Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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VETERINARY COMPOSITIONS COMPRISING AVERMECTIN-OXIME DERIVATIVES AND
PRAZIQUANTEL
The invention described herein relates to the provision of a combination
therapy in the field of treatment (including prophylaxis) of parasitic
infestations
and consequences thereof, particularly in veterinary medicine. In particular
the
invention relates to antiparasitic therapy using a combination of avermectin-
like compounds, specifically 13-monosaccharide-5-oxime compounds, and
praziquantel.
EP 0 717 993 describes a synergistic combination of
avermectins/milbemycins with praziquantel, in particular for the treatment of
cestode and nematode infestations in horses. Particular species mentioned
therein include Anoplocephala perfiolata, Strongylidae, Gasterophilus spp.,
and Parascari aquorum. Particular avermectins mentioned therein include
ivermectin, abamectin, moxidectin and doramectin.
GB 2252730, EP 0 930 077, WO 98/06407 and WO 95/05181 also describe
combinations of avermectins with praziquantel.
Selamectin, or 5-oximino-22,23-dihydro-25-cyclohexylavermectin B1, is
disclosed as Example 5 in International Patent Application, publication no.
W094/15944, herein incorporated by reference.
Formulations of selamectin in di(C2.~ glycol) mono(C~~ alkyl) ethers,
including
dipropylene glycol monomethyl ether (DPGMME), and alcohols such as
ethanol and isopropy alcohol (IPA) are disclosed in International Patent
Application, publication no. W000/30449, herein incorporated by reference.
Selamectin is the active ingredient of the product marketed under the trade
names RevolutionT"", StrongholdT"", etc. by Pfizer Inc. and associated
companies, particularly for the treatment (including prophylaxis) of endo- and
ecto-parasite infestations in companion animals such as cats and dogs.
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Praziquantel is 2-(cyclohexylcarbonyl)-1,2,3,6,7-11b-hexahydro-4H-
pyrazino[2,1-a]isoquinolin-4-one, also known as an active ingredient in
EMBAY 8440T"", BiltricideT"", CesoIT"", and DroncitT"". It is mentioned in the
Merck Index, 11th edition, para.7714, and references therein, herein
incorporated by reference.
Workers at Pfizer disclosed efficacy data for selamectin vs. gastrointestinal
nematodes in cats and ascarids in dogs in Veterinary Parasitology 91 (2000)
321; 333.
We have now discovered that a combination of a 13-monosaccharide 5-oxime
avermectin derivative, preferably selamectin, with praziquantel, gives good
broad spectrum activity vs. endo- and ecto-parasites in companion animals
such as dogs and especially cats.
Desirable attributes, in particular for a topical application for
administration to
companion animals such as cats and dogs, and especially in relation to a
treatment for the control of flea, heartworm and tapeworm infestation,
include:
efficacy; persistence of efficacy; low volume; cosmetically acceptable;
convenient; need for small number of applications for broad spectrum parasite
control; compliant treatment; safe; suitable pharmacokinetic profile; suitable
transdermal flux profile; rapid rate of onset; low dose of active
ingredient(s);
cutaneous tolerability; and stability on storage.
Efficacy
We have demonstrated excellent efFicacy against tapeworms (Dipylidium and
Taenia spp) for praziquantel dosed topically to cats at a dose of 1 mg/kg, in
combination with selamectin at 8mg/kg in a DPGMME / IPA formulation.
Reducing the dose of praziquantel to 0.5 mg/kg reduced efficacy levels
against Dipylidium spp. Praziquantel and selamectin loading in the
formulation were 1 % and 8% respectively, and animals were dosed with a
single topical administration between the shoulder blades (0.1 ml / kg). Cats
harbouring natural tapeworm infections were used, and randomised to
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treatment based on pre-trial infections. Animals were killed 30 days after
treatment, and post mortem tapeworm counts were conducted.
Summary of topical co-formulation efficacy : selamectin / praziquantel
combinations in cats
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Trial "A"
TreatmentDose Mean Dipylidium% Efficacy
(mg/kg)post mortem
count (n=4
/ gp)
Control 12.2
Selamectin8 7.2 40%
Praziquant1 3.25 74%
e1
Sela + 8 & 0.2 92%
1
Prazi
Trial "B"
TreatmentDose Mean Dipylidium% EfficacyMean Taenia % Efficacy
(mg/kg)post mortem post mortem
count (n=5 count (n=5 /
/ gp) gp)
Control 9 4.2
Selamectin8 No infection N/A No infection N/A
Praziquant1 1 89% 1.2 72%
e1
Praziquant0.5 7.6 16% 0 100%
e1
Sela + 8 & 0 100% 0 100%
1
Prazi
Sela + 8 & 1.4 85% 0.6 86%
0.5
Prazi
The efficacy of praziquantel against tapeworm infections after oral dosing is
summarised in the FOI for Cutter Tape Tabs, an oral tablet approved for use
in dogs and cats in the USA. Abstracted information can be found below. In
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summary, acceptable efficacy was established as 100% elimination of the
tapeworm parasites in all animals dosed. Initial oral studies were done with a
range of dosages, some as low as 0.5 mg/kg body weight. The results were
not always reproducible, and the recommended dosage schedule for cats is a
single tablet (23mg praziquantel) for animals weighing 5 - 11 pounds (2.3-5.0
kg) (ie approx 5 -10mg/kg).
Our topical data indicate that 1 mg/kg praziquantel, in combination with
selamectin, will control tapeworm infections.
Praziquantel has a widespread use in animals orally at higher doses than
those which we have tested.
Cutter Tape Tabs FOI abstract
Preclinical Safety Evaluation:
The preclinical safety evaluations for this praziquantel tablet formulation
were
conducted in the United States by or under the direction of Mobay
Corporation, Animal Health Division.
Dr. J.A. Shmidl in Shawnee, Kansas treated two cats orally with doses of 25
and 50 mg/kg. There were no signs of clinical toxicity or evidence of gross
lesions in the gastrointestinal tract.
Three cats received two oral 100 mg/kg treatments at 14 day intervals in a
study by Dr. Shmidl. Only nausea and vomiting occurred in two animals with
no additional clinical signs observed. No significant clinical pathology or
histopathology changes occurred.
Dr. S.M. Kruckenberg reports on the oral treatment of seven cats (6 females
and 1 male) with a 5 mg/kg dose during all critical periods of reproduction.
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Two groups of seven cats (6 females and 1 male) each were also treated
subcutaneously and intramuscularly with a praziquantel injectable solution
with a 5 mg/kg dose during all critical periods of reproduction. Dr.
Kruckenberg further evaluated the oral use of praziquantel in one male and
three female cats in a controlled study. Two groups of 4 cats (1 male and 3
females) each were also treated subcutaneously and intramuscularly with the
praziquantel injectable solution. All treated cats received 3X the label rate.
Four females and 1 male served as untreated controls.
The treated males received 7 treatments at 2-week intervals throughout the
breeding season. Each treated female received a treatment prior to breeding,
during the embryogenic period of pregnancy, during late pregnancy and again
during lactation. The study confirmed the lack of effects on fertility,
conception, fetal development or pregnancy when praziquantel was
administered at 3X dosage levels.
Eight cats received three oral doses by Dr. Shmidl at 14-day intervals of
either 5X or 10X the labeled rate. No significant clinical signs of toxicity
were
observed, nor did changes occur for hematology, clinical chemistry and
histopathology.
Dr. Shmidl further treated two kittens (4 1/2 to 7 1/2 weeks old) twice at a
14-
day interval. The dosage rate was 5X the label dose. Slight depression was
observed in one kitten. No significant clinical toxicity signs or clinical
pathology
and histopathology changes were attributed to this dosage rate.
Clinical Field Trial Safety
The tablet formulation was further administered to 135 cats (eight weeks to 13
years of age and two to 191b) in clinical field trials. One instance of
diarrhea
and one of salivation (total = 2, 1.5%) were reported and were rated as non-
significant.
Safety Summary
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In summary, the safety index for the use of praziquantel tablets in cats has
been derived from controlled studies using the final tablet formulation
(vomiting was the only effect with dual treatments of 100 mg/kg at a 14-day
interval). Vomiting at high dosage rates is the typical reaction which
prevents
significant clinical toxicity signs from occurring. The safety factor is at
least 5X
the label rate when the product is administered at 14 day intervals to kittens
5
1 /2 weeks of age and older.
Efficacy of Oral Praziquantel in Cats (F01 Summary)
Indications for cats
The approved oral product CUTTER Tape-Tabs (praziquantel) Tapeworm
Tablets will remove the common tapeworms, Dipylidium caninum and Taenia
taeniaeformis , from cats and kittens.
Dosage Form(s), Routes) of Administration and Recommended Dosage(s):
CUTTER Tape-Tabs (praziquantel) Tapeworm Tablets for Cats and Kittens
are sized for easy administration to either adult cats or kittens. The tablets
may be given directly in the mouth or crumbled and mixed with the food.
Dosage Schedule for Cats and Kittens*
CUTTER Tape-Tabs Tapeworm Tablets
Each tablet contains 23 mg of praziquantel
4 pounds and under 1/2 tablet
- 11 pounds 1 tablet
Over 11 pounds 1 1/2 tablets
* Not intended for use in kittens less than 6 weeks of age.
Effectiveness:
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Studies were conducted to determine the dosage and formulation of
praziquantel which produced the most reliable results when used for the
removal of tapeworms from cats.
Acceptable efficacy was established as 100% elimination of the tapeworm
parasites in all animals dosed. Initial oral studies were done with a range of
dosages, some as low as 0.5 mg/kg body weight. The results were not always
reproducible.
Twenty-five separate well-controlled critical anthelmintic studies (which
involves the sacrificing of animals and examination to determine the number
of parasites in the intestinal tract) were conducted with the final tablet
formulation in dogs and cats. Investigators for these studies were Dr. M.L.
Sharp, Vernon Texas; Dr. S.M. Kruckenberg, Manhattan, KS; Dr. A.C. Todd,
Madison, WI; and Drs. D.D. Cox and R.G. Arther, Mobay Corporation, Animal
Health Division, Shawnee, KS.
A summary table of the investigators' results appears below. Two hundred
and ninety-two animals were studied; 157 (100 dogs and 57 cats) were
treated with praziquantel tablets orally or in food and 135 (80 dogs and 55
cats) served as untreated controls. Both natural and experimental infections
were studied with some animals being infected with two species of
tapeworms. All dogs and cats treated according to the
recommended dosage schedule, and some treated at less than the
recommended dosage schedule, were cleared of their tapeworm infections. At
the same time, the untreated control animals, confirmed as positive before
treatment, maintained their tapeworm infections, with the exception of four
dogs and one cat that lost their infections spontaneously. In these studies,
praziquantel tablets were 100% effective in the treatment of tapeworm
infections of dogs and cats due to Taenia pisiformis , Taenia taeniaeformis
and Dipylidium caninum. Additionally praziquantel effectively (100%)
eliminated experimental T. taeniaeformis infections as young as seven (7)
days from cats.
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Summary of Preclinical Effectiveness Data for Praziquantel Tablets
in Cats
Efficacy Against Tapeworms
Investigator/ Treated
Location Cats T. taeniaeformis D. caninum
M.L. Sharp 4 Not Studied 100
Vernon, TX
S.M. Kruckenberg 24 100 100
Manhattan, KS
D.D Cox/
R.G. Arther 29* w 100** 100
Mobay Corporation
Animal Health Div.
Shawnee, KS
TOTAL 57
* One animal underdosed was not cleared of its infection.
** Includes cats with experimentally induced immature (7-day old)
infections.
Field investigations of praziquantel tablets were conducted by 12
investigators
geographically distributed as follows:
1. Dr. Donald E. Berdan, Wenatchee, Washington
2. Dr. Harold Brauetigam, Frankenmuth, Michigan
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3. Dr. W.F. Braunschweig, San Rafael, California
4. Dr. S.F. Cheesman, Pine Bluff, Arkansas
5. Dr. John Durling, Fort Scott, Kansas
6. Dr. J.S. Elder, Youngstown, Ohio
7. Dr. Douglas R. Funk, Wenatchee, Washington
8. Dr. M.A. Groh, Blue Springs, Missouri
9. Dr. Robert Isenhart, Wenatchee, Washington
10. Dr. Larry E. Martin III, Turlock, California
11. Dr. E.E. Schobert, Tampa, Florida
12. Dr. H. Travasos, Abbeville, Louisiana
The field trials were well-controlled using bunamidine hydrochloride as the
positive control drug. Overall, 279 dogs and 173 cats were studied, including
a
wide range of ages, breeds, and weights of both sexes. Praziquantel Tablets
were administered to 218 dogs and 135 cats while 61 dogs and 38 cats were
dosed with bunamidine hydrochloride. Dosing was administered according to
label directions. The animals were observed for the presence of tapeworms
proglottids 10-14 days post-treatment; any proglottid found was identified.
Investigators were asked to evaluate praziquantel for ease of administration,
efficacy and safety on a scale of excellent, good, fair and poor.
Investigators
rated efficacy in dogs as excellent to good in 97% of the cases in dogs and
cats. These trials confirmed preclinical efficacy results and demonstrated
that
praziquantel tablets, when used according to label directions, did have the
effect it purports in its labeling.
FORMULATION
A range of solubility studies have shown that in any ratio of IPA/DPGMME,
praziquantel has a solubility above 60 mg/g (6% w/w) even in the presence of
selamectin at up to 120 mg/g (12% w/w). Above 50% IPA however, this
solubility may be increased to over 90 mg/g (9% w/w) in the supersaturated
state. These data indicate that a formulation of selamectin and praziquantel
in
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combination, with levels of up to 9% w/w praziquantel /12% w/w selamectin
would be possible in IPA/DPGMME mixtures.
As part of a feasibility study into the development of a
selamectin/praziquantel
combination topical formulation, the solubility of praziquantel in the IPA /
DPGMME type vehicle used for development of Selamectin Topical Solution
(StrongholdT""/RevolutionTM), was determined. To achieve this a series of
solutions of varying IPA / DPGMME ratio were prepared. To help minimise
any solubility issues, which could arise due to the presence of selamectin in
a
formulation, a constant amount of selamectin was added to each solution.
After achieving saturated solubility in these solutions and following
filtration to
remove excess undissolved praziquantel, the level of praziquantel (and
selamectin) in solution was determined by HPLC.
Preparation of. Solutions
A series of IPA / DPGMME mixtures were prepared in duplicate as outlined in
Table 1. To these were added a fixed amount of selamectin to provide a
constant concentration of 120 mg per ml i.e. the maximum selamectin
concentration found in StrongholdT"".
After preparation these solutions were placed at 30°C and rolled
continuously
for 48 hours. On inspection it was found that complete dissolution of the
praziquantel had occurred and so further praziquantel was added until a
saturated solution was obtained.
Tab a 1:
SOLVENT MIXTURES FOR PRAZIQUANTEL SOLUBILITY STUDIES
Solution IPA DPGMME
VN % VIV
1 A 100 0
1 B 100 0
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2A 75 25
2B~'' 75 25
3A 50 50
3B 50 50
4A 25 75
4B 25 75
5A 0 100
5B 0 100
[') Solution 2B was broken during preparation and so only a single solution
(2A) was assayed.
Praziquantel Analysis
Praziquantel was analysed using an gradient HPLC method modified from
that developed for selamectin. This method was validated with respect to
praziquantel linearity over the range 10 to 200 mg per ml of praziquantel (in
the solubility test solutions) and in the presence of 120 mg per ml of
selamectin. This same method was also used to check on the selamectin
content in these same solutions.
RESULTS
The solubility of praziquantel and selamectin in the IPA/DPGMME solutions
was calculated as both mg per g and mg per ml. The mass of a 1 ml solution
taken for analysis was also measured so that an approximate density could be
calculated. This data is shown in Table 2 and the mean values are shown
graphically in the Figure below.
T BLE
SOLUBILITY RESULTS FOR PRAZIQUANTEL AND SELAMECTIN IN IPA/DPGMME
SOLUTIONS
Concentration Density..:Coricentcation
(mg per (mg. per
ml) g)
Solution
PraziquantelSelamectin g/ml P~aziquantelSefaiTiectin
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1 A 87.1 103 0.84 103.7 123
1 B 84.4 103 0.84 100.5 123
2A 80.2 103 0.87 92.2 118
3A 81.7 103 0.91 89.8 113
3B 82.2 103 0.91 90.3 113
4A 74.9 107 0.95 78.8 113
4B 74.9 103 0.95 78.8 108
5A 65.6 103 0.99 66.3 104
5B 68.2 102 0.99 68.9 103
F'ig ui re 1:
130
120
110-
..
on
E 100
..
90
0
0
~'80
Praziquantel
70 I ~ Selamectin
60
0
100
IPA Concentration (% V/V)
For both praziquantel and selamectin there is a relationship between % IPA in
the solvent mixture and increasing solubility, although this is much less
marked for selamectin. If the solubility data are taken solely on a mg/ml
basis
then this trend is still present but it is much less visible. The reasons for
this
are two fold. Firstly as the solvent mixture changes from IPA to DPGMME the
density of the solution increases (given that the densities of IPA and
DPGMME are 0.787 and 0.950 g/cm3 respectively) and secondly as the
amount of praziquantel dissolved in solution increases, so does the total
amount of solids and so this leads to an increase in density. Given that
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solubility increases with increasing IPA, then these two effects work counter
to
each other. A better guide to solubility effects is therefore found by using
the
mass/mass data.
The data in table 2 and shown graphically in figure 1, both indicate that
praziquantel solubility is increased as the IPA concentration increases. The
range of praziquantel solubilities found (based on mean values) are between
68 mg/g (67 mg/ml) in 100% DPGMME, increasing to 102 mg/g (86 mg/ml) for
a 100% IPA solution. It should be noted that above 50% IPA the solubility of
praziquantel changes relatively little increasing IPA level and is always
above
the 90 mg/g level. There is also a decrease in selamectin solubility as the
IPA
concentration reduces although this never goes below 100 mg/g. In fact this
process is used in selamectin topical solution to create a selamectin
saturated
DPGMME solution as the IPA evaporates on the back of the treated animals
and so drive the selamectin through the dermal layer.
Exam,ale formulations -:
Experimental data shows, that in a solvent mixture of IPA / DPGME, varying
from 0 to 100 %v/v IPA, praziquantel can be solubilised at concentrations of
up to 10%w/w in the presence of up to 12%w/w selamectin. Given the
requirement to ensure that both selamectin and praziquantel remain
solubilised after evaporation of the IPA, and to minimise the risk of
selamectin
and praziquantel precipitation from the formulation on storage, an Example
formulation is:
Example 1
Ingredient Composition (% w/v) Function
Selamectin 6.0 (note a) Active ingredient
Praziquantel6.0 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Notes:
(a) Assumes potency - the actual
100% amount used is adjusted
according to assay
value
(b) Assumes potency - the actual
100% amount used is adjusted
according to assay
value
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(c) The quantity of IPA is adjusted to correct for the amounts of selamectin
and praziquantel
used.
The formulation as detailed in Examples 1-5 can be prepared by the following
method:-
1 ) Add the appropriate amount of IPA to mixing vessel.
2) Add the appropriate amount of DPGMME to mixing vessel.
3) Mix the two solvents together until homogeneous.
4) Add the BHT to the solution and mix until dissolved.
5) Add the appropriate amount selamectin to the solution.
6) Add the appropriate amount of praziquantel to the solution.
7) Mix until all the selamectin and praziquantel have dissolved.
Further Examples of formulations containing selamectin and praziquantel are
shown below, wherein the composition within the formulation is expressed
weight by volume:
Example 2
Ingtedient Comcosition (% w/v) Function
Selamectin 8.0 (note a) Active ingredient
Praziquantel 0.5 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Example 3
Ingredient Composition (% w/v) unction
Selamectin 8.0 (note a) Active ingredient
Praziquantel 1.0 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Example 4
n redie t Composition (% w/v) Function
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Selamectin 12.0 (note a) Active ingredient
Praziquantel9.0 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Example 5
In a lent Composition (% w/v) Function
Selamectin 6.0 (note a) Active ingredient
Praziquantel 3.0 (note b) Active ingredient
BHT 0.08 Antioxidant
DPGMME 5.6 Solubiliser
IPA to volume (note c) Solubiliser
Notes:
(a) Assumes 100% potency - the actual amount used is adjusted according to
assay value
(b) Assumes 100% potency - the actual amount used is adjusted according to
assay value
(c) The quantity of IPA is adjusted to correct for the amounts of selamectin
and praziquantel
used.
An aspect of the invention is the provision of a combination therapy using a
formulation comprising a 13-monosaccharide 5-oxime avermectin such as
selamectin at around 6-12% w/v, and praziquantel at around 3-9% w/v
(preferably around 6% w/v), in a veterinarily acceptable carrier, diluent or
adjuvant.
Preferably the (13-monosaccharide 5-oxime avermectin such as selamectin)-
containing formulation comprises a di(C2~ glycol) mono(C» alkyl) ether and
an optional skin-acceptable solvent.
Preferably the (13-monosaccharide 5-oxime avermectin such as selamectin)-
containing formulation is suitable for topical, preferably spot-on,
application.
Another aspect of the invention is the provision of an antiparasitic
combination
therapy whereby a 13-monosaccharide 5-oxime avermectin such as
selamectin is provided at around 6-12mg/kg (re. host animal) and praziquantel
is provided at up to 18mg/kg (re. host animal). Preferably the selamectin is
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present in the formulation at about 1 % to about 16% (w/v), more preferably
about 4% to about 12% w/v, and most preferably about 6% to about 12% w/v.
Specific preferred formulations contain selamectin at about 6% w/v and about
12% w/v.
Preferably the praziquantel is present in the formulation at about 0.5 to
about
10% w/v, more preferably about 3 to about 9% w/v , most preferably about 6%
w/v.
Preferably the di(C2~ glycol) mono(C» alkyl) ether is diethylene glycol
monomethyl ether (DEGMME) or dipropylene glycol monomethyl ether
(DPGMME), more preferably DPGMME.
Preferably the skin-acceptable solvent is present and is ethanol or
isopropanol, more preferably isopropanol.
Preferably the formulation containing the avermectin 13-monosaccharide
oxime has a w/v to v/v ratio of avermectin 13-monosaccharide oxime to the
glycol monomethyl ether is in the range (0.5 to 2) to 1, more preferably (0.7
to
1.4) to 1, yet more preferably (0.9 to 1.1 ) to 1, most preferably about 1:1.
A preferred formulation according to the invention also contains antioxidant,
preferably selected from propylgallate, BHA (2-t-butyl-4-methoxyphenol), and
BHT (2,6-di-f-butyl-4-methylphenol), more preferably BHT.
A preferred formulation according to the invention consists of:
(a) selamectin, at a level of 1 % to 16% w/v;
(b) DEGMME or DPGMME at 1 to 16% w/v, and at a w/v or v/v ratio of active
compound to DEGMME/DPGMME of about 1:1;
(c) praziquantel at 0.5 to 10% w/v;
(d) isopropanol to volume (100%);
and, optionally (e) BHT (at less than 0.1 % w/v).
A more preferred formulation consists of
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(a) selamectin at a level of 6% to 12% w/v;
(b) DEGMME or DPGMME 6 to 12% w/v , and at a w/v or v/v ratio of active
compound to DEGMME/DPGMME of about 1:1;
(c) praziquantel at 3-9 % w/v;
(d) isopropanol to volume (100%);
and, optionally (e) BHT (at less than 0.1 % w/v).
The most preferable formulations are those described in the Examples,
especially Example 1.
Further aspects of the invention include:
(a) a method of treatment (including prophylaxis) of parasitic infestation of
flea
and/or heartworm and tapeworm in a mammal which comprises treatment
with a 13-monosaccharide 5-oxime avermectin, such as selamectin, and
praziquantel; .
(b) a method of treatment as in (a) wherein the 13-monosaccharide 5-oxime
avermectin such as selamectin and praziquantel are administered separately
in different formulations;
(c) a method of treatment as in (a) wherein the 13-monosaccharide 5-oxime
avermectin such as selamectin and praziquantel are administered in the same
formulation;
(d) a method of treatment as in (a) or (b) wherein the 13-monosaccharide 5-
oxime avermectin such as selamectin and praziquantel are administered via
the same route;
(e) a method of treatment as in (a) or (b) wherein the 13-monosaccharide 5-
oxime avermectin such as selamectin and praziquantel are administered via
different routes;
(f) a pharmaceutical or veterinary composition which comprises a 13-
monosaccharide 5-oxime avermectin such as selamectin and praziquantel
and a pharmaceutical or veterinary carrier;
(g) the use of selamectin and praziquantel in the manufacture of a
medicament for the treatment of a parasitic infestation, or condition mediated
by a parasitic infestation, on or in a mammal, especially a companion animal
such as a cat;
CA 02443068 2003-09-30
WO 02/094288 19 PCT/IB02/01025
(g) a kit useful in the treatment of a parasitic infestation of flea and/or
heartworm and tapeworm in a mammal, which comprises a 13-
monosaccharide 5-oxime avermectin, such as selamectin, and praziquantel
and a pharmaceutical or veterinary carrier, and instructions for the treatment
of a parasitic infestation of flea and/or heartworm and tapeworm in a mammal.
