U.S. patent application number 13/914978 was filed with the patent office on 2013-12-26 for local topical administration formulations containing indoxacarb.
The applicant listed for this patent is E. I. du Pont de Nemours and Company. Invention is credited to Keith Alan Freehauf, Frank Guerino, Peter Andrew O'Neil, Roger Mervyn Sargent, Robert D. Simmons, Chen-Chao Wang.
Application Number | 20130345210 13/914978 |
Document ID | / |
Family ID | 38927068 |
Filed Date | 2013-12-26 |
United States Patent
Application |
20130345210 |
Kind Code |
A1 |
Guerino; Frank ; et
al. |
December 26, 2013 |
LOCAL TOPICAL ADMINISTRATION FORMULATIONS CONTAINING INDOXACARB
Abstract
The present invention provides formulations and methods useful
in the control of ectoparasites on a domestic animal, using a
formulation comprising Indoxacarb and a veterinarily acceptable
carrier that is applied topically to 10% or less of the total
surface area of a domestic animal. Other embodiments include these
formulations also including one or more additional pesticides such
as fipronil.
Inventors: |
Guerino; Frank; (Monroe
Township, NJ) ; Freehauf; Keith Alan; (Stockton,
NJ) ; Sargent; Roger Mervyn; (Camden, AU) ;
O'Neil; Peter Andrew; (Kirkham, AU) ; Simmons; Robert
D.; (Martinsville, NJ) ; Wang; Chen-Chao;
(West Windsor, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
E. I. du Pont de Nemours and Company |
Wilmington |
DE |
US |
|
|
Family ID: |
38927068 |
Appl. No.: |
13/914978 |
Filed: |
June 11, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12439351 |
Nov 10, 2009 |
8475818 |
|
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PCT/US2007/019096 |
Aug 30, 2007 |
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13914978 |
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60841846 |
Sep 1, 2006 |
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Current U.S.
Class: |
514/229.2 |
Current CPC
Class: |
A01N 47/38 20130101;
A61K 47/14 20130101; A61K 47/10 20130101; A61K 9/0017 20130101;
A61P 33/14 20180101; A01N 53/00 20130101; A61K 31/215 20130101;
A01N 43/88 20130101; A61K 31/5395 20130101; A01N 47/38 20130101;
A01N 2300/00 20130101; A01N 53/00 20130101; A01N 47/38 20130101;
A01N 2300/00 20130101; A01N 53/00 20130101 |
Class at
Publication: |
514/229.2 |
International
Class: |
A01N 43/88 20060101
A01N043/88; A01N 53/00 20060101 A01N053/00 |
Claims
1. A local, topical, spot-on formulation for control of
ectoparasites on a domestic animal comprising an ectoparasitically
effective amount of Indoxacarb, a veterinarily acceptable carrier,
and a pyrethroid pesticide.
2. The formulation of claim 1, wherein said ectoparasite is an
Arthropod.
3. The formulation of claim 2, wherein said Arthropod is an
Insecta.
4. The formulation of claim 3, wherein said Insecta is a flea, fly,
or louse.
5. The formulation of claim 2, wherein said Arthropod is an
Arachnida.
6. The formulation of claim 1, wherein the concentration of
Indoxacarb in said formulation is at least 200 g/L.
7. The formulation of claim 1, wherein the concentration of
Indoxacarb in said formulation is at least 150 g/L.
8. The formulation of claim 1, wherein the concentration of
Indoxacarb is at least 100 g/L.
9. The formulation of claim 1, wherein said veterinarily acceptable
carrier comprises one or more of a solvent, crystallization
inhibitor, adjuvant, co-solvent, colorant, surfactant, spreading
oil, antioxidant, light stabilizer or tackifier.
10. The formulation of claim 9, wherein said solvent comprises a
glycol ether.
11. The formulation of claim 10, wherein said glycol ether
comprises dipropylene glycol monomethyl ether.
12. The formulation of claim 9, wherein said solvent comprises an
alkyl acetate.
13. The formulation of claim 12, wherein said alkyl acetate is
ethyl acetoacetate.
14. The formulation of claim 9, wherein said crystallization
inhibitor is triacetin.
15. The formulation of claim 1, wherein said domestic animal is a
mammal.
16. The formulation of claim 15, wherein said mammal is a canine or
feline.
17-24. (canceled)
25. A method for the control of ectoparasites on a domestic animal
comprising topically applying to a localized region having a
surface area of less than or equal to 10% of the total surface area
of said domestic animal the formulation of claim 1.
26. The method of claim 25, wherein said localized region has a
surface area less than or equal to 5% of the total surface area of
said domestic animal.
27. The method of claim 25, wherein said domestic animal is a
canine or a feline and said localized region of said canine or
feline is less than 10 cm.sup.2.
28. The method of claim 25, wherein said formulation maintains
persistent efficacy on said domestic animal to the extent that no
less than 5% decrease in efficacy occurs within 1 month after
application of said formulation.
29. The method of claim 25, wherein said formulation maintains
persistent efficacy on said domestic animal to the extent that no
less than 5% decrease in efficacy occurs after 1 aqueous solution
washing of said domestic animal.
30-39. (canceled)
40. The formulation of claim 1, wherein said pyrethroid pesticide
is permethrin.
41. The formulation of claim 40, said formulation comprising, by
weight 1-50% Indoxacarb; 0.05-80% permethrin; and ethyl
acetoacetate.
42. The formulation of claim 40, said formulation comprising, by
weight 1-50% Indoxacarb; 0.05-80% permethrin; and dipropylene
glycol monomethyl ether.
43. The formulation of claim 40, said formulation comprising, by
weight 5-25% Indoxacarb; 30-75% permethrin; and ethyl
acetoacetate.
44. The formulation of claim 40, said formulation comprising, by
weight 5-25% Indoxacarb; 30-75% permethrin; and dipropylene glycol
monomethyl ether.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional
Application No. 60/841,846, filed Sep. 1, 2006, which is
incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] Animals are often susceptible to infestations by
ectoparasites (e.g. flies and lice), and infections by
endoparasites (e.g. filariae and intestinal roundworms).
[0003] Domesticated animals, such as cats and dogs, are often
infested with one or more of the following ectoparasites: cat and
dog fleas (Ctenocephalides felis, Ctenocephalides canis, and the
like), ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp.,
Amblyoma spp. and the like), and mites (Demodex spp., Sarcoptes
scabei., Otodectes cynotis. and the like).
[0004] Fleas are a particular problem because not only do they
adversely affect the health of the animal or human, but they also
cause a great deal of psychological stress. Moreover, fleas are
also vectors of pathogenic agents in animals, such as dog tapeworm
(Dipylidium caninum), including humans.
[0005] Similarly, ticks are also harmful to the physical and
psychological health of the animal or human. However, the most
serious problem associated with ticks is that they are the vector
of pathogenic agents, agents which cause diseases in both humans
and animal. Major diseases which are caused by ticks include
borrelioses (Lyme disease caused by Borrelia burgdorfen),
babesioses (or piroplasmoses caused by Babesia sp.) and
rickettsioses (also known as Rocky Mountain spotted fever). Ticks
also release toxins which cause inflammation or paralysis in the
host. Occasionally, these toxins are fatal to the host. Moreover,
mites are particularly difficult to combat since there are very few
active substances which act on these parasites and they require
frequent treatment.
[0006] Likewise, farm animals are also susceptible to parasite
infestations. For example, cattle are affected by a large number of
parasites. A parasite which is very prevalent among farm animals is
the tick genus Boophilus, especially B. microplus (cattle tick), B.
decoloratus and B. anulatus. Ticks, such as Boophilus microplus,
are particularly difficult to control because they live in the
pasture where the farm animals graze. Other important parasites of
cattle include the myiases-producing flies such as Dermatobia
hominis (known as Berne in Brazil) and Cochlyomia hominivorax
(screwworm) whose larvae infest the tissue of the host animal.
Additionally, the species Lucilia sericata (greenbottles), Lucilia
cuprina (damage caused by this fly is commonly known as blowfly
strike in Australia, New Zealand and South Africa) are important
causes of myiases in sheep. Insects whose adult stage constitutes
the parasite include: Haematobia irritans (horn fly); lice such as
Linognathus vituli, etc.; and mites such as Sarcoptes scabiei and
Psoroptes ovis.
[0007] The above list is not exhaustive and other ectoparasites are
well known in the art to be harmful to animals and humans. These
include, for example migrating dipterous larvae such as Hypoderma
spp. and Oestrus ovis.
[0008] Control of ectoparasites on domestic animals have been
attempted using flea collars containing various insecticides. The
ectoparasites, however, remain present in the general vicinity of
the animal, such as within the house of a pet owner. The
eradication of ectoparasites within the animal environment is
difficult unless the environment is permanently covered in an
insecticidal substance, in which case toxicity and reinfestation
are problematic. Thus, there is a need in the art for persistent
and effective agents for eradication of ectoparasites on a domestic
animal in order to reduce the periodicity and the cost of
anti-ectoparasite agents, wherein such agents must be convenient to
store and apply, and present insignificant risk of toxicity to such
domestic animal and its environment.
[0009] U.S. Pat. No. 5,462,938 discloses novel arthropodicidal
compositions and methods relating to oxadiazinyl carboxanilides
compounds having efficacy against household, foliar and
soil-inhabiting agronomic and non-agronomic pests. A compound
disclosed therein, (S)-methyl
7-chloro-2,5-dihydro-2-[[methoxycarbonyl) [4 (trifluoromethoxy)
phenyl]amino]carbonyl]indeno
[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate; common name:
Indoxacarb, or DPX-KN128 has been registered by the EPA as a
"reduced-risk" pesticide, Chemical Code 067710, CAS No.
173584-44-6, U.S. EPA PC 067710 (S-isomer). British Journal of
Pharmacology (2001) 132, 587-595; doi:10.1038/sj.bjp.0703853
entitled "Indoxacarb, an Oxadinzine Insecticide, Blocks Insect
Neuronal Sodium Channels", discloses a study investigating the mode
of action of Indoxacarb as an neuronal sodium channel inhibitor in
Periplaneta Americana. Research Disclosure, May 1997, Number 39786
entitled "Mixtures of Arthropodicides and Fungicides" discloses the
use of Indoxacarb in combination with other arthropodicides in land
or aerially applied pesticide formulations for the protection of
plants against arthropodal pests. U.S. Pat. No. 6,395,765 B1
relates to compositions for the treatment and protection of
parasitic pests on domestic animals that utilize topical
application to a localized region of the domestic animal's
body.
BRIEF SUMMARY OF THE INVENTION
[0010] In one aspect, the present invention provides a composition
and method for control of ectoparasites on a domestic animal,
including eradication of ectoparasites on a domestic animal,
decreasing the number of ectoparasites on a domestic animal, and/or
preventing ectoparasite infestation on a domestic animal. The
method includes topically applying to a localized region or regions
having a cumulative surface area of less than or equal to 10% of
the total surface area of the domestic animal an ectoparasitically
effective amount of a topical formulation comprising Indoxacarb and
veterinarily acceptable carrier. The present composition can also
optionally include an additional pesticide.
[0011] In a preferred aspect, the present invention provides a
composition and method for control of ectoparasite infestation in a
domestic animal comprising applying to a localized region or
regions having a surface area of less than or equal to 10% of the
total surface area of the domestic animal an ectoparasitically
effective amount of a local topical formulation comprising
Indoxacarb in a veterinarily acceptable solvent and optionally
further comprising a crystallization inhibitor.
[0012] Preferred solvents, crystallization inhibitors, modes of
application and dosages in such formulations are disclosed.
DETAILED DESCRIPTION OF THE INVENTION
[0013] Applicants specifically incorporate the entire content of
all cited references in this disclosure. Further, when an amount,
concentration, or other value or parameter is given as either a
range, preferred range, or a list of upper preferable values and
lower preferable values, this is to be understood as specifically
disclosing all ranges formed from any pair of any upper range limit
or preferred value and any lower range limit or preferred value,
regardless of whether ranges are separately disclosed. Where a
range of numerical values is recited herein, unless otherwise
stated, the range is intended to include the endpoints thereof, and
all integers and fractions within the range. It is not intended
that the scope of the invention be limited to the specific values
recited when defining a range.
[0014] Applicant has found that it is possible to effectively
control ectoparasite infestation of domestic animals using a
specific type of Indoxacarb formulation: a topical formulation
applied to a localized region or regions having a surface area of
less than or equal to 10% of the total surface area of the domestic
animal. The formulations and methods are especially advantageous
for animals in situations where it is difficult or time-consuming
to treat all the animals orally or via injection. Thus, the present
invention provides topical formulations useful in control of
ectoparasites comprising Indoxacarb and a veterinarily acceptable
solvent. It has been found by Applicant that certain Indoxacarb
local topical formulations are surprisingly effective and
persistent.
DEFINITIONS
[0015] The following definitions relating to Applicant's disclosure
are provided.
[0016] The term "control of ectoparasites on a domestic animal" as
used herein includes eradication of ectoparasites on a domestic
animal, decreasing the number of ectoparasites on a domestic
animal, and/or preventing ectoparasite infestation on a domestic
animal.
[0017] As used herein, the term "domestic animal" includes any
animal that is kept by humans as a companion animal, pet, working
animal or as livestock for food, fur, leather, wool or other animal
product; or an animal that is found in association with humans such
that control of ectoparasites on such animal is desirable. Common
domestic animals in which the present invention will be
particularly useful include a cow, horse, ass, pig, camel, bird,
dog, cat, deer, sheep, or goat.
[0018] As used herein, the term "ectoparasites" includes parasites,
in any stage of life including eggs, larvae or adult form, that
live on the outside of an animal's body. Common ectoparasites that
are problematic on domestic animals include, for example, fleas,
lice, ticks and mites.
[0019] Arthropod ectoparasites of mammals and birds are often of
particular concern. Exemplary athropods include those summarized in
Table A, as follows.
TABLE-US-00001 TABLE A Summary Of Taxonomy for Important Arthropod
Pests Subphylum Class Order Examples Trilobita Cheliceratac
helicera and pedipalps Merostomata Arachnida Araneae spiders
Scorpionida scorpions Acari mites and ticks Uniramia Chilopoda
centipedes Diplopoda millipedes Pauropoda Soft bodied myriapods
Insecta Hymenoptera bees, wasps Lepidoptera moths, butterflies
Hoptera grasshoppers Diptera true flies Hemiptera true bugs
Coleoptera beetles
[0020] Thus, insect pests include, e.g., biting insects, such as
flies and mosquitoes, mites, ticks, lice, fleas, true bugs,
parasitic maggots, and the like.
[0021] Biting insects include, e.g., migrating diperous larvae as
Hypoderma sp. in cattle, Gastrophilus in horses, and Cuterebra sp.
in rodents, as well as biting flies and mosquitoes of all types.
For example, bloodsucking adult flies include, e.g., the horn fly
or Haematobia irritans, the horse fly or Tabanus spp., the stable
fly or Stomoxys calcitrans, the black fly or Simulium spp., the
deer fly or Chrysops spp., the louse fly or Melophagus ovinus, the
tsetse fly or lossina spp. Parasitic fly maggots include, e.g., the
bot fly (Oestrus ovis and Cuterebra spp.], the blow fly or
Phaenicia spp., the screwworm or Cochliomyia hominivorax, the
cattle grub or Hypoderma spp., and the fleeceworm. Mosquitoes,
include, for example, Culex spp., Anopheles spp., and Aedes
spp.
[0022] Mites include Mesostigmata spp., e.g., mesostigmatids such
as the chicken mite, Dermanyssus gallinae; itch or scab mites such
as Sarcoptidae spp., for example, Sarcoptes scabiei; mange mites
such as Psoroptidae spp., including Chorioptes bovis and Psoroptes
ovis; chiggers, e.g., Trombiculidae spp., for example the North
American chigger, Trombicula alfreddugesi.
[0023] Ticks include, e.g., soft-bodied ticks including Argasidae
spp., for example Argas spp. and Ornithodoros spp.; hard-bodied
ticks including Ixodidae spp., for example Rhipicephalus
sanguineus, and Boophilus spp.
[0024] Lice include, e.g., sucking lice, e.g., Menopon spp. and
Bovicola spp.; biting lice, e.g., Haematopinus spp., Linognathus
spp. and Solenopotes spp.
[0025] Fleas include, e.g., Ctenocephalides spp., such as dog flea
(Ctenocephalides canis) and cat flea (Ctenocephalides fells);
Xenopsylla spp., such as oriental rat flea (Xenopsylla cheopis);
and Pulex spp., such as human flea (Pulex irritans).
[0026] True bugs include, e.g., Cimicidae or e.g., the common bed
bug (Cimex lectularius); Triatominae spp., including triatomid bugs
also known as kissing bugs; for example Rhodnius prolixus and
Triatoma spp.
[0027] Generally, flies, fleas, lice, mosquitoes, gnats, mites,
ticks and helminths cause tremendous losses to the livestock and
companion animal sectors. Arthropod parasites also are a nuisance
to humans and can vector disease-causing organisms in humans and
animals.
[0028] Numerous other arthropod pests and ectoparasites are known
to the art, and are also contemplated to be treated by the
compounds of the invention. These are enumerated in great detail in
MEDICAL AND VETERINARY ENTOMOLOGY, by D. S. Kettle, Publ. John
Wiley & Sons, New York and Toronto; CONTROL OF ARTHROPOD PESTS
OF LIVESTOCK: A REVIEW OF TECHNOLOGY, by R. O. Drummand, J. E.
George, and S. E. Kunz, Publ. CRC Press, Boca Raton, Fla., the
contents of both of which are incorporated by reference herein in
their entireties.
[0029] As used herein an "ectoparasitically effective amount" is an
amount effective to eradicate ectoparasites on a domestic animal,
decrease the number of ectoparasites on a domestic animal, and/or
prevent ectoparasite infestation on such animal.
[0030] As used herein the term "Indoxacarb" or DPX-KN128 or the
designation KN128 refers to the S isomer of Formula I
##STR00001##
[0031] wherein * represents an optically active center.
[0032] The systematic chemical name for Indoxacarb is (S)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]ami-
no]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate. The
R isomer of Formula I or (R)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]ami-
no]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate does
not display insecticidal activity. WO/9963825 describes the use of
various mixtures of the active S isomer and the inactive R isomer
as well as the substantially pure S isomer. The S isomer has been
designated as DPX-KN128 and the R isomer as DPX-KN127 by DuPont and
that nomenclature will used for the sake of convenience in this
specification. Indoxacarb, or DPX-KN128 has been registered as CAS
No. 173584-44-6,
[0033] The compounds of Formula I can be prepared by one or more of
the methods disclosed in WO 92/11249, WO 95/29171 and WO 98/05656
as shown in Scheme 1.
##STR00002##
[0034] As used herein, a "local topical formulation" is a fluid
formulation applied externally to less than or equal to 10% of the
total surface area of an animal. The "local topical formulation"
may be referred to herein as "the formulation of the present
invention." The local, topical formulation will be a fluid
(including aqueous suspensions) such as pour-on formulations and
spot-on formulations, spray-on formulations, emulsions, oils,
creams, and ointments. As used herein, a "local topical
administration formulation" is a fluid formulation including an
amount of Indoxacarb and a veterinarily acceptable carrier that is
effective in eradicating ectoparasites on a domestic animal,
decreasing the number of ectoparasites on a domestic animal, and/or
preventing ectoparasite infestation on a domestic animal when
applied to less than or equal to 10% of the total surface area of a
domestic animal. The "local topical formulation" may be referred to
herein as "the formulation of the present invention." In some
preferred embodiments, the local topical formulation may include a
crystallization inhibitor. A "fluid formulation" includes, for
example, liquid formulations such as pour-on formulations, spot-on
formulations and spray-on formulations which maybe in the form of
solutions, emulsions (oil-in-water or water-in-oil),
suspoemulsions, microemulsions, suspensions (aqueous or
non-aqueous), oils, creams and ointments. A "fluid formulation" may
also include dusts, water dispersible granules, wettable powders
and aerosols. The "fluid formulation" may be ready-to-use or
require preparation such as dilution with water prior to use.
[0035] As used herein the term "persistent efficacy," means that a
formulation of the present invention maintains the ability to
control ectoparasites (i.e., eradicate ectoparasites on a domestic
animal, decrease the number of ectoparasites on a domestic animal,
and/or prevent ectoparasite infestation on a domestic animal) over
a specified period of time or conditions; for example, throughout a
given number of aqueous washes, or over a given number of days,
weeks or months. In some embodiments, efficacy is sufficiently
persistent such that no more than a 20%, 10%, or 5% decrease in
efficacy is seen after a single treatment. In this context the term
"efficacy" refers to the ability of a formulation to control
ectoparasite infestation.
[0036] As used herein, the terms "spot-on" and "pour-on" refer to
formulations applied to a localized region or regions on an animal
having a cumulative surface area of less than or equal to 10% of
the total surface area of the animal, and also to the method of
applying a composition to a localized surface area of an animal
wherein said localized area or areas cumulatively comprise less
than or equal to 10% of the total surface area of the animal.
[0037] As used herein, the term "veterinarily acceptable" refers to
ingredients, compositions or methods of treatment that do not cause
significant adverse reactions in or on a domestic animal, and
additionally do not pose a danger of human toxicity or other
adverse reactions in the surrounding environment of such animal in
situations where humans may be exposed to such environment.
[0038] The term "veterinarily acceptable carrier," as used herein,
refers to all of the ingredients within a composition of the
invention except Indoxacarb, or in the case of a composition
containing Indoxacarb plus one or more additional pesticidally
active ingredients, the ingredients in such composition except the
Indoxacarb and the other pesticidally active ingredients. Examples
of ingredients or compounds that may be comprised within the
veterinarily acceptable carrier include solvents, crystallization
inhibitors, antioxidants, adjuvants, cosolvents, colorants,
surfactants, oils, light stabilizers, tackifiers, suspending
agents, propellants, bulking agents and fragrance enhancers or
maskers.
[0039] As used herein, the words "comprises" or "comprising" are
intended as open-ended transition phrases meaning the inclusion of
the named elements, but not necessarily excluding other unnamed
elements.
[0040] As used herein, the phrases "consists essentially of" and
"consisting essentially of" are intended to mean the exclusion of
additional components and/or agents that have a material effect on
the basic properties of the formulations of the invention. In
particular, an additional component and/or agent that inhibits the
crystallization of Indoxacarb and/or a pesticide agent in a
formulation would have a material effect on the formulation.
Therefore, such a crystallization inhibitor would not be included
when the terms "consists essentially of" and "consisting
essentially of" are employed, unless that crystallization inhibitor
was explicitly included in that formulation.
[0041] The phrases "consisting of" or "consists of" are intended as
a transition meaning the exclusion of all but the recited elements
with the exception of only minor traces of impurities.
Methods and Formulations Targeting Ectoparasites on Domestic
Animals
[0042] In one aspect, the present invention provides a method for
controlling ectoparasite infestation on a domestic animal (e.g.
elimination and/or prevention of infestations of ectoparasites such
as adult fleas or ticks.) The method includes topically applying to
a localized region of skin on the animal, having a surface area of
less than or equal to 10% of the total surface area of the domestic
animal, an ectoparasitically effective amount of a local topical
formulation comprising Indoxacarb and a veterinarily acceptable
carrier.
[0043] The formulations of the present invention include so called
"pour-on" and "spot-on" formulations. In addition to application of
the formulations of the invention onto the surface of healthy or
normal regions of the skin of domestic animals, such localized
regions may also include, or may be wholly comprised of, a wound to
the dermal layer, such as a cut or sore. Thus, in some embodiments,
the present invention is also useful in treating ectoparasite
infection of a wound.
[0044] In some embodiments, the formulation is applied to a single
localized region that is equal to or less than 10%, 5% or 2% of the
total surface area of the animal, or is applied to a combination of
two or more localized regions or areas of the skin of a domestic
animal that together comprise less than 10%, 5% or 2% of the total
surface area of the animal. Without being limited by any particular
mechanism of action, it is believed that the active ingredient,
Indoxacarb diffuses after localized topical application beyond the
localized region to provide ectoparasitic control over the entire,
or a significant portion of the domestic animal's body. In
preferred embodiments, the formulations of the present invention
are applied onto a single spot or region of the skin using
"spot-on" or "pour-on" applications to the skin of the animal. In
some embodiments especially useful for cats and dogs, this
application is localized over a surface area equal to or less than
10 cm.sup.2, especially between 5 and 10 cm.sup.2. In some
particularly preferred embodiments, the formulation is applied at
one or more points along the backline of the animal. For example,
for low dose volumes a single spot between the shoulders will be
suitable; however for high dose volumes multiple locations along
the back is recommended.
[0045] In some preferred embodiments, the formulations are
particularly advantageous due to their efficacy, persistency, and
the pleasant appearance of the animal's fur after application and
drying, in that such preferred formulations have been designed to
minimize or eliminate crystallization on the hairs and maintain the
cosmetic appearance of the coat without stickiness or a sticky
appearance, even when high concentrations of active material are
present. Thus, in another aspect, the present invention provides a
local topical formulation for eradication, reduction and/or
prevention of ectoparasite infestation in a domestic animal
comprising an effective amount of Indoxacarb and a veterinarily
acceptable carrier comprising a crystallization inhibitor. A
crystallization inhibitor as used herein is a substance that
minimizes formation of visible Indoxacarb crystals or precipitates
of Indoxacarb and/or any other pesticide agent from the formulation
after application to the animal. Candidate compounds for use as
crystallization inhibitors may be tested using assays commonly
known in the art. For example, the candidate crystallization
compound(s) may be added to Indoxacarb and a veterinarily
acceptable solvent on a glass slide at 20.degree. C. for 24 hours,
after which the composition is observed with the naked eye to
determine whether crystals are formed. Alternatively, a local
topical formulation including a candidate compound may be applied
to a domestic animal at room temperature, after which the animal is
observed with the naked eye to determine whether crystals are
formed.
[0046] Examples of other crystallization inhibitors include:
triacetin, polyvinylpyrrolidone, polyvinyl alcohols, copolymers of
vinyl acetate and vinylpyrrolidone, polyethylene glycols,
polyethoxylated sorbitan esters; lecithin, acrylic derivatives such
as methacrylates and others, anionic surfactants such as alkali
metal stearates, especially of sodium, of potassium or of ammonium;
calcium stearate; triethanolamine stearate; sodium abietate;
alkylsulphates, especially sodium laurylsulphate and sodium
cetylsulphate; sodium dodecylbenzenesulphonate, sodium
dioctylsulphosuccinate; fatty acids, especially those derived from
copra oil, cationic surfactants such as water-soluble quaternary
ammonium salts of formula N+R'R''R'''R'''', Y-- in which the R
radicals are optionally hydroxylated hydrocarbon radicals, and Y--
is an anion of a strong acid, such as halide, sulphate and
sulphonate anions; cetyltrimethylammonium bromide is among the
cationic surfactants utilizable, the amine salts of formula
N+R'R''R''' in which the R radicals are optionally hydroxylated
hydrocarbon radicals; octadecylamine hydrochloride is among the
cationic surfactants utilizable, the non-ionic surfactants such as
optionally polyethoxylated sorbitan esters, in particular
Polysorbate 80, polyethoxylated alkyl ethers; polyethylene glycol
stearate, polyethoxylated castor oil derivatives, polyglycerol
esters, polyethoxylated fatty alcohols, polyethoxylated fatty
acids, copolymers of ethylene oxide and propylene oxide, amphoteric
surfactants such as substituted lauryl betaine compounds, or
preferably a mixture of at least two of these.
[0047] The crystallization inhibitor may be present in any
appropriate proportion and concentration so as to be effective in
inhibiting crystallization of the particular dosage of Indoxacarb
within the selected formulation. A combination of crystallization
inhibitors may also be used. In some embodiments, the proportion of
crystallization inhibitor(s) is present from 1 to 60% (W/V), from 5
to 50% (W/V), or from 10 to 40% (W/V). Thus, in the most preferred
embodiments, once deposited, the formulation diffuses over the
animal's body and then dries without crystallizing or modifying the
appearance (in particular absence of any whitish deposit or dusty
appearance) or the feel of the fur or skin of the animal.
[0048] Preferred formulations are sufficiently persistent in terms
of efficacy so as to reduce the periodicity and the cost associated
with administration of the formulation to the domestic animal. In
some cases, the formulation is applied no more than twice per week,
no more than once per week, no more than once per month, or no more
than once every three months. Thus, certain formulations of the
present invention maintain persistent efficacy for at least 48
hours, 1 week, 1 month, 2 months or in some cases up to 3 months.
The formulations may also be sufficiently persistent to withstand
washing of the domestic animal with an aqueous solution (e.g. soap
and water.) Thus, the formulation may maintain persistent efficacy
after at least one or even five aqueous solution washes.
[0049] A variety of ectoparasites may be targeted using the
formulations of the present invention. In some embodiments, the
ectoparasite is a flea, fly, or louse, including flea eggs, flea
larvae, fly eggs or fly larvae. Where the formulations of the
present invention are designed to target flea eggs, flea larvae,
fly eggs or fly larvae, the life-cycle of the flea and/or fly is
broken thereby reducing environmental population pressures. For the
purposes of the present invention, the term flea is understood to
refer to all the usual or accidental species of parasitic flea of
the order Siphonaptera, and in particular the genus
Ctenocephalides, in particular the cat flea (C. felis) and dog flea
(C. canis), rat flea (Xenopsylla cheopis) and human flea (Pulex
irritans).
[0050] Any appropriate domestic animal may be treated with the
formulations of the present invention in situations where it is
desirable to control ectoparasites on such animal, or in the
environs of such animal. In certain preferred embodiments, the
domestic animal is a mammal such as a cow, horse, ass, pig, bird,
camel, dog, cat, deer, sheep, or goat.
[0051] The local topical formulations may be prepared by simply
mixing the constituents as defined above, or in cases where the
carrier is an emulsion, suspension or suspoemulsion, aggressive
mixing or homogenization will be required and in the cases where
the Indoxacarb (DPX-KN128) is present in solid form (suspensions,
susopemusions, dusts, powders and granules) milling will be
required to reduce the Indoxacarb (DPX-KN128) particle size.
Methods of preparations of the formulations of the invention will
be obvious to one skilled in this art due to the chemically-defined
nature of Indoxacarb and the preferred ingredients in the claimed
formulations. For example, the active material may be mixed in the
veterinarily acceptable solvent and other components of the
veterinarily acceptable carrier are then added, or the veterinarily
acceptable carrier may be constituted to comprise all of the
ingredients of the formulation except Indoxacarb, and then the
Indoxacarb (and optionally other pesticidally active ingredients)
are then added to the veterinarily acceptable carrier
composition.
[0052] In some embodiments, an additional component within the
carrier will be an antioxidant. Useful antioxidants include, for
example, butylhydroxyanisole, butylhydroxytoluene, ascorbic acid,
sulphites, metabisulphites, or thiosulphates (e.g. sodium
thiosulphate, sodium metabisulphite, potassium metabisulphite,
etc.), propyl gallate, and/or tocopherol, or a mixture of not more
than two of these agents.
[0053] One or more additional pesticidal agents may be included
within the formulations of the invention. Useful pesticides include
insect growth regulators, organophosphate pesticides, carbamate
pesticides, organochlorine pesticides, pyrethrin pesticides,
pyrethroid pesticides, nicotine pesticides, neonicotinoid
pesticides, copper-containing pesticides, anthelmintic agents,
benzimidazole pesticides, salicylanilide pesticides, substituted
phenol pesticides, pyrimidine pesticides, and imidazothiazole
pesticides. Particularly preferred are formamidine insecticides
such as amitraz, semicarbazone insecticides such as metaflumazone
and phenylpyrazoles such as fipronil. Fipronil has been described
in U.S. Pat. Nos. 5,232,940, 6,096,329, 6,395,765 and 6,716,442,
the contents of which are incorporated herein by reference. In one
such embodiment the formulation includes an effective amount of
fipronil and Indoxacarb.
[0054] In some embodiments, the imidazothiazole pesticide is
levamisole. The pyrimidine pesticide may be pyrantel. The
substituted phenol pesticide may be nitroxynil. The salicylanilide
pesticide may be closantel or oxyclozanide. The benzimidazole
pesticide may be albendazole or triclabendazole. The anthelmintic
agent may be a macrocyclic lactone such as an avermectin (e.g.,
ivermectin) or a milbemycin (e.g., moxidectin). The organophosphate
pesticide may be dicrotophos, terbufos, dimethoate, diazinon,
disulfoton, trichlorfon, azinphos-methyl, chlorpyrifos, malathion,
oxydemeton-methyl, methamidophos, acephate, ethyl parathion, methyl
parathion, mevinphos, phorate, carbofenthion, phosalone,
naphthalophos or pyraclofos. The carbamate pesticide may be
carbaryl, carbofuran, aldicarb, or carbofuran. The pyrethroid
pesticide may be allethrin, resmethrin, permethrin, deltamethrin or
tralomethrin. The copper-containing pesticide may be copper (II)
hydroxide, or copper oxychloride sulfate (i.e. (Cu2Cl(OH)3) mixed
with (Cu4(OH) 6(SO4)). The neonicotinoid pesticide may be
imidacloprid, nitenpyram or dinotefuran.
[0055] Additionally, in some embodiments, the pesticide agent is a
pyrethrin pesticide, Bacillus thuringensis toxin, chlorobenzilate,
cyfluthrin, cypermethrin, dicofol, endosulfan, esfenvalerate,
fenvalerate, lambda-cyhalothrin, methoxychlor, sulfur, cyclodiene,
ryania, KT-199 (an antihelminthic antibiotic), or praziquantel.
[0056] The insect growth regulator may be a chitin synthesis
inhibitor or a juvenile growth hormone mimic. In certain
embodiments, the insect growth regulator is azadirachtin,
diofenolan, fenoxycarb, hydroprene, kinoprene, methoprene,
pyriproxyfen, tetrahydroazadirachtin, chlorfluazuron, cyromazine,
diflubenzuron, fluazuron, flucycloxuron, flufenoxuron,
hexaflumuron, lufenuron, novaluron, tebufenozide, teflubenzuron,
and triflumuron.
[0057] These additional pesticidal agents may be present in amounts
to optimize and efficacy and persistency of the formulation.
Particularly. These additional pesticidal agents may be present
from about 0.05% to about 80%. In a preferred embodiment, the
additional pesticidal agent in the formation is permethrin, present
an amount from about 30% to about 75%. In another preferred
embodiment, the additional pesticidal agent is fipronil, present in
an amount from about 5% to about 25%.
[0058] In another preferred embodiment, the additional pesticidal
agent is ivermectin, present in an amount from about 0.05% to about
10%. In another preferred embodiment, the additional pesticidal
agent is abamectin, present in an amount from about 0.05% to about
10%. In another preferred embodiment, the additional pesticidal
agent is moxidectin, present in an amount from about 0.05% to about
10%. In another preferred embodiment, the additional pesticidal
agent is doramectin, present in an amount from about 0.05% to about
10%. In another preferred embodiment, the additional pesticidal
agent is eprinomectin, present in an amount from about 0.05% to
about 10%. In another preferred embodiment, the additional
pesticidal agent is selamectin, present in an amount from about
0.05% to about 10%. In another preferred embodiment, the additional
pesticidal agent is methoprene, present in an amount from about 1%
to about 20%. In another preferred embodiment, the additional
pesticidal agent is S-methoprene, present in an amount from about
1% to about 20%.
[0059] Although the selection of an appropriate solvent for the
Indoxacarb will be important aspect in preparation of an effective,
persistent and cosmetically-desirable formulation, a variety of
veterinarily acceptable solvents are useful in the present
invention. A "veterinarily acceptable solvent," as used herein, is
a solvent that is non-toxic when topically applied to a domestic
animal and is capable of sufficiently solvating indoxacarb to form
a solution. For example, veterinarily acceptable solvents of the
present invention do not cause rashes or inflammation of the dermal
layer on a domestic animal. The veterinarily acceptable solvent is
typically not easily ignited, or if ignited, does not burn rapidly.
The veterinarily acceptable solvent may also appear non-greasy
after applying to said domestic animal.
[0060] In some embodiments the veterinarily acceptable solvent has
a dielectric constant of between 0 and 40, between 0 and 20, or
between 0 and 10.
[0061] Examples of veterinarily acceptable solvents are useful in
the present invention, including diethylene glycol monobutyl ether,
glycerin triacetate, diethylene glycol monomethyl ether, diethylene
glycol monoethyl ether, benzyl benzoate, ethylene glycol monobutyl
ether, ethyl lactate, dipropylene glycol monomethyl ether, ethylene
glycol monobutyl ether acetate, isopropyl alcohol, benzyl alcohol,
ethyl acetoacetate, 2-pyrrolidinone, dimethyl isosorbide, diacetone
alcohol, tetrahydrofurfuryl alcohol, propylene glycol monomethyl
ether, ethanol, propylene carbonate, diethyl phthalate, glycerine
triacetate heptyl acetate, methyl caprylate/caprate, N,N-dimethyl
caprylamide, pentyl acetate, hexyl acetate, cyclohexyl acetate,
ethylene glycol diacetate, methoxypropyl acetate, furfuryl alcohol,
dibutyl phthalate, N-methylpyrrolidinone, glycerol formal,
2,6-dimethyl-4-heptanone, methyl ethyl ketone, methyl isobutyl
ketone and cyclohexanone.
[0062] In some preferred embodiments, the veterinarily acceptable
solvent for Indoxacarb is a glycol ether or alkyl acetate, such as
ethyl acetoacetate. In certain especially preferred embodiments the
veterinarily acceptable solvent is ethyl acetoacetate or
dipropylene glycol monomethyl ether.
[0063] Some of the formulations of the present invention may also
include additional agents such as adjuvants, co-solvents,
colorants, surfactants, spreading oils, antioxidants, light
stabilizers, suspending agents, propellants, bulking agents and/or
tackifiers. Colorants are all colorants which are licensed for use
on animals and which can be dissolved or suspended. The selection
and use of such additional agents to achieve certain desirable
characteristics in topical formulations are well known in this
art.
[0064] Examples of light stabilizers are substances from the
benzophenone class, or novantisolic acid.
[0065] Examples of tackifiers are cellulose derivatives, starch
derivatives, polyacrylates, polyvinyl pyrrolidone, and natural
polymers such as alginates and gelatin.
[0066] Adjuvants may include spreading oils such as isopropyl
myristate, dipropylene glycol pelargonate, silicone oils, fatty
acid esters, triglycerides and fatty alcohols. For example, pour-on
and spot-on formulations may advantageously comprise carriers that
assist rapid distribution over the surface of the skin and in the
coat of the host animal and are generally termed spreading oils.
Many spreading oil/solvent combinations are suitable, e.g., oily
solutions; alcoholic and isopropanolic solutions, e.g., solutions
of 2-octyl dodecanol or oleyl alcohol; solutions in esters of
monocarboxylic acids, such as isopropyl myristate, isopropyl
palmitate, lauric acid oxalic ester, oleic acid oleyl ester, oleic
acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate,
caproic acid esters of saturated fatty alcohols of chain length
C.sub.12-C.sub.18; solutions of esters of dicarboxylic acids, such
as dibutyl phthalate, diisopropyl isophthalate, adipic acid
diisopropyl ester, di-n-butyl adipate or solutions of esters of
aliphatic acids, e.g., glycols. It may be advantageous for a
dispersant known from the pharmaceutical or cosmetic industry also
to be present. Examples are pyrrolidin-2-one,
N-alkylpyrrolidin-2-one, acetone, polyethylene glycol and its
ethers and esters, propylene glycol or synthetic triglycerides.
[0067] The formulations of the present invention may further
include sorbitan monolaurate, dipropylene glycol monomethyl ether,
triethanolamine, benzyl alcohol, isopropyl alcohol, and/or ethyl
acetoacetate.
[0068] Useful anionic surfactants include alkaline stearates, in
particular sodium, potassium or ammonium stearate; calcium
stearate; triethanolamine stearate; sodium abietate; alkyl
sulphates, in particular sodium lauryl sulphate and sodium cetyl
sulphate; sodium dodecylbenzenesulphonate, sodium
dioctylsulphosuccinate; fatty acids, in particular those derived
from coconut oil.
[0069] Useful cationic surfactants include water-soluble quaternary
ammonium salts of formula N.sup.+R'R''R'''R'''', Y.sup.- in which
the radicals R are optionally hydroxylated hydrocarbon radicals and
Y.sup.- is an anion of a strong acid such as the halide, sulphate
and sulphonate anions; cetyltrimethylammonium bromide is among the
cationic surfactants which can be used.
[0070] Useful cationionic surfactant include amine salts of formula
N.sup.+R'R''R''' in which the radicals R are H or optionally
hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is
among the cationic surfactants which can be used.
[0071] Useful nonionic surfactants include polyoxyethylenated
sorbitan esters, in particular polysorbate 80, polyoxyethylenated
alkyl ethers; polyethylene glycol stearate, polyoxyethylenated
derivatives of castor oil, polyglycerol esters, polyoxyethylenated
fatty alcohols, polyoxyethylenated fatty acids, copolymers of
ethylene oxide and propylene oxide. Useful amphoteric surfactants
include substituted lauryl compounds of betaine.
[0072] The dose and concentration of Indoxacarb in the formulations
of the present invention are chosen to optimize the efficacy and
persistency of the formulations. In some embodiments, the
concentration of Indoxacarb in the formulation is at least 100 g/L,
150 g/L, or 200 g/L; or from 1 to 50% (w/v), 5 to 35% (w/v), or 10
to 20% (w/v). In some preferred embodiments, the concentration is
about 200 g/L or 20% (w/v). In certain applications (e.g. where the
domestic animal is a pet), the concentration is also chosen to
minimize any undesired appearance (e.g. white crystals of
Indoxacarb) of the animal after application of the formulation. The
total amount of Indoxacarb administered to the domestic animal is
typically from 1 to 50 mg per kg of body weight, 2 to 25 mg per kg
of body weight, or 5 to 15 mg per kg of body weight.
[0073] In some embodiments, the formulation is applied to the
animal's back and at several points or along the line of the back,
and applied in low volume, such as 5 to 20 ml per 100 kg, or 10 ml
per 100 kg. In some embodiments, the total volume is 10 to 150 ml
per animal, sometimes limited to 50 ml. For example, the volume
applied to cats may be from about 0.3 to 1 ml for cats, and from
about 0.5 to 5 ml for dogs, according to the weight of the
animal.
[0074] In some embodiments, the veterinarily acceptable carrier may
be in the form of an emulsion or solution for application to a
localized region of the animal's skin (e.g. between the two
shoulders as in spot-on type applications). Formulations may
include solutions to be sprayed, poured, spread, or spotted onto
the animal, oils, creams, ointments or any other appropriate fluid
formulation for topical administration. Pour-on and spot-on
formulations may be poured, spotted or sprayed onto limited areas
of the skin. Pour-on and spot-on formulations may be prepared by
dissolving, suspending or emulsifying the active compound in
suitable solvents or solvent mixtures which are tolerated by the
skin. The formulation maybe in the form of a
stable-at-room-temperature, ready-to-use solution that is applied
topically and locally on the animal.
[0075] Veterinarily acceptable emulsions are either of the
water-in-oil type or of the oil-in-water type. They are prepared by
dissolving the Indoxacarb either in the hydrophobic or in the
hydrophilic phase and homogenizing this phase with the solvent of
the other phase, with the aid of suitable emulsifiers and, if
appropriate, other adjuvants such as colorants, absorption
accelerators, preservatives, antioxidants, light stabilizers,
and/or viscosity-increasing substances.
[0076] Examples of hydrophobic phase (oils) include paraffin oils,
silicone oils, natural vegetable oils such as sesame seed oil,
almond oil, castor oil, synthetic triglycerides such as
caprylic/capric acid biglyceride, triglyceride mixture formed from
vegetable fatty acids of chain length C.sub.8-12 or with other
specifically selected natural fatty acids, partial glyceride
mixtures of saturated or unsaturated fatty acids which may also
contain hydroxyl groups, and mono- and diglycerides of the
C8/C10-fatty acids. Fatty acid esters such as ethyl stearate,
di-n-butyryl adipate, hexyl laurate, dipropylene glycol
pelargonate, esters of a branched fatty acid of medium chain length
with saturated fatty alcohols of chain length C16-C18, isopropyl
myristate, isopropyl palmitate, caprylic/capric esters of saturated
fatty alcohols of chain length C12-C18, isopropyl stearate, oleyl
oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid
esters such as dibutyl phthalate, diisopropyl adipate, ester
mixtures related to the latter, and fatty alcohols such as
isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol and
oleyl alcohol.
[0077] Hydrophilic phase solvents include water, alcohols,
propylene glycol, glycerol, sorbitol and their mixtures.
Emulsifiers include non-ionic surfactants, for example
polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate,
sorbitan monostearate, glycerol monostearate, polyoxyethyl
stearate, alkylphenol polyglycol ethers; ampholytic surfactants
such as di-sodium N-lauryl-.beta.-iminodipropionate or lecithin;
anionic surfactants such as sodium lauryl sulphate, fatty alcohol
ether sulphates, the monoethanolamine salt of mono/dialkyl
polyglycol ether orthophosphoric esters; cationic surfactants such
as cetyltrimethylammonium chloride.
[0078] Useful viscosity-increasing substances and substances which
stabilize the emulsion include carboxymethylcellulose,
methylcellulose and other cellulose and starch derivatives,
polyacrylates, alginates, gelatin, gum arabic,
polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl
ether and maleic anhydride, polyethylene glycols, waxes, colloidal
silica, or mixtures of the substances mentioned.
EXAMPLES
[0079] The materials and methods of the present invention are
further illustrated by the examples which follow. These examples
are offered to illustrate, but not to limit, the claimed
invention.
Example 1
Dose Response Study on Canines Against Fleas Using Indoxacarb Local
Topical Administration Containing Dimethyl Isosorbide and Propylene
Glycol Monomethyl Ether
[0080] A non-blinded prospective longitudinal artificial
infestation parasite efficacy pen study was conducted with a fully
randomized design (ranking and blocking based on breed and
pre-treatment flea count). There were 5 treatment groups of 6 dogs
each, and an untreated control group.
[0081] Thirty-three (33) adult dogs (Labrador Retrievers and Jack
Russell Terriers) were inducted, clinically examined, weighed,
identified and allocated to study pens on Day -7. Each dog was
artificially infested with 100 fleas (Ctenocephalides felis) on Day
-5 and again on Day -2. On Day -1 flea thumb counts were performed
on all dogs and 30 dogs were selected for inclusion. These dogs
were randomly allocated to 5 similar groups of 6 animals on the
basis of breed and flea counts, and groups were allocated to study
pens. On Day 0, Groups B, C, D and E were treated with a local
topical administration formulation containing Indoxacarb (DPX-K128)
dissolved in a mixture of Dimethyl Isosorbide (DMI) and Propylene
Glycol Monomethyl Ether (90% Dimethyl Isosorbide (DMI) and 10%
Propylene Glycol Monomethyl Ether by volume) to form a total
concentration of 75, 100, 125 or 150 g/L of Indoxacarb (DPX-K128).
The starting material to prepare the formulation was a mixture of
DPX-K128- and DPX-KN127 (the R-isomer of Formula 1) and contained
70.43% Indoxacarb (DPX-K128). Hence for every 1 gram of Indoxacarb
(DPX-K128) required, 1.42 grams of this mixture was used. The
formulation was administered via spot-on application (i.e. applying
in liquid form to less than or equal to 10% of the surface area of
the animal) to the dorsal midline at the rate of 0.1 mL/1 kg. Group
A remained untreated as controls. Group B was dosed at the rate of
7.5 mg/kg; Group C at the rate of 10.0 mg/kg; Group D at the rate
of 12.5 mg/kg; and Group E at the rate of 15.0 mg/kg.
[0082] Flea thumb counts were performed at 24 hours. Flea comb
counts were performed at 48 hours post-treatment and all dogs then
treated with Capstar.RTM. oral tablets (Nitenpyram, Novartis Animal
Health) to remove all fleas prior to the next infestation. Animals
were re-infested with 100 adult fleas at 7, 14, 21 and 28 days
post-treatment. At 24 hours after each infestation, flea comb
counts were performed followed by Capstar treatment.
[0083] In the first 48 hours post treatment Group D (12.5 mg/kg)
and Group E (15.0 mg/kg) showed 99.0% and 100% reduction of flea
infestation at 24 hrs and 100% and 99.4% reduction at 48 hrs
respectively. Group B (7.5 mg/kg) and C (10.0 mg/kg) also showed
excellent knockdown efficacy, both achieving 97.9% reduction at 24
hrs and 99.4% and 100% respectively at 48 hrs.
[0084] All four groups showed excellent persistent efficacy being
at or near 100% reduction (all .gtoreq.99%) from the 48 hour count
until 29 days post-treatment.
Example 2
Effect of Washing on Persistency
[0085] At completion of the study described in Experiment 1 above,
a further washing study was conducted using the six dogs in Group E
for a further two weeks.
[0086] During the two-week period, four of the six dogs from Group
E were washed twice weekly in a non-insecticidal hydrobath, while
the other two dogs from Group E were not washed and acted as
controls. On Day 43 post-treatment, the 6 dogs were infested with
100 fleas and then had their ability to retain a flea infestation
assessed on Day 44 by a flea comb count. The results are shown in
Table 1 below.
TABLE-US-00002 TABLE 1 Group Average Dog No. Group Flea Count Count
5 Treated Wash 4 3 25 Treated Wash 5 35 Treated Wash 1 38 Treated
Wash 2 19 Treated Non-Wash 0 0 44 Treated Non-Wash 0
[0087] These results demonstrated that all the dogs had low flea
counts and were still resistant to maintaining a flea infestation,
suggesting excellent persistence at 44 days even after 4 thorough
shampoo hydrobath washes.
Example 3
Efficacy Study on Canines Against Fleas Using 15 Mg/Kg Indoxacarb
Local Topical Administration Formulations
[0088] The study was a non-blinded, prospective longitudinal
randomized clinical efficacy pen study with groups of 3 dogs each
receiving one of 5 treatments; 4 test formulation treatments, and a
negative control (no treatment). Animals were ranked on the basis
of breed and pre-treatment flea count, then randomly allocated to
groups from blocks. Animals were artificially infested and parasite
counts performed according to standardized methods.
[0089] Twenty (20) adult dogs (Labrador Retrievers and Jack Russell
Terriers) were inducted into the study on Day -6 and each
artificially infested with 100 fleas (Ctenocephalides felis) on Day
-4. On Day -1, flea counts were performed and 18 dogs selected for
inclusion. The dogs were randomly allocated to 6 similar groups of
3 animals on the basis of breed and flea counts, and groups were
randomly allocated to study pens. Each dog was again infested with
100 fleas. On Day -1 flea counts were again performed on all dogs.
On Day 0, Groups B, C, D and E were treated with one of 4 different
15.0 mg/kg Indoxacarb (DPX-KN128) local topical administration
formulations as shown in Table 2 below. A 3:1 mixture of
DPX-KN128:DPX-KN127 on silica was the starting material for the
formulations. This material contained 56.2% Indoxacarb (DPX-KN128).
Hence for every 1 milligram of Indoxacarb (DPX-KN128) required,
1.78 milligrams of this mixture was used. The formulations were
applied as a spot-on dose from the base of the neck to the
shoulders. The vehicle for Groups B, C and D was Dimethyl
Isosorbide (DMI) and the vehicle for Group E contained 40 g/L
Polyvinyl Pyrrolidone, 47 g/L Ethoxylated Castor Oil, 33 g/L
Ethanol and was diluted to volume with 1-Methyl-2-Pyrrolidinone.
Group A remained untreated.
TABLE-US-00003 TABLE 2 Dose Rate Dose Volume Group and Formulation
(ml/kg) A (control) -- -- B 15.0 mg/kg Indoxacarb 1.8 mL/15 kg C
15.0 mg/kg Indoxacarb 1.8 mL/15 kg 6.0 mg/kg (S)-Methoprene D 15.0
mg/kg Indoxacarb 2.5 mL/15 kg 6.0 mg/kg (S)-Methoprene 47.9 mg/kg
Permethrin E 15.0 mg/kg Indoxacarb 4.0 mL/15 kg
[0090] Flea counts were performed at 24 and 48 hours post
treatment. Flea infestations were repeated at 7, 14, 21, 28, 35 and
42 days post treatment and flea counts were performed at 24 and 48
hours following each infestation.
[0091] Treatment with all formulations resulted in excellent (at or
near 100% reduction) flea control for 44 days post-treatment with
the exception of Group B, for which excellent control was observed
for 37 days post-treatment. These results are presented in Table
3.
TABLE-US-00004 TABLE 3 Group % Reduction in Flea Counts as Compared
to Contemporary Control Counts. 15 16 22 GROUP 24 Hr 48 HR 8 days 9
days days days days B 77.4% 96.2% 94.3% 98.0% 100.0% 95.7% 100.0% C
82.8% 98.7% 98.1% 100.0% 100.0% 100.0% 98.6% D 98.9% 100.0% 100.0%
100.0% 100.0% 100.0% 99.3% E 73.1% 97.4% 100.0% 100.0% 100.0%
100.0% 100.0% 23 29 30 36 37 43 44 GROUP days days days days days
days days B 99.2% 98.7% 98.0% 100.0% 100.0% 95.5% 100.0% C 100.0%
100.0% 100.0% 99.1% 100.0% 99.0% 100.0% D 100.0% 100.0% 100.0%
96.6% 98.9% 73.3% 85.4% E 100.0% 100.0% 100.0% 98.3% 100.0% 96.0%
99.0%
Example 4
Exemplary Formulations
[0092] Table 4 below provides a listing of certain prepared topical
administration formulations.
TABLE-US-00005 TABLE 4 Formulation % Number Ingredients w/v 1
Indoxacarb 10 Dipropylene glycol monomethyl ether QS 2 Indoxacarb
10 Isopropyl myristate 2.0 Span 20 2.0 Dipropylene glycol
monomethyl ether QS 3 Indoxacarb 10 Ethylene glycol monobutyl ether
QS acetate 4 Indoxacarb 10 Ethyl lactate 40 Isopropyl myristate 5.0
Triethanolamine 0.02 Isopropyl alcohol QS 5 Indoxacarb 10 Ethyl
acetoacetate 50 Isopropyl myristate 5.0 Triethanolamine 0.02
Isopropyl alcohol QS 6 Indoxacarb 20 Triacetin 30 Triethanolamine
0.02 Ethyl acetoacetate QS 7 Indoxacarb 20 Triacetin 25 Polysorbate
80 10 Triethanolamine 0.02 Ethyl acetoacetate QS 8 Indoxacarb 20
Isopropyl myristate 25 Triethanolamine 0.02 Ethyl acetoacetate QS 9
Indoxacarb 20 Isopropyl myristate 10 Propylene carbonate 35
Triethanolamine 0.02 Ethyl acetoacetate QS 10 Indoxacarb 20
Isopropyl myristate 10 Dipropylene glycol monomethyl ether 30
Triethanolamine 0.02 Ethyl acetoacetate QS 11 Indoxacarb 20
Polysorbate 80 10 Polyvinyl pyrrolidone K-17 5 Triethanolamine 0.02
Ethyl acetoacetate QS 12 Indoxacarb 20 Isopropyl myristate 10
Benzyl alcohol 30 Triethanolamine 0.02 Ethyl acetoacetate QS 13
Indoxacarb 20 Fipronil 10 Ethyl acetoacetate QS 14 Indoxacarb 20
Fipronil 10 Dipropylene glycol monomethyl ether QS
Example 5
Evaluation of the Safety, Appearance and Run-Off Potential of
Topical Solutions Containing Indoxacarb when Applied on Dogs
[0093] A series of studies were conducted to evaluate the safety,
appearance and potential for run-off of various topical solutions
of Indoxacarb following application on adult beagle dogs. For all
experiments set forth in Table 5, male and female dogs weighing
between 10 and 20 kg were randomly assigned to each formulation
group. A dose volume of 1.5 mL was applied to each dog, which
delivered a minimum dose of 15 mg indoxacarb/kg body weight. At the
time of application, hair at the treatment site was parted and the
formulations were applied directly to the skin in a single location
between the shoulder blades. The application site and hair coat
were then observed closely for spread of the solution, signs of
residue and wetness, and to determine if any of the solution ran
off the animal following treatment (at 5, 15, 30, 60 and 180
minutes and 24 hours). Skin and hair in proximity to the treatment
site were examined for any adverse reactions at 24 hours following
treatment.
[0094] Table 5 provides a listing of the ingredients of the
formulations that were tested in sixteen separate experiments. Each
formulation was applied to four dogs in each study with the
exception of Study Number X07-055-12 (6 dogs/formulation) and
Studies X07-055-13 and X07-055-14 (36 dogs/formulation).
[0095] All of the formulations were safe and there were no adverse
effects on the skin or hair of treated dogs. Formulations V, Z, AB,
AC, AE, AF, AG and AH were identified as having preferred
characteristics of a commercial spot-on treatment. These preferred
characteristics included: lack of drips or run-off upon
application, minimal appearance of residue or crystals upon drying
and relatively fast drying of the application site. The
formulations with the least desirable characteristics (i.e.,
appearance of drips/run-off, residue and wetness) were Formulations
C, E, G, J, Q, and S. The characteristics of the remaining
formulations were intermediate.
TABLE-US-00006 TABLE 5 Formulation Study No. Formulation (% w/v) ID
X07-055-1 20% KN128, 30% triacetin, 0.02% A triethanolamine, ethyl
acetoacetate (qs) 20% KN128, 30% triacetin, 0.02% B
triethanolamine, 1.5% PVP-90, ethyl acetoacetate (qs) 20% KN128,
30% triacetin, 0.02% C triethanolamine, 5% Tween-20, ethyl
acetoacetate (qs) 20% KN128, 30% triacetin, 0.02% D
triethanolamine, 5% Ethyl oleate, ethyl acetoacetate (qs) X07-055-2
20% KN128, 30% triacetin, 0.02% E triethanolamine, 2.5% Ethyl
oleate, ethyl acetoacetate (qs) 20% KN128, 30% triacetin, 0.02% C
triethanolamine, 5% Ethyl oleate, ethyl acetoacetate (qs) 20%
KN128, 30% triacetin, 0.02% F triethanolamine, 10% Ethyl oleate,
ethyl acetoacetate (qs) X07-055-3 20% KN128, 30% triacetin, 0.02% G
triethanolamine, 5% Miglyol 840, ethyl acetoacetate (qs) 20% KN128,
30% triacetin, 0.02% H triethanolamine, 10% Miglyol 840, ethyl
acetoacetate (qs) 20% KN128, 30% triacetin, 0.02% I
triethanolamine, 5% Brij 30, ethyl acetoacetate (qs) X07-055-4 20%
KN128, 20% triacetin, 0.02% J triethanolamine, ethyl acetoacetate
(qs) 20% KN128, 20% triacetin, 0.02% K triethanolamine, 5% PVP
K-30, ethyl acetoacetate (qs) 20% KN128, 20% triacetin, 0.02% L
triethanolamine, 10% Miglyol 840, ethyl acetoacetate (qs) X07-055-5
20% KN128, 20% triacetin, 0.02% M triethanolamine, 10% Miglyol 812,
ethyl acetoacetate (qs) 20% KN128, 20% benzyl alcohol, 0.02% N
triethanolamine, 5% PVP K-30, ethyl acetoacetate (qs) 20% KN128,
20% benzyl alcohol, 0.02% O triethanolamine, 10% Miglyol 840, ethyl
acetoacetate (qs) X07-055-6 20% KN128, ethyl lactate (qs) P 20%
KN128, ethyl acetoacetate (qs) Q 20% KN128, triacetin (qs) R
X07-055-7 20% KN128, propylene carbonate (qs) S 20% KN128,
dipropylene glycol T monomethyl ether (qs) 20% KN128, benzyl
alcohol (qs) U X07-055-8 20% KN128, 25% triacetin, 25% ethyl V
acetoacetate, isopropyl alcohol (qs) 20% KN128, 25% triacetin, 25%
ethyl W acetoacetate, Miglyol 812 (qs) 20% KN128, 25% triacetin,
25% ethyl X acetoacetate, dipropylene glycol monomethyl ether (qs)
X07-055-9 20% KN128, 25% triacetin, dipropylene Y glycol monomethyl
ether (qs) 20% KN128, 25% triacetin, ethyl lactate (qs) Z 20%
KN128, 47.9% permethrin, ethyl AA acetoacetate (qs) X07-055-10 20%
KN128, 25% triacetin, 25% ethyl AB acetoacetate, isopropyl alcohol
(qs) 20% KN128, 20% triacetin, 25% ethyl AC acetoacetate, isopropyl
alcohol (qs) 20% KN128, 15% triacetin, 25% ethyl AD acetoacetate,
isopropyl alcohol (qs) X07-055-11 20% KN128, 25% triacetin, 25% AE
dipropylene glycol monomethyl ether, isopropyl alcohol (qs) 20%
KN128, 25% benzyl alcohol, 25% AF dipropylene glycol monomethyl
ether, isopropyl alcohol (qs) 20% KN128, 25% benzyl alcohol, 25%
ethyl AG acetoacetate, isopropyl alcohol (qs) X07-055-12 20% KN128,
20% triacetin, 25% ethyl AC acetoacetate, isopropyl alcohol (qs)
20% KN128, 20% triacetin, 25% AH dipropylene glycol monomethyl
ether, isopropyl alcohol (qs) X07-055-13 20% KN128, 20% triacetin,
25% AH dipropylene glycol monomethyl ether, isopropyl alcohol (qs)
X07-055-14 20% KN128, 20% triacetin, 25% ethyl AC acetoacetate,
isopropyl alcohol (qs) E07-118-01 150 mg/mL KN128, 479 mg/mL
permethrin, AI ethyl acetoacetate (qs) 150 mg/mL KN128, 479 mg/mL
permethrin, AJ dipropylene glycol monomethyl ether (qs) 150 mg/mL
KN128, 479 mg/mL permethrin, AK benzyl alcohol, isopropyl alcohol
(qs) E07-119-01 200 mg/mL KN128, 598 mg/mL permethrin, AA ethyl
acetoacetate (qs) 200 mg/mL KN128, 598 mg/mL permethrin, AL
dipropylene glycol monomethyl ether (qs) 200 mg/mL KN128, 598 mg/mL
permethrin, AM benzyl alcohol, isopropyl alcohol (qs)
* * * * *