SINGLE DOSE ORAL FORMULATION S AND METHODS FOR TREATMENT OF CATS WITH ECTOPARASITICIDAL SPINOSAD
Among the most common ectopara sites of cats world-wide are cat fleas, Ctenocephalides
felis, also referred to as C.felis. Fleas may annoy both the animal it infests and the owner
of the companion animal. Frequently, fleas cause more serious problems by inducing
flea-allergy dermatitis. It has beers estimated that flea-related diseases account for over
50% of the dermatological cases reported to veterinarians [D. E. Bevier-Tournay, "Flea
and Flea Control" Curr. Vet. Therapy 10: 586-592 (1989)]. In addition, the cat flea is
known to transmit tapeworms in cats and dogs and has been implicated in the
transmission of cat scratch disease and murine typhus. Furthermore, economic expenses
involved in flea control are high. In the United States, for example, pet owners spend
over $1 billion dollars for flea control products annually [R. Conniff, "When It Comes to
Pesky Flea, Ignorance is Bliss," Smithsonian: 26: 76-85 (1995)].
Treatments currently available achieve varying degrees of success. Most treatments
involve chemicals applied to indoor and outdoor surfaces, as well as to the pet. The
chemicals used include a variety of carbamates, organophosphates, pyrethrins and
pyrethroids. These compounds often have toxic side effects can be a problem for both the
pet and its owner. For example, concentrated forms of pyrethroids available are lethal to
cats and, thus, cannot and should not be used on cats. Tn addition, there is evidence that
the use of these chemicals has led to multiple examples of insecticide resistance [N. K.
Rust and M.W. Dryden, Ann. Rev. Eniomol. 42: 451-473 (1997)].
The spinosyns (also known as A83453 factors) are agricultural insecticides that have
shown activity against southern armyworm and other insects in the order Lepidoptera,
and cotton aphid and other members of the order Homoptera. Spinosyns are naturally
derived fermentation productsthat are produced by cultivation of Saccharopolyspora
spinosa. The fermentation produces many factors, including spinosyn A and spinosyn D
(also called A83543A and A8354D). Spinosyn A and spinosyn D are the two spinosyns
that are most active as insecticides. A product comprised mainly of these two spinosyns is
available commercially under the common name "spinosad" (see, e.g., U.S. Patent No.
6,664,237), and is also sold in the United States under the name of Comfortis * which is
the first FDA-approved, chewable, beef-flavored tablet that kills fleas and prevents flea
infestations on dogs for a full month.
In addition, the long-term effectiveness of treatments is of great concern to pet owners.
In this regard, a treatment to control C. felis infestation on cats that can be conveniently
given to the cat at a minimal dosing frequency but that is effective for an extended period
of time is highly desirable ideally, such a treatment would provide prolonged residual
control of a C.felis infestation on a cat following administration of a single dose of
treatment.
Therefore, there exists a need for extended control of a C. felis infestation on a cat
utilizing a predictable dose scheduleof an ectoparasicidal compound. Accordingly, the
present invention provides a single-dose oral formulation of spinosad which exhibits
desirable properties and provides related advantages as well
This invention provides a single-dose ora formulation of spinosad for the extended
control of a C.felis infestation on a cat at a predictable dose of spinosad that is suitable
for administration once every 30 days (i.e., one month). The invention also provides
methods of using the formulation of spinosad.
The present invention provides a single dose of spinosad for controlling a C. felis
infestation on a cat that is unexpected in light of comparison studies with other animal
species. The present invention provides greater residual efficacy in cats at a longer postadministration
duration, (e.g., 35 days or 37 days) after the single dose of spinosad is
administered. The present invention may be orally administered to a cat once per month
and maintain systemic efficacy for the entirety of the treatment period. The present
invention may be orally administered as a tablet at a single dosage, including as a
chewable tablet, and may advantageously be administered with or without food.
One aspect of the present invention provides a single-dose oral formulation for
controlling a C.feiis infestation on a cat. The formulation comprises an ectoparasiticidal
amount of spinosad, microcrystalline cellulose, hydroxypropylcellulose, colloidal silicon
(anhydrous), croscarmellose sodium, and magnesium stearate wherein the formulation is
a . tablet or capsule suitable for administration once every 30 days at a dose of at least
about 50 milligrams (mg) of spinosad per kilogram (kg) of body weight of the cat. In
some embodiments, the formulation further comprises an artificial beef flavor
Spinosad can react to form physiologically acceptable derivatives or salts that are also
useful i the methods a d formulations of this invention. The salts can be prepared using
standard procedures for salt preparation. The term "pharmaceutically acceptable salt"
refers to an addition salt that exists in conjunction with the acidic or basic portion of
spinosad. Such salts include the pharmaceutically acceptable salts listed in HANDBOOK
OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, P. H. Stall!
and C. G Wermuth (Eds.), Wiley-VCH, New York, 2002 which are known to the skilled
artisan. Pharmaceutically acceptable salts of an acid addition nature are formed when
spinosad and any of its intermediates containing a basic functionality are reacted with a
pharmaceutically acceptable acid. Pharmaceutically acceptable acids commonly
employed to form such acid addition salts include inorganic and organic acids.
Pharmaceutically acceptable salts of a base addition nature are formed when spinosad and
any of its intermediates containing an acidic functionality are reacted with a
pharmaceutically acceptable base. Pharmaceutically acceptable bases commonly
employed to form base addition salts include organic and inorganic bases.
For example, spinosyn A can be neutralized with an appropriate acid to form an ac
addition salt. The acid addition salts include salts formed by reaction with either an
organic or inorganic acid such as, for example, sulfuric, hydrochloric, phosphoric, acetic,
succinic, citric, lactic, maleic, fumaric, cholic, pamoic, mucic, glutamic, camphoric,
glutaric, giycolic, phthalic, tartaric, formic, iauric, stearic, salicylic, mefhanesufonic,
benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
In addition to pharmaceutically acceptable salts, other salts are included in the present
invention. They may serve as intermediates in the purification of compounds or in the
preparation of other pharmaceutical] y-acceptable salts, or are useful for identification,
characterization or purification
Spinosad is a natural product composed of spinosyn factors A and D, in normally a 17:3
ratio, the structures of which are:
Spinosyn A
Spinosyn D
Systemic efficacy (ingestion of blood containing spinosad by the blood feeding parasites,
such as fleas) provides different mode of exposure compared to topically applied
ectoparasiiicides where contact with the parasite at the skin surface is the mode of
exposure. The advantages of oral systemic treatments and killing of parasites from
ingestion of blood, compared to topical applications and contact killing, include: a)
reduced exposure to the human applicator and children and objects in the animal's
environment (e.g., flooring, carpets, furniture); b) no worry about loss from exposure of
the animal to water (lakes, streams, bathing, etc.) or from loss due to rubbing; c) no
concern about V exposure and degradation; d) no problems with oxidation from oils on
skin, etc.; and e) assurance that the entire dose is administered (compared to a topical
application where some of the dose may drip off, rub off and/or remain in the dispensing
tube immediately after treatment).
The formulations of this invention may further include, in combination with the spinosyn
component, one or more other active compounds, including those that have activity
against the C.felis to be controlled, such as, for example, synthetic pyrethroids, natural
pyrethins, organophosphates, organochlorines, carbamates, foramidines, avermectins,
milbemycins, insect growth regulators (including chitin synthesis inhibitors, juvenile
hormone analogs, and juvenile hormones), nitromethylenes, pyridines and pyrazoles.
All ratios, percentages, and parts discussed herein are "by weight" unless otherwise
specified.
The term "oral formulation" means that spinosad, either alone or in combination with one
or more of the other types of compounds listed supra, is formulated into a product or
formulation suitable for administering to the animal by mouth. These products or
formulations include, but are not limited to, tablets, capsules, liquids, gels, pastes, oral
sprays, buccal formulations, powders and chewable treats or animal feeds containing the
active component or components. Generally, such formulations include a physiologically
acceptable carrier. Such carriers a e well known in the veterinary arts. Animal feeds are
particularly useful carriers.
The term "controlling a C. felis infestation" refers to prevention of C. felis infestations,
treatment of C. felis infestations, or prevention and treatment of C. felis infestations.
Furthermore, "controlling a C. felis infestation" includes preventing, minimizing or
eliminating an infestation by C. felis. In some embodiments, the C. felis presents at a
stage selected from the group consisting of egg, larvae, and adult.
The term "single-dose formulation" means that one dose of the formulation effectively
controls the C. felis infestation for a prolonged time. The term "prolonged time"
comprises a period of at least 30 days. The term "long-acting" means that the activity
lasts for a prolonged time, for example a period of 35 days or 37 days. "Suitable for oral
administration once every 30 days" means an oral administration which provides the
requisite period of protection (at least about every 30 days) while maintaining the
requisite efficacy, as defined below.
The formulations of the present invention may advantageously provide long-acting
control (e.g., residual efficacy) of C. felis infestation in cats. In some embodiments, the
formulation has greater than 75% residual efficacy at 30 days post-administration. In
other embodiments, the formulation has greater than 90% residual efficacy at 30 days
post-administration. In yet other embodiments, the formulation has greater than 95%
residual efficacy at 30 days post-administration. In some embodiments, the fonnulation
has greater than 75% residual efficacy at 35 days post-administration. In other
embodiments, the formulation has greater than 90% residual efficacy at 35 days postadministration.
In some embodiments, the formulation has greater than 75% residual
efficacy at 37 days post-administration. In other embodiments, the formulation has
greater than 90% residual efficacy at 37 days post-administration.
The formulations of the present invention comprise an effective amount of spinosad
administered orally to the cat. The terms "effective amount" and "ectoparasiticidal
amount" refer to the amount needed to control the C.felis infestation. As those in the art
will understand, this amount will vary depending upon a number of factors. These factors
include, for example, the breed of cat being treated, its weight, and general physical
condition.
In general, an effective amount refers to a dose of at least about 50 mg of spinosad per kg
of body weight of the cat. The term "about 50 mg of spinosad" refers to a dose of
spinosad well known to a person of ordinary skill in the art. As such, a person of ordinary
skill in the art would understand the range of doses encompassed by the term "about 50
mg of spinosad." For example, a dose of 49.8 mg to 50.2 mg of spinosad is "about 50 mg
of spinosad."
In one embodiment, the dose is at least about 50 mg to about 100 mg of spinosad per kg
of body weight of the cat. In another embodiment, the dose is at least about 75 mg of
spinosad per kg of body weight of the cat. The term "about 75 mg of spinosad" refers to
a dose of spinosad well known to a person of ordinary skill in the art. As such, a person
of ordinary skill in the art would understand the range of doses encompassed by the term
"about 75 mg of spinosad." In yet another embodiment, the dose is at least about 100 mg
of spinosad per kg of body weight of the cat. The ter "about 00 mg of spinosad" refers
to a dose of spinosad well known to a person of ordinary skill in the art. As such, a
person of ordinary skill in the art would understand the range of doses encompassed by
the term "about 100 mg of spinosad." Fo example, a dose of 94.4 mgto 102 9 mg, or
98.9 mg to 102 9 mg, of spinosad is "about 100 mg of spinosad."
An example dosing schedule according to the present invention is found in Table I .
Table 1. Example Dosing Schedule of Spinosad
In some embodiments of the present invention, the formulation comprises components at
specific weight/weight percentages. For example, in one embodiment, the formulation
comprises the following weight/weight percentages:
The amount of pharmaceutical grade spinosad Active Pharmaceuticai Ingredient (API)
may be adjusted to take into account varying potency of spinosyn Factors A + D
Accordingly, the amount of mierocrystalfine cellulose may be adjusted to compensate for
a potential change in the weight of spinosad. The amount pharmaceutical grade spinosad
API listed above assumes 100% potency of spinosyn Factors A ÷ D Furthermore, the
purified water (USP/Ph.Eur.) is used in the manufacturing process of the formulation, but
it is evaporated during processing of the formulation. Thus, the amount of purified water
is based on the intragranular components of the formulation and may vary to achieve
suitable granulation of the formulation.
In another embodiment, the formulation comprises the following weight/weight
percentages:
According to the present invention, the term "cat" refers to all members of the Felis catus
species. In some embodiments, the cat is a kitten.
In some embodiments of the present invention, the formulation is a tablet. Conventional
oral tablets generally consist of spinosad, a diluent to assist in increasing the powder mass
to a . convenient size and improve compressibility, a binder to hold the compressed powder
together and a lubricant to assist in densification and ejection from the tablet die. They
may also contain a disintegrate to improve disintegration and dissolution as well as
stabilizers, colors and flavors. Tablets are often coated to improve appearance or taste or
to alter the dissolution properties. Tablets can be designed to dissolve fast or slow, and
depending on the actual volume and compressibility of the drug, large or small. Tablets
can be made to be chewable or to dissolve under the tongue or in the pouch of the
clieek. In some embodiments, the tablet is a chewable tablet. n other embodiments of
the present invention, the formulation is a . capsule.
In some embodiments of the present invention, the formulation further comprises one or
more excipients. In one embodiment, the one o mo e excipients is selected from the
group consisting of microcrystalline cellulose, artificial beef flavor,
hydroxypropyicellulose, colloidal silicon (anhydrous), croscarmellose sodium, and
magnesium stearate. In another embodiment, the formulation further comprises
microcrystalline cellulose, hydroxypropyicellulose, colloidal silicon (anhydrous),
croscarmellose sodium, and magnesium stearate. In yet another embodiment, the
formulation further comprises microcrystalline cellulose, artificial beef flavor,
hydroxypropyicellulose, colloidal silicon (anhydrous), croscarmellose sodium, and
magnesium stearate.
Another aspect of the present invention provides a method of treating a C. felis infestation
on a cat. The method comprises orally administering a single-dose oral formulation
comprising an ectoparasiticidal amount of spinosad, microcrystalline cellulose,
hydroxypropyicellulose, colloidal silicon (anhydrous), croscarmellose sodium, and
magnesium stearate, wherein the formulation is a tablet or capsule suitable for
administration once every 30 days at a dose of at least about 50 mg of spinosad per kg of
body weight of the cat. The embodiments described above with respect to the single-dose
oral formulation are also applicable to the methods of the present invention.
Another aspect of the present invention provides a single-dose oral tablet for controlling a
C.felis infestation on a cat. In one embodiment, the tablet comprises spinosad,
microcrystalline cellulose, artificial beef flavor, hydroxypropyicellulose, colloidal silicon
(anhydrous), croscarmellose sodium, and magnesium stearate, wherein the spinosad is
present at a dose of 90 mg, and wherein the tablet is suitable for administration once
every 30 days. In some embodiments, the tablet comprises the components at the
following amounts:
Pharmaceutical grade spinosad (API) 90 mg
Artificial powdered beef flavor PC-0125 (gamma irradiated) 33.75 mg
Microcrystalline cellulose, NF/Ph.Eur. 23.91 mg
Hydroxypropyf cellulose, NF/Ph.Eur. 8.44 mg
Croscarmellose sodium, NF/Ph.Eur. 10.13 mg
Colloidal silicon dioxide, NF/Ph.Eur. 0.84 mg
Magnesium stearate, NF/Ph.Eur. (non-bovine) 1.69 mg
Purified Water, USP/Ph.Eur q.s.
n another embodiment, the tablet comprises spinosad, microcrystalline cellulose,
artificial beef flavor, hydroxypropyiceliulose, colloidal silicon (anhydrous),
croscarmellose sodium, and magnesium stearate, wherein the spinosad is present at a dose
of 140 mg, and wherein the tablet is suitable for administration once every 30 days. In
some embodiments, the tablet comprises the components at the following amounts:
In another embodiment, the tablet comprises spinosad, microcrystalline cellulose,
artificial beef flavor, hydroxypropyiceliulose, colloidal silicon (anhydrous),
croscarmellose sodium, and magnesium stearate, wherein the spinosad is present at a dose
of 270 mg, and wherein the tablet is suitable for administration once ever}' 30 days. In
some embodiments, the tablet comprises t e components at the following amounts:
Pharmaceutical grade spinosad (API) 270 mg
Artificial powdered beef flavor PC-0125 (gamma irradiated) 101.26 mg
Macrocrystalline cellulose, NF/Ph.Eur. 74.74 mg
Hydroxypropyl cellulose, NF/Ph.Eur. 25.31 mg
Croscarmellose sodium, NF/Ph.Eur. 30.38 mg
Colloidal silicon dioxide, NF/Ph.Eur. 2.53 mg
Magnesium stearate, NF/Ph.Eur. (non-bovine) 5.06 mg
Purified Water, USP/Ph.Eur q.s.
In another embodiment, the tablet comprises spinosad, microcrystalline cellulose,
artificial beef flavor, hydroxypropyiceliulose, colloidal silicon (anhydrous),
croscarmellose sodium, and magnesium stearate, wherein the spinosad is present at a dose
of 560 mg, and wherein the tablet is suitable for administration once every 30 days. In
some embodiments, the tablet comprises the components at the following amounts:
The embodiments described above with respect to the single-dose oral formulation, as
they apply to a tablet, are also applicable to the single-dose oral tablets of the present
invention.
Dose Determination Effectiveness of Spinosad Administered Orally to Cats With C.
The "knockdown" and "residual" effectiveness of spinosad can be evaluated following
oral administration at four different single dosages, compared to a non-treated control
group, against the adult cat lea (Ctenocephalidesfelis) on experimentally infested cats.
A minimum effective ora dose in cats can be evaluated based on knockdown efficacy
(i.e., on Day 1 following administration) and on residual efficacy (i.e., on Day 30
following administration) against the cat flea (Ctenocephalides felis).
Forty cats can be evaluated in a randomized complete block design with cat gender and
pretreatment live flea counts used as blocking factors. Five treatment groups of four
female and four male cats per group can be orally dosed on Test Day 0 : Group ( ) can be
administered 0 mg kg vehicle control (empty gelatin capsule); Group (2) can be
administered spinosad in a gelatin capsule at a dose of 35 mg kg body weight; Group (3)
can be administered spinosad in a gelatin capsule at a dose of 40 mg/kg body weight;
Group (4) can be administered spinosad in a gelatin capsule at a dose of 45 mg/kg body
weight; and Group (5) can be administered spinosad in a gelatin capsule at a dose of 50
mg kg body weight. A l cats can consume canned cat food just prior to dosing to ensure
they were in a fed state. Each cat can be infested with approximately 00 newly emerged,
unfed adult fleas (C. felis), on Test Days -6, -1, 5, 12, 19, 28 and 35. Individual animal
flea counts can be performed approximately 48-hours post-infestation using the
laboratory's comb counting method on Test Days -4, , 7, 14, 2 , 30 and 37. The Day
-4 pre-treatment live flea counts can be used to allocate animals to the five treatment
groups. The Day , 7, 14, 21, 30 and 37 ilea counts can be used to evaluate the
knockdown (Day 1) and residual flea efficacy in each of the treated groups compared to
the vehicle (negative) control group.
All four spinosad treated groups demonstrated excellent knockdown (100% at Day 1) and
post-treatment residual flea efficacy >90% up to and including Day 2 1 post-treatment as
seen in the following table using geometric means (GM). The 50 mg/kg group had zero
fleas at each comb count up through Day 21. At Day 30 post-treatment, only the 50
mg/kg group demonstrated consistently high residual flea efficacy (97.33%) based on GM
while two (35 and 45 mg/kg) of the three lower spinosad dosage groups had dropped
below 90% efficacy at Day 30 as compared to the vehicle control group. The differences
in the treatment groups are shown in Table 2.
Table 2. Geometric Mean Percent Reduction (Geometric Mean Counts) of Adult C.
feiis Compared to Untreated Control Group in Cats Treated Orally with Spinosad
Spinosad, Days Post Treatment
Oral
The differences in flea count compared to the control group were statistically significant
(p<0.05) for all four of the spinosad treated groups at Days 1, 7, 14 and 2 1 and for the 40
mg/kg and 50 mg/kg groups on Day 30 using both parametric and non-parametric
statistical testing.
The present example demonstrates a single oral dose of spinosad at 50 mg kg provides
excellent knockdown (100%) as well as 30 days of residual effectiveness (97.33%) using
a geometric mean count against adult C.fells on experimentally infested cats and
demonstrated statistically significant differences at ail time points compared to the control
group. In addition, at 37 days post-treatment, a single oral dose of spinosad at 50 mg/kg
provides residual effectiveness (87 50%) using a geometric mean count against adult C
felis. Spinosad was well tolerated throughout the example.
EXAMPLE 2
) r co netic i d
Tablets 80 mg/kg) Following Oral Administration to Cats
The plasma concentrations and resulting pharmacokinetics of spinosad tablets when
administered orally to adult cats in the fed or fasted state can be evaluated. Twenty four
cats ( male and 12 female) can be dosed with approximately 80 mg/kg spinosad, as
either API in gelatin capsules or as spinosad formulated chewable tablets. Serial blood
samples can be collected through 672 hours (28 days) after dose administration. Blood
samples can be collected within 10% of nominal time (4 samples at 0.5 hours were
collected within 23%). Samples can be immediately mixed by inversion several times
and stored on ice until centrifuged. The plasma can be collected, split into two
approximately equal aliquots and stored frozen at approximately -70°C until shipped for
analysis, and/or analyzed by a validated LC/MS/MS assay.
The post-treatment plasma concentrations and pharmacokinetic parameters of the major
factors of spinosad (spinosyn A and D) were determined. Non-compartmental analyses
were used to analyze the data for this study to determine the systemic exposure as
measured by AUClast and AUC 0-Q as well as the Cmax, Tmax and elimination half-life
(tl/2) for both spinosyns A and D. As the mean doses between treatment groups varied
[treatment group 1 (spinosad API in gel capsules to fed animals) = 74.3 ± 3.99 mg/kg,
treatment group 2 (spinosad tablet to fed animals) 96.1 ± 13.6 mg/kg and treatment
group 3 (spinosad tablet to fasted animals) = 76 5 ± 11.4 mg kg], AUCO- and Cmax
were normalized to dose.
Tl e spinosyn A and D pharmacokinetic results for Cmax, t 2 and Tmaxas well as AUCiast
and AUCo were comparable between treatment groups 1 (80 mg kg spinosad API in gel
capsules to fed animals) and 2 [80 mg/kg spinosad tablets to fed animals]. For example,
the mean normalized AUCo- values for spinosyn A (the major factor of spinosad) were
comparable at 4,460 ± 1410 hr*ng*kg/mg*mL for group 1 and 4,480 ± 180
lir*ng*kg/mg*mL for group 2. The mean normalized Cmax values for spinosyn A were
comparable at 60 ± 18 and 46 ± 14 ng*kg/mg*mL for treatment groups 1 and 2,
respectively. The mean elimination half-lives (tm) for spinosyn A were comparable at
327 ± 84.3 and 277 ± 75.5 hours for treatment groups 1 and 2, respectively. The mean
Tmax values for spinosyn A were comparable at 2 ± 5 2 and 10 ± 3.0 hours for
treatment groups 1 and 2, respectively. Spinosyn D values were observed to follow the
same trends as spinosyn A . There were no clinically significant sex differences observed
in the pharmacokinetic parameters for spinosyns A and D. As the pharmacokinetic
results were comparable, it is expected that administration of either spinosad API in gel
capsules or spinosad tablets to fed animals would produce similar safety and effectiveness
results.
The spinosyn A and D pharmacokinetic results for tm and T in treatment group 3 [80
mg kg spinosad tablets to fasted animals] were numerically lower than, but comparable to,
values from groups 1 and 2. For example, the mean ti/2 for spinosyn A was 193 ± 60.5
hours in treatment group 3, compared to 327 ± 84.3 and 277 ± 75.5 hours in treatment
groups 1 and 2, respectively. The mean Tmax was 6.0 ± 3.7 hours in treatment group 3
compared to 12 ± 5.2 and 10 ± 3.0 hours in treatment groups 1 and 2, respectively.
Systemic exposure as measured by AUCo- and Cmax we e substantially greater in fed
animals (groups 1 and 2) than in tasted animals (group 3). On average, AUCo- values
ranged from 5-10 times greater and Cmax values were 4-7 times higher in fed animals. For
example, the mean normalized spinosyn A AUCo- value for treatment group 3 was 78
± 406 hr*ng*kg/mg*mL, compared to 4,460 ± 1410 and 4,480 ± 80 hr*ng*kg/mg*mL
for treatment groups 1 and 2, respectively. The mean normalized C ax value was 11 ± 6.6
ng*kg/mg*mL for treatment group 3, compared to 60 ÷ 8 and 46 ± 14 ng*kg/mg*mL for
treatment groups 1 and 2, respectively. Thus, a prandial effect was observed in cats and
cats should be in the fed state for maximum absorption of the test article. In conclusion,
the pharmacokinetics and biosimiiarity of spmosad API (80 mg/kg) and spinosad tablets
(80 mg/kg) were comparable following oral administration to cats.
EXAMPLE 3
Dose Confirmation Study to Evaluate Efficacy of a Flavored Spinosad Tablet
The treatment effect (insecticidal efficacy) of a beef flavored spinosad tablet when
administered orally at a dose of 50-75 mg/kg against fleas (Ctenocephalidesfelis) on
experimentally infested cats can be evaluated at one day pos -administration and for the
post-treatment prevention effect (residual efficacy) on Days 7, 14, 1 and 28.
In total, twenty-two (22) cats can be acclimatized for the study and from these, 7 can be
selected based on pre-treatment weight and flea retention counts to be randomized into
either a treated or control group. Nine cats can be assigned to the control group and eight
cats can be assigned to the treatment group based on flea retention counts from Day -5.
Cats in the treated group can be dosed on Day 0 with the intended final formulation, a
beef flavored tablet containing spinosad at a dose rate of 50-75 mg/kg spinosad/body
weight, while the cats in the control group can be dosed with a vehicle control tablet.
Each cat can be infested with approximately 100 fleas on Days -I, 7, 14, 2 and 28 and
then combed and the fleas counted on Days 1, 9, 6, 23 and 30 respectively.
The spinosad treatment group showed significantly better efficacy (p-value =<0.0001)
against adult C. felis when compared to the control group at Days 1, 9, 16, 23 and 30.
Residual efficacy is calculated on the day of infestation and not on the day the fleas were
counted. The percentage efficacy at each study time point is shown in Table 3.
Mean Percent Reduction (Geometric Mean Counts) of Adult
Untreated Control Group in Cats Treated Orally with Spinosai
Spinosad, Days Post Treatment
Ora
Seventeen eats were randomized based on pre-treatment flea infestation counts into either
a treated or control group. Eight cats were dosed on Day 0 with a beef flavored tablet
containing spinosad with an overall dose range of 51.47 to 76.06 mg kg spinosad body
weight. The other nine cats were dosed with a vehicle control tablet.
Flea counts in the treatment group were significantly reduced (p-value = <0.0001) posttreatment
compared to control at all study time points. As shown in Table 3, the
percentage efficacy in the spinosad treated group at all study timepoints (Day I to Day
28) based on geometric means, demonstrate both the insecticidal and residual efficacy of
spinosad at a minimum dose of 50 mg/kg. Ail 17 cats completed the study and
adequately tolerated the spinosad.
In conclusion, this example demonstrates that the flavored spinosad tablet given orally at
a dose of 50-75 mg/kg significantly reduced flea counts at one day pos -treatment and for
a period of at least 28 days post-treatment.
EXAMPLE 4
Dose Confirmation Study to Evaluate Efficacy of a Flavored Spinosad Tablet
(minimum dose of 5 mg kg) Administered Orally to Cats against Adult Cat Fleas
ten e hMdes e s
Confirmation of the efficacious dose of spinosad can be evaluated in cats experimentally
infested with adult fleas (Ctenocephalidesfelis).
Twenty-four (24) cats that meet the inclusion/exclusion criteria and had the highest pretreatment
live flea (C. felis) counts can be included in a . randomized complete block
design with pre-treatment live flea counts used as a blocking factor. Each cat can be
infested with approximately 100 unfed adult fleas (C. felis) on Test Day -9 Pre-treatment
live flea counts can be conducted using the laboratory's comb counting method on Test
Day -7. The Test Day -7 live ilea counts can be used to allocate cats to one of two
treatment groups. The two treatment groups of ! 2 cats per group can be orally dosed on
Test Day 0 . One group (5 male: 7 female) can receive vehicle control (0 mg kg placebo
tablets) and the second group (7 male: 5 female) can receive flavored spinosad tablets at a
dose rate of 50 75 mg/kg body weight. Cats can consume canned cat food just prior to
dosing and can be offered their daily maintenance diet after dosing. Each cat can be
infested with approximately 100 unfed adult fleas ( .felis) on Test Days -1, 5, 12, 19, 28
and 35. Individual animal live flea counts can be performed on Test Days 1, 7, 14, 21, 30
and 37. Efficacy against experimentally induced adult C. felis populations can be
determined by comparing post-treatment fl ea counts from the treated and vehicle control
groups.
The pre-treatment geometric mean (GM) flea count was 70.1 (range 59-86) in the vehicle
control group and 70.5 (range 60-99) in the spinosad treated group. The control group
GM ranged between 63.7 and 74.3 on post-treatment count days. The level of infestation
was adequate in both groups pre-treatment and comparable between the groups prior to
treatment based on WAAVP Guidelines (2007). Retention remained high in the vehicle
control group post-treatment.
Spinosad provided 100% knockdown on Study Day 1. The residual efficacy based on
geometric means was 99.78%, 99.57%, 95.83%, 90.77% and 90.36% for Days 7, 14, 21,
30 and 37, respectively. The difference between the control and spinosad groups was
significant on all study days (Days 1, 7, 14, 21, 30 and 37; pO.0001 on each day).
This example indicates the effectiveness of spinosad against adult C. felis was confirmed
at the lower half of the unit dosage range for oral administration to cats as a flavored
tabiet. n summary, flavored spinosad tablets administered orally to cats (50-75 mg kg
spinosad) were both safe and efficacious (based on geometric means) delivering excellent
knockdown (100% on Day 1 post-treatment) and residual (90.77% at Day 30 posttreatment)
adult flea control on experimentally infested cats evaluated under laboratory
conditions. n addition, 50-75 mg/kg of flavored spinosad tablets administered orally to
cats demonstrated 90.36% residual efficacy at Day 37 post-treatment.
CLAIMS:
. A single-dose oral formulation for controlling a C. fells infestation
on a cat comprising an ectoparasiticidal amount of spinosad, microcry stall in cellulose,
liydroxypropylceliulose, colloidal silicon (anhydrous), croscarmellose sodium, and
magnesium stearate, and optionaliy an artificial flavor, wherein the formulation is suitable
for oral administration once every 30 days at a dose of at least about 50 mg of spinosad
per kg of body weight of the cat
2. The formulation of claim I , wherein the dose is at least about 75
mg of spmosad per kg of body weight of the cat
3. The formulation of claim 1 or claim 2, wherein the dose is at least
about 00 mg of spinosad per kg of body weight of the cat.
4. The formulation of any one of claims 1 to 3, wherein the
formulation comprises the following weight/weight percentages:
5. The formulation of any one of claims 1 to 3, wherein the
formulation comprises the following weight/weight percentages:
Pharmaceutical grade spinosad (API) 53.33%
Artificial powdered beef flavor PC-0125 (gamma 20.00%
-2.2-
6. The formulation of any one of claims 1 to 5, wherein the
formulation has greater than 75% residual efficacy at 30 days post-administration.
7. The formulation of any one of claims 1 to 6, wherein the
formulation has greater than 90% residual efficacy at 30 days post-administration.
8. The formulation of any one of claims 1 to 7, wherein the
formulation has greater than 95% residual efficacy at 30 days post-administration.
9. The formulation of any one of claims 1 to 8, wherein the
formulation is a tablet or capsule.
0 . method of controlling a C felis infestation on a cat, the method
comprising orally administering a single-dose oral formulation comprising an
ectoparasiticidal amount of spinosad, macrocrystalline cellulose, hydroxypropyiceliulose,
colloidal silicon (anhydrous), croscarmellose sodium, and magnesium stearate, and
optionally an artificial flavor, wherein the formulation is suitable for oral administration
once every 30 days at a dose of at least about 50 mg of spinosad per kg of body weight of
the cat.
The method of any of claim 10, wherein the dose is at least about
75 mg of spinosad per kg of body weight of the cat.
12. The method of claim 10 or 11, wherein the dose is at least about
100 mg of spinosad per kg of body weight of the cat.
13. The method of any one of claims 10-12, wherein the formulation
comprises the following weight/weight percentages:
14. The method of any one of claims 10-12, wherein the formulation
comprises the following weight/weight percentages:
15. The method of any one of claims 10-14, wherein the formulation
has greater than 75% residual efficacy at 30 days post-administration.
6 The method of any one of claims 10-15, wherein the formulation
has greater than 90% residual efficacy at 30 days post-administration.
7. The method of any one of claims 10-16, wherein the formulation
has greater than 95% residual efficacy at 30 days post-administration.
8. The method of any one of claims 10-17, wherein the formulation
a tablet or capsule.
19. A single-dose oral tablet for controlling a C.felis infestation on a
\0 cat comprising spinosad, microcrystalline cellulose, artificial beef flavor,
hydroxypropylcellulose, colloidal silicon (anhydrous), croscarmellose sodium, and
magnesium stearate, wherein the spinosad is present in an amount of at least about 90 mg,
and wherein the tablet is suitable for oral administration once every 30 days.
5 20 The tablet of claim 9, wherein the tablet comprises the following
amounts:
. The tablet of claim 9, wherein the spinosad is present in an
amount of 140
The tablet of claim 21, wherein the tablet comprises the following
amounts:
Pharmaceutical grade spinosad (API) 40 mg
Artificial powdered beef flavor PC-0125 (gamma 52.50 mg
irradiated)
Macrocrystalline cellulose, NF/Ph.Eur. 37.20 mg
Hydroxypropyl cellulose, NF/Ph.Eur. 13.13 mg
Croscarmellose sodium, NF/Ph.Eur. 15.75 mg
Colloidal silicon dioxide, NF/Ph.Eur. 1.3 mg
Magnesium stearate, NF/Ph.Eur. (non-bovine) 2.63 mg
Purified Water, SP/ h.Eur q.s.
23. The tablet of claim , wherein the spinosad is present in an
amount of 270 mg.
24. The tablet of claim 23, wherein the tablet comprises the following
amounts:
25. The tablet of claim 19, wherein the spinosad is present in an
amount of 560 mg.
26. The tablet of claim 25, wherein the tablet comprises the following
amounts:
Pharmaceutical grade spinosad (API) 560 mg
Artificial powdered beef flavor PC-0125 (gamma 210 nig
irradiated)
Macrocrystalline cellulose, NF/Ph.Eur. 148.8 mg
Hydroxypropyl cellulose, NF/Ph.Eur. 52.52 mg
Croscarmellose sodium, NF/Ph.Eur. 63 mg
Colloidal silicon dioxide, NF/Ph.Eur. 5.24 mg
Magnesium stearate, NF/Ph.Eur. (non-bovine) 10.52 mg
Purified Water, USP/Ph.Eur q.s.
27. The tablet of any one of claims 19-26, wherein the tablet has
greater tha 75% residual efficacy at .30 days post-administration.
28. The tablet of any one of claims 19-27, wherein the tablet has
greater than 90% residual efficacy at 30 days post-administration.
29. The tablet of any one of claims 19-28, wherein the tablet has
greater than 95% residual efficacy at 30 days post-administration.