useful surfactants for use with an
organic solvent diluent are non-ionic surfactants such as polyethoxylated castor oil,
sold under the tradename Cremophor® EL by BASF Corporation.
The carrier solvent for the compositions of the present invention may be a
single solvent, or a mixture of solvents. Due to the instability of metaflumizone in the
presence of primary alcohols, preferred solvents are non-hydroxyl-group-containing
solvents, especially those such as y-hexalactone (gamma-hexalactone). Optionally,
other such solvents such as N,N-diethyl-m-toluamide, eucalyptol, dimethyl
isosorbide, diisopropyl adipate and/or methoxypropyl acetate (1-methoxy-2-propyl
acetate) can be utilized in combination with the y-hexalactone to comprise the carrier
solvent.
To manufacture the high load concentrate composition of the present
invention, the metaflumizone is dissolved in the carrier solvent or solvents, and the
surfactant and bridging agent, if desired added to the mixture. This composition can
then be utilized as a high load spot-on, or further diluted for additional uses.
An especially preferred composition for topical administration to warm-
blooded animals comprises, on a weight to volume basis, about 20% to about 30%
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35

metaflumizone; 0.5% moxidectin, about 10% of a bridging or penetrating agent,
especially dimethyl sulfoxide, about 2 to-about 8%, and especially about 5%, of a
non-ionic, low foam surfactant, and about 50-60% carrier solvent, especially
y-hexalactone.
The high load concentrate compositions of this invention may further
comprise other agents known in the art, such as preservatives (e.g., methylparaben
and propylparaben), colorants, antioxidants, and the like. Generally, these agents
would be present in the compositions in an amount up to about 2% on a weight to
volume basis.
When topically administered, the compositions of this invention are highly
effective for preventing or treating ectoparasitic infection and infestation for
prolonged periods of time in warm-blooded animals such as cows, sheep, horses,
camels, deer, swine, goats, dogs, cats, birds, and the like. Additionally, the
composition is highly effective against endoparasitic infections.
In order to facilitate a further understanding of the invention, the following
examples are presented primarily for the purpose of illustrating specific embodiments
thereof. The invention is not to be deemed limited thereby, except as defined in the
claims.
EXAMPLE 1
Preparation of metaflumizone/moxidectin High Load Concentrate, suitable for use as
a Spot-on
A 100 gram weight of dimethyl sulfoxide (DMSO) is added to 400 grams y-
hexalactone. To this solvent system is added 200 grams metaflumizone. Dissolve
metaflumizone in the solvent system. Weigh 10 grams of moxidectin and add it to
the current solution containing metaflumizone. Allow the moxidectin to dissolve. To
the resulting solution, add 60 grams alcohol alkoxylate surfactant (sold under the
tradename Synperonic® NCA) and allow the surfactant to dissolve. Lastly, bring the
solution to 1000 ml with γ-hexalactone
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EXAMPLE 2
Preparation of metaflumizone/moxidectin Pour-On from High Load Concentrate of
Example 1
To 25 ml of the high load concentrate prepared in Example 1 is added q.s. to
100 ml γ-hexalactone. This provides a pour-on formulation having sufficient
metaflumizone and moxidectin and volume to treat 5 head of cattle weighed 200 Kg
each at 5 mg/kg dose rate metaflumizone and 0.25 mg/kg dose rate moxidectin.
EXAMPLE 3
Preparation of High Load Concentrate for use as a Concentrate to prepare
metaflumizone Spray or Feed/Water Supplement
12.59 grams of metaflumizone is added to methoxypropyl acetate using mild
heating (approximately 40°C). To this solution is added 109.92 grams
polyethoxylated castor oil (sold under the tradename Cremophor® EL), with stirring,
followed by 1.0 grams moxidectin and then brought to volume with methoxypropyl
acetate. The resultant solution is stored until ready for use, whereupon it can be
diluted with water for use as a spray (17 ml of concentrate diluted to 3500 ml with
water), or with water for use as a feed/water additive (in approximately the same
ratio) or additionally, applied directly as a backline pour-on.
EXAMPLE 4
Preparation of various formulations of a metaflumizone/moxidectin High Load
Concentrate, suitable for use as a Spot-on treatment

Formulation: 1 2 3 4 5 6 7 8 9

Moxidectin 0.1 0.5 2.5 0.1 0.5 2.5 0.1 0.5 2.5
Metaflumizone 30 30 30 20 20 20 5 5 5
Nonylphenol
ethoxylate 5 5 5
alcohol
ethoxylate, e.g. 5 5 5
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Synperonic®
NCA
Dioctyl sodium
sulfosuccinate 5 5 5
Cineole 10
DEET 10
IPM 10
Methoxypropyl
acetate 10 10 10 10 10
DMSO 10 10 10 10
γ-hexalactone qs qs qs qs qs qs qs qs qs
The preceding formulations are prepared using essentially the same procedures as
are listed in Example 1.
EXAMPLE 5
Preparation of various formulations of a metaflumizone/macrolide High Load
Concentrate, suitable for use as a Spot-on

Formulation: 10 10B 10C

Ivermectin 5
Abarmectin 5
Moxidectin 5
Metaflumizone 30 30 20
alcohol ethoxylate,
e.g. Synperonic NCA 5 5 5
Methoxypropyl acetate 10 10 10
y-hexalactone qs qs qs
The preceding formulations are prepared using essentially the same procedures as
are listed in Example 1.
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Example 6
Preparation of various formulations of a metaflumizone/moxidectin High Load
Concentrate, suitable for use as a Spot-on

Formulation: 11 12 14 15 16 17 18 19 20

Moxidectin 0.1 0.5 0.1 1 10 0.25 5 0.1 0.1
Metaflumizone 30 30 20 20 20 5 5 5 5
Cineole
DEET
Isopropyl myristate 5 1
polyethoxylated
castor oil 5 1 5 5 5 5
Sodium lauryl
sulfate 1
Methoxypropyl
acetate 5 5 5
DMSO 30 30
Dimethyl
isosorbide 30 30 30 30
γ-hexalactone qs qs qs qs qs qs qs qs qs
The preceding formulations are prepared using essentially the same procedures as
are listed in Example 1.
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WHAT IS CLAIMED IS:
1. A composition for topical administration which comprises on a
weight to volume basis from about 0.1 to about 10% of a substantially water-
insoluble anti-parasitic macrolide compound, about 5% to about 40% of
metaflumizone; about 0% to about 15% of a penetrating agent; about 2 to about 8%
of a surfactant; and about 50% to about 80% of a carrier solvent.
2. The composition according to Claim 1 which comprises from about
20% to about 30% of the metaflumizone.
3. The composition in Claim 1 or Claim 2 wherein the macrolide
compound is moxidectin, abamectin or ivermectin.
4. The composition according to any one of Claims 1 to 3 wherein the
surfactant is a non-ionic low foam surfactant.
5. The composition according to any one of Claims 1 to 4 wherein the
macrolide compound is moxidectin.
6. The composition according to any one of Claims 1 to 5 wherein the
penetrating agent is dimethyl sulfoxide.
7. The composition according to any one of Claims 1 to 6 wherein the
carrier solvent comprises gamma-hexalactone.
8. The composition according to any one of Claims 1 to 7 wherein the
carrier solvent comprises dimethyl isosorbide.
9. The composition according to any one of Claims 1 to 8 which
additionally contains up to about 2% of one or more preservatives, colorants,
antioxidants, or stabilizers.
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10. A method for preventing or treating endoparasitic and ectoparasitic
infection or infestation in a warm-blooded animal which method comprises topically
administering to the animal an effective amount of a composition according to any
one of Claims 1 to 9.
11 The method according to Claim 10 wherein the animal is selected
from the group consisting of a cow, a sheep, a horse, a camel, a deer, a swine, a
goat, a dog, a cat, and a bird.
12. The method according to Claim 10 or 11 wherein the composition
comprises about 20% to 30% of the metaflumizone; about 10% of a bridging agent,
about 2% to about 8% of a non-ionic low foam surfactant, and about 50-60% carrier
solvent.
13. The method according to any one of Claims 10 to 12 wherein the
composition comprises a gamma-hexafactone as the carrier solvent.
14. The method according to Claim 13 wherein the composition is further
diluted for use as a pour-on composition.
15.The method according to any one of Claims 10 to 12 wherein the
composition comprises dimethyl isosorbide as the carrier so/vent.
16. The method according to Claim 15 wherein the composition is further
diluted for use as a spray or feed/water additive.
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High load concentrate compositions comprising metaflumizone, a substantially water-insoluble anti-parasitic
macrolide compound,such as moxidectin, an optional bridging agent, a surfactant, and a suitable carrier solvent are prepared.
These compositions may be topically administered to animals, and are useful for preventing or treating ectoparasitic infestations
in warm-blooded animals for prolonged periods of time. Additionally, they may be further diluted to provide other types of
formulations useable for both topical and oral administration.