U.S. patent application number 15/433901 was filed with the patent office on 2017-06-22 for soft chewable pharmaceutical products.
This patent application is currently assigned to Intervet, Inc.. The applicant listed for this patent is Intervet, Inc.. Invention is credited to Susi Alteheld, Stefan Fuchs, Carina Hang, Jurgen Lutz.
Application Number | 20170172918 15/433901 |
Document ID | / |
Family ID | 49300034 |
Filed Date | 2017-06-22 |
United States Patent
Application |
20170172918 |
Kind Code |
A1 |
Alteheld; Susi ; et
al. |
June 22, 2017 |
SOFT CHEWABLE PHARMACEUTICAL PRODUCTS
Abstract
A soft chewable pharmaceutical product for delivery of a
pharmaceutically acceptable active ingredient to an animal
comprising pamoic acid or a pharmaceutically acceptable salt and a
process for the manufacture of such soft chewable pharmaceutical
product.
Inventors: |
Alteheld; Susi;
(Schwabenheim, DE) ; Fuchs; Stefan; (Essenheim,
DE) ; Hang; Carina; (Grolsheim, DE) ; Lutz;
Jurgen; (Wiesbaden, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Intervet, Inc. |
Summit |
NJ |
US |
|
|
Assignee: |
Intervet, Inc.
Summit
NJ
|
Family ID: |
49300034 |
Appl. No.: |
15/433901 |
Filed: |
February 15, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14390040 |
Oct 2, 2014 |
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PCT/EP2013/056987 |
Apr 3, 2013 |
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15433901 |
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61782434 |
Mar 14, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 47/12 20130101; A61K 47/26 20130101; A61K 31/7048 20130101;
A61K 47/20 20130101; A61K 9/5015 20130101; A61K 9/5123 20130101;
A61K 9/2013 20130101; A61K 31/365 20130101; A61K 31/422 20130101;
A61K 47/10 20130101; A61P 33/14 20180101; A61K 47/22 20130101; A61P
33/10 20180101; A61K 47/36 20130101; A61P 33/00 20180101; A61K
9/4858 20130101; A61P 33/12 20180101; A61K 9/0056 20130101; A61K
9/145 20130101; A61P 43/00 20180101; A61K 9/282 20130101; A61K
9/1617 20130101; A61K 47/44 20130101; A61K 47/42 20130101; A61K
31/35 20130101; A61K 31/42 20130101; A61P 17/00 20180101; A61K
47/16 20130101; A61K 47/38 20130101; A61K 47/18 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 47/26 20060101 A61K047/26; A61K 47/36 20060101
A61K047/36; A61K 45/06 20060101 A61K045/06; A61K 47/12 20060101
A61K047/12; A61K 47/42 20060101 A61K047/42; A61K 47/44 20060101
A61K047/44; A61K 47/10 20060101 A61K047/10; A61K 31/42 20060101
A61K031/42; A61K 47/20 20060101 A61K047/20 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 4, 2012 |
EP |
12163198.0 |
Claims
1-18. (canceled)
19. A soft chewable veterinary product for controlling a parasite
of an animal comprising: an isoxazoline active ingredient or a
pharmaceutically acceptable salt thereof and one or more
pharmaceutically acceptable nonactive ingredients.
20. The soft chewable veterinary product of claim 19, wherein the
pharmaceutically acceptable nonactive ingredients comprise a
filler, a flavoring, a forming agent, a solvent, a surfactant, a
humectant, optionally an antioxidant, and optionally, a
preservative.
21. The soft chewable veterinary product of claim 20, wherein the
filler comprises corn starch, the flavoring comprises beef, pork,
liver or an edible artificial food-like flavoring, the forming
agent comprises polyvinylpyrrolidone or polyethylene glycol, and
the humectant comprises glycerol.
22. The soft chewable veterinary product of claim 19, wherein the
soft chewable veterinary composition further comprises pamoic acid
or a pharmaceutically acceptable salt thereof.
23. The soft chewable veterinary product of claim 19, wherein the
isoxazoline active ingredient is present in an amount from 0.1% to
40%.
24. The soft chewable veterinary product of claim 23, wherein the
isoxazoline active ingredient is present in an amount between 5%
and 20%.
25. The soft chewable veterinary product of claim 19, wherein the
isoxazoline active ingredient is
4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-m-
ethyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide.
26. The soft chewable veterinary product of claim 20, wherein: a)
the filler comprises corn starch and is present at a concentration
of about 10% to about 20% w/w; b) the forming agent is
polyvinylpyrrolidone or polyethylene glycol and is present at a
concentration of about 5% to about 30% w/w; c) the humectant is
glycerol or propylene glycol and is present at a concentration of
7.5% w/w; d) the surfactant is sodium lauryl sulphate and is
present at a concentration of 2% w/w; e) the flavoring is pork,
liver, beef, or an edible artificial food-like flavoring and is
present at a concentration of 20% w/w.
27. The soft chewable veterinary product of claim 19, further
comprising at least a second active ingredient of another
isoxazoline active ingredient, an avermectin or a milbemycin.
28. The soft chewable veterinary product of claim 27, wherein the
second active ingredient is eprinomectin, ivermectin, selamectin,
milbemycin oxime, or moxidectin.
29. The soft chewable veterinary product of claim 19, wherein the
isoxazoline active ingredient is
4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-m-
ethyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide and the
second active ingredient is milbemycin oxime or moxidectin.
30. The soft chewable veterinary product of claim 19, wherein the
parasite is a flea or tick.
31. The soft chewable veterinary product of claim 20, wherein the
solvent is a non-aqueous liquid solvent.
32. The soft chewable veterinary product of claim 19, wherein the
product further comprises one or more oils.
33. The soft chewable veterinary product of claim 19, wherein the
one or more oils is palm oil, corn oil, castor oil, canola oil,
safflower oil, cotton-seed oil, soybean oil, olive oil, peanut oil
or a mixture thereof.
34. A method for controlling a parasite infestation of an animal
comprising administering to the animal an effective amount of a
soft chewable veterinary composition comprising: an isoxazoline
active ingredient or a pharmaceutically acceptable salt thereof,
and one or more pharmaceutically acceptable nonactive
ingredients.
35. The method of claim 34, wherein the pharmaceutically acceptable
nonactive ingredients comprise a filler, a flavoring, a forming
agent, a solvent, a surfactant, a humectant, optionally an
antioxidant, and optionally, a preservative.
36. The method of claim 35, wherein the filler comprises corn
starch, the flavoring comprises beef, pork, liver or an edible
artificial food-like flavoring, the forming agent comprises
polyvinylpyrrolidone or polyethylene glycol, and the humectant
comprises glycerol.
37. The method of claim 34, wherein the soft chewable veterinary
composition further comprises at least a second active ingredient
of another isoxazoline active ingredient, an avermectin or a
milbemycin.
38. The method of claim 37, wherein the second active ingredient is
eprinomectin, ivermectin, selamectin, milbemycin oxime, or
moxidectin.
39. The method of claim 35, wherein the parasite is a flea or
tick.
40. The method of claim 39, wherein the animal receives a dosage of
the soft chewable veterinary composition every 2 months, 3 months,
4 months, 5 months or 6 months.
41. A method for controlling a flea or tick infestation of an
animal comprising administering to the animal an effective amount
of a soft chewable veterinary composition comprising: an
isoxazoline active ingredient or a pharmaceutically acceptable salt
thereof, and a filler comprising corn starch, a flavoring of beef,
pork, liver or an edible artificial food-like flavoring, a forming
agent comprising polyvinylpyrrolidone or a polyethylene glycol, and
a humectant of glycerol.
42. The method of claim 41, wherein soft chewable veterinary
composition comprises a second active ingredient of milbemycin
oxime or moxidectin.
43. The method of claim 41, wherein the animal receives a dosage of
the soft chewable veterinary product every 2 months, 3 months, 4
months, 5 months or 6 months.
44. The method of claim 42, wherein the wherein the animal receives
a dosage of the soft chewable veterinary product every 2 months, 3
months, 4 months, 5 months or 6 months.
Description
FIELD OF THE INVENTION
[0001] The invention relates to the field of orally administrable
pharmaceutical dosage units such as soft chews, especially for
administration to non-human animals.
BACKGROUND OF THE INVENTION
[0002] Chewable pharmaceutical products for drug delivery are well
known. Formulation of a drug into a chewable dosage form can
increase (animal) patient acceptance of the medication that tend to
resist swallowing hard tablets or capsules.
[0003] Texture is important for the acceptance of such oral
products by (animal) patients. One of the most commonly used form
for chewable pharmaceutical products is a chewable compressed
tablet, whose ingredients, however, can make the tablet gritty or
otherwise unappealing, especially to non-human animals. Thus, a
preferred alternative dosage form for non-human animals is the
"soft chew" generally a meat-like mass also widely found in
consumable pet treats.
[0004] Soft chews have been described in prior art. U.S. Pat. No.
6,387,381 discloses an extrudate which is formed of a matrix having
starch, sugar, fat, polyhydric alcohol and water.
[0005] WO 2004/014143 relates to compositions and processes for the
delivery of an additive to an organism in a form suitable for
consumption, and in particular, in the form of a soft chew.
[0006] US 2009/0280159 and US 2011/0223234, relate to palatable
edible soft chewable medication vehicles. The processes described
herein relate to the problem that heat generated during the
extrusion process causes deterioration in the stability of the
active ingredient in the mixture.
[0007] Machines for the high volume production of molded food
patties have been described to be useful for the manufacturing of
soft chews for administration to non-human animals. Such machines
are molding machines developed for use in producing molded food
products, for example Formax F6.TM. molding machine made by the
Formax Corporation or 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.
[0008] Such machines are originally used to form hamburger patties
from a supply of ground beef by forcing the ground beef under
pressure into a multi-cavity mold plate which is rapidly shuttled
on a linear slide between a fill position and a discharge position
in which vertically reciprocable knock-outs push the patties from
the mold cavities.
[0009] For use in the manufacturing of soft chews, a dough mass is
prepared with ingredients that lead to the meat-like texture of the
resulting soft chew after forming and drying. For the manufacturing
of a veterinary medicament on an industrial scale it is necessary
to produce the soft chews by a forming machine that is able to
produce high volume.
[0010] However, it has been observed that some soft chew components
of the dough, that is fed to the forming equipment, cause the
blocking of the movable parts, especially the mold plates in the
forming machine. Accordingly, the art field is in search of soft
chew compositions that are easily processable in forming equipment
on an industrial scale.
[0011] Salts of pamoic acid are known as pamoates or embonates and
are conventionally used as a counter ion of certain basic active
ingredients to obtain long-acting pharmaceutical formulations.
Examples of pamoate salts of active ingredients in veterinary
medicine are the anthelmintic compounds pyrantel pamoate and
oxantel pamoate and the antihistamine hydroxycine pamoate. A number
of active ingredients used in human health are pamoate salts, e.g.
as disclosed in WO 94/25460, WO 05/016261, WO 04/017970, or WO
05/075454.
[0012] The use of pamoic acid or a pharmaceutically acceptable salt
thereof as excipient in soft chew formulations has not been
described.
[0013] It has now been found that the soft chews that comprise
pamoic acid or a pharmaceutically acceptable salt thereof can be
easily processed in a forming machine and that pamoic acid or a
pharmaceutically acceptable salt thereof facilitates manufacturing
of such soft chews on an industrial scale using a forming
machine.
SUMMARY OF THE INVENTION
[0014] The invention provides a new soft chewable pharmaceutical
product for administration to non-human animals and a process for
its manufacture.
[0015] Accordingly, in one embodiment the present invention relates
to a soft chewable veterinary pharmaceutical product (a "soft
chew") comprising as ingredients, [0016] pamoic acid or a
pharmaceutically acceptable salt thereof, provided that such pamoic
acid or pharmaceutically acceptable salt thereof is not an active
pharmaceutical ingredient, [0017] one or more active pharmaceutical
ingredients, [0018] a liquid component, [0019] a forming agent, and
[0020] optionally one or more excipients.
[0021] In one embodiment the invention provides a soft chewable
veterinary pharmaceutical product comprising as ingredients, [0022]
pamoic acid or a pharmaceutically acceptable salt thereof, provided
that such pamoic acid or pharmaceutically acceptable salt thereof
is not an active pharmaceutical ingredient, [0023] optionally one
or more active pharmaceutical ingredients, [0024] a liquid
component, [0025] a forming agent, and [0026] optionally one or
more excipients.
[0027] In a preferred embodiment the product comprises sodium
pamoate.
[0028] In one embodiment the amount of pamoic acid or the
pharmaceutically acceptable salt thereof is between 1.5 and 30%
w/w, preferably between 2 and 5% w/w.
[0029] In another embodiment a soft chewable veterinary
pharmaceutical product is provided comprising as ingredients,
[0030] a pamoate salt of an active pharmaceutical ingredient,
provided that such active pharmaceutical ingredient is not pyrantel
pamoate or oxantel pamoate, [0031] optionally another active
pharmaceutical ingredient, [0032] a liquid component, [0033] a
forming agent, [0034] optionally pamoic acid or a pharmaceutically
acceptable salt thereof, and [0035] optionally one or more
excipients.
[0036] In one embodiment the product as described above
additionally comprise one or more of the following excipients:
[0037] a filler, [0038] a stabilizer component, [0039] a flavoring
component, and/or [0040] a sugar component.
[0041] In one embodiment the active pharmaceutical ingredient is an
isoxazoline compound of Formula (I)
##STR00001##
wherein R.sup.1=halogen, CF.sub.3, OCF.sub.3, CN, n=integer from 0
to 3, preferably 1, 2 or 3, R.sup.2=C.sub.1-C.sub.3-haloalkyl,
preferably CF.sub.3 or CF.sub.2Cl, T=5- or 6-membered ring, which
is optionally substituted by one or more radicals Y, Y=methyl,
halomethyl, halogen, CN, NO.sub.2, NH.sub.2--C.dbd.S, or two
adjacent radicals Y form together a chain, especially a three or
four membered chain; Q=X--NR.sup.3R.sup.4 or a 5-membered
N-heteroaryl ring, which is optionally substituted by one or more
radicals; X=CH.sub.2, CH(CH.sub.3), CH(CN), CO, CS,
R.sup.3=hydrogen, methyl, haloethyl, halopropyl, halobutyl,
methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl,
haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl,
ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,
haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,
tetrahydrofuryl, methylaminocarbonylmethyl,
(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,
cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,
haloethylaminocarbonylcyclopropyl,
##STR00002## ##STR00003##
wherein Z.sup.A=hydrogen, halogen, cyano, halomethyl (CF.sub.3);
R.sup.4=hydrogen, ethyl, methoxymethyl, halomethoxymethyl,
ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl,
ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl,
methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl,
ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl,
cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; Or
R.sup.3 and R.sup.4 together form a substituent selected from the
group consisting of:
##STR00004##
or a salt or solvate thereof.
[0042] In a specific embodiment the active pharmaceutical
ingredient is
4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-m-
ethyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide.
[0043] In a specific embodiment the active pharmaceutical
ingredient is
4-[5-[3-Chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-
-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalen-
ecarboxamide.
[0044] In a specific embodiment the active pharmaceutical
ingredient is
4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl--
N-(thietan-3-yl)benzamide.
[0045] In a specific embodiment the active pharmaceutical
ingredient is
5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-
-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxam-
ide.
[0046] In one embodiment more than one active pharmaceutical
ingredient is present.
[0047] In a preferred embodiment the combination of active
pharmaceutical ingredients comprises one or more
antiparasitics.
[0048] Another aspect of the current invention is a process for the
manufacture of a product as described above in a forming machine
comprising the steps of [0049] a) mixing the ingredients into a
dough, [0050] b) filling a mold with dough, and [0051] c) removing
the dough from the mold, wherein in the mixing step a) the pamoic
acid or the pharmaceutically acceptable salt thereof is mixed with
the other ingredients.
[0052] In one aspect the current invention is directed to the use
of pamoic acid or a pharmaceutically acceptable salt thereof in the
process as described above to increase lubricity of a product as
described above when filling the mold with dough or when removing
the dough from the mold or both.
[0053] In another aspect the current invention is directed to the
use of the soft chewable veterinary pharmaceutical product as
described above in the manufacture of a medicament for controlling
a parasitic insect, acarid or nematode infestation of an
animal.
[0054] Another aspect of the current invention is a soft chewable
veterinary pharmaceutical composition comprising an isoxazoline
compound of Formula (I) for use in a method of controlling a
parasitic insect, acarid or nematode infestation of an animal
DETAILED DESCRIPTION OF THE INVENTION
[0055] The inventors identified, that the addition of pamoic acid
or a pharmaceutically acceptable salt thereof to a soft chew dough,
improves the processability of such soft chew in the forming
equipment by increasing lubricity on the surface of the soft chew
when filling the mold with dough or when removing the dough from
the mold or both.
[0056] "Soft chew" or "Soft chewable veterinary pharmaceutical
product" is intended to mean a product which is solid at room
temperature and that is soft to chew and which is functionally
chewy because the product has some plastic texture during the
process of mastication in the mouth. Such soft chews have a
softness that is similar to a cooked ground meat petty.
[0057] Pamoic acid, also called embonic acid, is a naphthoic acid
derivative. The chemical name of pamoic acid is
4,4'-methylenebis(3-hydroxy-2-napthalenecarboxylic acid). In one
aspect of the invention a salt of pamoic acid is used. In one
aspect of the invention, the pharmaceutically acceptable salt of
pamoic acid is the sodium or potassium salt. In one embodiment
sodium pamoate is used, especially disodium pamoic acid. Salts of
pamoic acid are readily commercially available, e.g. pamoic acid
disodium salt from APAC Pharmaceutical LLC, Columbia, US. Different
hydrate forms of pamoic acid salts are suitable for use in the
current invention. In one embodiment the monohydrate form is used.
In an alternative embodiment the anhydrate form is used.
Alternatively esters of pamoic acid can be used in the current
invention.
[0058] In one aspect the active pharmaceutical ingredient by itself
does not provide a lubricating effect and pamoic acid or salts
thereof are included in the soft chew composition as an
(non-active) ingredient or excipient. Hence the composition
comprises pamoic acid or salts thereof provided that such pamoic
acid or pharmaceutically acceptable salt thereof is not an active
pharmaceutical ingredient. In one example such pamoic acid or salts
is sodium pamoate.
[0059] In addition to pamoic acid as a (non-active) ingredient (or
excipient) the soft chew can comprise a pamoate salt of an active
pharmaceutical ingredient.
[0060] In another aspect, the invention relates to a product of the
invention wherein a pamoate salt of an active pharmaceutical
ingredient is present in the soft chew of the current invention,
but no additional pamoic acid or salts thereof are included as
non-active ingredient, provided that such active pharmaceutical
ingredient is not pyrantel pamoate or oxantel pamoate.
[0061] The presence of pamoic acid or a pharmaceutically acceptable
salt thereof has been proven to increase the lubricity of the soft
chew so that the soft chew can now be processed in a forming
machine. The amount of pamoic acid or a pharmaceutically acceptable
salt thereof necessary to provide the required lubricity depends on
the specific composition of the various ingredients and can be
determined by the skilled person in each case. In general, a w/w %
of at least 1% already displays the favourable processing
parameters of the soft chew.
[0062] In one aspect the invention relates to a product according
to the invention wherein the amount of pamoic acid or the
pharmaceutically acceptable salt thereof is between 1 and 50% w/w.
In another aspect the amount of pamoic acid or the pharmaceutically
acceptable salt thereof is between 1.5 and 30% w/w. In still
another aspect the amount of pamoic acid or the pharmaceutically
acceptable salt thereof is not higher than 10% w/w. In a further
aspect, the amount of pamoic acid or the pharmaceutically
acceptable salt thereof is between 2.0 and 5.0% w/w.
[0063] Another aspect of the present invention is the use of pamoic
acid or a pharmaceutically acceptable salt thereof in the
manufacture of a soft chew. The addition of pamoic acid, or a
pharmaceutically acceptable salt thereof to a soft chew dough,
improves the processability of such soft chew dough in the forming
equipment by increasing lubricity on the surface of the soft chew
product when filling the mold with dough or when removing the dough
from the mold or both. Lubricity means and refers to the measure of
the reduction in friction including reduction of adherence of
soft-chew mixture to the mold plate or knock out cups.
[0064] In one embodiment the pamoic acid or pharmaceutically
acceptable salt thereof is not an active pharmaceutical
ingredient.
[0065] The soft chew according to the invention in general
comprises an active pharmaceutical ingredient.
[0066] As used herein, an active pharmaceutical ingredient (or
active ingredient, or pharmaceutically active ingredient or
pharmaceutically acceptable active ingredient) is a substance used
in a pharmaceutical product, intended to furnish pharmacological
activity or to otherwise have direct effect in the diagnosis, cure,
mitigation, treatment or prevention of disease, or to have direct
effect in restoring, correcting or modifying physiological
functions in humans or animals.
[0067] Any orally administrable pharmaceutically active ingredient
or other biologically active compound may be provided in the soft
chews of the invention. Those of ordinary skill in the veterinary
pharmaceutical arts will be entirely familiar with the identity of
such active ingredients which may include, without limitation,
antibiotics, analgesics, antivirals, antifungals, antiparasitics
such as endo- and ecto-parasticides, hormones and/or derivatives
thereof, anti-inflammatories (including non-steroidal
anti-inflammatories), steroids, behavior modifiers, vaccines,
antacids, laxatives, anticonvulsants, sedatives, tranquilizers,
antitussives, antihistamines, decongestants, expectorants, appetite
stimulants and suppressants, cardiovascular drugs, minerals and
vitamins.
[0068] The active ingredients are preferably antiparasitics, more
preferably selected from the group consisting of isoxazoline
compounds, avermectins (e.g., ivermectin, selamectin, doramectin,
abamectin, and eprinomectin); milbemycins (moxidectin and
milbemycin oxime); pro-benzimidazoles (e.g., febantel, netobimin,
and thiophanate); benzimidazole derivatives, such as a thiazole
benzimidazole derivatives (e.g., thiabendazole and cambendazole),
carbamate benzimidazole derivatives (e.g., fenbendazole,
albendazole (oxide), mebendazole, oxfendazole, parbendazole,
oxibendazole, flubendazole, and triclabendazole); imidazothiazoles
(e.g., levamisole and tetramisole); tetrahydropyrimidine (morantel
and pyrantel), salicylanilides (e.g., closantel, oxyclozanide,
rafoxanide, and niclosamide); nitrophenolic compounds (e.g.,
nitroxynil and nitroscanate); benzenedisulfonamides (e.g.,
clorsulon); pyrazinoisoquinolines (e.g., praziquantel and
epsiprantel); heterocyclic compounds (e.g., piperazine,
diethylcarbamazine, and phenothiazine); dichlorophen, arsenicals
(e.g., thiacetarsamide, melorsamine, and arsenamide);
cyclooctadepsipeptides (e.g., emodepside); paraherquamides (e.g.
derquantel); and amino-acetonitrile compounds (e.g. monepantel, AAD
1566); amidine compounds (e.g., amidantel and tribendimidin),
including all pharmaceutically acceptable forms, such as salts,
solvates or N-oxides.
[0069] In one embodiment the pharmaceutically active ingredient is
an isoxazoline compound. Isoxazoline compounds are known in the art
and these compounds and their use as antiparasitic are described,
for example, in US patent application US 2007/0066617, and
International Patent applications WO 2005/085216, WO 2007/079162,
WO 2009/002809, WO 2009/024541, WO 2009/003075, WO 2010/070068 and
WO 2010/079077, the disclosures of which, as well as the references
cited herein, are incorporated by reference. This class of
compounds is known to possess excellent activity against
ectoparasites, i.e. parasitic insect and acarids, such as ticks and
fleas and endoparasites such as nematodes.
[0070] In one embodiment the soft chewable pharmaceutical product
according to the invention comprises an isoxazoline compound of the
Formula (I)
##STR00005##
wherein R.sup.1=halogen, CF.sub.3, OCF.sub.3, CN, n=integer from 0
to 3, preferably 1, 2 or 3, R.sup.2=C.sub.1-C.sub.3-haloalkyl,
preferably CF.sub.3 or CF.sub.2Cl, T=5- or 6-membered ring, which
is optionally substituted by one or more radicals Y, Y=methyl,
halomethyl, halogen, CN, NO.sub.2, NH.sub.2--C.dbd.S, or two
adjacent radicals Y form together a chain CH--CH.dbd.CH--CH,
N--CH.dbd.CH--CH, CH--N.dbd.CH--CH, CH--CH.dbd.N--CH, or
CH--CH.dbd.CH--N, HC.dbd.HC--CH, CH--CH.dbd.CH, CH.dbd.CH--N,
N--CH.dbd.CH; Q=X--NR.sup.3R.sup.4 or a 5-membered N-heteroaryl
ring, which is optionally substituted by one or more radicals
Z.sup.A, Z.sup.B Z.sup.D; X=CH.sub.2, CH(CH.sub.3), CH(CN), CO, CS,
R.sup.3=hydrogen, methyl, haloethyl, halopropyl, halobutyl,
methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl,
haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl,
ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino,
haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl,
tetrahydrofuryl, methylaminocarbonylmethyl,
(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl,
cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl,
haloethylaminocarbonylcyclopropyl,
##STR00006## ##STR00007##
R.sup.4=hydrogen, ethyl, methoxymethyl, halomethoxymethyl,
ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl,
ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl,
methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl,
ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl,
propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl,
cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; or
R.sup.3 and R.sup.4 together form a substituent selected from the
group consisting of:
##STR00008##
wherein Z.sup.A=hydrogen, halogen, cyano, halomethyl
(CF.sub.3).
[0071] In one preferred embodiment in Formula (I) T is selected
from
##STR00009## ##STR00010## ##STR00011##
wherein in T-1, T-3 and T-4 the radical Y is hydrogen, halogen,
methyl, halomethyl, ethyl, haloethyl.
[0072] In an preferred embodiment in Formula (I) Q is selected
from
##STR00012##
Wherein R.sup.3, R.sup.4, X and Z.sup.A are as defined above.
##STR00013## ##STR00014##
[0073] Preferred compounds of Formula (I) are:
TABLE-US-00001 (R.sup.1).sub.n R.sup.2 R.sup.3 R.sup.4 T Y Q Z X
3-Cl, 5Cl CF.sub.3 CH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 CH.sub.2CH.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3
CH.sub.2CH.sub.2OCH.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-2 -- Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-2 -- Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-2 -- Q-1 -- C(O) 3-CF.sub.3,
5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O)
3-CF.sub.3, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-2 --
Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3 -- T-2 -- Q-6 Z.sup.B-7 3-Cl, 5Cl
CF.sub.3 -- -- T-2 -- Q-7 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 --
Q-5 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 -- Q-2 Z.sup.D-1 3-Cl,
5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 --
C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CC H T-3 CH.sub.3 Q-1
-- C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CN H T-3 CH.sub.3
Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-3
CH.sub.3 Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H
T-3 CH.sub.3 Q-1 -- C(O) 3-Cl, 4-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O) 3-Cl,
4-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-3 CH.sub.3
Q-1 -- C(O) 3-Cl, 4-F, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3
H T-3 CH.sub.3 Q-1 -- C(O) 3-Cl, 4-F, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-3 CH.sub.3 Q-1 -- C(O) 3-Cl,
5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-20 -- Q-1 -- C(O)
3-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-20 -- Q-1 --
C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3
CH.sub.3 T-20 -- Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 CH.sub.3 T-20 -- Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-20 -- Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-20 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 -- Q-1 --
C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3
H T-21 -- Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 -- Q-1 -- C(O) 3-Cl, 5-Cl
CF.sub.3 CH.sub.2C(O)NHCH.sub.2CH.sub.3 H T-21 -- Q-1 -- C(O) 3-Cl,
5-Cl CF.sub.3 CH.sub.2CH.sub.2SCH.sub.3 H T-21 -- Q-1 -- C(O) 3-Cl,
4-Cl, 5-Cl CF.sub.3 C(O)CH.sub.3 H T-22 F Q-1 -- CH.sub.2 3-Cl,
4-Cl, 5-Cl CF.sub.3 C(O)CH(CH.sub.3).sub.2 H T-22 F Q-1 -- CH.sub.2
3-Cl, 4-Cl, 5-Cl CF.sub.3 C(O)-cyclo-propyl H T-22 F Q-1 --
CH.sub.2 3-Cl, 4-F, 5-Cl CF.sub.3 C(O)CH.sub.3 H T-22 F Q-1 --
CH.sub.2 3-Cl, 4-Cl, 5-Cl CF.sub.3 C(O)CH.sub.2CH.sub.3 H T-22 F
Q-1 -- CH.sub.2 3-Cl, 4-F, 5-Cl CF.sub.3 C(O)CH.sub.3 H T-22 Cl Q-1
-- CH.sub.2 3-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-1 CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CH H T-1 CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl
CF.sub.3 R.sup.3-1 (Z) H T-1 CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl
CF.sub.3 R.sup.3-1 (E) H T-1 CH.sub.3 Q-1 -- C(O)
[0074] Especially preferred compounds of Formula (I) are
TABLE-US-00002 (R.sup.1).sub.n R.sup.2 R.sup.3 R.sup.4 T Y Q Z X
3-Cl, 5Cl CF.sub.3 CH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 CH.sub.2CH.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3
CH.sub.2CH.sub.2OCH.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 --
C(O) 3-CF.sub.3, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2
-- Q-1 -- C(O) 3-Cl, 5Cl CF.sub.3 -- T-2 -- Q-6 Z.sup.B-7 3-Cl, 5Cl
CF.sub.3 -- -- T-2 -- Q-7 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 --
Q-5 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 -- Q-2 Z.sup.D-1 3-Cl,
5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 --
C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CC H T-3 CH.sub.3 Q-1
-- C(O) 3-Cl, 5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CN H T-3 CH.sub.3
Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O) 3-Cl,
4-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3
Q-1 -- C(O) 3-Cl, 4-F, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3
H T-3 CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-20 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 CH.sub.3 T-20 --
Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-20 -- Q-1 -- C(O) 3-CF.sub.3,
5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 -- Q-1 --
C(O) 3-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 --
Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3 CH.sub.2CH.sub.2SCH.sub.3 H T-21 --
Q-1 -- C(O) 3-Cl, 4-Cl, 5-Cl CF.sub.3 C(O)CH.sub.3 H T-22 F Q-1 --
CH.sub.2 3-Cl, 4-Cl, 5-Cl CF.sub.3 C(O)CH(CH.sub.3)2 H T-22 F Q-1
-- CH.sub.2 3-Cl, 4-Cl, 5-Cl CF.sub.3 C(O)-cyclo-propyl H T-22 F
Q-1 -- CH.sub.2 3-Cl, 4-F, 5-Cl CF.sub.3 C(O)CH.sub.3 H T-22 F Q-1
-- CH.sub.2 3-Cl, 4-Cl, 5-Cl CF.sub.3 C(O)CH.sub.2CH.sub.3 H T-22 F
Q-1 -- CH.sub.2 3-Cl, 4-F, 5-Cl CF.sub.3 C(O)CH.sub.3 H T-22 Cl Q-1
-- CH.sub.2 3-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-1 CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3 R.sup.3-1 (Z) H T-1
CH.sub.3 Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3 R.sup.3-1 (E) H T-1
CH.sub.3 Q-1 -- C(O)
[0075] A more preferred compound has the Formula (II),
##STR00015##
wherein R.sup.1a, R.sup.1b, R.sup.1c are independently from each
other hydrogen, Cl or CF.sub.3, preferably R.sup.1a and R.sup.1c
are Cl or CF.sub.3 and R.sup.1b is hydrogen,
T is
##STR00016##
[0076] wherein Y is methyl, bromine, Cl, F, CN or C(S)NH.sub.2, and
Q is as described above.
[0077] In another preferred embodiment in R.sup.3 is H and R.sup.4
is --CH.sub.2--C(O)--NH--CH.sub.2--CF.sub.3,
--CH.sub.2--C(O)--NH--CH.sub.2--CH.sub.3,
--CH.sub.2CH.sub.2--CF.sub.3 or --CH.sub.2CF.sub.3.
[0078] In one embodiment the compound of Formula (I) is
4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-m-
ethyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN
864731-61-3-USAN fluralaner).
[0079] In another embodiment the compound of Formula (I) is
(Z)-4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-
-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN
928789-76-8).
[0080] In another embodiment the compound of Formula (I) is
4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl--
N-(thietan-3-yl)benzamide (CAS RN 1164267-94-0) that was disclosed
in WO2009/0080250--Compound B.
[0081] In another embodiment the compound of Formula (I) is
4-[5-[3-Chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-
-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalen-
ecarboxamide (CAS RN 1093861-60-9, USAN-afoxolaner) that was
disclosed in WO2007/079162--Compound C.
[0082] In another embodiment the compound of Formula (I) is
5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-
-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxam-
ide (CAS RN 1231754-09-8) that was disclosed in
WO2010/070068-Compound D.
[0083] An especially preferred compound is
##STR00017##
[0084] Especially preferred compounds of Formula (II) are:
TABLE-US-00003 (R.sup.1).sub.n R.sup.2 R.sup.3 R.sup.4 T Y Q Z X
3-Cl, 5Cl CF.sub.3 CH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-2 -- Q-1 -- C(O) 3-CF.sub.3, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-2 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 -- T-2 -- Q-6 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 --
Q-7 Z.sup.B-7 3-Cl, 5Cl CF.sub.3 -- -- T-2 -- Q-5 Z.sup.B-7 3-Cl,
5Cl CF.sub.3 -- -- T-2 -- Q-2 Z.sup.D-1 3-Cl, 5Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-3 CH.sub.3 Q-1 -- C(O) 3-Cl, 4-Cl, 5-Cl CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3 Q-1 -- C(O) 3-Cl,
4-F, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-3 CH.sub.3
Q-1 -- C(O) 3-Cl, 5-Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-20 -- Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 CH.sub.3 T-20 -- Q-1 -- C(O)
3-CF.sub.3, 5-CF.sub.3 CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H
T-20 -- Q-1 -- C(O) 3-CF.sub.3, 5-CF.sub.3 CF.sub.3
CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 -- Q-1 -- C(O) 3-Cl, 5Cl
CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-21 -- Q-1 -- C(O) 3-Cl,
5Cl CF.sub.3 CH.sub.2C(O)NHCH.sub.2CF.sub.3 H T-1 CH.sub.3 Q-1 --
C(O) 3-Cl, 5Cl CF.sub.3 R.sup.3-1 (Z) H T-1 CH.sub.3 Q-1 -- C(O)
3-Cl, 5Cl CF.sub.3 R.sup.3-1 (E) H T-1 CH.sub.3 Q-1 -- C(O)
[0085] Isoxazoline compounds are known in the art and these
compounds and their use as parasiticide are described, for example,
in US patent application No. US 2007/0066617, and International
Patent applications WO 2007/079162, WO 2009/002809, WO 2009/024541,
WO 2009/003075, WO2009/080250, WO 2010/070068, WO 2010/079077, WO
2011/075591 and WO 2011/124998, the disclosures of which, as well
as the references cited herein, are incorporated by reference. This
class of compounds is known to possess excellent activity against
ectoparasites such as ticks and fleas.
[0086] The isoxazoline compounds may exist in various isomeric
forms. A reference to an isoxazoline compound always includes all
possible isomeric forms of such compound. Unless otherwise stated,
a compound structure that does not indicate a particular
conformation is intended to encompass compositions of all the
possible conformational isomers of the compound, as well as
compositions comprising fewer than all the possible conformational
isomers. In some embodiments, the compound is a chiral compound. In
some embodiments, the compound is a non-chiral compound.
[0087] Isoxazoline compounds of Formula (I) can be prepared
according to one or other of the processes described e.g. in Patent
Applications US 2007/0066617, WO 2007/079162, WO 2009/002809, WO
2009/080250, WO 2010/070068, WO 2010/079077, 2011/075591 and WO
2011/124998 or any other process coming within the competence of a
person skilled in the art who is an expert in chemical synthesis.
For the chemical preparation of the products of the invention, a
person skilled in the art is regarded as having at his disposal,
inter alia, the entire contents of "Chemical Abstracts" and of the
documents which are cited therein.
[0088] In one embodiment the isoxazoline compound is
4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-m-
ethyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN
[864731-61-3])-USAN furalaner--Compound A.
[0089] This invention is also directed to soft chews with
combinations comprising more than one pharmaceutically active
ingredient. Preferred combinations comprising active ingredients
selected from the group consisting of isoxazolines of Formula (I)
and avermectins and milbemycins. In one embodiment the soft chew
comprises a combination of isoxazolines, especially
fluralaner--compound A, or afoxolaner with ivermectin. In another
embodiment the soft chew comprises a combination of isoxazolines,
especially fluralaner--compound A, or afoxolaner with milbemycin or
moxidectin.
[0090] Other combinations of the present invention can include
insect or acarid growth regulators (AGRs or IGRs) such as e.g.
fenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron,
fluazuron, cyromazine, methoprene, pyriproxyfen etc., thereby
providing both initial and sustained control of parasites (at all
stages of insect development, including eggs) on the animal
subject, as well as within the environment of the animal
subject.
[0091] The amounts of each of the components in the final product
may be varied considerably, depending upon the nature of the
pharmaceutically active ingredients, the weight and condition of
the subject treated, and the unit dosage desired. Those of ordinary
skill in the art will be able to adjust dosage amounts for
particular pharmaceutically active ingredients in the soft chews in
light of the teachings of this disclosure.
[0092] Generally, however, the pharmaceutically active ingredients
may be provided by range in weight based on the total weight of the
composition from about 0.001% to 75% (w/w), more preferably 0.1% to
40%, and most preferably not in excess of 50%.
[0093] For example, for administration for the control of
ectoparasites in dogs, such as Compound A for treatment of fleas
and ticks (see, Example 1) the amount of Compound A in the product
of the invention is between 5% and 20% w/w, especially about 9% w/w
or about 14% w/w.
[0094] The soft chew according to the invention comprises as
(non-active) ingredient a liquid component. As used herein the
liquid component includes aqueous and non-aqueous solvents, oils or
humectant components or mixtures of any of such liquids. In one
embodiment the liquid component is oil or a mixture of oils. In
another embodiment the liquid component comprises one or more oils
and one or more non-aqueous solvents. In one embodiment the liquid
component comprises one or more oils, one or more non-aqueous
solvents and a humectant.
[0095] The oil employed in the soft chew may be a saturated or
unsaturated liquid fatty acid, its glyceride derivatives or fatty
acid derivatives of plant or animal origin or a mixture thereof.
Suitable sources for vegetable fats or oils can be palm oil, corn
oil, castor oil, canola oil safflower oil, cotton-seed oil, soybean
oil, olive oil, peanut oil and mixtures thereof. Additionally,
animal oil or fats and a mixture of animal or vegetable oils or
fats are suitable for use in the product according to the
invention. Vegetable oils may also be utilized to lubricate the
soft chew mixture and maintain its softness. In one embodiment the
oily component is soybean oil.
[0096] As used herein, the term "non-aqueous solvent" is intended
to mean any liquid other than water in which a biological material
may be dissolved or suspended and includes both inorganic solvents
and, more preferably, organic solvents.
[0097] Illustrative examples of suitable non-aqueous solvents
include, but are not limited to, the following: acetone,
acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide
(DMA), dimethylsulfoxide (DMSO), dimethylformamide,
N,N-diethyl-3-methylbenzamide, dipropylene glycol n-butyl ether,
ethyl alcohol, isopropanol, methanol, butanol, phenylethyl alcohol,
isopropanol, ethylene glycol monoethyl ether, ethylene glycol
monomethyl ether, monomethylaceamide, dipropylene glycol monomethyl
ether, liquid polyoxyethylene glycols, propylene glycol,
N-methylpyrrolidone (NMP), 2-pyrrolidone, limonene, eucalyptol,
dipropylene glycol monomethyl ether, diethylene glycol monoethyl
ether, ethylene glycol, diethyl phthalate, polyethoxylated castor
oil, methyl ethyl ketone, ethyl-L-lactate, lactic acid, fructone,
glycerol formal, ethyl acetate, 1-methoxy-2-propyl acetate, ethyl
acetoacetate, geranyl acetate, benzyl benzoate, propylene
carbonate, methyl salicylate, isopropyl myristate, isopropylidene
glycerol, propylene glycol methyl ether, diethylene glycol
monoethyl ether, .gamma.-hexalactone. In one embodiment the
non-aqueous solvent is 2-pyrrolidone.
[0098] As used herein, the term "humectant" means and refers to a
hygroscopic substance. It can be a molecule with several
hydrophilic groups, e.g. hydroxyl groups, but amines and carboxyl
groups, sometimes esterified, can be encountered as well; the
affinity to form hydrogen bonds with molecules of water is crucial
here.
[0099] The humectant has the effect of keeping the soft chew dough
moist. Examples of humectants include propylene glycol, glyceryl
triacetate, vinyl alcohol and neoagarobiose. Others can be sugar
polyols such as glycerol, sorbitol, xylitol and maltitol, polymeric
polyols like polydextrose, or natural extracts like quillaia,
lactic acid, or urea. In one embodiment the humectant is
glycerol.
[0100] In an embodiment, the liquid component comprises about 5% to
about 50% w/w of the soft chew. In an alternate embodiment, a
liquid component comprises about 7.5% to about 40% w/w of the soft
chew. In an alternate embodiment, a liquid component comprises
about 10% to about 30% w/w of the soft chew. In an alternate
embodiment, a liquid component comprises about 15% to about 25% w/w
of the soft chew.
[0101] The forming agent is important for the texture of the soft
chew and the possibility to form single soft chews from the dough
that stay intact and separate. As used herein, the term "former" or
"forming agent" means and refers to an agent providing texture to
the soft chew product, like for example polyethylene glycol (PEG)
or polyvinylpyrrolidone (PVP).
[0102] In an embodiment, a forming agent of choice is polyethylene
glycol (PEG). Moreover, depending upon the desired consistency of
the soft chew, different molecular weight PEG may be utilized. In
an embodiment, PEG 3350 is utilized. However, the PEG chosen is a
matter of choice and the molecular weight may be higher or lower
than 3350, but preferably higher than 600. Alternatively PEG 8000
might be used.
[0103] In an embodiment, the forming agent comprises about 1% to
about 40% w/w of the soft chew. In an alternate embodiment, a
forming agent comprises about 5% to about 30% w/w % of the soft
chew. In an alternate embodiment, a forming agent comprises about
10% to about 20% w/w of the soft chew. In case the forming agent is
polyvinylpyrrolidone e.g. 2, 4, 5, 6 or 9% w/w are present in the
soft chew.
[0104] The product according to the current invention
conventionally further comprise physiologically acceptable
formulation excipients known in the art e.g. as described in
"Gennaro, Remington: The Science and Practice of Pharmacy" (20th
Edition, 2000) incorporated by reference herein. All such
ingredients, carriers and excipients must be substantially
pharmaceutically or veterinary pure and non-toxic in the amounts
employed and must be compatible with the pharmaceutically active
ingredients.
[0105] Additional excipients that can be present in the soft chew
are e.g. a filler, a flavour, or sugar components.
[0106] As used herein, the term "filler" or "filler component"
means and refers to those food-stuffs containing a preponderance of
starch and/or starch-like material. Examples of filler are cereal
grains and meals or flours obtained upon grinding cereal grains
such as corn, oats, wheat, milo, barley, rice, and the various
milling by-products of these cereal grains such as wheat feed
flour, wheat middlings, mixed feed, wheat shorts, wheat red dog,
oat, hominy feed, and other such material. Alternative non-food
stuff fillers such as e.g. lactose may be used. In one embodiment
the filler is starch, corn starch being preferred.
[0107] Flavours are commonly added to soft chewable pharmaceutical
products to enhance their palatability. For example, a veterinary
medication might include animal product-based flavourings such as
beef, pork, chicken, turkey, fish and lamb, liver, milk, cheese and
egg may be utilized.
[0108] Non-animal origin flavourings are plant proteins, such as
soy protein, yeasts, or lactose to which edible artificial
food-like flavourings has been added. Depending on the target
animal, other non-animal flavourings could include anise oil,
carob, peanuts, fruit flavours, herbs such as parsley, celery
leaves, peppermint, spearmint, garlic, or combinations thereof.
[0109] The sugar component may act as a sweetener, filler or
flavour or provides a texture that is appealing to the animal, e.g.
crunchy texture. As used herein, the term "sugar component" and any
conjugation thereof, means and refers to any saccharide which is at
least partially soluble in moisture, non-toxic, and preferably not
provide any undesirable taste effects. Further, the use of the term
"sugar" shall include a "sugar substitute" or an "artificial
sweetener". The sugar component may comprise white sugar, corn
syrup, sorbitol, mannitol, oligosaccharide, isomalto
oligosaccharide, fructose, lactose, glucose, lycasin, xylitol,
lactitol, erythritol, mannitol, isomaltose, polydextrose,
raffinose, dextrin, galactose, sucrose, invert sugar, honey,
molasses, polyhydric alcohols and other similar saccharides
oligomers and polymers and mixture thereof or artificial sweeteners
such as saccharine, aspartame and other dipeptide sweeteners. In
one embodiment the sweetener is aspartame.
[0110] Various embodiments further comprise additional excipients
such as surfactants, stabilizer, flow agents, disintegration
agents, preservatives and/or lubricating agents.
[0111] Surfactant components are well-known in the art. A suitable
surfactant is e.g. sodium lauryl sulphate.
[0112] Suitable stabilizer components are citric acid, sodium
citrate, and/or the like and antioxidants such as BHT, BHA,
Ascorbic acid, Tocopherol, EDTA.
[0113] Flow agents typically may include silica dioxide, modified
silica, fumed silica, talc and any other suitable material to
assist bulk movement of active components and/or the combination
during delivery and/or manufacture.
[0114] Disintegration agents typically may include 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 and any other suitable material to help breakdown the
dosage form and to assist in delivery of active ingredients.
[0115] Preservative for oral formulations are known in the art and
are included in order to retard growth of microorganisms such as
bacteria and fungi. An embodiment of preservative includes products
such as potassium sorbate, sodium benzoate or calcium
propionate.
[0116] Lubricating agents are e.g. magnesium stearate, fumaric
acid, sodium stearyl fumarate.
Process of Manufacturing
[0117] Preferably, dry ingredients of the chew mixture are blended
first; then the liquid components (e.g., oil, humectants or
solvents) are added and blended therein to form a thoroughly
blended mixture. After blending, the soft chew mixture is
discharged from a port through the blender into a suitable
container for processing into individual dosage units by hand or
preferably with a forming machine.
[0118] 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.
[0119] Preferred forming equipment for use in the invention
includes the Formax F6.TM. molding machine made by the Formax
Corporation. The F6 machine has the capabilities of 60 strokes per
minute. A square forming die of 6'' by 6'' can be used to form
approximately 16-25 chunk-like 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 sizes or shapes (e.g., bone
shaped chews) may also be utilized.
[0120] In such a machine, rotating screws and a plunger cause the
chew mixture to move through a product tunnel to fill cavities in a
mold plate. The mold plate is advanced from the filling position to
the discharge position. There a knockout mechanism, with cups
aligned with the cavities, ejects the molded mixture from all the
mold plate cavities simultaneously. After discharge, the mold plate
is retracted so the cycle can begin again.
[0121] Each batch of chews may be packaged in bulk or, preferably,
each soft chew is then individually packaged for storage. Examples
of suitable packaging materials include HDPE bottles, blister or
foil/foil packaging.
Methods of Using the Soft Chews
[0122] In one embodiment the product of the invention is intended
for use for controlling a parasitic insect- and acarid or helminth,
especially parasitic nematode infestation. The term "controlling a
parasitic insect- and acarid infestation" refers to preventing,
reducing or eliminating an infestation by such parasites on animals
preferably by killing the insects and/or acarids or nematode
parasites within hours or days.
[0123] The term "parasitic insect- and acarid" refers to
ectoparasites e.g. insect and acarine pests that commonly infest or
infect animals. Examples of such ectoparasites include the egg,
larval, pupal, nymphal and adult stages of lice, fleas, mosquitoes,
mites, ticks biting or nuisance fly species. Especially important
are the adult stages of fleas and ticks.
[0124] In general, the product according to the invention will
contain an effective amount of the active ingredients, meaning a
non-toxic but sufficient amount to provide the desired control
effect. A person skilled in the art using routine experimentation
may determine an appropriate "effective" amount in any individual
case. Such an amount will depend on the age, condition, weight and
type of the target animal. The soft chews may be formulated to
contain an amount of active ingredients that is adjusted to animals
in a specific weight range. The animals may receive a dosage every
2, 3, 4, 5 or 6 months or receives a monthly, weekly or daily
dosage. The treatment can, for example, be continuing or
seasonal.
[0125] In general the product according to the current invention
can be administered to all species of animals that have insect- or
acarid- or helminth parasite infestation. The recipient of the
product may be a livestock animal, e.g. sheep, cattle, pig, goat or
poultry; a laboratory test animal, e.g. guinea pig, rat or mouse;
or a companion animal, e.g. dog, cat, rabbit, ferret or horse. The
product according to the invention is especially suitable for use
in companion animals, e.g. dogs, cats or ferrets.
[0126] As used herein, the term "w/w" designates weight/weight, the
term "w/v" designates weight/volume, and the term "mg/kg"
designates milligrams per kilogram of body weight. As used herein,
% w/w represents the percentage by weight of an Ingredient in the
recipe of the product.
[0127] The invention having been fully described, its practice is
illustrated by the examples provided below. The examples do not
limit the scope of the invention, which is defined entirely by the
appended claims.
Example 1
Soft Chew According to the Invention
Exemplary Method of Manufacture for Soft Chews of the Invention
[0128] Dry powdery ingredients which exhibited aggregates were
sieved through an 800 .mu.m screen. All dry powdery ingredients
were weighed in and placed in the mixing vessel of a horizontal
ploughshare or planetary mixing blender and mixed until the blend
was visually practically homogeneous, i.e. approximately 10
minutes.
[0129] The defined amount of glycerol was added slowly followed by
a short mixing. Oily components were added slowly followed again by
a short mixing. If necessary, the mixer was heated to a temperature
inhibiting a too fast precipitation of the PEG which introduced in
the next step.
[0130] The PEG 3350 was molten. The defined amount of the molten
PEG was added relatively quickly to the chew mixture, which was
then mixed until the mixture was homogeneous and could be separated
from the wall. The mixture resembled a "cookie dough-like"
appearance.
[0131] The mixture was formed into individual chunks using a Formax
F6.TM. molding machine with dies for production of chunk-like
shapes, and packaged for storage.
[0132] Examples of soft chews according to the invention comprising
4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-m-
ethyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide--Compound
A as active ingredients are set forth below.
TABLE-US-00004 Substance mass [mg] % Formulation A Active
ingredient 500.0 8.93 Flavour 1120.0 20.00 Sucrose 392.0 7.00 Corn
starch (filler) 883.2 15.77 Sodium lauryl sulfate 112.0 2.00 Sodium
pamoate 140.0 2.50 Magnesium stearate 42.0 0.75 Aspartame 14.0 0.25
Glycerol 420.0 7.50 Soybean oil (0.1% BHT- 1024.8 18.30 stabilized)
Polyethylene glycol 952.0 17.00 3350 SUM 5600.0 100.00 Formulation
B Active ingredient 500.00 8.93 Flavor 1120.00 20.00 Sucrose 392.00
7.00 Corn starch (filler) 1163.20 20.77 Sodium lauryl sulfate
112.00 2.00 Sodium pamoate 112.00 2.00 Magnesium stearate 42.00
0.75 Aspartame 14.00 0.25 Glycerol 420.00 7.50 Soybean oil (0.1%
BHT- 688.80 12.30 stabilized) Polyethylene glycol 1036.00 18.50
3350 SUM 5600.00 100.00 Formulation C Active ingredient 500.00 8.93
Flavor 560.00 10.00 Sucrose 1148.00 20.50 Corn starch (filler)
1135.20 20.27 Sodium lauryl sulfate 112.00 2.00 Sodium pamoate
112.00 2.00 Magnesium stearate 42.00 0.75 Aspartame 14.00 0.25
Glycerol 224.00 4.00 Soybean oil (0.1% BHT- 716.80 12.80
stabilized) Polyethylene glycol 1036.00 18.50 3350 SUM 5600.00
100.00 Formulation D Active ingredient 500.00 8.93 Flavor 1120.00
20.00 Sucrose 392.00 7.00 Corn starch (filler) 1135.20 20.27 Sodium
lauryl sulfate 112.00 2.00 Sodium pamoate 112.00 2.00 Magnesium
stearate 42.00 0.75 Aspartame 14.00 0.25 Glycerol 420.00 7.50
Soybean oil (0.1% BHT- 800.80 14.30 stabilized) Polyethylene glycol
952.00 17.00 3350 SUM 5600.00 100.00 Formulation E Active
ingredient 500.00 13.89 Flavor 720.00 20.00 Sucrose 252.00 7.00
Corn starch (filler) 569.20 15.81 Sodium lauryl sulfate 72.00 2.00
Sodium pamoate 72.00 2.00 Magnesium stearate 27.00 0.75 Aspartame
9.00 0.25 Glycerol 270.00 7.50 Soybean oil (0.1% BHT- 442.80 12.30
stabilized) Polyethylene glycol 666.00 18.50 3350 SUM 3600.00
100.00 Formulation F Active ingredient 500.00 13.89 Flavor 720.00
20.00 Sucrose 288.00 8.00 Corn starch (filler) 569.20 15.81 Sodium
lauryl sulfate 72.00 2.00 Sodium pamoate 72.00 2.00 Magnesium
stearate 27.00 0.75 Aspartame 9.00 0.25 Glycerol 234.00 6.50
Soybean oil (0.1% BHT- 442.80 12.30 stabilized) Polyethylene glycol
666.00 18.50 3350 SUM 3600.00 100.00
[0133] The mixture was formed into individual chunks using a Formax
F6.TM. molding machine and the processing was without any problems
like stopping of the movable parts.
[0134] Soft chews according to the invention were prepared
comprising the following alternative isoxazoline compounds
##STR00018##
TABLE-US-00005 TABLE 3 Test formulations Excipient 13-009 13-010
13-011 13-012 13-013 13-014 Compound B 13.64% 4.27% Compound C
13.64% 4.27% Compound D 13.64% 4.27% 2-pyrrolidone 10.19% 10.19%
10.19% microcrystalline 24.27% 24.27% 24.27% cellulose sodium
starch 4.95% 4.95% 4.95% glycolate flavor 20.0% 14.56% 20.0% 14.56%
20.0% 14.56% sucrose 7.0% 7.0% 7.0% corn starch 16.06% 16.06%
16.06% sodium lauryl 2.0% 3.4% 2.0% 3.4% 2.0% 3.4% sulfate sodium
2.0% 2.43% 2.0% 2.43% 2.0% 2.43% pamoate magnesium 0.75% 0.49%
0.75% 0.49% 0.75% 0.49% stearate aspartame 0.25% 0.49% 0.25% 0.49%
0.25% 0.49% glycerin 7.5% 2.91% 7.5% 2.91% 7.5% 2.91% soybean oil
12.3% 16.75% 12.3% 16.75% 12.3% 16.75% PEG 3350 18.5% 18.5% 18.5%
PEG 8000 15.29% 15.29% 15.29%
Example 2
Comparative Example Soft Chew
[0135] Examples of soft chews that do not contain pamoic acid or
salts or esters thereof are set forth below.
TABLE-US-00006 mass Substance [mg] % Result Formulation G Active
ingredient 500 8.93 Forming machine stops while in process. The
Flavor 1120 20 addition of 2% w/w soybean oil did not result
Aspartame 28 0.5 in a proper process. The addition of further 2%
w/w Sucrose 392 7 soybean oil and 2.5% w/w Corn starch (filler) 634
11.32 magnesium stearate did not improve the Magnesium stearate 42
0.75 process. Sodium lauryl sulfate 112 2 Lactose monohydrate 560
10 Soybean oil (BHT- 896 16 stabilized) Glycerol 420 7.5
Polyethylene glycol3350 896 16 SUM 5600 100 Formulation H Active
ingredient 502.01 8.93 Forming machine stops during process. After
Flavor 1120.00 20.00 addition of 1% w/w Sodium pamoate machine
Sucrose 1008.00 18.00 stops again. After addition of Sodium Corn
starch (filler) 575.99 10.32 pamoate to reach a final amount of
1.5% w/w Sodium lauryl sulfate 112.00 2.00 the process runs
properly. Magnesium stearate 42.00 0.75 Aspartame 28.00 0.50
Glycerol 420.00 7.50 Soybean oil (0.1% BHT- 896.00 16.00
stabilized) Polyethylene glycol 896.00 16.00 3350 SUM 5600.00
100.00 Formulation I Active ingredient 200.00 6.25 2-Pyrrolidone
294.40 9.20 Microcrystalline cellulose 769.60 24.05 Colloid Silicon
dioxide 64.00 2.00 Micronized poloxamer 160.00 5.00 407 (Lutrol
Micro 127) Sodium lauryl sulfate 160.00 5.00 Flavor 480.00 15.00
Sodium pamoate 0.00 0.00 Aspartame 16.00 0.50 Magnesium stearate
32.00 1.00 Labrasol 64.00 2.00 Soy bean oil (0.1% BHT- 464.00 14.50
stabilized) Polyethylene glycol 8000 496.00 15.50 SUM 3200.00
100.00
[0136] The initial formulation containing no sodium pamoate is not
processable. After addition of 2.5% sodium pamoate the forming
process runs properly.
Example 4
[0137] Efficacy Against Brown Dog Ticks (R. sanguineus) on Dogs
[0138] A composition according to the invention with the following
excipients was prepared.
TABLE-US-00007 Excipient Composition (% w/w) Fluralaner- Compound A
4.27% 2-pyrrolidone 10.19% microcrystalline cellulose 24.27% sodium
starch glycolate 4.95% flavor 14.56% sodium lauryl sulfate 3.40%
sodium pamoate 2.43% aspartame 0.49% magnesium stearate 0.49%
glycerol 2.91% soybean oil 16.75% Polyethylene Glycol 8000
15.29%
[0139] Dogs were randomly assigned to 4 treatment groups of 8
animals each, and one untreated control group of 8 animals. The
dogs in the treatment groups were treated with the composition as
described above on Day Zero as shown in Table 6:
TABLE-US-00008 TABLE 6 Treatment Groups Group Treatment A Untreated
control B 4.27% fluralaner chewable tablet 8 mg/kg bw C 4.27%
fluralaner chewable tablet 10 mg/kg bw D 4.27% fluralaner chewable
tablet 12 mg/kg bw E 4.27% fluralaner chewable tablet 20 mg/kg
bw
[0140] The dogs were infested on Day -2 with approximately 50 adult
unfed ticks (R. sanguineus) and on Day 28 and 56. Ticks were
counted approximately 48 h post infestation and on Days 30 and 58
(approximately 48 hour after each post-treatment re-infestation) to
evaluate the acaricidal activity in the treated groups.
[0141] Table 7 shows the observed tick counts:
TABLE-US-00009 TABLE 7 Brown Dog Ticks (R. sanguineus) on dogs-
Tick counts - Group Day 2 Day 30 Day 58 A 21.25 23 25.9 B 0 0 0 C
0.125 0 0 D 0 0 1.13 E 0 0 0
* * * * *