U.S. patent application number 15/730565 was filed with the patent office on 2018-03-22 for systemic treatment of blood-sucking and blood-consuming parasites by oral administration of a parasiticidal agent.
The applicant listed for this patent is BAYER HEALTHCARE LLC. Invention is credited to William R. Campbell, Douglas I. Hepler, Roland H. Johnson, Kathleen G. Palma.
Application Number | 20180078537 15/730565 |
Document ID | / |
Family ID | 42073871 |
Filed Date | 2018-03-22 |
United States Patent
Application |
20180078537 |
Kind Code |
A1 |
Johnson; Roland H. ; et
al. |
March 22, 2018 |
SYSTEMIC TREATMENT OF BLOOD-SUCKING AND BLOOD-CONSUMING PARASITES
BY ORAL ADMINISTRATION OF A PARASITICIDAL AGENT
Abstract
Pharmaceutically acceptable single parasiticidal agent
compositions of imidacloprid for oral delivery to mammals to
systemically control targeted blood-sucking or blood-consuming
parasites, such as fleas, ticks and certain species of helminthes
and scabies.
Inventors: |
Johnson; Roland H.;
(Lexington, NC) ; Hepler; Douglas I.;
(McLeansville, NC) ; Palma; Kathleen G.;
(McLeansville, NC) ; Campbell; William R.;
(Jamestown, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BAYER HEALTHCARE LLC |
Shawnee |
KS |
US |
|
|
Family ID: |
42073871 |
Appl. No.: |
15/730565 |
Filed: |
October 11, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12471129 |
May 22, 2009 |
9820977 |
|
|
15730565 |
|
|
|
|
61102774 |
Oct 3, 2008 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 33/00 20180101;
A61K 9/0056 20130101; A61K 31/44 20130101; A61P 33/10 20180101;
A61P 33/14 20180101 |
International
Class: |
A61K 31/44 20060101
A61K031/44; A61K 9/00 20060101 A61K009/00 |
Claims
1. A pharmaceutically acceptable composition of a parasiticidally
effective, subtoxic amount of imidacloprid for oral delivery to
mammals to control blood-sucking or consuming parasites thereon,
wherein imidacloprid is the only parasiticidal agent present in the
pharmaceutical composition.
2. The composition according to claim 1, wherein the composition
provides imidacloprid in a single dose level of 0.01 mg/kg to 10
mg/kg.
3. The composition according to claim 1, wherein the imidacloprid
is provided at a single dose level of 0.25 mg/kg.
4. The composition according to claim 1, wherein the composition is
formulated as a chewable soft treat.
5. The composition according to claim 2, further comprising
packaging and a label therefor, wherein the label directs use of
the composition as a treatment for fleas.
6. The composition according to claim 1, wherein the
parasiticidally effective amount is sufficient to kill adult
fleas.
7. The composition according to claim 1, wherein the composition
provides imidacloprid in a single dose level of 0.01 mg/kg to 30
mg/kg.
8. The composition according to claim 1, wherein the imidacloprid
is provided at a single dose level of 3 mg/kg.
9. The composition according to claim 7, further comprising
packaging and a label therefor, wherein the label directs use of
the composition as a treatment for ticks.
10. The composition according to claim 1, wherein the
parasiticidally effective amount is sufficient to kill adult ticks
or tick nymphs.
11. The composition according to claim 1, wherein the
parasiticidally effective amount is sufficient to kill
blood-sucking or consuming helminthes.
12. The composition according to claim 1, wherein the
parasiticidally effective amount is sufficient to kill
blood-sucking or consuming scabies.
13. The composition according to claim 1, wherein the
parasiticidally effective amount is sufficient to kill flea larvae
or flea eggs.
14. The composition according to claim 1, wherein the
parasiticidally effective amount is sufficient to kill tick larvae
or tick eggs.
15. The composition according to claim 1, further comprising a
flavoring.
16. The composition according to claim 1, wherein the composition
is formulated as a pill, tablet or capsule.
17. The composition according to claim 1, wherein the mammal is a
cat or dog.
18. The composition according to claim 1, wherein the composition
provides imidacloprid in a single dose level of 0.25 mg/kg to 10
mg/kg.
19. The composition according to claim 1, wherein the composition
provides imidacloprid in a single dose level of 0.5 mg/kg to 6
mg/kg and the parasite is a flea, flea larvae, or flea eggs.
20. The composition according to claim 1, wherein the composition
provides imidacloprid in a single dose level of 15 mg/kg to 30
mg/kg and the parasite is a tick, tick larvae, or tick eggs.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 12/471,129, filed May 22, 2009, which claims
priority under 35 U.S.C. .sctn. 119(e) of U.S. Provisional
Application No. 61/102,774, filed Oct. 3, 2008, the contents of
each are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0002] The invention relates to the oral administration of
parasiticidal agents. More particularly, the invention relates to
administration of a parasiticidal agent, such as a neonicotinoid,
to mammals to treat external blood-sucking and blood-consuming
parasites and certain internal blood-sucking or blood-consuming
parasites.
BACKGROUND OF THE INVENTION
[0003] With the exception of lufenuron, an insect growth regulator,
the market for ectoparasite control in mammals has long been
dominated by compositions for topical administration. The latter
includes the two top-selling topical products for flea and tick
control, ADVANTAGE.RTM. (imidacloprid) with efficacy against fleas
(but not ticks), sold for use on dogs and cats, and FRONTLINE.RTM.
(fipronil) with efficacy against fleas, ticks and scabies, also
sold for use on dogs and cats. Both imidacloprid and fipronil are
toxic at relatively low oral dosages. Fipronil is also known to
cause emesis when given orally to control fleas, while oral
efficacy of imidacloprid against targeted parasites has not been
reported. Indeed, even when given topically, imidacloprid alone is
reported to have little or no effect on ticks. Instead, a further
active admixed with imidacloprid is required, such as the
permethrin used in the ADVANTIX.RTM. product, which has some
efficacy against ticks.
[0004] Although these products have efficacy against at least fleas
when applied topically, the route of administration raises concerns
regarding the active compounds' potentially toxic effect on humans.
For both products, it is generally advised that humans not contact
the administration site for several hours after application.
Compliance with this advice as to treatment of domestic pets can be
difficult, especially for children. In addition, the carriers used
for such topical products often contain waxes, oils or other
spreading agents, and so remain on the treated animal's skin for a
length of time sufficient to risk environmental contamination or
staining. Furthermore, certain products containing these actives
include other agents that are toxic to other species. For example,
permethrin is suitable for use in dogs but is potentially lethal to
cats, making topical use of such products problematic in
multi-species environments.
[0005] It is therefore desirable to provide an orally deliverable
compound for control of targeted parasites. It is especially
desirable to provide such a compound in a readily consumable dosage
form.
SUMMARY OF THE INVENTION
[0006] The invention is based in part on the surprising discovery
that imidacloprid, when given orally at relatively low sub-toxic
doses, systemically kills blood-sucking and blood-consuming
parasites ("targeted parasites") of mammals quickly and
comprehensively, and can do so in the absence of other
parasiticidal agents.
[0007] The invention therefore provides pharmaceutically acceptable
parasiticidal compositions of imidacloprid for oral delivery to
mammals to control targeted parasites. The parasiticidal
compositions of the invention may be formulated in any suitable
oral form; for example, a chewable treat.
[0008] In an embodiment of the invention, the targeted parasites
are adult fleas, adult ticks or tick nymphs. In a further
embodiment of the invention, the targeted parasites are flea or
tick larvae or eggs.
[0009] In a further embodiment of the invention, the targeted
parasites are fleas, and the imidacloprid is provided at a single
dosage level of 10 mg/kg or less, with dosages as low as about 0.25
mg/kg being sufficient to eliminate an infestation from the treated
animal within 1-24 hours of dosing. Optionally, dosing may be
repeated at the same or higher dosage (up to 10 mg/kg) to control
or prevent reinfestation.
[0010] In a further embodiment of the invention, the targeted
parasites are ticks, tick nymphs or tick eggs, and the imidacloprid
is provided at a single dosage level of 30 mg/kg or less, with
dosages as low as about 3.0 mg/kg being sufficient to eliminate an
infestation from the treated animal within 1-72 hours of dosing.
Optionally, dosing may be repeated at the same or higher dosage (up
to 30 mg/kg) to control or prevent reinfestation.
[0011] In a further embodiment of this aspect of the invention, the
imidacloprid composition is orally administered as often as
necessary to control the parasites. It can be reasonably expected
that at least about 60% of all adult ticks and tick nymphs will be
killed within 1-24 hours following administration of a single dose
in accord with the invention, and that about 100% of all adult
fleas will be killed within 1-24 hours following administration of
a single dose in accord with the invention.
[0012] The invention further relates to use of fipronil as an oral
parasiticidal agent, when given orally at doses that are sub-toxic
to the treated animals, kills targeted parasites quickly,
comprehensively and without emesis when provided in certain oral
dosage formats. The invention therefore provides pharmaceutically
acceptable compositions of fipronil for oral delivery to mammals to
control targeted parasites.
[0013] In another embodiment of this aspect of the invention, the
targeted parasites are adult fleas, adult ticks or tick nymphs. In
a further embodiment of the invention, the targeted parasites are
flea or tick larvae or eggs.
[0014] In a further embodiment of this aspect of the invention, the
parasiticidal agent present in the pharmaceutical composition is
fipronil, without derivation or modification of the compound. In
another aspect of this embodiment, this fipronil active is the only
parasiticidal agent present in the pharmaceutical composition.
[0015] In a further embodiment of the invention, the targeted
parasites are blood-sucking or consuming helminthes.
DESCRIPTION OF THE INVENTION
A. Active Ingredients of the Pharmaceutically Acceptable
Parasiticidal Compositions of the Invention.
[0016] By "pharmaceutically acceptable parasiticidal composition"
and "parasiticidal composition" it is meant that the active
parasiticidal agent present is formulated for oral delivery in a
manner rendering the composition product acceptable for
administration to warm-blooded mammals (humans or animals). The
preferred parasiticidal active agents are the central nervous
system active neonicotinoids, a class that includes acetamiprid,
clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid
and thiamethoxam. The presently preferred neonicotinoid active is
imidacloprid, whose chemical formula follows:
##STR00001##
[0017] Imidacloprid: E or Z isomer (preferably E) of
1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine.
[0018] Those of ordinary skill in the art will recognize that
modifications to neonicotinoid compounds compound are possible,
such as pegylation. Substitutents may also be introduced to the
compound. However, the introduction of substituents including
halogens, alkoxy groups, alkyls and others into the 5-position of
the pyridine ring of imidacloprid in particular may reduce
imidacloprid's neuroblocking activity. The introduction of alkoxy
groups at this position may also be unfavorable for activity. As
such, imidacloprid without modification of substituents at the
5-position of the pyridine ring might desirably be avoided in the
invention. Unmodified, underivatized imidacloprid is highly
effective as used according to the invention, and its use is
therefore preferred.
[0019] Another active class whose use is contemplated by the
invention is the phenylpyrazoles, such as fipronil, or its
desulfinyl, sulfinyl, sulfide, or sulfone metabolites. The chemical
structure of fipronil follows:
##STR00002##
[0020] Fipronil:
5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)su-
lfinyl]-1H-pyrazole-3-carbonitrile. As noted, certain metabolites
of fipronil may also be useful in the invention. However, in a
preferred embodiment, it is not necessary to modify the active
compound itself to avoid adverse effects on the treated host, such
as emesis.
[0021] Also, it is not necessary to include other active agents in
the pharmaceutically acceptable compositions of neonicotinoids or
phenylpyrazoles to achieve the desired level of efficacy.
B. Ectoparasite Targets
[0022] The active compounds in the formulations of the invention
are suitable for the control of blood-sucking or consuming
parasites which can be found in humans and mammalian animals,
including domestic animals, productive livestock, zoo animals,
laboratory animals, experimental animals and pets, while having
favorable toxicity to mammals at the dosages provided by the
invention. The productive livestock and breeding animals include
mammals such as, for example, cattle, horses, sheep, pigs, goats,
camels, water buffalo, donkeys, rabbits, fallow deer, reindeer,
fur-bearing animals such as, for example, mink, chinchilla,
raccoon, birds such as, for example, chickens, geese, turkeys and
ducks. Laboratory and experimental animals include mice, rats,
guinea pigs, golden hamsters, dogs and cats. Pets include dogs and
cats.
[0023] The pharmaceutical composition is parasiticidally active
against all developmental stages of bloodsucking or blood consuming
parasites, including larvae, nymphs and eggs. Targeted parasites
are those which bite the host or otherwise gain access to its blood
during infestation, and include the order Siphonaptera (fleas)
extending, for example, to the genera Ctenocephalides.,
Echidnophaga, Pulex and Ceratophyllus; the order Ixodida (ticks)
including all infraorders, with emphasis on the family Ixodidae
extending, for example, to the genera Ixodes, Dermacentor,
Rhipicephalus, Amblyomma, Haemaphysalis and Boophilus as well as
the family Argasidae extending, for example, to the genera
Argasinae, Ornithodorinae, Otobinae, Antricolinae and Nothoaspinae;
the order Anoplura (blood-sucking lice) extending, for example, to
the genera Haematopinus, Linognathus, Solenopotes, Pediculus and
Pthirus; the order Mallophaga (consuming lice) extending, for
example, to the genera Trimenopon, Menopon, Eomenacanthus,
Menacanthus, Trichodectes, Felicola, Damalinea and Bovicola; the
order Diptera extending, for example, to the consuming species,
such as those of the genus Ceratopogonidae; the order Astigmata
extending, for example, to the genus Sarcoptes (in the presence of
blood); and the order Strongiloidae extending to those species that
bite and/or suck blood, such as hookworms, tapeworms and
heartworms.
C. Dosage Forms for the Parasiticidal Compositions of the
Invention.
[0024] 1. Dosage Ranges.
[0025] Parasiticidal control according to the invention can be
effected prophylactically as well as therapeutically. To those
ends, eradication of a flea infestation can be achieved with a
single neonicotinoid dose in the range of 0.01 to 10 mg/kg,
preferably about 0.25 to about 0.5 mg/kg, optionally 1, 3, 6 or 10
mg/kg, including all dosages in between the stated ranges. As
demonstrated in the Examples, a single dose of parasiticidal
composition providing 0.25 mg/kg of imidacloprid was 100% effective
against a flea infestation on treated animals within as little as
an hour of administration of the dose.
[0026] To control against reinfestation without redosing the
animal, higher initial dosing with a neonicotinoid is more
effective, with the maximal 10 mg/kg level for imidacloprid having
greatest effect at one week post-dosing, as illustrated in Table 3
of Example II. However, repeated dosing at lower levels will be as
effective, without risk of toxicity. Therefore, parasiticidal
compositions of the invention for use against fleas may be provided
in single or multiple dose packaging, with each dose being the same
or different to achieve the treatment results best suited to a
particular case.
[0027] Further, eradication of a tick and/or tick nymph infestation
can be achieved with a single dose in the range of 0.01 to 30 mg/kg
per day. In apparently anomalous results, as illustrated by Example
II, Tables 4 and 5, dosing at about the 3 mg/kg level was
significantly more effective against a tick infestation than dosing
at the 10 mg/kg level, and more effective than dosing at the 15
mg/kg level. As dosing approached the maximal sub-toxic level of 30
mg/kg, efficacy increased to about the same level achieved at the 3
mg/kg level. Therefore, a single dose of parasiticidal composition
providing 3 mg/kg of imidacloprid was at least 60% effective
against a tick infestation on treated animals within as little as
24-48 hours of administration of the dose.
[0028] It can be expected that, as observed with respect to fleas,
higher dosages might sustain longer half-lives and therefore a
degree of efficacy against reinfestation over longer periods of
time than lower dosages. As such, dosing in the 15, 22 or 30 mg/kg
levels (and all points in between that range) can be provided to
avoid a need for re-dosing, or multiple doses can be provided at
lower dosage levels (e.g., 3 mg/kg), without risk of toxicity.
Therefore, parasiticidal compositions of the invention for use
against ticks may be provided in single or multiple dose packaging,
with each dose being the same or different to achieve the treatment
results best suited to a particular case.
[0029] Effective dosage ranges of the pharmaceutical formulations
of a phenylpyrazole compound such as a fipronil composition for
oral administration are in the range of 0.01 to 0.3 mg/kg per day,
preferably about 0.05 to about 0.3 mg/kg per day.
[0030] Following oral administration of the pharmaceutical
compositions of the present invention, the active agent passes
though the mucosal barriers of the GI tract and is absorbed into
the blood stream where it can be detected in the plasma of
subjects. The level of active agent in the bloodstream as measured
in the plasma is dose-dependent. The active agent facilitates the
absorption of the drug (active agent) administered therewith
(either in the same dosage form, or simultaneously therewith), or
sequentially (in either order, as long as both the active agent and
the drug are administered within a time period which provides both
in the same location, e.g., the stomach, at the same time). By
measuring plasma concentrations and with dose response studies, the
daily dosage for the imidacloprid of the invention may be modified
for less frequent administration.
[0031] 2. Dosage Formats.
[0032] The parasiticidal compositions of the invention can be
provided in any therapeutically acceptable pharmaceutical form. For
example, the compositions can be formulated for oral administration
as drug powders, crystals, granules, small particles (which include
particles sized on the order of micrometers, such as microspheres
and microcapsules), particles (which include particles sized on the
order of millimeters), beads, microbeads, pellets, pills,
microtablets, compressed tablets or tablet triturates, molded
tablets or tablet triturates, and in capsules, which are either
hard or soft and contain the composition as a powder, particle,
bead, solution or suspension. The parasiticidal compositions can
also be formulated for oral administration as a solution or
suspension in an aqueous liquid, as a liquid incorporated into a
gel capsule or as any other convenient formulation for
administration, or for rectal administration, as a suppository,
enema or other convenient form. The parasiticidal composition can
also be provided as a controlled release system (see, e.g., Langer,
1990, Science 249: 1527-1533).
[0033] As to oral dosage forms of the present invention that are
solid, the active may simply be provided in gelatin capsules, with
or without optional pharmaceutical excipients. Suitable
pharmaceutical excipients are known to those of ordinary skill in
the art and include, in addition to those mentioned with respect to
the chewable treat dosage form, the following: acidifying agents
(acetic acid, glacial acetic acid, citric acid, fumaric acid,
hydrochloric acid, diluted hydrochloric acid, malic acid, nitric
acid, phosphoric acid, diluted phosphoric acid, sulfuric acid,
tartaric acid); aerosol propellants (butane,
dichlorodifluoro-methane, dichlorotetrafluoroethane, isobutane,
propane, trichloromonofluormethane); Air displacements (carbon
dioxide, nitrogen); alcohol denaturants (denatonium benzoate,
methyl isobutyl ketone, sucrose octacetate); alkalizing agents
(strong ammonia solution, ammonium carbonate, diethanolamine,
diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium
borate, sodium carbonate, sodium hydroxide, trolamine); anticaking
agents, such as glidants; antifoaming agents (dimethicone,
simethicone); antimicrobial preservatives (benzalkonium chloride,
benzalkonium chloride solution, benzethonium chloride, benzoic
acid, benzyl alcohol, butylparaben, cetylpyridinium chloride,
chlorobutanol, chlorocresol, cresol, dehydroacetic acid,
ethylparaben, methylparaben, methylparaben sodium, phenol,
phenylethyl alcohol, phenylmercuric acetate, phenylmercuric
nitrate, potassium benzoate, potassium sorbate, propylparaben,
propylparaben sodium, sodium benzoate, sodium dehydroacetate,
sodium propionate, sorbic acid, thimerosal, thymol); antioxidants
(ascorbic acid, acorbyl palmitate, butylated hydroxyanisole,
butylated hydroxytoluene, hypophosphorous acid, monothioglycerol,
propyl gallate, sodium formaldehyde sulfoxylate, sodium
metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol,
tocopherols excipient); buffering agents (acetic acid, ammonium
carbonate, ammonium phosphate, boric acid, citric acid, lactic
acid, phosphoric acid, potassium citrate, potassium metaphosphate,
potassium phosphate monobasic, sodium acetate, sodium citrate,
sodium lactate solution, dibasic sodium phosphate, monobasic sodium
phosphate); capsule lubricants (see tablet and capsule lubricant);
chelating agents (edetate disodium, ethylenediaminetetraacetic acid
and salts, edetic acid); coating agents (sodium
carboxymethyl-cellulose, cellulose acetate, cellulose acetate
phthalate, ethylcellulose, gelatin, pharmaceutical glaze,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate, methacrylic acid
copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate
phthalate, shellac, sucrose, titanium dioxide, carnauba wax,
microcrystalline wax, zein); colorants (caramel, red, yellow, black
or blends, ferric oxide); complexing agents
(ethylenediaminetetraacetic acid and salts (EDTA), edetic acid,
gentisic acid ethanolamide, oxyquinoline sulfate); desiccants
(calcium chloride, calcium sulfate, silicon dioxide); emulsifying
and/or solubilizing agents (acacia, cholesterol, diethanolamine
(adjunct), glyceryl monostearate, lanolin alcohols, lecithin, mono-
and di-glycerides, monoethanolamine (adjunct), oleic acid
(adjunct), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene
50 stearate, polyoxyl 35 caster oil, polyoxyl 40 hydrogenated
castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether,
polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate
60, polysorbate 80, propylene glycol diacetate, propylene glycol
monostearate, sodium lauryl sulfate, sodium stearate, sorbitan
monolaurate, soritan monooleate, sorbitan monopalmitate, sorbitan
monostearate, stearic acid, trolamine, emulsifying wax); filtering
aids (powdered cellulose, purified siliceous earth); flavors and
perfumes (anethole, benzaldehyde, ethyl vanillin, menthol, methyl
salicylate, monosodium glutamate, orange flower oil, peppermint,
peppermint oil, peppermint spirit, rose oil, stronger rose water,
thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin);
glidants and/or anticaking agents (calcium silicate, magnesium
silicate, colloidal silicon dioxide, talc); humectants (glycerin,
hexylene glycol, propylene glycol, sorbitol); plasticizers (castor
oil, diacetylated monoglycerides, diethyl phthalate, glycerin,
mono- and di-acetylated monoglycerides, polyethylene glycol,
propylene glycol, triacetin, triethyl citrate); polymers (e.g.,
cellulose acetate, alkyl celloloses, hydroxyalkylcelluloses,
acrylic polymers and copolymers); solvents (acetone, alcohol,
diluted alcohol, amylene hydrate, benzyl benzoate, butyl alcohol,
carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl
acetate, glycerin, hexylene glycol, isopropyl alcohol, methyl
alcohol, methylene chloride, methyl isobutyl ketone, mineral oil,
peanut oil, polyethylene glycol, propylene carbonate, propylene
glycol, sesame oil, water for injection, sterile water for
injection, sterile water for irrigation, purified water); sorbents
(powdered cellulose, charcoal, purified siliceous earth); carbon
dioxide sorbents (barium hydroxide lime, soda lime); stiffening
agents (hydrogenated castor oil, cetostearyl alcohol, cetyl
alcohol, cetyl esters wax, hard fat, paraffin, polyethylene
excipient, stearyl alcohol, emulsifying wax, white wax, yellow
wax); suspending and/or viscosity-increasing agents (acacia, agar,
alginic acid, aluminum monostearate, bentonite, purified bentonite,
magma bentonite, carbomer 934p, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, carboxymethylcellulose sodium 12,
carrageenan, microcrystalline and carboxymethylcellulose sodium
cellulose, dextrin, gelatin, guar gum, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium
aluminum silicate, methylcellulose, pectin, polyethylene oxide,
polyvinyl alcohol, povidone, propylene glycol alginate, silicon
dioxide, colloidal silicon dioxide, sodium alginate, tragacanth,
xanthan gum); sweetening agents (aspartame, dextrates, dextrose,
excipient dextrose, fructose, mannitol, saccharin, calcium
saccharin, sodium saccharin, sorbitol, solution sorbitol, sucrose,
compressible sugar, confectioner's sugar, syrup); tablet binders
(acacia, alginic acid, sodium carboxymethylcellulose,
microcrystalline cellulose, dextrin, ethylcellulose, gelatin,
liquid glucose, guar gum, hydroxypropyl methylcellulose,
methylcellulose, polyethylene oxide, povidone, pregelatinized
starch, syrup); tablet and/or capsule diluents (calcium carbonate,
dibasic calcium phosphate, tribasic calcium phosphate, calcium
sulfate, microcrystalline cellulose, powdered cellulose, dextrates,
dextrin, dextrose excipient, fructose, kaolin, lactose, mannitol,
sorbitol, starch, pregelatinized starch, sucrose, compressible
sugar, confectioner's sugar); tablet disintegrants (alginic acid,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, starch,
pregelatinized starch); gablet and/or capsule lubricants (calcium
stearate, glyceryl behenate, magnesium stearate, light mineral oil,
polyethylene glycol, sodium stearyl fumarate, stearic acid,
purified stearic acid, talc, hydrogenated vegetable oil, zinc
stearate); tonicity agents (dextrose, glycerin, mannitol, potassium
chloride, sodium chloride); flavoring vehicles, including flavored
and/or sweetened fluids (aromatic elixir, compound benzaldehyde
elixir, iso-alcoholic elixir, peppermint water, sorbitol solution,
syrup, tolu balsam syrup); oil vehicles, (almond oil, corn oil,
cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl
palmitate, mineral oil, light mineral oil, myristyl alcohol,
octyldodecanol, olive oil, peanut oil, persic oil, seame oil,
soybean oil, squalane); carrier vehicles (sugar spheres);
viscosity-increasing agents (see suspending agent); water repelling
agents (cyclomethicone, dimethicone, simethicone); and wetting
and/or solubilizing agents (benzalkonium chloride, benzethonium
chloride, cetylpyridinium chloride, docusate sodium, nonoxynol 9,
nonoxynol 10, octoxynol 9, poloxamer, polyoxyl 35 castor oil,
polyoxyl 40, hydrogenated castor oil, polyoxyl 50 stearate,
polyoxyl 10 oleyl ether, polyoxyl 20, cetostearyl ether, polyoxyl
40 stearate, polysorbate 20, polysorbate 40, polysorbate 60,
polysorbate 80, sodium lauryl sulfate, sorbitan monolaurate,
sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate,
tyloxapol). This list is not meant to be exclusive, but instead
merely representative of the classes of excipients and the
particular excipients which may be used in any oral dosage forms of
the present invention.
[0034] The parasiticidal compositions of the invention may also be
formulated to have an enteric coating along with another
pharmaceutically acceptable vehicle. For example, a tablet can be
formed by compression of the composition, without excipients, into
a tablet of pharmaceutically acceptable hardness and friability),
optionally with a lubricant (e.g., magnesium stearate) and enteric
coated.
[0035] Polymers which are useful for the preparation of enteric
coatings include, but are not limited to, shellac, starch and
amylose acetate phthalates, styrine-maleic acid copolymers,
cellulose acetate succinate, cellulose acetate phthalate (CAP),
polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose
phthalate (grades HP-50 and HP-55), ethylcellulose, fats, butyl
stearate, and methacrylic acid-methacrylic acid ester copolymers
with acid ionizable groups ("EUDRAGIT.TM."), such as "EUDRAGIT.TM.
L 30D", "EUDRAGIT.TM. RL 30D", "EUDRAGIT.TM. RS 30D", "EUDRAGIT.TM.
L 100-55", and "EUDRAGIT.TM. L 30D-55".
[0036] The disintegration of the enteric coating occurs either by
hydrolysis by intestinal enzymes or by emulsification and
dispersion by bile salts, depending upon the type of coating used.
For example, esterases hydrolyze esterbutyl stearate to butanol and
stearic acid and, as the butanol dissolves, the stearic acid flakes
off of the medicament. Additionally, bile salts emulsify and
disperse ethylcellulose, hydroxypropylmethylcellulose, fats and
fatty derivatives. Other types of coatings are removed depending on
the time of contact with moisture, for example coatings prepared
from powdered carnauba wax, stearic acid, and vegetable fibers of
agar and elm bark rupture after the vegetable fibers absorb
moisture and swell. The time required for disintegration depends
upon the thickness of the coating and the ratio of vegetable fibers
to wax.
[0037] Application of the enteric coating to the parasiticidal
composition can be accomplished by any method known in the art for
applying enteric coatings. For example, but not by way of
limitation, the enteric polymers can be applied using organic
solvent based solutions containing from 5 to 10% w/w polymer for
spray applications and up to 30% w/w polymer for pan coatings.
Solvents that are commonly in use include, but are not limited to,
acetone, acetone/ethyl acetate mixtures, methylene
chloride/methanol mixtures, and tertiary mixtures containing these
solvents. Some enteric polymers, such as methacrylic
acid-methacrylic acid ester copolymers can be applied using water
as a dispersant. The volatility of the solvent system must be
tailored to prevent sticking due to tackiness and to prevent high
porosity of the coating due to premature spray drying or
precipitation of the polymer as the solvent evaporates.
[0038] Furthermore, plasticizers can be added to the enteric
coating to prevent cracking of the coating film. Suitable
plasticizers include the low molecular weight phthalate esters,
such as diethyl phthalate, acetylated monoglycerides, triethyl
citrate, polymethyl glycoltributyl citrate and triacetin.
Generally, plasticizers are added at a concentration of 10% by
weight of enteric coating polymer weight. Other additives such as
emulsifiers, for example detergents and simethicone, and powders,
for example talc, may be added to the coating to improve the
strength and smoothness of the coating. Additionally, pigments may
be added to the coating to add color to the pharmaceutical
formulation.
[0039] In general, the parasiticidal compositions of the invention
can also be prepared in granulated or powder form (e.g., for use in
a feed-through dosing regimen) using any method known in the art,
such as but not limited to, crystallization, spray-drying or any
method of comminution, including wet or dry granulation.
Granulating agents which are useful for preparing the parasiticidal
composition granules, include but are not limited to, cellulose
derivatives (including carboxymethylcellulose, methylcellulose, and
ethylcellulose), gelatin, glucose, polyvinylpyrrolidone (PVP),
starch paste, sorbitol, sucrose, dextrose, molasses, lactose,
acacia gum, sodium alginate, extract of Trish moss, panwar gum,
ghatti gum, mucilage of isapol husks, Veegum and larch
arabogalactan, polyethylene glycol, and waxes. Granulating agents
may be added in concentrations ranging from 1 to 30% of the mass of
the particles or granules.
[0040] Parasiticidal composition granules or powder particles can
also be suspended in a solution for oral administration as a
liquid. The suspension can be prepared from aqueous solutions to
which thickeners and protective colloids are added to increase the
viscosity of the solution to prevent rapid sedimentation of the
coated powder particles or granules. Any material which increases
the strength of the hydration layer formed around suspended
particles through molecular interactions and which is
pharmaceutically compatible with the parasiticidal composition can
be used as a thickener, such as but not limited to, gelatin,
natural gums (e.g., tragacanth, xanthan, guar, acacia, panwar,
ghatti, etc.), and cellulose derivatives (e.g., sodium
carboxymethylcellulose, hydroxypropylcellulose, and
hydroxypropylmethylcellulose, etc.). Optionally, a surfactant such
as Tween may be added to improve the action of the thickening
agent.
[0041] The parasiticidal compositions of the invention may also be
formulated or administered with a non-parasiticidal substance that
inactivates or inhibits the action of stomach enzymes, such as
pepsin. Alternatively, the pharmaceutical composition containing
the parasiticidal composition is administered either concurrent
with or subsequent to administration of a pharmaceutical
composition active to inactivate or inhibit the action of stomach
enzymes. For example, but not by way of limitation, protease
inhibitors, such as aprotin, can be used to inactivate stomach
enzymes. In another embodiment, the parasiticidal composition is
formulated or administered with a compound or compounds which
inhibit the secretion of stomach acid. Compounds which are useful
for inhiconsuming the secretion of stomach acid include, but are
not limited to, ranitidine, nizatidine, famotidine, cimetidine, and
misoprostol.
[0042] One especially useful delivery format for animals is the
soft (mildly friable under pressure) chewable treat for edible
consumption. Preferably, a manufacturing process is utilized to
produce edible soft treats for delivery of the parasiticidal
compositions of the invention wherein the blending of actives into
the chew mixture is achieved without generation of heat at a level
that would cause the active to wholly or partially degrade. The
method is preferably performed so the chew mixture and formed
treats are not exposed to temperatures at or above those typically
generated by compression and/or shear stress exerted in extrusion,
which may be measured by means known to those of ordinary skill in
the manufacturing arts (see, e.g., Vermeulen et al., Chemical
Engineering Science (1971) 26: 1445-1455; Chung et al., Polymer
Engineering and Science (1977) 17: 9-20; Mount et al., Polymer
Engineering and Science (1982) 22(12): 729-737; Lindt, J. T.,
Conference Proceedings, ANTEC '84, Society of Plastics Engineers
(1984) 73-76; Rauwendaal, C., Conference Proceedings, ANTEC '93,
Society of Plastics Engineers (1993) 2232-2237; Miller et al.,
Conference Proceedings, ANTEC '74, Society of Plastics Engineers
(1974) 243-246; Derezinski, S. J., Conference Proceedings, ANTEC
'88, Society of Plastics Engineers (1988) 105-108; Derezinski, S.
J., Journal of Materials Processing & Manufacturing Science
(1997) 6(1): 71-77; Derezinski, S. J., Conference Proceedings,
ANTEC '96, Society of Plastics Engineers (1996) 417-421).
[0043] In one aspect of the preferred soft treat manufacturing
process, the chew mixture and formed treats are not exposed to
temperatures of more than about 10.degree. above room temperature
(20.degree. C.), may be exposed to temperatures as low as 0.degree.
to about 10.degree. below room temperature, and most preferably are
maintained at room temperature throughout the blending and forming
steps. As such, the actives in the chew mixture and formed treats
are not exposed to heats above or below the temperatures stated
during performance of the blending and forming steps, whether by
admixture with ingredients at temperatures outside the stated
ranges, by application of heat generated by a heat source or
compression, or by other means. Stability of the actives is
therefore preserved during mixing and formation of the edible soft
treats, and a well-blended, soft texture is provided.
[0044] In general, edible soft chewable medications and treats
include as inactive ingredients matter such as binding agents,
vitamins, and colors to enhance the manufacturability, texture and
appearance of the product. Those of ordinary skill in the art will
be familiar with such inactive ingredients, which need not include
water for use in the invention. No inedible ingredients are present
within the soft treats.
[0045] No inactive ingredients of the edible soft chew should be of
less than food grade quality and may be of higher quality (e.g.,
USP or NF grade). In this context, "food grade" refers to material
that does not contain or impart chemicals or agents hazardous to
health. Thus, a food grade flavoring, if of animal origin, will be
one that has been prepared to substantially reduce or eliminate the
presence of infectious agents or contaminants therein; e.g., by
processes such as pasteurization, pressurization or
irradiation.
[0046] The latter process in particular can effectively eliminate
infectious agents such as E. coli O157:H7, Salmonella and
Campylobacter from a wide variety of food and animal-derived
substances, such as raw meat products, vegetables, grains and
fruits. Preferably, however, edible soft treats of the invention
will not contain any animal origin ingredients, and most preferably
will not contain any animal origin flavorings. All ingredients
should be pharmaceutically acceptable (e.g., food grade, USP or NE,
as appropriate).
[0047] Flavorings are preferably present in the treats and are at
least food grade in quality, and most preferably exclude animal
origin flavorings where accepted by the treated species. Preferred
non-animal origin flavorings are plant proteins, such as soy
protein, to which edible artificial food-like flavorings has been
added (e.g., soy-derived bacon flavoring). Depending on the target
animal, other non-animal flavorings could include anise oil, carob,
peanuts, fruit flavors, sweeteners such as honey, sugar, maple
syrup and fructose, herbs such as parsley, celery leaves,
peppermint, spearmint, garlic, or combinations thereof.
[0048] A particularly preferred flavoring for use in the invention
is Provesta.TM. 356, made by Ohly, Inc. It is a light tan,
water-soluble powder that builds on the properties of yeast
extracts and reaction flavors to provide a pleasant smoky, cured
bacon flavor. Provesta 356 contains no animal derived
ingredients.
[0049] For administration to horses and other grazing animals, as
well as small animals such as rabbits, hamsters, gerbils, and
guinea pigs, grains and seeds are especially appealing additional
flavoring agents. The grains may be present in any form consistent
with the production of the chew including flour, bran, cereal,
fiber, whole grain and meal forms, including gluten meals, and may
be rolled, crimped, ground, dehydrated or milled. Minerals may also
be added as flavorings, such as salt and other spices. Preferably,
the grain utilized is dehydrated, milled or flaked. Vegetables such
as dehydrated carrots and seeds such as safflower seeds or milo
seeds are especially appealing to small animals and may be
included.
[0050] Further, agents which enhance the manufacturability and
texture of a edible soft chew may include softening agents (which
may be an anti-sticking agent), an anti-caking agent or lubricant,
and a humectant or wetting agent. Illustrative examples of
lubricants or anti-caking agents which may be used in the invention
include magnesium stearate, calcium stearate, solid polyethylene
glycols. If melted, the agents are returned to room
temperature+/-10.degree. before admixture with an active, sodium
lauryl sulfate, or mixtures thereof. Magnesium stearate is
particularly preferred for lubrication and as a component to aid in
setting the edible soft treats after molding.
[0051] Other additives and excipients are described further herein.
For example, glycerin is a preferred humectant useful in
maintaining the softness of the edible soft chew over the shelf
life of the product. Glycerin is a clear, colorless, odorless,
viscous, hydroscopic liquid.
[0052] An anti-sticking agent, preferably polyethylene glycol and
most preferably PEG 3350 (Dow Chemical), will preferably be
included in the edible soft chew mixture before molding at a volume
of about 1.0% to 3.0% w/w. After molding, the edible soft treats
with the added anti-sticking agent will set-up, usually over a
period of 8 to 24 hours for PEG 3350. PEG 3350 congeals quickly,
softens the chew mixture, and prevents the edible soft chew units
from sticking together after molding.
[0053] Softening agents utilized are those which limit density and
hardness of the edible soft chew product. Such agents may include
polysaccharides and fiber. A polysaccharide may be included in the
form of a complex food such as a fruit, a plant starch such as
potato or tapioca starch. Polysaccharide may also be provided
separately, for example, in the form of chondroitin sulfate or
glucosamine HCl.
[0054] Fiber may be also provided as filler or as a bulking agent
and to provide or maintain porosity in the edible soft chew. Fibers
used to this end may be derived from fruits, grains, legumes,
vegetables or seeds, or provided in forms such as wood fiber, paper
fiber or cellulose fiber such as powdered cellulose fiber. A
particularly preferred such bulking agent for use in the invention
is bran, such as oat bran.
[0055] Binders utilized in edible soft treats may be a sticky
substance, but will preferably give the product a food-like
texture. A particularly preferred binder is Starch 1500, a
pregelatinized starch made by Colorcon Corporation. Pregelatinized
starch is a starch that has been chemically and/or mechanically
modified to rupture all or part of the starch granules and so
render the starch flowable. It contains 5% of free amylase, 15% of
free amylopectin and 80% unmodified starch. The source is from
corn.
[0056] Powdered sugar (sucrose) serves well as a sweetener as well
as a binder. Sucrose is obtained from either sugar cane or sugar
beets. Salt and/or other spices may be added as appropriate, with
salt being especially preferred to enhance flavor.
[0057] A preservative such as potassium sorbate, sodium benzoate or
calcium propionate may be included in order to retard growth of
microorganisms and fungi. Tenox 4 is a combination of BHA and BHT
anti-oxidants, made by Eastman Chemicals. It is a preferred and
convenient preservation system.
[0058] Vitamins may be provided according to the nutritional
requirements of the target animal, and may be provided as an
element of oils utilized. Vitamins are also present in various oils
that may be added as softening agents; for example, canola oil,
corn oil, soybean oil and vegetable oil.
[0059] For formation of an active suspension, as well as a flavor
enhancer and softening agent, oils are utilized. Vegetable oils
(such as corn, safflower, cottonseed, soybean and olive oils) are
especially preferred, with soybean oil being most preferred.
[0060] Excipients that may be utilized include starches, cellulose,
or derivatives or mixtures thereof, in amounts ranging, for
example, from about 1 to about 60 percent (w/w), preferably from
about 2 to about 50 percent, more preferably from about 15 to 50
percent. For example, the excipient may consist of sodium starch
glycolate, pregelatinized corn starch (Starch 1500), crospovidone
(Polyplasdone XL.TM., International Specialty Products), and
croscarmellose sodium (Ac-Di-Sol.TM., FMC Corp.), and derivatives
thereof.
[0061] Excipients may be used to create a trituration of an active.
For example, to create a 10% trituration, 100 grams of the active
is combined with 900 grams of an excipient, such as a preferred
excipient, Starch 1500. Ideally, a geometric dilution of the active
is performed, whereby it is first dissolved in a suitable alcohol
solvent; e.g., ethyl alcohol. The dissolved active is then combined
with the excipient, and the alcohol allowed to evaporate. This step
enables a small amount of active to be comprehensively and evenly
mixed throughout the starch. The dry mixture is sifted through a
screen mesh, fluidized, and is then preferably coated.
[0062] If a coating is to be provided (to help protect the
stability of the active and mask its taste), food grade coatings
are preferred, such as an aqueous film coat from Colorcon
Corporation sold as OPADRY.TM.. OPADRY is a methylcellulose based
product with a plasticizer and pigment. Since the coating is
aqueous based, no special handling precautions are required during
manufacture of the edible soft chew. However, after administration,
the aqueous film coat will start to erode and/or dissolve within
minutes when exposed to water or other liquids in the stomach.
Therefore, disintegration and dissolution of the edible soft chew
should not be delayed after it is administered to the subject.
[0063] The formula described for the exemplary product may be
easily modified for delivery of actives to other species. For
example, equine edible soft treats may be based on the same basic
formula, substituting molasses powder, oat bran and apple for the
bacon. Flavorings particularly appealing to cats include artificial
soy based compounds with a fish-like flavor. Human recipients may
prefer sweeter flavorings, such as sugars or molasses.
[0064] 3. Processes for Manufacturing a Chewable Dosage
Vehicle.
[0065] Preferably, a chew mixture formulated as described above,
including active and inactive ingredients, is added to a mixing
vessel of a mixer capable of blending the material and casting it
against the side of the mixing vessels. This action permits the
ingredients to be well and consistently blended without application
of heat or addition of pharmaceutical grade water to the
mixture.
[0066] Suitable mixers include horizontal mixers, which generally
comprise a mixing chamber, an elongated, horizontal mixing shaft
which rotates, and a plurality of mixing tools which depend
generally perpendicularly from the horizontal shaft to rotate
around the inside of the chamber (see, e.g., U.S. Pat. No.
5,735,603, the disclosure of which is incorporated herein by this
reference). The mixing tools are configured and dimensioned as
required for the mixing process to follow the shape of the chamber
walls as rotated for proper mixing of all of material present. Some
such mixing chambers are cylindrically shaped, while others are
trough-shaped, such as mixers which are commonly referred to in the
art as double-arm mixers or ribbon mixers.
[0067] In general, a horizontal mixer will have a horizontal mixing
shaft extending out of the chamber at both ends. In a motorized
mixer, at one end of the shaft, referred to as the drive end, the
shaft is operably coupled to a drive motor for rotating the shaft.
At the drive end, the shaft is typically coupled through a bearing
structure located between the drive motor and the chamber. The
bearing structure provides support of the shaft drive end and also
ensures smooth rotation. A separate seal structure is often
provided further in along the length of the shaft to seal it
against leakage of material into and out of the mixing chamber.
[0068] A particularly preferred mixer for use in the invention used
is a plough type ribbon mixer with optional agitating blades, sold
under the FXM Series.TM. trademark by Littleford Day Corporation. A
200 kg capacity blender can be used for commercial scale
production, and is capable of producing as little as 50 kg of chew
mixture for research scale work. No heat is applied during mixing,
and the blended product produced has a consistent weight,
ingredient distribution and texture from batch to batch.
[0069] Preferably, dry ingredients of the chew mixture are blended
first, then an oil suspension of the active blended therein,
followed by admixture with the liquid ingredients (e.g., humectants
and softening agents) to form a thoroughly blended mixture. After
blending, the chew mixture is discharged without compression from a
port through the blender into a suitable container for processing
into individual dosage units with a forming machine.
[0070] A variety of forming equipment may be utilized in the
invention, but those particularly preferred for use are molding
machines developed for use in producing molded food products, such
as pre-formed hamburger patties and chicken nuggets. For example,
the molding machines disclosed in U.S. Pat. Nos. 3,486,186;
3,887,964; 3,952,478; 4,054,967; 4,097,961; 4,182,003; 4,334,339;
4,338,702; 4,343,068; 4,356,595; 4,372,008; 4,535,505; 4,597,135;
4,608,731; 4,622,717; 4,697,308; 4,768,941; 4,780,931; 4,818,446;
4,821,376; 4,872,241; 4,975,039; 4,996,743; 5,021,025; 5,022,888;
5,655,436; and 5,980,228 (the disclosures of which are incorporated
herein) are representative of forming equipment that may be
utilized in the invention.
[0071] Preferred forming equipment for use in the invention are
molding machines that do not apply compression heat to the chew
mixture, such as the Formax F6.TM. molding machine made by the
Formax Corporation. The F6 machine has the capabilities of 60
stokes per minute. A square forming die of 6'' by 6'' can be used
to form approximately 16 chunk-like edible soft chew units per
stroke, each unit weighing 4 grams and being approximately 5/8'' by
5/8'' in size. Dies for production of other shapes (e.g., bone
shaped treats) may also be utilized.
[0072] In such a machine, a rotary valve opens to cause the chew
mixture to flow through fill slots beneath into a first set of mold
cavities. A mold plate is advanced, forcing the chew mixture into a
second set of cavities, then the mold plate is retracted so the
cycle can begin again. The molding mechanism is hydraulic, and
works by light pressure on the molding plate, without application
of heat.
[0073] A knockout mechanism is provided with cups that align with
the cavities to eject molded mixture from all the mold plate
cavities simultaneously. For molding edible soft treats of the
invention, such a machine could produce an output per hour of
approximately 57,600 units, assuming use of a blender mixture
yielding 50,000 units per sub batch. Each batch of treats may be
packaged in bulk or, preferably, each chew is then individually
packaged for storage.
[0074] The invention having been fully described, its practice is
illustrated (but not limited) by the following examples. Standard
abbreviations and measurements apply throughout the examples unless
a contrary definition is given.
Example I
Test Animals and Protocols
Test System
[0075] Flea Species: Ctenocephalides felis [0076] Number:
.about.100 unfed adults per dog per infestation with a sex ratio of
50/50 [0077] Flea Source: Stillmeadow, Inc. flea colony, Sugarland,
Tex. [0078] Tick Species: Rhipicephalus sanguineus [0079] Number:
.about.50 unfed adults per dog per infestation (.about.25 male and
.about.25 females) [0080] Tick Source: Ecto Services, Inc.,
Henderson, N.C.
Host Animals
[0080] [0081] Species/Strain/Source: Dog/beagles/Stillmeadow, Inc.
dog colony [0082] Justification of Species: The dog is a target
animal [0083] Age of Animals: Adult [0084] Body Weights (Pretest):
7.2 to 17.6 kg [0085] Identification: Tattoos and cage cards
Animal Husbandry
[0085] [0086] Cage Type: 3'-4'.times.4' aluminum pens; [0087]
Housing: Individual [0088] Environmental Controls Set to Maintain:
[0089] Temperature range of 20.degree..+-.3.degree. C. [0090]
Humidity range of 30-70% [0091] 12-hour light/dark cycle [0092]
10-12 air changes per hour [0093] Food: PMI Canine High Density
Diet 5L18 [0094] Water Type: Municipal water supply, available ad
libitum, analyzed by the Texas Commission on Environmental Quality
(TCEQ) Water Utilities Division [0095] Water System: Water bowl
Protocols
[0096] Body weights were recorded during the pretest period. Six
dogs were selected for study, weighed and randomly assigned to two
groups of three and infested with either 100 fleas or 50 ticks. For
the flea study whose results are shown in Table 3, repeat 100 flea
infestations were performed on Days 2 and 5, without additional
dosing. For all studies, the Group I dogs served as untreated
controls. All animals except those in Group II of the study whose
results are reported in Table 1 were dosed orally with the test
article in gelatin capsules. The Group II, Table 1 animals received
5 mg of imidacloprid active in a chewable drug delivery
vehicle.
[0097] For blood collections, drawn blood was collected into
lavender top Vacutainer.RTM. tubes. The tubes were centrifuged and
plasma was drawn off and frozen at approximately -20.degree. C.
pending possible future shipment to the sponsor for analysis of
levels of test article in the plasma. Comb and pan counts were
conducted as noted in the Tables, following dosing. The number of
live fleas and ticks removed during the comb counts was recorded as
were, where noted in the Tables, dead tick counts.
Example II
Efficacy of Oral Imidacloprid Against Flea and Tick
Infestations
[0098] In general, orally dosed imidacloprid was 100% efficacious
against pre-existing C. felis infestations when dosed at a rate as
low as 0.25 mg/kg. Increasing dosage therefore did not increase
efficacy against an initial infestation. However, increasing
initial dosage levels substantially improved resistance to
reinfestation, especially at 5 days following administration of the
dose.
[0099] For use against R. sanguineus ticks, increasing dosage
beyond a threshold level tested (3 mg/kg) had the counterintuitive
effect of not improving (at the 22 and 30 mg/kg levels) or even
reducing (at 10 and 15 mg/kg levels) efficacy, although efficacy
could slightly improve over days following initial dosing.
Therefore, relatively low doses of oral imidacloprid (e.g., 3
mg/kg) suffice to substantially control tick infestations, while
higher (but still sub-toxic) dosages may optionally be utilized
where the risk of reinfestation is significant
TABLE-US-00001 TABLE 1 Flea Counts and Results (Dose as Low as 0.25
mg/kg). 1 hour 3 hour Comb Animal pan pan Count Mean Number counts
counts Day 1 Efficacy Group I - Untreated 4113-M 1 0 19 4115-M 0 0
65 4144-F 0 0 70 Mean 0.0 0.0 56.3 NA S.D. 0.0 0.0 14.4 Group II -
Imidacloprid Oral 0.25 mg/kg 3652-M 0 2 0 3949-M 0 9 0 Mean 0.0 5.5
0.0 100.0 S.D. 0.0 17.1 0.0 Group II - Imidacloprid chewable (5.0
mg to animals 4-20 lbs) 4114-M 0 14 0 4141-F 0 25 0 4142-F 1 18
Mean 0.3 19.0 0.0 100.0 S.D. 0.6 5.6 0.0
TABLE-US-00002 TABLE 2 Flea Counts and Results (Dose at 0.5 and 1.0
mg/kg). 4 hour # Live 6 hour # Live Animal pan Fleas pan Fleas Mean
Number counts Removed counts Removed Efficacy Group I - Untreated
4163-M 0 56 0 52 4164-M 2 50 0 35 4174-F 0 51 0 49 Mean 0.0 52.3
0.0 45.3 NA S.D. 0.0 0.0 0.0 9.1 Group II - Imidacloprid Oral 0.5
mg/kg 4162-M 5 31 39 0 4166-M 45 2 33 0 4173-F 15 35 47 0 Mean 0.0
22.7 39.7 0.0 100.0 S.D. 0.0 18.0 7.0 0.0 Group II - Imidacloprid
Oral 1.0 mg/kg 4161-M 44 4 35 0 4171-F 41 12 44 0 4177-F 40 11 53 0
Mean 41.7 9.0 44.0 0.0 100.0 S.D. 2.1 4.4 9.0 0.0
TABLE-US-00003 TABLE 3 Flea Counts and Results (Doses at 3, 6 and
10 mg/kg). Comb Comb Average Average Comb Count Count Animal 1 hour
3 hour Count Day 2 Day 5 Number pan counts pan counts Day 1
(reinfested) (reinfested) Group I - Untreated 3767-M 1 0 70 19 19
4086-M 0 0 65 65 65 3886-F 0 0 40 70 70 Mean 0.0 0.0 58.3 56.3 56.3
NA NA NA Group II - Imidacloprid Oral 3.0 mg/kg 2859-M 2 7 0 15 32
3880-M 1 9 0 40 80 3045-F 1 11 0 12 42 Mean 1.3 9.0 0.0 22.3 25.3
Efficacy -- -- 100.0 68.1 42.1 Group III - Imidacloprid Oral 6.0
mg/kg 3184-M 5 13 0 0 7 3895-F 6 22 0 0 17 3896-F 12 27 0 0 31 Mean
7.6 19.6 0.0 0.0 12.1 Efficacy -- -- 100.0 100.0 79.3 Group IV -
Imidacloprid Oral 10.0 mg/kg 3171-F 10 14 0 0 0 3175-F 16 25 0 0 5
3897-F 8 18 0 0 1 Mean 11.3 19.0 0.0 0.0 2.0 Efficacy -- -- 100.0
100.0 97.7
TABLE-US-00004 TABLE 4 Tick Counts and Results (Doses at 3 and 10
mg/kg). Ticks Removed Attached Dead Mean Live Attached Dead
Attached Live Free Dead Free Number Day 2 Day 2 Efficacy Day 6 Day
6 Day 6 Day 6 Efficacy Group I - Untreated 2923 21 0 9 1 0 0 3176
25 0 33 0 0 0 3180 17 1 17 0 0 0 Mean 21 0 20 0 0.0 0.0 S.D. 4 1 NA
12 1 0.0 0.0 NA Group II - Imidacloprid Oral 3 mg/kg 2922 17 1 6 2
1 0 2942 8 1 4 2 0 0 3196 28 0 13 0 0 0 Mean 18 1 8 0 0 0.0 S.D. 10
1 15.9 5 1 1 0.0 61.0 Group III - Imidacloprid Oral 10 mg/kg 2849
16 2 14 1 1 0 3943 22 0 8 0 0 0 3194 23 6 28 0 0 0 Mean 20 3 17 0 0
0 S.D. 4 3 3.2 10 1 1 0 15.3
TABLE-US-00005 TABLE 5 Tick Counts and Results at Day 1 (Doses at
15, 22 and 30 mg/kg). Mean Animal Live Ticks Dead Ticks Efficacy
Group I - Untreated 3172 26 0 3582 30 0 3583 32 0 Mean 29 0 S.D. 3
0 NA Group II - Imidacloprid Oral at 15 mg/kg 3170 33 0 3201 2 3
3581 10 1 Mean 15 1 S.D. 16 2 48.9 Group II - Imidacloprid Oral at
22 mg/kg 3356 3 2 3357 12 1 3529 13 0 Mean 9 1 S.D. 6 2 68.2 Group
II - Imidacloprid Oral at 30 mg/kg 3197 10 7 3200 12 0 3210 11 0
Mean 11 2 S.D. 1 4 62.5
TABLE-US-00006 TABLE 6 Tick Counts and Results at Days 2 and 3
(Dose at 30 mg/kg). Hand Count Comb Count Comb Count Mean Animal
Day 2 Day 3 Live Day 3 Dead Efficacy Group I - Untreated 3353-M Not
done 27 0 3172-M Not done 28 0 3582-F Not done 18 0 Mean -- 24 0
S.D. -- 6 0 NA Group II - Imidacloprid Oral at 30 mg/kg 3197-M 8 6
0 3200-M 13 5 2 3201-F 7 4 0 Mean 9 5 1 S.D. 3 1 1 79.5
[0100] The invention having been fully described, those of ordinary
skill in the art will recognize that it extends to equivalents and
modifications thereof, without departing from the scope of the
invention, which is defined by the appended claims.
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