ECTOPARASITICIDAL METHODS AND FORMULATIONS
Ectoparasites such as fleas, lice, blowflies, mosquitoes, ticks and mites are
problematic for man and animal alike. Such pests seriously impact productivity in the
domesticated animal industry by reducing weight gain, causing poor quality hide, wool,
and meat, and in some cases resulting in death. Ectoparasites also cause disease and
discomfort in companion animals. Ectoparasites are known to carry bacteria and viruses
which are pathogenic to humans. The diseases which ectoparasites cause include malaria,
lymphatic filariasis, trachoma, trypanosomiasis, and river blindness, for example.
Efforts for controlling ectoparasites have included the use of insecticides
and pesticides. For example, spinosyns, which are naturally derived fermentation
products, have been employed as ectoparasiticides in animals and humans. (Snyder,
US 6,063,771 and US 6,664,237; Kassebaum et al, US 6,933,318; and Janssen et al,
7,030,095).
Derivatives of spinosyns have been employed in agricultural applications.
(DeAmicis et al, US 6,001,981). Spinetoram is the common name for a mixture of 25-
90%, preferably 50-90% (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR)-2-(6-deoxy-3-0-
ethyl-2,4-di-0-methy-l-. alpha. -L-mannopyranosyloxy)-13-[(2R,5S, 6R)-5-
(dimethylamino)tetrahydro—6-methylpyran-2-yloxy]-9-ethyl-
2,3,3a,4,5,5a,5b,6,9,10,l 1,12,13, 14,16a,16b-hexadecahydro-14-methyl-lH-asindaceno[
3,2-d]oxacyclododecine-7,15-dione (referred to as "dihydro-Et-J", formula I
below), and 10-75%, preferablyl0-50% (2R,3aR,5aS,5bS,9S,13S,14R,16aS,16bS)-2-(6-
deoxy-3-0-ethyl-2,4-di-0-methy- l-.alpha.-L-mannopyranosyloxy)-13-[(2R,5S,6R)-5-
(dimethylamino)tetrahydro—6-methylpyran-2-yloxy]-9-ethyl-
2,3,3a,5a,5b,6,9,10,l 1,12,13, 14,16a,16b-tet-radecahydro-4,14-dimethyl-lH-asindaceno[
3,2-o]oxacyclododecine-7,15-dione (referred to as "Et-L", formula II below).
Formula II
(Podhorez et al, US 2008/0108800A1). Spinetoram is described as
providing long-lasting control of a broad spectrum of insect pests in a variety of crops
(Dow AgroSciences Spinetoram Technical Bulletin, November 2006). It has been
reported spinetoram has been registered in New Zealand as an insecticide in the pome
fruit market ("Dow AgroSciences Receives First Global Registration for Spinetoram
Insecticide," Dow AgroSciences Newsroom, Corporate News, August 10, 2007).
Spinetoram has been developed and commercialized as a topical flea
control product in the USA, and is marketed under the trade name Assurity™. Assurity
received authorization for marketing in November 2010. The formulation of Assurity
contains, in % w/w: 39.6% of spinetoram (210 mg), about 54% benzyl alcohol, about
0.1% of butylated hydroxytoluene, and about 0.1% of citric acid.
While the use of spinosyns and other insecticides and pesticides have been
beneficial, alternative or improved formulations and methods are needed. Desirable
formulations and methods would not only provide alternative therapies, but would also
overcome one or more limitations of current therapies. Such limitations include toxicity,
safety, efficacy (potency and duration), resistance, and side effect issues. One such
benefit is reducing the amount of active ingredient used and thus also reducing the
amount of active ingredient exposed to the environment and target animal. Also
impacting the beneficial use of insecticides and pesticides are administration obstacles,
which include mode and recurrence of administration, as well as undesirable side effects,
such as irritation or hair loss. For example, reducing the frequency of administration
while maintaining efficacy is desirable, as dosing animals is often inconvenient and/or
difficult.
The present invention encompasses ectoparasiticidal methods and
formulations, particularly for use in cats, which provide alternative options for combating
ectoparasiticite infestations. Further, the formulations of the present invention overcome
one or more limitations in the use of current insecticides and pesticides, particularly in
providing efficacious, long term, safe, topical control of ectoparasites. The invention
provides excellent speed-of-kill and residual efficacies.
The invention provides methods of controlling ectoparasite infestations of
a cat by topically administering an effective amount of spinetoram, or a pharmaceutically
acceptable salt thereof, to the cat. The invention also provides pharmaceutical
formulations for topically controlling ectoparasite infestations using spinetoram, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The
invention also provides methods for controlling flea infestations of a cat by topically
administering an effective amount of spinetoram or a pharmaceutically acceptable salt
thereof to said cat. Another aspect of the methods and formulations using spinetoram is
the ability to provide long term topical control of ectoparasite infestations, thus
decreasing the recurrence of dosing an animal, such as no more than every one or two
weeks, or every month or more, as well as initial knock-down efficacy.
The term "cat" includes Felis catus and Felis silvestris catus. While the
inventions may be used with a cat of any age, the cat preferably is eight weeks or older.
Mature cats generally weigh from 2.5 to 6 kg, while kittens generally weigh 0.7 to 1.2 kg.
Ectoparasites include insect and acarine pests which commonly infest or
infect cats, and include the egg, larval, pupal, nymphal, and adult stages thereof. Such
pests include fleas, lice, mosquitoes, mites, ticks, and blood-sucking, biting or nuisance
fly species. A particular target is fleas, and more particularly Ctenocephalides felis,
wherever located in the world, including those found in Europe.
"Controlling" refers to either ameliorating or eliminating a current
infestation, or preventing an infestation, in a cat.
"Topically" is defined as applying to the outside surface area of cat, and
includes the skin or hair. Preferably, topically is not a non-trivial systemic, such as
transdermal, application.
"Effective amount" refers to the amount of spinetoram, or a
pharmaceutically acceptable salt thereof, sufficient to control an ectoparasite, and
includes causing a measurable reduction in the ectoparasite infestation population. This
control may be the result of spinetoram or its conjugate or salt entering the system of the
pest when it feeds, or through a repellant action due to the presence of spinetoram or its
conjugate or salt thereof.
"Pharmaceutically acceptable" as used in this application, for example
with reference to salts and formulation components such as carriers and ingredients,
includes "veterinary acceptable" and "dermatological acceptable".
Pharmaceutically acceptable salts and common methodology for preparing
them are known in the art. See, e.g., P. Stahl, et al, HANDBOOK OF PHARMACEUTICAL
SALTS: PROPERTIES, SELECTION AND USE, (VCHAAViley-VCH, 2002); S.M. Berge, et al,
"Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January
1977.
The term "about" when used with amounts, is to be read as including the
amount(s) specified, and amounts within + 2% of the amount(s).
The term "carrier" is used herein to describe any ingredient other than the
active components in a formulation. The choice of carrier will to a large extent depend on
factors such as the particular mode of administration, the effect of the carrier on solubility
and stability, and the nature of the dosage form. As such, the present formulations can
also contain other optional ingredients, such as: antioxidants, buffering agents,
preservatives, surfactants, chelating agents, humectants, miscibilizing agents, UVabsorbing
compounds or photostabilizers, viscosity-modifying agents, antimicrobial
agents, dyes, perfumes, conditioners, deodorants and physiologically or dermatological
acceptable diluents, excipients or adjuvants. Such agents are known in the art.
Spinetoram and its salts may be formulated as liquid pharmaceutical
compositions for topical administration, and preferably in unit dose form. The
pharmaceutical formulations of this invention include benzyl alcohol and propylene
carbonate. The composition in one aspect contains about 70-100 mg of spinetoram. In
another aspect, the composition contains about 85-95 mg of spinetoram. In another
aspect, the composition contains about 9 1 mg of spinetoram, or a pharmaceutically
acceptable salt thereof.
The term "unit dose" or "unit dosage" form means physically discrete units
suitable as unitary dosages for administration, each unit containing a predetermined
quantity of active material calculated to produce the desired therapeutic effect, in
association with one or more pharmaceutically acceptable carriers.
In one aspect of the invention, the wt % of spinetoram, or a
pharmaceutically acceptable salt thereof, in the formulation is about 8-14 wt/wt %. In
another aspect of the invention, the wt % of spinetoram, or a pharmaceutically acceptable
salt thereof, in the formulation is about 10-12 wt/wt %. In another aspect of the
invention, the wt % of spinetoram, or a pharmaceutically acceptable salt thereof, in the
formulation is about 11.2 wt/wt %. Preferably, the total amount of the formulation is
about 0.7 mL.
In one aspect of the invention, the amount of benzyl alcohol is about 15-20
wt of the formulation. In another aspect of the invention, the amount of benzyl alcohol
is about 17-19 wt of the formulation. In another aspect of the invention, the amount of
benzyl alcohol is about 18 wt of the formulation. Preferably, the total amount of the
formulation is about 0.7 mL.
In one aspect of the invention, the amount of propylene carbonate is about
65-75 wt of the formulation. In another aspect of the invention, the amount of
propylene carbonate is about 67-71 wt of the formulation. In another aspect of the
invention, the amount of propylene carbonate is about 69 wt of the formulation.
Preferably, the total amount of the formulation is about 0.7 mL.
In one aspect of the invention, the range for spinetoram, or a
pharmaceutically acceptable salt thereof, is from about 11-142 mg/kg weight of the target
animal. In another aspect of the invention, the range for spinetoram, or a pharmaceutically
acceptable salt thereof, is from about 14-135 mg/kg weight of the target animal. In
another aspect of the invention, the range for spinetoram, or a pharmaceutically
acceptable salt thereof, is from about 15- 130 mg/kg weight of the target animal.
In one aspect of the invention, the formulation is a topical liquid
pharmaceutical formulation comprising about 8-14 wt/wt% of spinetoram, or a
pharmaceutically acceptable salt thereof, about 15-20 wt wt of benzyl alcohol, and
about 65-75 wt wt of propylene carbonate, and optionally one or more pharmaceutically
acceptable carriers. Preferably, the total amount of this formulation is about 0.7 mL.
In one aspect of the invention, the formulation is a topical liquid
pharmaceutical formulation comprising about 11.2 wt/wt% of spinetoram, about 18
wt wt of benzyl alcohol, and about 69 wt wt of propylene carbonate, and optionally
one or more pharmaceutically acceptable carriers. Preferably, the total amount of this
formulation is about 0.7 mL.
Administration of spinetoram or a pharmaceutically acceptable salt thereof
may be topically administered by any suitable application. The compound and
formulations can be administered topically to an animal by the direct laying on or
spreading of the composition on the skin or hair. Preferably, the formulation is applied at
the base of the skull. Formulations can be applied by spot-on application, plunge or spray
dipping, jetting with a hand held spray or in a race, or as a back-line spray or pour-on.
The administration can occur daily, weekly, biweekly, or monthly, depending on the
severity of the infestation and exposure to the pest, for instance. While monthly
administration is normally preferred in most situations, it should be understood sufficient
residual efficacy after dosing extends 5, 6, 7, 8, or 9 weeks or more in some instances.
The following clauses further help define the invention.
Clause 1. A topical liquid pharmaceutical formulation comprising
about 8-14 wt wt of spinetoram, or a pharmaceutically acceptable salt thereof, about 15-
20 wt wt of benzyl alcohol, and about 65-75 wt wt of propylene carbonate, and
optionally one or more pharmaceutically acceptable carriers.
Clause 2. The formulation of clause 1, wherein said spinetoram, or a
pharmaceutically acceptable salt thereof, is present in an amount of about 70-100
milligrams.
Clause 3. The formulation of clause 1 or clause 2, wherein said
spinetoram, or a pharmaceutically acceptable salt thereof, is present in an amount of
about 85-95 milligrams.
Clause 4. The formulation of any of clauses 1 to 3, wherein said
spinetoram, or a pharmaceutically acceptable salt thereof, is present in an amount of
about 9 1 milligrams.
Clause 5. The formulation of any of clauses 1 to 4, wherein said
spinetoram, or a pharmaceutically acceptable salt thereof, is present in an amount of
about 10-12 wt wt .
Clause 6. The formulation of any of clauses 1 to 5, wherein said
spinetoram, or a pharmaceutically acceptable salt thereof, is present in an amount of
about 11.2 wt wt .
Clause 7. The formulation of any of clauses 1 to 6, wherein said
benzyl alcohol is present in an amount of about 17-19 wt wt .
Clause 8. The formulation of any of clauses 1 to 7, wherein said
benzyl alcohol is present in an amount of about 18 wt wt .
Clause 9. The formulation of any of clauses 1 to 8, wherein said
propylene carbonate is present in an amount of about 67-71 wt wt .
Clause 10. The formulation of any of clauses 1 to 9, wherein said
propylene carbonate is present in an amount of about 69 wt wt .
Clause 11. The formulation of any of clauses 1 to 10, wherein said
pharmaceutical formulation has a volume of about 0.7 ml.
Clause 12. A topical liquid pharmaceutical formulation comprising
about 11.2 wt wt of spinetoram, about 18 wt wt of benzyl alcohol, and about 69
wt wt of propylene carbonate, and optionally one or more pharmaceutically acceptable
carriers.
Clause 13. The formulation of clause 12, wherein said formulation has
a volume of about 0.7 ml.
Clause 14. The formulation of any of clauses 1 to 13 wherein said
formulation is in unit dosage form.
Clause 15. A method of controlling an ectoparasite infestation on a cat
which comprises topically administering a formulation of any of clauses 1 to 14 on said
cat.
Clause 16. The method of clause 15, wherein said administration is
spot-on, plunge or spray dipping, jetting with a hand held spray or in a race, or as a backline
spray or pour-on.
Clause 17. The method of clause 15 or clause 16, wherein said
administration is carried out no more than biweekly.
Clause 18. The method of any of clauses 15 to 17, wherein said
administration is carried out no more than monthly.
Clause 19. The method of any of clauses 15 to 18, wherein said
ectoparasite is a flea.
Clause 20. The method of any of clauses 15-19, wherein said
ectoparasite is Ctenocephalidesfelis.
Clause 21. The use of a formulation of any of clauses 1 to 14 for the
manufacture of a topical medicament for controlling an ectoparasite infestation on a cat.
Clause 22. A formulation of any of clauses 1 to 14 for use in
controlling an ectoparasite infestation on a cat by topical administration.
The following formulation is tested for speed to kill, residual efficacy, and
side effect profile.
Formulation 1
Formulation Specific Gravity: 1.16
Spinetoram: 11.2 wt wt (91 mg)
Benzyl alcohol 18.0 wt wt
Propylene carbonate -69 wt wt
Butylated hydroxytoluene 0.1 wt wt
Citric acid 0.1 wt wt
A residual flea speed-of-kill study is conducted on cats to illustrate
Formulation I begins killing within 30 minutes and that it reaches 90% kill within 8 hours
on fleas. As seen in Table 1, Formulation 1 meets the criteria on day one of
administration for both killing within 30 minutes as well as being greater than 90% kill at
8 hours. After 4 weeks, approximately 97% kill is still achieved within 12 hours.
TABLE 1
Arithmetic Mean %
Efficacy 52.52 95.89 99.78 100 —
Geometric Mean %
Efficacy 55.32 97.61 99.84 100 —
Median (Live Flea Count) 35.5 2.5 0.0 0.0 —
Min, Max (Live Flea
Count) 21, 64 0, 12 0, 1 0, 0 —
+ Std. Dev. 16.31 4.50 0.41 0.00 —
Arithmetic Mean %
Efficacy 23.69 79.36 86.65 96.01 —
Geometric Mean %
Efficacy 25.84 80.54 91.16 97.66 —
Median (Live Flea Count) 66.0 14.0 6.5 1.5 —
Min, Max (Live Flea
Count) 32, 72 11, 32 1, 28 0, 10 —
+ Std. Dev. 15.07 7.91 10.41 3.82 —
Residual activity of Formulation 1 is tested twice. Results are shown in Table 2.
Outstanding efficacy is illustrated through Day 30 and Day 37.
TABLE 2
Residual Study II
Measured Parameter Day 2 Day 9 Day 16 Day 23 Day 30 Day 37
Arithmetic Mean %
Efficacy 100 100 100 99.04 99.79 96.73
Geometric Mean %
Efficacy 100 100 100 99.37 99.84 97.85
Median (Life Flea 1.5
Count) 0.0 0.0 0.0 0.0 0.0
Min, Max (# Live 0, 7
Fleas) 0, 0 0, 0 0, 0 0, 1 0, 1
Mean 0.00 0.00 0.00 0.75 0.13 2.00
(SD) (0.00) (0.00) (0.00) (1.16) (0.35) (2.45)
A study is conducted to evaluate the safety and side effect profile of Formula 1 on
cats. Formulation 1 is well tolerated in cats, particularly in that there is no or little hair
loss observed.
The studies illustrate that the desired efficacy and side effect profile is provided
by the invention. As the amount of spinetoram used in the invention is lower than what is
commercially available, the exposure of the environment and the target animal to the
active ingredient is reduced. Additionally, the invention's solvent system provided the
desired safety and side effect profile while other solvents/solvent systems failed to do so.
WE CLAIM:
1. A topical liquid pharmaceutical formulation comprising about 8-
14 wt wt of spinetoram, or a pharmaceutically acceptable salt thereof, about 15-
20 wt wt of benzyl alcohol, and about 65-75 wt wt of propylene carbonate, and
optionally one or more pharmaceutically acceptable carriers.
2. The formulation of claim 1, wherein said spinetoram, or a
pharmaceutically acceptable salt thereof, is present in an amount of about 70-100
milligrams.
3. The formulation of claim 1 or 2, wherein said spinetoram, or a
pharmaceutically acceptable salt thereof, is present in an amount of about 9 1 milligrams.
4. The formulation of any of claims 1 to 3, wherein said spinetoram,
or a pharmaceutically acceptable salt thereof, is present in an amount of about
11.2 wt/wt%.
5. The formulation of any of claims 1 to 4, wherein said benzyl
alcohol is present in an amount of about 18 wt wt .
6. The formulation of any of claims 1 to 5, wherein said propylene
carbonate is present in an amount of about 69 wt wt .
7. The formulation of any of claims 1 to 6, wherein said
pharmaceutical formulation has a volume of about 0.7 ml.
8. The formulation of any of claims 1 to 7, wherein said formulation
is in unit dosage form.
8. A method of controlling an ectoparasite infestation on a cat which
comprises topically administering a formulation of any of claims 1 to 8 on said cat.
9. The method of any of claim 8, wherein said administration is
carried out no more than monthly.
9. The method of claim 8 or 9, wherein said ectoparasite is
Ctenocephalidesfelis.
10. A formulation of any of claims 1 to 8 for use in controlling an
ectoparasite infestation on a cat by topical administration.