Note: Descriptions are shown in the official language in which they were submitted.
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TOPICAL ENDOPARASITICIDE AND ECTOPARASITICIDE FORMULATIONS
10011 This application claims the benefit (AILS. Provisional Application
No.
60/607,900, filed September 8, 2004, and U.S. Application No. 11/181,344,
filed July 14, 2005.
BACKGROUND OF INVENTION
[002] This invention relates generally to topical formulations that can
have significant
parasiticidal activity as insecticides, endoparasites, ectoparasiticides and
acaricides in animal
health, such as one suitable to use on house pets such as dogs and cats.
[003] The infestation of companion animals with endoparasites and/or
ectoparasites
such as heartworms, roundworms, hookworms, whipworrns, fleas, ticks, flies,
mites and the like
is highly undesirable and as such, it is beneficial to include multiple
pharmaceutical drugs in the
same fomiulation in order to target a wider variety of parasites.
Additionally, it has become
common to administer both topical and internal insecticides to livestock and
pets. Topical =
applications can be desirable since many formulations are acceptably safe when
used topically,
but not when used internally.
[004] However, various topical pharmaceutical formulations have drawbacks.
Some
formulations require a large volume to be applied to the animal. This can
cause considerable -
mess and can lead to an unpleasant smell. Additionally, if the dosage of a
topical formulation is
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in a large volume, it can be easily shaken off by the animal thereby reducing
the effectiveness of
the formulation. Also, when the animal is a house pet, there is a further
complication in that the
formulation should be safe for human contact. It should also not lead to
staining of furniture,
carpeting and the like. Finally, even if safe, topical formulations should not
be irritating or lead
to rashes, hair loss or exhibit other unpleasant side effects.
[005] There is therefore a need for an improved topical formulation for the
treatment of
endoparasites and ectoparasites that overcomes drawbacks of the prior art.
SUMMARY OF THE INVENTION
[006] Generally speaking, in accordance with the invention, a topical
pharmaceutical
formulation comprising a macrocyclic lactone, together with a neo-nicotinoid
and/or an insect
growth regulator, particularly one for use on cats and dogs, is provided.
Formulations in
accordance with the invention can be safe to use and avoids many common
deleterious side
effects of conventional topical formulations.
[007] The invention provides a topical formulation that contains a
combination of
insecticides and insect growth regulators, which can be effective to kill
endoparasites and
ectoparasites such as heartworm, fleas, flea eggs, flea larvae, ticks, tick
eggs, tick larvae, tick
nymphs, mites and mosquitoes. The selection of the combination of insecticides
and insect
growth regulators produces a composition having high parasitical activity,
thereby providing
broad protection against a variety of endoparasites and ectoparasites with a
single application of
the topical formulation. The compositions derived herein can also be useful to
improve the
speed of result and decrease the reoccurrence, compared to other formulations.
[008] The invention provides a topical formulation that contains a
combination of a first
active ingredient comprising a macrocyclic lactone and a second active
ingredient comprising a
neo-nicotinoid. Preferably, the topical formulation further contains an insect
growth regulator
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(IGR). In a preferred embodiment of the invention, the macrocyclic lactone in
the composition
comprises at least one of ivermectin, selamectin, doramectin, moxidectin or
eprinomectin. The
neo-nicotinoid can comprise a (tetrahydro-3-furanyl) methylamine derivative of
formula (1), as
identified below. In another embodiment of the invention, the neo-nicotinoid
comprises a
chloronicotinyl insecticide, preferably acetamiprid. The insect growth
regulator (IGR)
preferably comprises pyriproxyfen and/or methoprene. As used herein, the
identification of an
active ingredient, e.g., ivermectin, is intended to also refer to other
pharmaceutically active forms
of the active ingredient, such as esters, salts, hydrochlorides, acid or base
forms, isomers and so
forth.
[009] In another embodiment of the invention, the topical formulation
also contains a
pyrethroid such as permethrin or phenothrin in order to provide additional
acaricide efficacy and
to repel and kill mosquitoes.
[0010] It has been determined that it is..difficult to form a high
concentration of
dinotefuran or acetamiprid and permethrin or phenothrin, and it is likely to
result in a solution
that can be unstable when stored at room temperature for reasonable amounts of
time.
Therefore, it has been found preferable to produce a first formulation
comprising a macrocyclic
lactone and a neo-nicotinoid and a second formulation comprising permethrin or
phenothrin, and
to keep these formulations separated until prior to, preferably immediately
prior to application.
Preferably, topical formulation also contains an IGR, which may be packaged
with either the first
or second formulation or in yet another container.
[0011] The first and second formulations are advantageously produced and
packaged in a
manner so that the first and second formulations can be prevented from
interacting prior to
application of the formulation to the animal. Preferably, the first and second
formulations can be
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stored separately from each other in a package or container having two
associated, preferably
attached, but individual chambers to prevent the mixing of the first and
second formulations
prior to administration of the first and second formulation to the animal. The
first and second
formulations can be advantageously packaged in a container or chamber that is
opaque in order
to prevent the photodegradation of the active ingredients in the formulations.
Prior to
administration, the packages containing the first and second formulations in
their respective
separate chambers are opened, and the first and second formulations are
dispensed
simultaneously or at least at about the same time, to the animal.
[0012] Accordingly, it is an object of the invention to provide an
improved topical
formulation that is effective against a variety of parasites.
[0013] Another object of the invention is to provide a method for
controlling parasites.
[0014] Another object of the invention is to provide a topical
formulation that works
more rapidly and/or more permanently than other topical formulations.
[0015] Another object of the invention is to provide an improved method
of making an
insecticide.
[0016] Another object of the invention is to provide a new insecticide
packaging system.
[0017] Other objects and features will be in part apparent and in part
pointed out.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0018] In accordance with the invention, insecticidal compositions are
provided which
contain a combination of a macrocyclic lactone, a neo-nicotinoid and
preferably, an insect
growth regulator, that are effective against endoparasites and ectoparasites
such as heartworm,
fleas, flea eggs, ticks, and mites. The combination of active ingredients
produces topical
formulations that provides broad protection against endoparasites and
ectoparasites using a
single application of the formulation.
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[0019] Preferably, insecticidal compositions of the invention comprise a
first active =
ingredient comprising a macrocyclic lactone such as ivermectin, selamectin,
doramectin
moxidectin or eprinomectin, combined with a second active ingredient
comprising a neo-
nicotinoid such as dinotefuran or acetamiprid, in a suitable solvent solution.
It should be noted
that in embodiments where the first active ingredient is dinotefuran and the
second active
ingredient is acetamiprid, a solvent comprising ethyl lactate and water should
not be utilized.
Rather, it has been determined that an effective solvent for the
solubilization of high
concentrations of dinotefuran and acetamiprid comprises ethanol.
[0020] The treatment of different endoparasites and ectoparasites can be
targeted by
including a particular macrocyclic lactone in the formulation. Accordingly, in
preferred
embodiments of the invention, the topical formulation further comprises an
insect growth
regulator (IGR). The combination of the macrocyclic lactone and the neo-
nicotinoid with an
IGR preferably results in a topical formulation having effective insecticidal
activity against e.g.,
flea larvae and flea eggs.
[0021] In one preferred embodiment of the invention, the first component
in the
formulation comprises a macrocyclic lactone such as ivermectin, selamectin,
doramectin,
moxidectin or eprinomectin, the second component is dinotefuran or N-((6-
chloro-3-
pyridinyl)methyl)-N'-cyano-N-methyl-ethanimidamide (acetamiprid), and the IGR
is .
pyriproxyfen and/or methoprene.
[0022] In another preferred embodiment of the invention, the macrocyclic
lactone in the
formulation comprises at least one of ivermectin, selamectin, doramectin,
moxidectin and
eprinomectin, the neo-nicotinoid comprises a (tetrahydro-3-furanyl)methylamine
derivative of
following formula (1), and the IGR comprises pyriproxyfen and/or methoprene.
The (tetrahydro-
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3-furanyl)methylamine derivatives of the formula (1) have an excellent
insecticidal activity even
in the absence of a pyridylmethyl group or a thiazolylmethyl group in their
molecular structure.
X7 X6
X5
0 X4 Ri
> C-N
H2
R2
Xi X3 11 -
X2
Formula (1)
[0023] where Xi, X25 X35 X45 X5, X6 and X7 each represent each a hydrogen
atom or an
alkyl group having from 1 to 4 carbon atoms; Ri represents a hydrogen atom, an
alkyl group
having from 1 to 5 carbon atoms, an alkenyl group having 3 carbon atoms, a
benzyl group, an
alkoxyalkyl group having from 2 to 4 carbon atoms (in its whole group), an
alkyloxycarbonyl
group having from 1 to 3 carbon atoms, a phenoxy carbonyl group, an
alkylcarbonyl group
having from 1 to 6 carbon atoms, an alkenylcarbonyl group having from 2 to 3
carbon atoms, a
cycloalkylcarbonyl group having from 3 to 6 carbon atoms, a benzoyl group, a
benzoyl group
substituted by alkyl group(s) having from 1 to 4 carbon atoms, a benzoyl group
substituted by
halogen atom(s), a 2-furanylcarbonyl group or an N,N-dimethylcarbamoyl group;
R2 represents a
hydrogen atom, an amino group, a methyl group, an alkylamino group having from
1 to 5 carbon
atoms, a di-substituted alkylamino group having from 2 to 5 carbon atoms (in
its whole group), a
1-pyrrolidinyl group, an alkenylamino group having 3 carbon atoms, an
alkynylamino group
having 3 carbon atoms, a methoxyamino group, an alkoxyalkylamino group having
from 2 to 4
carbon atoms (in its whole group), a methylthio group or --N(Yi)Y2 (where Yi
represents an
alkyloxycarbonyl group having from 1 to 3 carbon atoms, a phenoxycarbonyl
group, an
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alkylcarbonyl group having from 1 to 6 carbon atoms, an alkenylcarbonyl group
having from 2
to 3 carbon atoms, a cycloalkylcarbonyl group having from 3 to 6 carbon atoms,
a benzoyl
group, a benzoyl group substituted by alkyl group(s) having from 1 to 4 carbon
atoms, a benzoyl
group substituted by halogen atom(s), a 2- furanylcarbonyl group, an N,N-
dimethylcarbamoyl
group, a (tetrahydro-3- furanypmethyl group or a benzyl group, and Y2
represents a hydrogen
atom or an alkyl group having from 1 to 5 carbon atoms); and Z represents =N-
NO2, =CH-NO2
or =N-CN.
[0024] Intermediates for producing the compounds of the formula (1) are
represented by
a formula (2):
X7 X6
X5
0 x4 H2C CH2
C-N ,N-R11
=
H2
X1 X3
X2
N -NO2 Formula (2)
where X1, X2, X3, X4, X5, X6 and X7 each represent each a hydrogen atom or an
alkyl group
having from 1 to 4 carbon atoms; R10 represents an alkyl group having from 1
to 5 carbon atoms
or a benzyl group; and R11 represents an alkyl group having from 1 to 5 carbon
atoms or a benzyl
group.
[0025] The (tetrahydro-3-furanyl)methylamine derivatives of the formula
(1) and formula
(2) according to the invention are excellent compounds having a high
insecticidal activity and
broad insecticidal spectrum. Further, agricultural chemicals containing the
(tetrahydro-3-
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furanyl)methylamine derivatives of formula (1) and (2) according to the
invention have
outstanding characteristics as insecticides and hence are useful.
[0026] Specific examples of the alkyl group for X1, X2, X3, X4, X5, X6
and X7 in the
above formulae (1) and (2) include a methyl group, an ethyl group, an n-propyl
group, an iso-
propyl group, a tert-butyl group, and the like, preferably a methyl group.
[0027] Specific examples of the alkyl group for R1 include a methyl
group, an ethyl
group, an n-propyl group, an iso-propyl group, an n- butyl group, an iso-butyl
group, a sec-butyl
group, a tert-butyl group, an n-pentyl group, and the like.
[0028] Specific examples of the alkenyl group for R1 include a 1-propenyl
group, a 2-
propenyl group, and the like.
[0029] Specific examples of the alkoxyalkyl group for R1 include a
methoxymethyl
group, an ethoxymethyl group, an n-propoxymethyl group, an iso-propoxymethyl
group, a
methoxyethyl group, an ethoxyethyl group, and the like.
[0030] Specific examples of the alkyloxycarbonyl group for R1 include a
methyloxycarbonyl group, an ethyloxycarbonyl group, an n-propyloxycarbonyl
group, an iso-
propyloxycarbonyl group, and the like.
[0031] Specific examples of the alkylcarbonyl group for R1 include a
methylcarbonyl
group, an ethylcarbonyl group, an n-propylcarbonyl group, an iso-
propylcarbonyl group, an n-
butylcarbonyl group, an iso-butylcarbonyl group, a sec-butylcarbonyl group, a
tert-butylcarbonyl
group, an n-pentylcarbonyl group, an n-hexylcarbonyl group, and the like.
[0032] Specific examples of the alkenylcarbonyl group for R1 include a
vinylcarbonyl
group, a 1-methylvinylcarbonyl group, and the like.
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[0033] Specific examples of the cycloalkylcarbonyl group for R1 include a
cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl
group, a
cyclohexylcarbonyl group, and the like.
[0034] Specific examples of the benzoyl group substituted by alkyl
group(s) for R1
include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a 4-methylbenzoyl
group, a 4-tert-
butylbenzoyl group, and the like.
[0035] Specific examples of the benzoyl group substituted by halogen
atom(s) for Ri
include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a 4-chlorobenzoyl
group, a 3,4-
dichloro-benzoyl group, a 4- fluorobenzoyl group, and the like.
[0036] Although R1 can take various substituents as described above, it
is preferably a
hydrogen atom, an alkylcarbonyl group having from 1 to 4 carbon atoms or a
cyclopropylcarbonyl group.
[0037] Specific examples of the alkylamino group for R2 include a
methylamino group,
an ethylamino group, an n-propyl-amino group, an iso-propylamino group, an n-
butylamino
group, an iso-butylamino group, a sec-butylamino group, a tert-butylamino
group, an n-
pentylamino group, and the like, preferably a methylamino group.
[0038] Specific examples of the di-substituted alkylamino group for R2
include a
dimethylamino group, a diethylamino group, an N-methyl-N-ethylamino group, an
N-methyl-N-
n-propylamino group, an N-methyl-N-n-butylamino group, and the like,
preferably a
dimethylamino group.
[0039] Specific examples of the alkenylamino group for R2 include a 1-
propenylamino
group, a 2-propenylamino group, and the like.
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[0040] Specific examples of the alkynylamino group for R2 include a
propargylamino
group, and the like.
[0041] Specific examples of the alkoxyalkylamino group for R2 include a
methoxymethylamino group, an ethoxymethylamino group, an n-propoxymethylamino
group, an
iso-propoxymethylamino group, a methoxyethylamino group, an ethoxyethylamino
group, and
the like.
[0042] Specific examples of the alkyloxycarbonyl group denoted by Yi for
R2 include a
methyloxycarbonyl group, an ethyloxy-carbonyl group, an n-propyloxycarbonyl
group, an iso-
propyloxy-carbonyl group, and the like.
[0043] Specific examples of the alkylcarbonyl group denoted by Yi for R2
include a
methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an
iso-
propylcarbonyl group, an n-butylcarbonyl group, an isobutylcarbonyl group, a
sec-butyl-
carbonyl group, a tertbutylcarbonyl group, an n-pentylcarbonyl group, an n-
hexylcarbonyl group,
and the like, preferably a methylcarbonyl group, an ethylcarbonyl group, an n-
propylcarbonyl
group, an iso-propylcarbonyl group, an n-butylcarbonyl group, an iso-
butylcarbonyl group, a
sec-butylcarbonyl group and a tert-butylcarbonyl group.
[0044] Specific examples of the alkenylcarbonyl group denoted by Yi for
R2 include a
vinylcarbonyl group, a 1-methyl-vinylcarbonyl group, and the like.
[0045] Specific examples of the cycloalkylcarbonyl group denoted by Y1
for R2 include a
cyclopropylcarbonyl- group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl
group, a cyclo-
hexylcarbonyl group, and the like, preferably a cyclopropyl-carbonyl group.
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=
[0046] Specific examples of the benzoyl group substituted byalkyl
group(s) denoted by
Y1 for R2 include a 2-methylbenzoyl group, a 3-methylbenzoyl group, a 4-
methylbenzoyl group,
a 4-tert-butylbenzoyl group, and the like.
[0047] Specific examples of the benzoyl group substituted by halogen
atom(s) denoted
by Yi for R2 include a 2-chlorobenzoyl group, a 3-chlorobenzoyl group, a 4-
chlorobenzoyl
group, a 3,4-dichlorobenzoyl group, a 4-fluoro benzoyl group, and the like.
[0048] Specific examples of the alkyl group denoted by Y2 for R2 include
a methyl
group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl
group, an iso-butyl
group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and the like,
preferably a methyl
group.
[0049] In the formula (1), compounds in which R1 and Yi are concurrently
an
alkylcarbonyl group having from 1 to 4 carbon atoms or a cyclopropylcarbonyl
group are
preferred from the viewpoint of both insecticidal activity and production
method.
[0050] In a preferred embodiment of the invention, the macrocyclic
lactone comprises at
least one ivermectin, selamectin, doramectin, moxidectin or eprinomectin, the
neo-nicotinoid
comprises 1-{(tetrahydro-3-furanyl)methy1}-2-nitro-3-methylguanidine
(dinotefuran), and the
insect growth regulator preferably comprises pyriproxyfen or methoprene.
Dinotefuran is an
insecticide that kills adult fleas, and pyriproxyfen and methoprene are insect
growth regulators
that kill flea larvae and prevent flea eggs from hatching. Accordingly, the
combination of .
dinotefuran and an IGR such as pyriproxyfen or methoprene provides for an
effective flea
control system since only about 5% of the existing fleas on an animal are
adults and the other
95% are in a juvenile state (eggs and larvae).
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[0051] It has been determined that it is advantageous to dissolve or
otherwise put the
actives into a liquid form for use as a topical spot products on animals. It
is of course, to be
understood that in certain embodiments of the invention, it may be
advantageous to isolate the
=
actives, such as by granulation (e.g., spray granulation), encapsulation, use
of micelles,
encapsulated microbeads and the like. Topical spot products are more
advantageous if the
amount of liquid applied to the animal can he minimized. This should be
balanced with the need
for appropriate dosage to achieve the desired pesticidal effect. Therefore, it
is desirable to
include a high concentration of insecticide so that the total=voltune of the
insecticide applied to
the animal can be minimized.
[0052] Preferably, dinotefttran is dissolved in the fommlation to a
concentration of
approximately 50 to 150 mg/ml, more preferably 100 to 150 mg/ml, and most
preferably,
=
approximately 150 mgiml. Dinotefunin may be dissolved in particularly
effective solvent
systems such as a combination of water and ethanol or isopropanol, as
disclosed in pending
U.S.S.N. 1000,55'), or in phenyl methanol or ethanol, as disclosed in U.S.
Patent 6,588,374, or
in ethyl lactate and water combinations.
[0053] The treatment of different endoparasites and cctoparasites are
targeted by
including, particular macrocyclic lactones specific: for the target
endoparasite or cctoparasitc in
the topical formulation. The combination of the macrocyclic !Wane and neo-
nicotinoid with an
insect growth regulator preferably results in a topical formulation having
effective insecticidai.
and parasiticidal activity against a variety of endoparasites and
ectoparasites.
[0054] In another preferred embodiment of the invention, the topical
formulation
comprises a pyrethroid such as 2,2-Dimethy1-3-(2-methyl-1-
propeny1)cyc1opropanecarboxyli6
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acid, (3-phenoxyphenyOmethyl ester (phenothrin) or cyclopropanecarboxylic
acid, 342,2-
dichloretheny0-2,2-dimethyl- (3-phenoxyphenyl)methyl ester (permethrin) in
order to provide
additional acaricide efficacy and to repel and kill mosquitoes. Compositions
containing
permethrin in accordance with the invention are particularly advantageous for
use on dogs,
compared to their use on cats.
[0055] It has been determined that it is difficult to form a high
concentration of
dinotefuran or acetamiprid and permethrin or phenothrin-, and it is likely to
result in a solution
that can be unstable when stored at room temperature for reasonable amounts of
time.
Therefore, it has been found preferable to produce a first formulation
comprising a macrocyclic
lactone and a neo-nicotinoid and a second formulation comprising permethrin or
phenothrin.
Preferably, the topical formulation further comprises an IGR, which can be
included in the first
or second formulation or even separately in yet another container. The first
and second
formulations are produced and packaged in a manner so that the first and
second formulations
are not permitted to interact prior to application of the total formulation to
the animal. In one
preferred embodiment of the invention, the first and second formulations are
stored separately
from each other in a package or container having two associated, preferably
attached, but
individual chambers to prevent the mixing of the first and second formulations
prior to
administration of the first and second formulation to the animal.
[0056] It should be noted that in embodiments where the formulation is
packaged using
separate chambers or containers, the percentage of an active ingredient
provided is the
percentage of that active ingredient in a single solution. For example, 1 to
2% pyriproxyfen is
the concentration of pyriproxyfen contained in the formulation in a single
chamber rather than
the concentration of pyriproxyfen in the total formulation of the combined
chambers.
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[0057] Macrocyclic lactones can be unstable in both acidic and basic
solutions. For =
example, ivermectin is hygroscopic and therefore tends to be undesirably
unstable. It has also
been seen that macrocyclic lactones such as ivermectin are unstable in both
acidic and basic
solutions and are susceptible to photodegradation and oxidative degradation.
Accordingly, in
embodiments where the first active ingredient of the composition comprises
ivermectin, it is
preferable that the first and second formulations are stored in an opaque
package or container to
prevent the photodegradation of ivermectin during storage of the formulation.
Even more
preferably, the formulation will further comprise an antioxidant such as 2,6
ditertiarybuty1-4-
methyl phenol (BHT) to prevent the oxidative degradation of ivermectin during
storage of the .
formulation for a reasonable amount of time.
[0058] Prior to administration, the packages containing the first and
second formulations
in their respective separate chambers are opened, and the first and second
formulations are
dispensed simultaneously or at least at about the same time to the animal. =
[0059] In one preferred embodiment of the invention, the first and second
formulations
can be packaged in a container having two associated, preferably attached, but
individual,
chambers to prevent the mixing of the formulations prior to the administration
of the first and
second formulations to the animal. Prior to administration, the container can
be opened and the
first and second formulations can be dispensed simultaneously or nearly
simultaneously to the
companion animal.
[0060] In another preferred embodiment of the invention, the insecticide
composition of
the invention can be packaged in a single dose package. Single dose containers
make storage .
and disposal more convenient for animal owners. Preferably, the composition is
packaged in a
container encompassing two associated, preferably attached but individual
chambers, which are
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separated by a barrier, preferably plastic, plastic coated paper or metal,
such as aluminum foil.
In one preferred embodiment of the invention, the first chamber and the second
chamber are
plastic tubes that are separate but fused together. In another embodiment of
the invention, the
first and second chambers are comprised of opaque plastic in order to prevent
the
photodegradation of the actives in the formulation.
[0061] During packaging, the first formulation, preferably comprising a
macrocyclic
lactone such as ivermectin, selamectin, doramectin, moxidectin or eprinomectin
and a neo-
nicotinoid, preferably dinotefuran or acetamiprid can be placed in the first
chamber. The second
formulation, preferably comprising permetluin or phenothrin can be placed in
the second
chamber. The topical formulation further comprises an IGR such as pyriproxyfen
or
methoprene, which may be included in the first or second formulation or in yet
another
container. Preferably, the first and second chambers can be separated by a
barrier that prevents
the interaction of the first and second formulations.
[0062] The entire container containing the first and second formulations
in separate
chambers is sealed, preferably with a tab or top, for use in opening the
container prior to
administration. After the container is sealed, the topical formulation can be
safely stored in the
container until administration of the formulation to the animal.
[0063] Prior to administration of the formulation to the animal, the
container is opened
by removing the tab or top. In one embodiment of the invention, the container
is opened by
twisting the tab thereby resulting in breaking or tearing of the barrier
separating the two
chambers, thereby allowing the first and second formulations to mix prior to
administration of,
the insecticide formulation to the animal. After the two formulations are
mixed, the two
formulations are dispensed by squeezing or collapsing the body of the
container either
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simultaneously or sequentially. In another embodiment of the invention, a dual
plunger system
can be employed to administer the formulation onto the animal.
[0064] It is of course understood that the first and second formulations
need not be mixed
together prior to administration of the topical formulation to the animal.
Accordingly, in another
embodiment of the invention, opening of the dual-chamber container does not
result in the
mixing of the first and second formulations. Rather, after the container is
opened, the first and
second formulations are dispensed onto-the animal by squeezing or collapsing
the container or
containers, either simultaneously or sequentially.
[0065] In one embodiment of the invention, the formulation is packaged
with
instructions, advising to mix the formulations. In other embodiments, the
instructions will direct
the user not to mix the formulation upon application. Because compositions in
accordance with
preferred embodiments of the invention can be formulated with a relatively
high concentration of
active ingredients, a relatively small application of a spot or line on the
animal can effectively
prevent and control endoparasite and ectoparasite infestation on the animal
for approximately
one to four weeks post-administration. Preferably, the topical formulation is
non-toxic and does
not irritate the animal's skin.
[0066] In a preferred embodiment of the invention, the volume of total
insecticide
formulation applied onto a companion pet is in the range of about 0.5 to 10
ml, preferably abou. t
2 to 5 ml, and most preferably, about 3 ml. In another embodiment of the
invention, the volume
of total insecticide formulation applied onto a small cat or kitten is in the
range of about 0.5 to
1.5 ml. It should be noted that the total insecticide formulation contains
solvents and other
additives in addition to active ingredients and therefore, the volume of total
insecticide
formulation applied onto the animal does not comprise only actives.
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[0067] In preferred embodiments of the invention, the dosages of active
ingredients in a
single application of the topical formulation comprise approximately 0.16 to
4.80 mg of a
macrocyclic lactone and approximately 90 to 1350 mg dinotefuran plus solvent,
and preferably
approximately 0.32 to 3.2 mg of a macrocyclic lactone and approximately 180 to
900 mg
dinotefuran plus solvent. In a preferred embodiment of the invention, the
formulation further
comprises an IGR such as pyriproxyfen or methoprene.
[0068] In embodiments of the invention where pyriproxyfen is added to the
formulation,
the dosage of pyriproxyfen in the total volume of a single application of the
formulation is
approximately 3.5 to 45 mg, and preferably, approximately 7 to 30 mg. In
embodiments of the
invention where methoprene is added to the formulation, the dosage of
methoprene in the total
volume of a single application of the formulation is approximately 10 to 135
mg, and preferably,
approximately 20 to 90 mg.
[0069] The treatment of different endoparasites and ectoparasites can be
targeted by
including a particular macrocyclic lactone in the formulation. It should be
understood that the
invention is not limited by the embodiments described herein.
[0070] In a preferred embodiment of the invention, the insecticide
formulation comprises
ivermectin, dinotefuran and pyriproxyfen for the treatment of endoparasites
and/or ectoparasites
on cats and dogs. It should of course be understood that the actual amount of
ivermectin in the
formulation will vary depending on the size of the dog or cat. In a preferred
embodiment the
ivermectin ranges approximately 0.2 to 1.75 mg per ml of formulation.
[0071] In one embodiment of the invention, up to 8 ml of the total
insecticide
composition can be administered to a dog weighing 55 to 120 pounds, and
preferably, up to 6 ml.
Such composition will preferably comprise at least about 1.6 to 4.8 mg of
ivermectin, at least
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about 450 to 1350 mg dinotefuran, and at least about 15 to 45 mg of
pyriproxyfen. Even more
preferably, the composition will comprise approximately 3.2 mg of ivermectin,
approximately
900 mg dinotefuran, and approximately 30 mg of pyriproxyfen. In embodiments
where the IGR
is methoprene, the composition comprises at least about 45 to 180 mg
methoprene. In another
preferred embodiment of the invention, approximately 6 to 8 ml of the total
composition can be
administered to a 55 to 120 lb dog, which advantageously comprises
approximately 675 to 2025
mg of permethrin or approximately 2015 to 5050 mg of phenothrin in order to
provide additional
acaricide efficacy and to repel and kill mosquitoes. =
[0072] In one embodiment of the invention, up to 4 ml of insecticide can
be
administered to a dog weighing 22 to 55 pounds. Such composition will
preferably comprise at
least about 1.0 to 3.0 mg of ivermectin, at least about 300 to 900 mg
dinotefuran, (and at least
about 10 to 30 mg of pyriproxyfen. Even more preferably, the composition will
comprise
approximately 2.0 mg of ivermectin, approximately 600 mg dinotefuran, and
approximately 20
mg of pyriproxyfen. In embodiments where the IGR is methoprene, the
composition comprises
at least about 30 to 90 mg methoprene. In another preferred embodiment of the
invention, the
composition further comprises approximately 450 to 1350 mg of permethrin or
approximately
1115 and 3345 mg of phenothrin in order to provide additional acaricide
efficacy and to repel
and kill mosquitoes.
[0073] In one embodiment of the invention, up to 2.1 ml of insecticide
can be
administered to an animal weighing 9 to 22 pounds. Such composition will
preferably comprise
at least about 0.4 to 1.2 mg of ivermectin, at least about 225 to 675 mg
dinotefuran, and at least
about 5 to 15 mg of pyriproxyfen. Even more preferably, the composition will
comprise
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approximately 0.8 mg of ivermectin, approximately 450 mg dinotefuran, and
approximately 10
mg of pyriproxyfen.
[0074] In another preferred embodiment, the composition further comprises
at least about
225 to 675 mg permethrin or about 560 to 1675 mg phenothrin in order to
provide additional
acaricide efficacy and to repel and kill mosquitoes. It should be noted that
formulations
containing permethrin are for application to dogs only. In embodiments where
the IGR is
methoprene, the composition comprises at leasfabout 15 to-45-mg methoprene.
[0075] In one embodiment of the invention, up to 1.5 ml of-insecticide
can be
administered to animals weighing 9 pounds or less. Such composition will
preferably comprise
at least about 0.15 to 0.60 mg of ivermectin, at least about 90 to 270 mg
dinotefuran, and at least
about 3.5 to 12 mg of pyriproxyfen. Even more preferably, the composition will
comprise
approximately 0.32 mg of ivermectin, approximately 180 mg dinotefuran, and
approximately 7
mg of pyriproxyfen. In embodiments where the IGR is methoprene, the
composition comprises
at least about 10 to 30 mg methoprene. In another preferred embodiment, the
composition
further comprises at least about 150 to 450 mg permethrin or about 475 to 1425
mg phenothrin in
order to provide additional acaricide efficacy and to repel and kill
mosquitoes. It should be
noted that formulations containing permethrin are for application for dogs
only.
[0076] In another preferred embodiment of the invention, the insecticide
formulation
comprises selamectin, dinotefuran and pyriproxyfen for the treatment of
endoparasites and/or
ectoparasites on cats and dogs. It has been determined that an effective
dosage for selamectin
contained in insecticide formulations according to the invention is
approximately 3 to 6 mg per
pound of animal body weight Therefore, the actual amount of selamectin in the
insecticide
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formulation will vary depending on the size of the dog or cat (for example,
approximately 30 to
210 mg per ml of formulation).
[0077] In a preferred embodiment of the invention, the insecticide
formulation comprises
moxidectin, dinotefuran and pyriproxyfen for the treatment of endoparasites
and/or ectoparasites
on cats and dogs. It has been determined that an effective dosage for
moxidectin contained in
insecticide formulations according to the invention is approximately 0.2 mg
per pound of animal
body weight. Therefore,- the -actual amount of mbxidectin in the-insecticide
formulation will vary
depending on the size of the dog or cat.
[0078] In another preferred embodiment of the invention, the insecticide
formulation
=
comprises doramectin, dinotefuran and pyriproxyfen for the treatment of
endoparasites and/or
ectoparasites on cats and dogs. It has been determined that an effective
dosage for doramectin
contained in insecticide formulations according to the invention is
approximately 0.02 mg per
pound of animal body weight. Therefore, the actual amount of doramectin in the
insecticide
formulation will vary depending on the size of the dog or cat.
[0079] In the preparation of a formulation for use on animals, there are
several
parameters that should be considered. These are:
(a) Concentration high enough to minimize the volume of the topical applied to
the animal (one would not want to put 20 ml, e.g., onto a small dog).
(b) Concentration low enough to achieve effective translocation of the topical
insecticide over the animal's skin.
(c) The formulation should be stable for six months at 40 F and 75% relative
humidity, room temperature and -10 F. This helps ensure that the formulation
remains stable under the conditions that it could meet in commerce.
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(d) Safe to use on the intended animal - particularly non-irritating to at
least the
intended animal, since the product is applied to the skin. Also safe if
ingested
by the animal; ingestion can occur when pets groom themselves.
(e) Safe to use by the consumer.
(f) Efficacious in use ¨ should kill greater than 90% of the fleas and ticks
up to
28 days and.kill or eliminate the endoparasitea.
(g) Efficacy would be reduced if crystallization occurred in the package.
(h) Needs to be aesthetically pleasing - "no oily drop" on the animal when
applied.
(i) Fast drying to reduce the chance of the animal shaking off the liquid
thereby
reducing efficacy.
(j) Microbiologically stable.
[0080] It can be advantageous for the insecticidal formulations of the
invention to contain
an enzyme inhibitor or a synergist such as piperonyl butoxide, N-
octylbicycloheptenedicarboximide, or triphenyl phosphate, which can increase
the efficacy of the
formulation. The topical formulations also contain one or more compounds to
increase the
efficacy and to reduce the irritation of pyrethroid insecticides to the skin
of animals. The
formulation can advantageously contain spreading agents such as n-octyl
pyrrolidone and
dioctylsulfosuccinimide, fragrances, and/or antioxidants.
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[0081] Other additives to the insecticidal composition include but are
not limited to
fragrances, surfactants and spreading agents to increase performance such as
polyoxyethylene
(20) sorbitan monolaurate (commerically available as polysorbate 20 or Tween
20) and
polyoxyethylene (20) sorbitan monooleate (commerically available as
polysorbate 80 or Tween
80), and isopropyl myristate. Polymers such as agar, gelatin, alginate, and
cationic polymers
such as cationic guar, cationic cellulose, cationic acrylates, and
polyoxymethylene urea may also
be added to provide enrobing of the insecticide- lb improve safety and
adhesion to skin and hair.
[0082] In practice, an effective amount of the insecticidal compositions
as described
herein may be applied to a companion animal, preferably a dog or a cat, as a
foaming shampoo,
dip, aerosol spray, pump spray, powder, lotion, emulsifiable concentrate,
aqueous or liquid
flowable, suspension concentrate and by any other methods suitable for
administering topical
compositions to animals. Formulations containing permethrin cannot be applied
to cats.
[0083] The following examples are given for purposes of illustration only
and are not
intended to be construed in a limiting manner.
EXAMPLES
Example 1 - Preparation of 1-{(tetrahydro-3-furany1)methy11-2-nitro-3-
methylguanidine
(dinotefuran)
[0084] A mixture comprising 10.0 g of (tetrahydro-3-furanyl)methanol, 29.
5 g of
trifluoromethanesulfonic anhydride, 10.0 g of pyridine and 200 ml of
dichloromethane was
stirred for an hour at room temperature. Water was poured into the reaction
solution to separate
the organic layer, which was washed with 1 N hydrochloric acid, water and a
saturated saline
solution, dried, and concentrated to obtain 20 g of 3-tetrahydro-furanylmethyl
triflate. 3.25 g of
60% sodium hydride were added to 12.5 g of 1,5-dimethy1-2-nitroiminohexahydro-
1,3,5-triazine
and 60 ml of DMF at room temperature, followed by stirring for an hour. 20.0 g
of the 3-
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tetrahydrofuranylmethyl triflate were added thereto, and the mixture was
stirred at 50 C for 2
hours. After cooling the mixture to room temperature, 50 ml of 2N hydrochloric
acid were added
thereto, followed by stirring at 50 C for 2 hours. The resultant mixture was
neutralized with
sodium bicarbonate and extracted with dichloromethane, and the extract was
dried and
concentrated. The residue thus obtained was purified by silica gel column
chromatography
(eluent: ethyl acetate/hexane=1/1) to obtain 7.8 g of 1-{(tetrahydro-3-
furanyl)methy1}- 2-nitro-
3-methylguanidine (dinotefuran). õ, -
-- -
Example 2: Ivermectin/Dinotefuran Formulations
[0085] Ivermectin (0.05 g) was dissolved in ethanol in a clean container
with stirring
until it was completely dissolved. This solution was added to a chamber in the
package in the
appropriate volume based on the dosage required.
[0086] A second solution containing dinotefuran was prepared by adding 25
g of
dinotefuran to 100 ml phenyl methanol with stirring until it dissolved. This
solution was added
to the other chamber in the package in the appropriate volume based on the
dosage required.
Example 3: Preparation of Compositions Containing Ivermectin, Dinotefuran and
Pyriproxyfen
[0087] A solution containing ivermectin was prepared using the
methodology of
Example 2 and placed in a chamber in the package in the appropriate volume
based on the dosge
required.
[0088] Pyriproxyfen (1 g) and Mackernium KP (1 g) were added to a clean
container,
and gently heated until the pyriproxyfen liquefied. Water (27.6 g) was added
with stirring,
followed by the addition of ethyl lactate (55.4 g). Dinotefuran (15 g) was
added and the solution
was mixed and heated at 50 degrees C until the dinotefuran dissolved. The
solution was cooled
to room temperature and the pH adjusted to 5.5 by the addition of sodium
carbonate (0.15 g of a
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25% aqueous solution). This solution was added to the other chamber in the
package in the
appropriate volume based on the dosage required.
Example 4: Preparation of Compositions Containing Ivermectin, Dinotefuran and
Methoprene
[0089] A solution containing iverrnectin was prepared using the
methodology of
Example 2 and placed in a chamber in the package in the appropriate volume
based on the
dosage required.
[0090] Methoprene (1g) and Mackerniurn Kr (1 g) were added to a clean
container, and
gently heated. Water (27.6 g) was added with stirring, followed by the
addition of ethyl lactate
(55.4 g). Dinotefuran (15 g) was added and the solution was mixed and heated
at 50 degrees C
until the dinotefuran dissolved. The solution was cooled to room temperature
and the pH
adjusted to 5.5 by the addition of sodium carbonate (0.15 g of a 25% aqueous
solution). This
solution containing dinotefuran and methoprene was added to the other chamber
in the package
in the appropriate volume based on the dosage required.
Example 5: Preparation of Compositions Containing Ivermectin, Dinotefuran,
Permethrin and
Pyriproxyfen
[0091] Permethrin (6.5 g) was dissolved in ethanol in a clean container
with stirring.
Ivermectin (0.05 g) was added to this solution with stirring until it was
completely dissolved.
Perrnethrin or phenothrin is preferably added to insecticide formulations
according to the present
invention in order to kill ticks and repel flies and mosquitoes. This solution
containing
permethrin and ivermectin was added to one of the chambers in the package in
the appropriate
volume based on the dosage required.
[0092] Pyriproxyfen (1 g) and Mackernium KP (1 g) were added to a clean
container,
and gently heated until the pyriproxyfen liquefied. Water (27.6 g) was added
with stirring,
followed by the addition of ethyl lactate (55.4 g). Dinotefuran (15 g) was
added and the solution
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was mixed and heated at 50 degrees C until the dinotefuran dissolved. The
solution was cooled
to room temperature and the pH adjusted to 5.5 by the addition of sodium
carbonate (0.15 g of a
25% aqueous solution). This solution was added to the other chamber in the
package in the
appropriate volume based on the dosage required.
Example 6: Preparation of Compositions Containing Ivermectin, Dinotefuran,
Phenothrin and
Pyriproxyfen
[0093] Phenothrin (6.5 g) was dissolved in ethanol in a clean container
with stirring.
Ivermectin (0.05 g) was added to this solution with stirring until it was
completely dissolved.
Permethrin or phenothrin is preferably added to insecticide formulations
according to the present
invention in order to kill ticks and repel flies and mosquitoes. This solution
containing
phenothrin and ivermectin was added to one of the chambers in the package in
the appropriate
volume based on the dosage required.
[0094] Pyriproxyfen (1 g) and Mackemium KP (1 g) were added to a clean
container,
and gently heated until the pyriproxyfen liquefied. Water (27.6 g) was added
with stirring,
followed by the addition of ethyl lactate (55.4 g). Dinotefuran (15 g) was
added and the solution
was mixed and heated at 50 degrees C until the dinotefuran dissolved. The
solution was cooled
to room temperature and the pH adjusted to 5.5 by the addition of sodium
carbonate (0.15 g of a
25% aqueous solution). This solution was added to the other chamber in the
package in the
appropriate volume based on the dosage required.
Example 7: Moxidectin/Dinotefuran Compositions
[0095] In a preferred embodiment of the invention, an insecticide
formulation containing
moxidectin and dinotefuran was prepared using the methodology described in
Example 3.
[0096] Preferably, the total volume of the formulation is approximately 6
ml, comprises
11 to 24 mg of moxidectin and approximately 15% dinotefuran, which is
approximately 900 mg
CA 02579844 2007-03-08
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=
dinotefuran for the treatment and prevention of fleas, prevention of
heartworm, the control of
roundworm, hookworms, and whipworms in dogs and cats. As used herein, it is to
be
understood that the prevention of a specific parasite implies that the active
ingredient precludes
the parasite from having an effect, i.e., the active ingredient prevents the
parasites from infesting
the animal because the parasites are killed as soon as they enter the animal.
Furthermore, it is to
be understood that controlling a parasites implies that the active ingredient
kills the parasites in
an already infested animal. -
[0097] Preferably, the formulation further comprises approximately 10
mg/ml
pyriproxyfen or approximately 30 mg/ml methoprene to kill flea larvae and
prevent flea eggs
from hatching. Even more preferably, the formulation also includes permethrin
or phenothrin to
kill ticks and repel mosquitoes and flies.
Example 8: Selamectin/Dinotefuran Compositions
[0098] In yet another preferred embodiment of the invention, an
insecticide composition
containing selamectin and dinotefuran was prepared using the methodology
described in
Example 2.
[0099] Preferably, the total volume of the formulation applied to the
companion animal is
approximately 6 ml, which comprises approximately 8% to 15% dinotefuran and
2.6 to 12%
selamectin. In a preferred embodiment of the invention, the formulation
comprises
approximately 480 to 900 mg dinotefuran and 155 to 720 mg selamectin dissolved
in solvent,
which is effective in killing fleas, preventing flea eggs from hatching,
preventing heartworm,
controlling and treating ear mites, sacroptic mange and controlling tick
infestation due to
Dermacentor variabilis in dogs. The formulation advantageously further
comprises
approximately 60 mg (10 mg/ml) pyriproxyfen or approximately 180 mg (30 mg/ml)
methoprene, which provides additional efficacy against flea eggs.
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Example 9: Compositions Containing Selamectin, Dinotefuran, Permethrin and
Pyriproxyfen
[00100] In another embodiment of the invention, permethrin (489.1 g) was
dissolved in
safflower oil (435.9g) in a clean container with stirring. Selamectin (75 g)
was added to this
mixture with stirring until it was completely dissolved. Permethrin or
phenothrin is preferably
added to insecticide formulations according to the present invention for
additional acaricide
efficacy and for the treatment of mosquitoes and flies. This solution
containing permethrin and
selamectin was added to one of the chambers in the package in the appropriate
volume based on
the dosage required.
[00101] Pyriproxyfen (1.5 g) and Mackernium KP (1 g) were added to a clean
container,
and gently heated until the pyriproxyfen liquefied. Water (22.7 g) was added
with stirring,
followed by the addition of ethyl lactate (47.8 g). Dinotefuran (15 g) was
added and the solution
was mixed and heated at 50 degrees C until the dinotefuran dissolved. The
solution was cooled
to room temperature and the pH adjusted to 5.5 by the addition of sodium
carbonate (0.15 g of a
25% aqueous solution). This solution was added to the other chamber in the
package in the
appropriate volume based on the dosage required.
[00102] It will thus be seen that the objects set forth above, among those
made apparent
from the preceding description, are efficiently attained and, since certain
changes may be made
in carrying out the above method and in the composition set forth without
departing from the
spirit and scope of the invention, it is intended that all matter contained in
the above description
shall be interpreted as illustrative and not in a limiting sense.
[00103] It is also to be understood that the following embodiments are
intended to cover
all of the generic and specific features of the invention herein described and
all statements of the
scope of the invention which, as a matter of language, might be said to fall
therebetween.
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[00104] Particularly it is to be understood that in said embodiments,
ingredients or
compounds recited in the singular are intended to include compatible mixtures
of such
ingredients wherever the sense permits.
28
