Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TOPICAL LIQUID INSECTICIDE COMPOSITIONS
[0001] BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates generally to insecticides and more particularly
to insecticidal
formulations for use on domestic animals such as cats and dogs.
[0004] 2. Description of Background Art
[0005] As dog and cat ownership increases, there has been a proliferation of
medical and
health services available for addressing the needs of sick and aging pets, as
well as the
maintenance of young and healthy animals. Veterinarians routinely examine pets
for diseases
and indications of infections including the presence of parasites or various
types of cancers.
Cats are particularly prone to feline leukemia and may develop diabetes.
[0006] Many diseases affecting the health of both cats and dogs are caused by
ticks and fleas
that act as vectors for viruses and parasites through bites which can transmit
blood borne
infections. The market for flea and tick products in the US is approximately
$552 million
and is dominated by about 9 businesses. Although growth between 2007-2012 was
0.6%, the
market is expected to increase over the next five years as there is an
increasing number of pet
owners, particularly those who consider pets as family members and are willing
to spend
money for the health and well-being of their pets.
[0007] There are several disadvantages in current flea/tick products for dogs
and cats.
Ideally, in order to address one or more of the deficiencies in currently
available flea/tick
formulations, a product should have: (1) a high concentration of active
ingredient(s) to
minimize the volume of a topical needed for application to a small dog or cat;
(2) liquid
formulations that are stable and effective such that flea kill continues for
up to at least 30
days from application; (3) a safe product for the consumer in case of skin
contact; (4) a
formulation that is stable at ambient, low and higher temperatures with a
commercially
appropriate shelf life; (5) a product that is nontoxic for a dog or cat if
ingested; and (6) a
product that is ideally equally safe and effective for use on both dogs and
cats.
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[0008] Many available flea/tick topical compositions are not safe and
effective for use in
both dogs and cats, the two most common household pets. Another drawback of
current
products is that higher more effective concentrations of the active
ingredients are unavailable
in stable liquid form.
[0009] An effective topical "spot on" application is a commercially desirable
feature,
particularly if formulations can be applied based on weight and not species
basis of the
animal. Some liquid spot products for dogs cannot be used on cats.
[0010] U.S. Patent No. 6,867,223 describes insecticide formulations consisting
of
pryiproxyfen and up to 25% by weight of dinotefuran dissolved in an alcohol,
which is
described as applicable for use on both dogs and cats. In U.S. Patent No
7,368,435, topical
endoparasiticidal and ectoparasiticidal formulations combine a macrocyclic
lactone and a
neo-nicotinoid in addition to permethrin and an insect growth regulator. The
first two
components are packaged separately to prevent interaction with the permethrin
and cannot be
supplied as a stable liquid.
[0011] Estimated Feline and Canine Populations
[0012] Domestic pets in the United States number in the millions with by far
the largest
contribution from cats and dogs. The United States cat population in 2012 was
estimated at
over 74 million cats. The US count does not include feral and community cat
populations,
which are believed to be approximately 50 million. 30-40 percent of households
in the US
own one or more cats or dogs. The mean veterinary expenditure per household
per year for
dogs is $378, comparable to that spent on horses, while for cats the cost
average is $191.
(2012 U.S. Pet Ownership & Demographics Sourcebook).
[0013] Table 1 shows the estimated number of cats and dogs in the top ten
countries with the
highest populations.
[0014] Canine and feline populations are highest in the United States;
however, cats are more
popular than dogs as pets in the United Kingdom and Germany.
[0015] Dogs and cats are a major business in the United States. Growth is
continuing in
development and expansion of dog and cat food with boutique brands and organic
feeds
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enjoying profitable niche markets. New breeds of dogs and cats are appearing,
with so-called
designer breeds such as labradoodles and cockapoos and the recognition of
additional
purebred dogs by such organizations as the American Kennel Club.
[0016] Consumers are also becoming more familiar with cat breeds, including
ancient
breeds, domestic and domestic/wild hybrids. There is inconsistency in breed
classification
among cat registries. At least 55 different breeds are recognized, but a huge
number of cats
are mixed breeds. Recognized breeds include natural, crossbreeds, and
mutations.
[0017] The list of recognized cat breeds is long and includes: Abyssinian,
Aegean, Australian
Mist, American Curl, American Bobtail, American Polydactyl, American
shorthair, American
Wirehair, Arabian Man, Asian, Asian Semi-longhair, Balinese, Bambino, Bengal,
Birman,
Bombay, Brazilian Shorthair, British Shorthair, British Longhair, Burmese,
Burmilla,
California Spangled Cat, Chantilly/Tiffany, Chartreux, Clausie, Cheetoh,
Colorpoint
Shorthair, Cornish Rex, Cymric, Cyprus cat, Devon Rex Doinskoy, Dragon Li,
Dwelf,
Egyptian Mau, European Shorthair, Exotic Shorthair, German Rex, Havana Brown,
Highlander, Himalayan/Colorpoint Persian, Japanese Bobtail, Javanese, Khao
Manee, Korat,
Kurilian Bobtail, LaPerm, Maine Coon, Manx, Mekong bobtail, Minskin, Munchkin,
Nebelung, Napoleon, Norwegian Forest Cat, Ocicat, Ojos Azules, Oregon Rex,
Oriental
Bicolor, Oriental Shorthair, Oriental Longhair, Persian, Peterbald, Pixie-bob,
Ragamuffin,
Ragdoll, Russian Blue, Russian Black, White or Tabby, Savannah, Scottish Fold,
Selkirk
Rex, Serengeti cat, Serrade petit, Siamese, Siberian Singapura, Snowshoe,
Sokoke, Somali,
Sphynx, Swedish forest cat, Thai, Tonkinese, Toyger, Turkish Angora, Turkish
Van,
Ukrainian Levkoy, and York Chocolate Cat.
[0018] The list of American Kennel Club recognized breeds includes
Affenpinscher, afghan
hound, Airedale Terrier, Akita, Alaskan Malamute, American English Coonhound,
American
Eskimo Dog, American Foxhound, American Staffordshire Terrier, American Water
Spaniel,
Anatolian Shepherd Dog, Australian Cattle Dog, Australian Shepherd, Australian
Terrier,
Basenji, Basset Hound, Beagle, Bearded Collie, Beauceron, Bedlington Terrier,
Belgian
Malinois, Belgian Sheepdog, Belgian Tervuren, Bernese Mountain dog, Bichon
Frise, Black
and Tan Coonhound, Black Russian Terrier, Bloodhound, Bluetick Coonhound,
Border
Collie, Border Terrier, Borzoi, Boston Terrier, Bouview des Flandres, Boxer,
Boykin Spaniel,
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Briard, Brittany, Brussels Griffon, Bull Terrier, Bulldog, Bullmastiff, Cairn
Terrier, Canaan
dog, Cane Corso, Cardigan Welsh Corgi, Cavalier King Charles Spaniel, Cesky
Terrier,
Chesapeake Bay Retriever, Chihuahua, Chinese Crested, Chinese Shar-Pei, Chow
Chow,
Cirneco dell'Etna, Clumber Spaniel, Cocker Spaniel, Collie, Curly-Coated
Retriever,
Dachshund, Dalmatian, Dandie Dinmont Terrier, Doberman Pinscher, Dogue de
Bordeaux,
English Cocker Spaniel, English Foxhound, English Setter, English Springer
Spaniel, English
Toy Spaniel, Entlebucher Mountain Dog, Field Spaniel, Finnish Lapphund,
Finnish Spitz,
Flat-Coated Retriever, French bulldog, German Pinscher, German Shepherd Dog,
German
Shorthaired Pointer, German Wirehaired Pointer, Giant Schnauzer, Glen of Imaal
Terrier,
Golden Retriever, Gordon Setter, Great Dane, Great Pyrenees, Greater Swiss
Mountain Dog,
Greyhound, Harrier, Havanese, Ibizian Hound Icelandic Sheepdog, Irish Red and
White
Setter, Irish Setter, Irish Terrier, Irish Water Spaniel, Irish Wolfhound,
Italian Greyhound,
Japanese Chin, Keeshond, Kerry Blue Terrier Komondor, Kuvasz, Labrador
Retriever,
Lakeland Terrier, Leonberger, Lhasa Apso, Lowchen, Maltese, Manchester
Terrier, Mastiff,
Miniature Bull Terrier, Miniature Pinscher, Miniature Schnauzer, Neapolitan
Mastiff,
Newfoundland, Norfolk Terrier, Norwegian Buhund, Norwegian Elkhound, Norwegian
Lundehund, Norwich Terrier, Nova Scotia Duk Tolling Retriever, Old English
Sheepdog,
Otterhound, Papillion, Parson Russell Terrier, Pekingese, Pembroke Welsh
Corgi, Petit
Basser Griffon Vendeen, Pharaoh Hound, Plott, Pointer, Polish Lowland
Sheepdog,
Pomeranian, Poodle, Portuguese Water Dog, Pug, Puli, Pyrencan Shepherd, Rat
Terrier,
Redbone Coonhound, Rhodesian Ridgeback, Rottweiler, Russsell Terrier, Saint
Bernard,
Saluki, Samoyed, Schipperke, Scottish Deerhound, Scottish Terrier, Sealyham
Terrier,
Shetland Sheepdog, Shiba mu, Shih Tzu, Siberian Husky, Silky Terrier, Skye
Terrier Smooth
Fox Terrier, Soft Coated Wheaten Terrier, Spinone Italiano, Staffordshire Bull
Terrier,
Standard Schnauzer, Sussex Spaniel, Swedish Vallhund, Tibetan Mastiff, Tibetan
Spaniel,
Tibetan Terrier, Toy Fox Terrier, Treeing Walker Coonhound, Vizsla,
Weimaraner, Welsh
Springer Spaniel, Welsh Terrier, West Highland White Terrier, Whippet, Wire
Fox Terrier,
Wirehaired Pointing Griffon, Xoloitzcuintli, and Yorkshire Terrier.
[0019] Flea and Tick Control Products
[0020] There are numerous flea and tick control products currently available
for use in
controlling fleas and ticks on felines. Products from the major manufacturers
are sold as
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monthly topicals, most as "spot on" applications to the skin of the animal.
All kill adult fleas
and, although most purport to kill ticks; the majority do not kill flea eggs.
Products
containing flpronil will kill lice but none of those products claim to repel
flies.
[0021] Most main line manufacturers of flea/tick products employ various
concentrations of
fipronil, dinotefuran, imidacloprid or etofenprox in combination with
pyriproxyfen or (S)
methoprene. Few botanicals appear to be effective except for a mixture of
natural botanical
oils sold by Sergeant's which is stated to be effective against adult fleas,
ticks and lice
comparable to products containing flpronil. Table 2 lists the active
ingredients for some
popular commercial products typically supplied as topical treatments.
[0022] SUMMARY OF THE INVENTION
[0023] The invention relates to new liquid formulations containing high
concentrations of
hydrophilic and hydrophobic insecticides, particularly relating to
compositions comprising
dinotefuran, etofenprox and pyriproxyfen as the active components. Dinotefuran
is a neo-
nicotinoid compound which is water soluble, while etofenprox is essentially
insoluble in
water. Other water soluble neo-nicotinoids such as nitenpyram could be used
although most
neo-nicotinoids are relatively insoluble in aprotic polar solvents and do not
dissolve
sufficiently to form a stable solution with the hydrophobic component. In most
preferred
formulations, the hydrophobic component is the ether pyrethrin etofenprox,
which can be
prepared in a weight percent range of 40-60% in an aprotic polar solvent with
dinotefuran
and pyriproxyfen. The weight percent of the solvent or mixed solvents is below
35%. The
active hydrophilic and hydrophobic components form stable solutions with a
shelf life of at
least several months.
[0024] There are several solvents and combinations of solvents that may be
employed to
solubilize the mixture of hydrophilic and hydrophobic active ingredients in
the disclosed
liquid formulations. Such solvents include N-methyl pyrrolidone (NMP),
propylene
carbonate, ethyl acetate, tetrahydrofurfuryl alcohol (THFFA), glycofurol,
glycerol formal,
solketal (alone or in combination with DMSO), 4-hydroxy-1,3-dioxane, 1,2-
glycerol-formal
and N-octylpyrrolidone. A preferred solvent is N-octylpyrrolidone, which can
be combined
with NMP or propylene carbonate.
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[0025] The invention provides a combination of active ingredients ("actives")
particularly
useful for topical treatment of not only ticks and fleas, but also flea eggs,
flea larvae, ticks,
tick eggs, tick nymphs, mites and mosquitoes in felines and canines.
[0026] A particularly surprising aspect of the disclosed formulation is the
high concentration
of hydrophilic and hydrophobic active substances which can be solubilized in
aprotic polar
liquids. Dinotefuran is hydrophilic and readily dissolves in water, while
etofenprox is
hydrophobic with essentially no solubility in water. Combinations of
dinotefuran and
etofenprox up to 40-60% by weight can be achieved in aprotic polar solvents.
The liquid
formulations containing high concentrations of an ether pyrethroid such as
etofenprox are
highly effective in controlling fleas and ticks and are nontoxic for use as
topicals. Products
that use permethrin rather than etofenprox cannot be used on felines due to
toxicity. The
disclosed formulations with high concentrations of etofenprox can be used
effectively and
safely on canines and felines, as well as other mammals such as rabbits, mice,
rats and guinea
pigs.
[0027] Topical solutions preferably comprise a mixture of dinotefuran,
etofenprox and
pyriproxyfen formulated in N-octylpyrrolidone or a mixture of N-
octylpyrrolidone and NMP.
Pyriproxyfen is an insect growth regulator that is present in 0.4-0.5 weight
percent. In a
typical preferred combination, dinotefuran is 4.95 weight percent, etofenprox
is 60 weight
percent, and pyriproxyfen is 0.44 weight percent in 34.6 weight percent N-
octylpyrrolidone
or a mixed solvent of 28.61 weight percent NMP and 6.00 weight percent N-
octylpyrrolidone. This solution provides over 65 weight percent active
ingredients and is
effective as a spot-on formulation to control and kill fleas and ticks in cats
and dogs.
[0028] DETAILED DESCRIPTION OF THE INVENTION
[0029] There are numerous products available for dogs, which act to kill or
prevent fleas and
ticks. A well-known spot topical treatment for dogs is a product containing
fipronil,
cyphenothrin and (S)-methoprene. The active ingredients in the composition for
dogs 45-88
lbs. are in the range of about 22.8 % by weight. The ingredients in Squeeze-On
for dogs are
cyphenothrin and fipronil. This combination of actives is stated to kill
fleas, flea eggs, flea
larvae and ticks. These flea/tick formulations cannot be used on cats.
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[0030] A typical flea treatment for cats is FRONTLINE Feline, which is sold
with only two
active ingredients: fipronil and S-methoprene. The latter is an insect growth
regulator. The
active ingredients make up only about 12% while inert ingredients make up over
78% of the
formulation. By comparison, the flea/tick formulations described here have
much higher
concentrations of active ingredients and are therefore more effective and long-
lasting.
[0031] Table 3 exemplifies topical formulations illustrating the invention,
preferably
containing dinotefuran, pyriproxyfen and etofenprox. Dinotefuran is a member
of the neo-
nicotinoid class of insecticides and etofenprox is an ether pyrethroid. Most
pyrethroids are
esters. Pyriproxyfen is an insect growth regulator. Dinotefuran will kill
fleas but not ticks;
etofenprox will kill both fleas and ticks. Dinotefuran provides "speed of kill
"that is not
provided by etofenprox. Table 3 shows formulations containing dinotefuran,
etofenprox and
pyriproxyfen that can be applied as a topical "spot on" to animals. The
formulations are
particularly effective for use as topical applications on canines and felines
to kill fleas, ticks
and flea eggs.
[0032] Dinotefuran is a hydrophilic compound that will dissolve in water
(approx. 40 g/L).
Other neo-nicotinoids with a few exceptions are less soluble, as shown in
Table 4. While
dinotefuran is most preferred, nitenpyram is highly hydrophilic and could be
used in
formulations where higher levels of neo-nicotinoid would be desirable. The
ether pyrethroid
etofenprox will dissolve in some aprotic polar solvents to provide up to 40-60
weight percent
while most ester pyrethroids had little solubility. Other ether pyrethroids
may be useful
provided they have insecticidal activity and may be desirable because of cost
and relatively
low hydrophobicity.
[0033] The described formulations are stable at temperatures from 0 F up to at
least 120 F.
for one month at tested temperatures of 0 , 32 , 70 and 120 F. Table 5 shows
the results of
several formulations stored at temperatures ranging from freezing to 50 F. No
precipitation
or crystallization was observed.
[0034] Etofenprox is a hydrophobic compound that is relatively insoluble in
water [1mg/L].
Both dinotefuran and etofenprox are soluble in pyrrolidone compounds. N-
octylpyrollidone is
a preferred solvent that can be used either alone or mixed with other aprotic
polar liquids.
Other solvent systems are suitable and are listed in Table 2.
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[0035] The new formulations are designed to be used on both canines and
felines.
Etofenprox is not toxic to felines, unlike other members of the pyrethroid
class of
insecticides. Most products available for dogs include pyrethoid esters which
are toxic to
felines and therefore cannot be used on cats. The formulations which have high
levels of the
ether pyrethroid etofenprox can be used on other mammals including rabbits,
mice, rats,
hamsters, and guinea pigs.
[0036] An important and unexpected aspect of the invention is the high
concentration of total
insecticide actives [approx. 45-65%] in solution that are stable at ambient
and lower
temperatures for extended periods of time. This is particularly unexpected
because
etofenprox is relatively insoluble in solvents that dissolve hydrophilic
substances. The
hydrophilic and hydrophobic actives in the described mixtures form stable
solutions with
good temperature stability. No precipitation or crystallization was observed
in liquid
formulations containing 40-60 weight percent etofenprox and up to 5%
dinotefuran, although
dinotefuran at 5% concentration may crystallize from many hydrophilic solvents
at 0 F and
32 F. Even with this high concentration of active ingredients, the solutions
are stable for 1
month at tested temperatures of 0 , 32 , 70 and 120 F.
[0037] Flea Diseases
[0038] A lethal disease in cats is cytauxzoonosis, which is a blood parasite
commonly found
from central Kansas southward and eastward to about Jacksonville, Florida.
There is no
effective treatment for cytauxzoonosis.
[0039] The most common problem with fleas in both cats and dogs is flea
allergy dermatitis.
Fleas inject saliva into the skin when they are feeding causing the animal to
itch where
salivary protein is deposited at the site of the bite. Subsequent scratching
can result in
significant hair loss in the area of the bite.
[0040] Fleas can cause allergic reactions in both pets and humans. Flea bites
on cats or dogs
can result in hives or rashes which may promote a serious skin infection; for
example, miliary
dermatitis in cats. Humans are often bitten by fleas transferred from infested
animals,
resulting in itching, redness and varying degrees of dermatitis.
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[0041] Anemia is an extremely serious condition which can result from fleas
feeding on red
blood cells in severe flea infestations. The condition is particularly serious
in kittens and
puppies where loss of red blood cells affects ability to efficiently carry
oxygen to the brain.
Even after treatment for anemia, the animals may have lasting brain damage.
[0042] Tape Worms are carried inside fleas and are transmitted to cats and
dogs when the
animals lick or chew on flea bites. The ingested tapeworm reproduces in the
digestive system
and can grow to several feet in length. Infected dogs or cats, particularly
young ones, fail to
thrive and are typically underweight.
[0043] Plague is a disease that affects humans even in modern times. The
disease is
transmitted to humans through flea bites, most frequently to pet owners in
areas with flea
infestations. Fleas typically are brought into homes by pets which may or may
not show
evidence of fleas.
[0044] Most common in the Southern states, murine typhus is carried by fleas,
from both
wild animals and pets such as cats or dogs. Typical symptoms of murine typhus
include
backache, abdominal pain, headache, nausea, vomiting, and a red rash. The
worst symptom
of this condition is the extremely high fever that it causes (of 105-106
degrees), which can
last for weeks.
[0045] Tick Diseases in pets
[0046] There are several diseases that can be transmitted to a pet from a tick
bite. The most
common tick-borne diseases seen in the United States are Lyme disease, Rocky
Mountain
spotted fever, ehrlichiosis, and tick paralysis. These and some of the other
tick-borne diseases
that particularly affect dogs and cats are listed below.
[0047] Also called borreliosis, Lyme disease is caused by the bacteria
Borrelia burgdorferi.
Deer ticks carry these bacteria, transmitting them to the animal while sucking
its blood. The
tick must be attached to the dog (or cat) for about 48 hours in order to
transmit the bacteria to
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the animal's bloodstream. If the tick is removed within a day or two,
transmission will
usually not occur.
[0048] Common signs of Lyme disease include lameness, fever, swollen lymph
nodes and
joints, and reduced appetite. In severe cases, animals may develop kidney
disease, heart
conditions, or nervous system disorders. Animals do not develop the tell-tale
"lyme disease
rash" that is commonly seen in humans with Lyme disease.
[0049] Blood tests are necessary to diagnose Lyme disease in pets. Oral
antibiotics are
generally prescribed if the tests are positive. Dogs that have recovered from
Lyme disease
can get the disease again because no immunity is conferred. A vaccine for Lyme
disease is
available for dogs, but unfortunately, the vaccine is not available for cats.
[0050] A disease seen commonly in dogs in the east, Midwest, and plains region
of the U.S.
is Rocky Mountain spotted fever Cats can be infected with RMSF, but the
incidence is much
lower for them. The organisms that cause RMSF are transmitted by the American
dog tick
and the Rocky Mountain spotted fever tick.
[0051] The tick must be attached to the dog or cat for at least five hours in
order for
transmission of the organism to occur. Signs of RMSF may include fever,
reduced appetite,
depression, pain in the joints, lameness, vomiting, and diarrhea. Some animals
may develop
heart abnormalities, pneumonia, kidney failure, liver damage, or even
neurological signs
(e.g., seizures, stumbling).
[0052] Blood tests are used to detect antibodies to the organism. This
indicates that at one
time the animal has been infected. Oral antibiotics are used for about two
weeks to treat the
infection. Unlike Lyme Disease, animals that clear the organism usually
recover and remain
immune to future infection. If the dog or cat has heart, liver, or kidney
damage, and/or the
nervous system has been affected by the infection, it may require additional
supportive
treatment, generally in hospital.
[0053] Currently, there is no vaccine available to prevent RMSF, so tick
control is important
for animals living in endemic areas.
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[0054] Ehrlichiosis is also a tick-borne disease affecting dogs. It is
transmitted by the brown
dog tick and the Lone Star Tick and is caused by a rickettsial organism. It
occurs worldwide
and is found in every state in the U.S. Common symptoms include depression,
reduced
appetite (anorexia), fever, stiff and painful joints, and bruising. Signs
typically appear less
than a month after a tick bite and last for about four weeks.
[0055] Special blood tests may be needed to test for antibodies to Ehrlichia.
Antibiotics are
usually given for up to four weeks to completely clear the organism. After
infection, the
animal may develop antibodies to the organism, but will not be immune to
reinfection. There
is no vaccine available for ehrlichiosis. Low doses of antibiotics may be
recommended for
animals during tick season in areas of the country that are endemic to this
disease.
[0056] Deer ticks and western black-legged ticks carry the bacteria that
transmit canine
anaplasmosis. Another form of anaplasmosis caused by a different bacterium is
carried by the
brown dog tick. Both dogs and cats are at risk for this condition. Because the
deer tick also
carries other diseases, some animals may be at risk for developing more than
one tick-borne
disease at the same time.
[0057] Signs of anaplasmosis are similar to ehrlichiosis and include pain in
the joints, fever,
vomiting, diarrhea, and possible nervous system disorders. Pets will usually
begin to show
signs of disease within a couple weeks after infection. Diagnosis of
anaplasmosis will usually
require blood tests, urine tests, and sometimes other specialized lab tests.
[0058] Oral antibiotics are given for up to a month for treatment of
anaplasmosis, depending
on the severity of the infection. When treated promptly, most pets will
recover completely.
Immunity is not guaranteed after a bout of anaplasmosis, so pets may be
reinfected if exposed
again.
[0059] Tick paralysis is caused by a toxin secreted by ticks. The toxin
affects the nervous
system in mammals. Dogs affected become weak and limp, while cats are usually
affected to
a lesser extent. Signs begin about a week after an animal is first bitten by
ticks. It typically
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begins with a weakness in the rear legs, eventually involving all four limbs,
followed by
difficulty breathing and swallowing. Death may result if the condition
progresses further.
[0060] If ticks are found on the animal, removal usually results in a rapid
recovery.
Depending on the severity of the condition, supportive treatment (e.g.,
breathing assistance)
may be needed for survival. An antitoxin is available, which can be given if
the condition is
discovered soon after infection.
[0061] Haemobartonellosis is a disease transmitted by both ticks and fleas. It
is caused by an
organism that targets red blood cells in the affected animal, leading to
anemia and weakness.
Both cats and dogs are affected. In cats, the condition is also known as
feline infectious
anemia. In dogs, the disease is usually not apparent unless the animal already
has underlying
issues.
[0062] Diagnosis of haemobartonellosis is by examining blood samples for the
organism.
Specialized lab tests are also available. Treatment with antibiotics must be
continued for
several weeks, and transfusions may be necessary for some animals.
[0063] Also known as rabbit fever, tularemia is caused by a bacteria carried
by four varieties
of ticks in North America. Fleas may also carry and transmit tularemia to dogs
and cats. Cats
are usually more affected by this condition than dogs. Symptoms in dogs are
reduced
appetite, depression, and a mild fever. Cats will exhibit high fever, swollen
lymph nodes,
nasal discharge, and possibly abscesses at the site of the tick bite. Younger
animals are
usually at higher risk of contracting tularemia.
[0064] Blood tests are generally used to look for antibodies to the bacteria
that cause
tularemia, the presence of which signifies exposure and probable infection.
Antibiotics are
given to treat this condition in positively identified animals. There is no
preventive vaccine
for this condition, so keeping cats indoors and using flea and tick control
measures are
important. Restricting your pet from hunting rodents, rabbits, and animals
that carry the
disease will also help protect your pet from acquiring the disease.
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[0065] Protozoa, those tiny single celled animal-like organisms, are the
parties to blame
when dogs and cats are diagnosed with babesiosis. Ticks transmit the protozoan
organism to
animals, where it sets itself up in the red blood cells, causing anemia.
Babesiosis is usually
seen in the southern U.S., but is also found in the northeastern part of the
country.
[0066] Signs of babesiosis in dogs are typically severe. They include pale
gums, depression,
dark-colored urine, fever, and swollen lymph nodes. In severe cases, the
animal may collapse
suddenly and go into shock. Blood and urine tests, as well as specialized
diagnostic testing,
are used to look for signs of the organism in the affected animal.
[0067] Dogs that survive the disease usually remain infected and future
relapses may occur.
There is no vaccine available for protection from babesiosis.
[0068] Cats are at risk for being infected with cytauxzoonosis. This parasitic
disease is
transmitted by ticks and is more commonly reported in the south central and
southeast United
States. Cats typically become very ill when infected because the parasite
affects many parts
of the body.
[0069] Cats may develop anemia, depression, high fever, difficulty breathing,
and jaundice
(i.e., yellowing of the skin). Treatment is often unsuccessful, and death
occurs in as short as
one week following infection.
[0070] Immediate and aggressive treatment with specialized drugs, intravenous
fluids and
supportive care are typically necessary. Cats that recover from cytauxzoonosis
but may be
carriers of the disease for life. There is no vaccine for this disease, so
tick prevention is
important.
[0071] Dogs in the south central and southeastern United States are at greater
risk for
contracting American canine hepatozoonosis (ACH). The Gulf Coast tick carries
this
particular disease. This tick-borne disease is caused by the actual ingestion
of a nymphal or
adult stage tick, rather than by transmission through attachment and biting of
the skin by the
tick. It is suspected that the ingestion takes place during self-grooming, or
when the dog eats
an infected animal.
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14
[0072] Infection is severe and often fatal. Symptoms include high fever,
stiffness and pain
upon movement, weight loss, and complete loss of appetite. The muscles will
begin to waste
away, an outward symptom that will become most apparent around the dog's head.
Discharge
from the eyes is also very common.
[0073] Tests can be done to find the parasites in the dog's blood, discharge,
or muscle tissue.
Treatment with anti-parasitic drugs, along with anti-inflammatories and
antibiotics, is
necessary for some time after diagnosis. If the dog recovers, follow-up
medication for several
years may be necessary, as a relapse of this disease is possible.
[0074] The most common problem with fleas in both cats and dogs is flea
allergy dermatitis.
Fleas inject saliva into the skin when they are feeding causing the animal to
itch where
salivary protein is deposited at the site of the bite. Subsequent scratching
can result in
significant hair loss in the area of the bite.
[0075] Ticks cause several diseases in both cats and dogs but only dogs get
Lyme disease.
Cats can acquire anaplasmosis and tularemia. Apparently rare, ticks can infect
cats with
Rocky Mountain spotted fever.
[0076] EXAMPLES
[0077] The following examples are provided as illustrations of the invention
and are in no
way to be considered limiting.
[0078] Example 1¨Flea/tick formulations
[0079] Exemplary formulations
[0080] (A) dinotefuran, 4.95 g and etofenprox, 60.0 g, is dissolved in 54.6 g
of N-
octylpyrrolidone. The solution can be stored at least for one month at ambient
temperatures.
Alternatively, a dry mixture of dinotefuran and etofenprox with a respective
mass weight
CA 02949342 2016-11-16
WO 2015/177587 PCT/1B2014/001594
ratio of 0.0825 can be shipped separately from N-octylpyrrolidone for
combining in amounts
to provide a weight % ratio of up to 60% for etofenprox and 4.95% for
dinotefuran.
[0081] (B) Dinotefuran 4.95 g, etofenprox, 40-60 g and pyriproxyfen, 0.44 g
are dissolved in
34-48 g of N-methylpyrrolidone and 6-10 g of N-octylpyrrolidone selected to
provide a
solution with a weight percent range of 40-60% of etofenprox, 4.95%
dinotefuran, 0.44%
pyriproxyfen and 6-10% N-octylpyrrolidone. The solution is stable at ambient
temperature
for at least one month.
[0082] (C) Dinotefuran 4.95 g, etofenprox, 40-60 g. pyriproxyfen, 0.44 g and
0.2g piperonyl
butoxide are dissolved in 34-48 g of N-methylpyrrolidone and 6-10 g of N-
octylpyrrolidone
selected to provide a solution with a weight percent ratio of 40-60% of
etofenprox, 4.95%
dinotefuran, 0.44% pyriproxyfen, 0.2% piperonylbutoxide and 6-10% N-
octylpyrrolidone.
The solution is stable at ambient temperature for at least one month.
[0083] Example 2¨Application of high concentration flea/tick formulations
[0084] The formulations of Example 1 (A-C) are prepared in an N-
octylpyrrolidone/N-
methylpyrrolidone solvent with a nominal 60-65% by weight concentration of
dinotefuran,
and etofenprox and, optionally, pyriproxyfen and piperonyl, each less than 0.5
weight %.
Topical applications are made monthly to a dog or cat in dosage amounts from
0.5-8 ml,
preferably from 1.2 ml up to 5.96 ml depending on the weight of the animal.
[0085] Example 3¨Dosage Applications in dogs.
[0086] Typically, the formulations in example 1 are applied to canines on a
weight basis.
Table 6 shows a typical dosage for a topical formulation with 55% etofenprox
mass weight
percent. The product can be applied as a spot at the base of the neck between
the shoulder
blades or as a stripe starting at the base of the neck and finishing at the
base of the tail.
[0087] Example 4¨Dosage applications in cats.
[0088] Cat weights, with the exception of kittens, do not show the same
variation as do dog
weights. A 40% by weight Etofenprox formulation prepared as in example 1 is
applied at a
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16
dosage of 1.8 ml. The product can be applied as a spot at the base of the neck
by the shoulder
blades or as a stripe starting at the base of the neck and finishing at the
base of the tail.
Table 1. Cat and Dog Populations
Country Number
Cats Dogs
United States 76,430,000 75,800,000
China 53,100,000 27,400,000
Russia 12,700,000 15,000,000
Brazil 12,466,000 35,700,000
France 9,600,000 7,400,000
Italy 9,400,000
UK 7,700,000
Ukraine 7,350,000
Japan 7,300,000 12,000,000
Germany 7,100,000
Philippines 22,600,000
India 10,200,000
Argentina 9,200,000
Romania 9,200,000
Table 2.
Product Name Active Percent Application Frequency
Ingredient
FRONTLINE PLUS Fibronil 9.8% Monthly
(S)methoprene 11/8%
SENTRY etofenprox 55% Monthly
pyriproxyfen 2.5%
BIOSPOT ON FOR CATS etofenprox 40% Monthly
(S)methoprene 3.6%
0
t..)
o
,..,
u,
Table 3.
,..,
-4
-4
Lot # Lot # Lot # Lot # Lot #
Lot # Lot # Lot # u,
cio
-4
12-06-90A 12-06-91B* 12-06-92C* 12-06-93D* 12-06-94E 12-06-95F 12-06-97H 12-06-
981
Ingredient %/w/w %/w/w %/w/w %/w/w %/w/w
%/w/w %/w/w %/w/w
Dinotefuran 4.95 4.95 4.95 4.95 4.95
4.95 4.95 4.95
Permethrin 36.08
Etofenprox 0.00 40.00 50.00 60.00 40.00
40.00 40.00 40.00
Pyriproxyfen 0.44 0.44 0.44 0.44 0.44
0.44 0.44 0.44
NMP 58.53 48.61 38.61 28.61 44.61
34.61 34.61 34.61 p
N-octylpyrrolidone 6.00 6.00 6.00 6.00 10.00
10.00 10.00 10.00
..'
Propylene
rt.
carbonate
10.00 rõ
THFFA
10.00
,
Ethyl lactate
10.00
100.00 100.00 100.00 100.00 100.00
100.00 100.00 100.00
'---.1
1-d
n
1-i
,..,
=
.6.
-a
=
u,
,.,
.6.
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PCT/1B2014/001594
18
Table 4.
Neo-Nicotinoids Water Solubility
(g/liter)
Acetamiprid 2.95
Clothianidin 0.327
Imidacloprid 0.5
Nitenpyram 840
Sulfoxaflor 0.568
Thiacloprid 0.185
Thiamethoxam 4.1
Dinotefuran 39.83
Nitenpyram and dinotefuran have high water solubility
and can be described as hydrophilic.
0
Table 5. Ambient, Freezer and Refrigerator storage
t..)
o
Lot # Lot # Lot # Lot # Lot #
Lot # Lot # Lot #
u,
12-06-90A 12-06-91B 12-06-92C 12-06-93D 12-06-94E 12-06-95F 12-06-97H 12-06-
981
-4
-4
Ingredient %/w/w %/w/w %/w/w %/w/w %/w/w
%/w/w %/w/w %/w/w u,
cao
-4
1 Dinotefuran 4.95 4.95 4.95 4.95 4.95
4.95 4.95 4.95
2 Permethrin 36.08
3 Etofenprox 0.00 40.00 50.00 60.00 40.00
40.00 40.00 40.00
4 Pyriproxyfen 0.44 0.44 0.44 0.44 0.44
0.44 0.44 0.44
NMP 52.53 48.61 38.61 28.61 44.61
34.61 34.61 34.61
6 N-octylpyrrolidone 6.00 6.00 6.00 6.00 10.00
10.00 10.00 10.00
Propylene
p
7 carbonate
10.00 2
..'
8 THFFA
10.00
t
9 ethyl lactate
10.00
100.00 100.00 100.00 100.00 100.00
100.00 100.00 100.00
,
S= soluble, H = Hazy, P= precipitate
Evaluation 02/20/13
Ambient Storage S S S S
S S S
Freezer (Immediately) S S S S
S S S od
After Freeze/Thaw S S S S
S S S n
,-i
5
t..)
Refrigerator S S S S
S S S
,-,
.6.
O-
o
50 C storage S S S S
S S S
u,
,o
.6.
C
t..)
Evaluation 02/28/13
c'
,-,
u,
Ambient Storage S S S S
S S S
-4
-4
u,
cio
Freezer (Immediately) S S S S
S S S -4
After Freeze/Thaw S S S S
S S S
Refrigerator S S S S
S S S
50 C storage S S S S
S S S
Evaluation 03/08/13
P
Ambient Storage S S S S
S S S 2
..'
t
Freezer (Immediately) S S S S
S S S
After Freeze/Thaw S S S S
S S S
'
,
Refrigerator S S S S
S S S
50 C storage S S S S
S S S
1.)
c)
,-o
n
,-i
,..,
=
.6.
-a
=
u,
,.,
.6.
CA 02949342 2016-11-16
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PCT/1B2014/001594
21
Table 6.
Weight Dosage
5-14 lbs. 0.5 ml
15-30 lbs. 1.95 ml
31-60 lbs. 3.90 ml
61-150 lbs. 6.50m1
