Note: Descriptions are shown in the official language in which they were submitted.
:~S~9
JAB 440
AQUEOUS NON-AGGRESSIVE ANTHEL~INTIC POUR-ON FORMULATIONS.
Description of the invention:
The method of systemically administering drugs by pouring or
spraying a composition, comprising the desired drug, onto any part
of the skin is generally known in veterinary medicine as the pour-on
method. Drugs, administered following this method, are absorbed by
the skin and, after they have penetrated through the skin, they are
transmitted systemically within the animal [see, for example, W.M.
~ogoff and P.~. Kohler, J. Econ. Ent., 53, 814-817 (1960) and B.
Idson, J. Pharm. Sci.,64, 901-924 (1975)].
In comparison with the parenteral administration methods the
pour-on method offers distinct advantages. For example, there is no
need to hold the animal, sterile precautions are not necessary and
specially trained staff is not required.
Furthermore, compared with the oral administration methods, the
pour-on method has the advantage that each animal receives an
exactly defined amount of the desired drug.
Tetramisole, being chemically designated as 2,3,5,6-tetrahydro-
6-phenylimida2O~2,1-b]thiazole and the laevo isomer thereof,
levamisole, have been described in U.S. Patent Nos. 3,274,209,
s~
respectively 3,463,786.
The compounds are powerful anthelmintic agents. Structurally,
tetramisole is represented by the formula
~ ~ ~ (I)
Anthelmintic pour-on compositions which contain tetramisole or
levamisole have been described in U.S. Patent Nos. 4,070,476 and
3,980,791. Said compositions have the disadvantage that the
carriers, which are the most effective for nelping the penetration
of the anthelmintic through the skin, are at the same time the most
aggressive to the treated skin, resulting in, for example, sub~
cutaneous bleedings, necrosis, hair and skin diseases and, at worst,
open wounds [severe skin irritations, caused by pour-on composi-
tions, are described, e.g., in Veterinar Medizinische Nachrichten
978 (1), 109-112)].
Tetramisole and/or levamisole containing pour-on compositions
having a strongly reduced aggressivity to the treated skin have also
been described in U.S. Patent No. 4,278,685 and in European Patent
No. 61,806. However, these formulations have some less advantageous
properties originating from their organic nature such as, for
example, their expense combined with less advantageous influences on
the environment and the safety and health of the applicator.
Additionally, these organic formulations, having good
penetration properties for cattle-skin, are less effective for
penetrating through the skin of sheep.
An additional limitation of the hereinabove-mentioned organic
formulations is their limited solubility of polar compounds in
general, and, more particularly, of the acid addition salts of
tetramisole and/or levamisole.
Additionally, as water is taught to be ineffective as a liquid
carrier for passing the compound through the skin of an animal (See,
for example, U.K Patent No. 1,464,552) useful aqueous pour-on
formulations for co~batting helmintic infestations in non-human
3~3
animals are hitherto unknown.
The present invention is concerned with aqueous pour-on
formulations for combatting helmintic infestations in non-human
animals containing besides a vehicle from 0. OL1 to 0.15 moles of
tetramisole or levamisole per 100 ml wherein the tetramisole or
levamisole is present in the form of a pharmaceutically acceptable
acid addition salt and the vehicle consists of f rom 1 to 60 v/v ~ of
a penetration enhancing and/or moistening agent in water.
Aqueous pour-on formulations wherein the vehicle consists of
from 10 to 60 v/v ~ of a penetrat:ion enhancing and/or moistening
agent in water are particularly preferred due to their excellent
spreading properties.
Vehicles which combine an effective penetration enhancing
property with a suitable moistening effect contain, for example,
lanolin and woolwax derivatives, e.g. Amerlate ~, Acetulan~, Aqua-
lose LL10 ~, Aqualose DL12~, Aqualose SL ~ Lanesta L~ and the like;
amido ether sulfate complexes; sulfonated aliphatic polyesters, e.g.
Humiîen~ esters, eg., 2-propyl myristate, 2-propyl palmilate, alk
oxylated myristyl propionate, lauric acid hexyl ester, caprionic
acid tri- glycerides and the like, addition products of 1 to oO
moles of ethylene oxide with 1 mole of a phenol which is further
substituted with at least one Cl-C15 alkyl group, e.g. Cemulsol
NP10~ and the like; addition products of 1 to 60 moles of ethylene
oxide with 1 mole of ricinus oil, e.g, Soprophor B~, Heliwet EO33
and the like; esters of hydroxy-substituted carboxylic acids, e.g.
Polysolvan O~; alcohols, e.g. 2-propanol, 2-butoxyethanol,
2-(2-butoxyethoxy)ethanol; 1,2,6-trihydroxyhexane, 2-methyl-2,4-
pentanediol and the like; donor-acceptor solvents, e.g. dimethyl
sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide
(DMA), N-methylpyrrolidone (NMP) and the like; 4-hydroxy-4-methyl-
2-pentanone; Cl-C6-alkyl esters of adipic-, glutaric and
succinic acid; and mixtures thereof.
Although the above-mentioned pour-on formulations are, as such,
very suitable for percutaneous administration, said vehicle may
possibly contain additives of any nature in minor proportions, which
.~252~:~3~
.,
additives do not introduce a significant deleterious effect on the
skin. Said additives may facilitate the administration to the skin
of the animals and/or may be helpful for preparing the desired for-
mulations. The concerned additives may also consist of substances
the taste of which deters animals from licking the applied formula-
tions off the animals treated, pigments making it possible to
recognize the animals, conservating agents, defoaming agents,
antioxidants and the like.
Besides a pharmaceutically acceptable acid addition salt of
tetramisole or levamisole and the vehicle the formulations of the
present invention may also contain other pharmaceutically active
compounds such as, for example, other substances with anthelmintic
and/or insecticidal properties.
Suitable acid addition salts of tetramisole or levamisole are
those formed by treating tetramisole or levamisole ~ith appropriate
acids such as, for example, inorganic acids such as hydrohalic
acids, e.g. hydrochloride, hydrobromic and the like, sulfuric acid,
nitric acid, phosphoric acid and the like; or organic acids such as,
for example, acetic, propanoic, hydroxyacetic; 2-hy2roxypropanoic,
2-oxo-propanoic, propanedioic, butanedioic, (Z)-2- butenedioic,
(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,
2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesul-
fonic, benzenesulfonic, Cl-C18alkylmethylbenzenesulfonic, cyclo-
hexanesulfonic, 2-hydroxyben oic, 4-amino-2-hydroxybenzoic,
salicyclic and the like acids.
Since the anthelminti_ activity of tetramisole is exerted
essentially by the laevo isomer, in a preferred embodiment acid-
addition salts of levamisole are employed as the anthelmintically
active agent.
The formulations of the present invention combine a good
stability and a desirable percutaneous absorption with the advan-
tages of aqueous mediums such as, for example, a high flash point
and the absence of disadvantageous influences on the environment and
the safety of the applicator.
Additionally, these aqueous formulations have not only good pene-
- ~S~339
--5--
tration properties for cattle-skin, but contrary to art-known formula-
tions the subject pour-on formulations have properties ~hich make them
very suitable Eor the percutaneous absorption of the sXin of any
warm-blooded animals, especially for the percutaneous absorption of sheep
skin and cattle skin, without causing any appreciable skin-irritation.
The formulations of the present invention may be prepared by mixing
an acid addition salt of tetramisole or levamisole with water, if desired
at elevated temperatures, subsequently adding the moistening and penetra-
tion enhancing agent and, if desired, suitable additives.
lOIt is evident that the acid addition salts of tetramisole and/or
levamisole may also be prepared in situ by mixing tetramisole and/or
levamisole with a sui-table amount of an appropriate acid.
The efficacy of the concerned anthelmintic pour-on formulations can
be illustrated by the eggs-per-gram count technique conducted on faeces
samples taken before and after treatment of sheep.
Experimental part
The following examples are intended to illustrate and not to limit
- the scope of the present lnvention. Unless otherwise stated all parts
therein are by weight.
In the following examples Cemulson NP10~ is a Trade Mark of a mix-
ture of addition products of nonylphenols with ethylene oxide, wherein an
average of 10 moles of ethylene oxide has been reacted with 1 mole of
nonylphenol; Soprophor ~ is a Trade Mark of a mixture of addition pro-
ducts of ricinus oil with ethylene oxide; Aqualose LL100~ is a Trade
~ark of a polyoxyalkylene co-condensate of lanolin oil with mixed
ethylene and propylene oxides, the mixed chains averaging 100 units;
Aqualose SL ~ is a homogeneous blend containing 20~ by weight of
natural lanolin oil with ethoxylated alcohols derived entirely from
lanolin and having a mean chain length of 20 ethylene oxide units;
Heliwet EO33 is a Trade Mark of polyethoxylated ricinus oil; Estasol~
is a Trade Mark of a mixture of 20~ dimethyl adipate, 60~ dimethyl
glutarate and 20~ dimethyl succinate; Atplus 300 ~ is a Trade Mark of a
mixture of surfactants and an anionic wetting agent; Aqualose DL12 is
~5~
a Trade Mark of a mixture of ethoxylated lanolin derivatives; Aqualose
A ~ is a Trade Mark of a mixture of ethoxylated lanolin derivatives;
Polysolvan O~ is a Trade Mark of butyl hydroxy acetic acid ester; and
Lanesta L~ is a mixture derived ~rom the isopropyl esters of the
natural fatty acids occurring in pharmaceutical anhydrous lanolin.
A. Preparation of formulations
Example I:0 Formulation 1: 15.4% w/v levamiso]e hydroxyacetic acid salt, 10% w/v
Cemulsol NP10~, ancl aqua dest. ad 100~.
_reparation:_ _ _ _
10 Parts of levamisole were added to a mixture containing 5.4 parts
of hydroxyacetic acid in 50 parts of water. After solubilization 10 parts
of Cemulsol NP10 were added and the mixture was diluted with water ad
100 ml while stirring.
Example II:
Formulation 2: 15.4% w/v levamisole hydroxyacetic acid salt, 10~ w/v
Cemulsol NP10~, 20~ v/v 2-propanol, and aqua dest. ad
100%.
_reparation:_ _ _ _
10 Parts of levamisole were added to a mixture containing 5.4 parts
of hydroxyacetic acid in 40 parts of water. After solubilization 10 parts
of Cemulsol NP10~ and 20 ml of 2-propanol were added and the mixture
was diluted with water ad 100 ml while stirring.
Example III:
Following the preparation-procedure described in example II the
following formulations were also prepared:
Formulation 3: 15.4% w/v levamisole hydroxyacetic acid salt, 10% w/v
Cemulsol NP10~, 20% v/v dimethylsulfoxide, and aqua
dest. ad 100~.
Formulation 4: 15.4~ w/v levamisole hydroxyacetic acid salt, 10~ w/v
3S Soprophor B~, 20~ v/v 2--propanol, and aqua dest. ad
~2~
--7--
100~ .
Formulation 5: 31.2~ w/v levamisole hydroxyacetic acid salt, 25~ w/v
Cemulsol NP10~, 10~ w/v 2-butoxyethanol, 4~ v/v Lanesta
L~ and aqua dest. ad 100~.
Example IV:
Formulation 6: 11.8% w/v levamisole hydrochloric acid salt, 10% w/v
Cemulsol NP10~, 20% v/v 2-propanol, and aqua dest. ad
100%.
Preparation-
_ _ _ _ _ _ .
11.8 Parts of levamisole hydrochloric acid salt were added to 40
parts of water. After solubilization 10 parts of Cemulsol NP10 and 20
ml of 2-propanol were added and the mixture was diluted with water ad 100
ml while stirring.
Example V:
Following the preparation-procedure described in example IV the
following formulations were also prepared:
Formulation 7: 23.6~ w/v levamisole hydrochloric acid salt, 25% w/v
Cemulsol NP10~, 10~ v/v 2-butoxyethanol, 43 Lanesta
L~, and aqua dest. ad 100%.
Formulation 8: 11.8% w/v levamisole hydrochloric acid salt, 25% w/v
Cemulsol NP10~, 20~ v/v 2-(2-butoxyethoxy)ethanol 5
Lanesta L~, and aqua dest. ad 100~.
25 Formulation 9: 11.8~ w/v levamisole-hydrochlorlc acid salt, 25~ w/v
Cemulsol N~1 ~, 10~ v/v 2-(2-butoxyethoxy)-ethanol 4%
v/v Lanesta L~, and aqua dest. ad 100%.
Formulation 10: 11.8~ w/v levamisole hydrochloric acid salt, 25% w/v
Aqualose LL100~, 10~ v/v 2-(2-butoxyethoxy)ethanol, and
aqua dest. ad 100~.
Formulation 11: 11~8% w/v levamisole hydrochloric acid salt, 25% w/v
Aqualose SL ~, and aqua dest. ad 100~.
Formulation 12: 11.8~ w/v levamisole hydrochloric acid salt, 25% w/v
Aqualose LL100~, and aqua dest. ad 100~.
Formulation 13: 11.8~ w/v levamisole hydrochloric acid salt, 25~ w/v
~s~
Cemulsol NP10~ 10~ v/v 2-butoxyethanol and 4~ v/v
Lanesta L , and aqua dest. ad 100~.
Formulation 14: 11.8~ w/v levamisole hydrochloric acid salt, 25~ w/v
Cemulsol NP10~, 10~ v/v 2-propanol 43 v/v Lanesta L~
and aqua dest. ad 100~.
Formulation 15: 23.6~ w/v levamisole hydrochloride, 25% w/v Cemulsol
NP10~, 10~ v/v 2-propanol, 4~ v/v Lanesta L and aqua
dest. ad 100%.
Formulation 16: 20% w/v levamisole hydrochloride, 25% w/v Cemulsol
NP10~, 10~ v/v 2-propanol, 4~ v/v Lanesta L~ and aqua
dest. ad 100~.
Formulation 17: 11.8% w/v levamisole hydrochloride, 20% w/v ~eliwet EO33
and aqua dest. ad 100~.
Formulation 18: 11.8% w/v levamisole hydrochloride, 20~ w/v Cemulsol
NP10~ and aqua dest. ad 100~.
Formulation 19: 11.8~ w/v levamisole hydrochloride, 20~ w/v Aqualose
DL12~ and aqua dest. ad 100~.
Formulation 20: 11.8~ w/v levamisole hydrochloride, 20~ w/v Cemulsol
NP10~, 10~ v/v NMP and aqua dest. ad 100~.
Formulation 21: 11.8~ w/v levamisole hydrochloride, 20~ w/v Cemulsol
NPl ~, 10~ v/v DMSO and aqua dest. ad 100~.
Formulation 22: 11.8% w/v levamisole hydrochloride, 20~ w/v Cemulsol
NP10~, 10~ Estasol~ and aqua dest. ad 1~0%.
Formulation 23: 10.0~ w/v levamisole base, 9.6~ w/v citric acid, 0.5% v/v
Atplus 300F~, 20~ v/v diacetone alcohol, 10~ v/v
Cemulsol NP10~ and aqua dest. ad. 1003.
Formulation 24: 10.0% w/v levamisole base, 9.6~ w/v citric acid, 20~ v/v
Cemulsol NP10~, 10~ v/v 2-propanol, 4~ v/v Lanesta L~
and aqua dest. ad. 100%.
Formùlation 25: 10.0% w/v levamisole base, 9.6% w/v citric acid, 20% w/v
Aqualose DL12~, 20~ v/v diacetone alcohol and aqua
des-t. ad. 100~.
Formulation 26: 10.0% w/v levamisole base, 9.63 w/v citric acid, 20% w/v
Aqualose DL12~, 20~ v/v NMP and aqua dest. ad. 1003.
Formulation 27: 11.8~ w/v levamisole hydrochloride, 20~ v/v N~IP, 20~ w/v
~s~
Aqualose DL12~ and aqua dest. ad 100%.
Formulation 28: 11.8~ w/v levamisole hydrochloride, 20~ v/v NMP, 20~ w/v
Cemulsol NP10~ and aqua dest. ad 100~.
Formulation 29: 11.8~ w/v levamisole hydrochloride, 30% v/v NMP, 15~ w/v
5Aqualose DL12 and aqua dest. ad 100%.
Formulation 30: 11.8~ w/v levamisole hydrochloride, 30% v/v N~5P, 10~ w/v
Aqualose DL12~ and aqua dest. ad 100%.
Formulation 31: 11.8~ w/v levamisole hydrochloride, 20% v/v NMP, 7.5% w/v
Aqualose DLl ~ and aqua dest. ad 100%.
10Formulation 32: 11.8~ w/v levamisole hydrochloride, 30g v/v NMP, 5.0~ w/v
Aqualose DL12~ and aqua dest. ad 100~.
Formulation 33: 11.8~ w/v levamisole hydrochloride, 10% v/v NMP, 10~ w/v
~qualose DL12 and aqua dest. ad 100~.
Formulation 34: 10~ w/v levamisole base, 5.4% w/v glycolic acid 70%, 15%
15v/v NMP, 10~ w/v Aqualose DL12~ and aqua dest. ad 100~.
For~ulation 35: 10% w/v levamisole base, 5.4% w/v glycolic acid 70%, 10%
w/v Aqualose LL100~, 103 v/v NMP and aqua dest. ad 100%.
Formulation 36. 10% w/v levamisole base, 15.73 w/v dobanic acid, 10~ v/v
NMP, 10% w/v Aqualose LL100~ and aqua dest. ad 100%.
Formulation 37: 10% w/v levamisole base, 6.8% w/v salicylic acid, 20% v/v
NMP, 10~ w/v Aqualose DL12~ and aqua dest. ad 100%.
Formulation 38: 10% w/v levamisole base, 6.8~ w/v salic~ylic acid, 10~ v/v
NMP, 10~ w/v Aqualose LL10 ~ and aqua dest. ad 100%.
Formulation 39: 10% w/v levamisole base, 5~ v/v acetic acid, 10~ w/v
~qualose DL12~ and aqua dest. ad 100~.
Formulation 40: 10% w/v levamisole base, 5% acetic acid, 20~ v/v NMP, 10%
v/v Aqualose LL100~ and aqua dest. ad 100~.
Formulation 41: 10~ w/v levamisole base, 5.4% w/v glycolic acid 70~, 50%
v/v NMP, 10% w/v Aqualose DLl ~ and aqua dest. ad 100%.
Formulation 42: 10% w/v levamisole base, 5~ w/v o-phosphoric acid 98%,
10% w/v Aqualose DL12~, 50% v/v NMP and aqua dest. ad
1009~ .
Formulation 43: 11.8~ w/v levamisole hydrochloride, 50% v/v ethanol and
aqua dest. ad 100~.
Formulation 44: 10% w/v levamisole base, 5.4g w/v glycolic acid 70~, 50%
~.2~ 3
--10--
v/v ethanol and aqua dest. ad 100~.
Formulation 45: 10~ w/v levamisole base, 5~ w/v o-phosphoric acid 98g,
50% v/v ethanol and aqua dest. ad 100~.
Formulation 46: 10~ w/v levamisole base, 5.~ w/v glycolic acid 70g, 503
v/v butyldioxitol and aqua dest. ad 100~.
Formulation 47: 10~ w/v levamisole base, 5~ w/v o-phosphoric acid 98~,
10~ w/v Aqualose L;L100~, 10% v/v NMP and aqua dest. ad
10 0% .
Formulation 48: 10% w/v levamisole base, 10% Aqualose DL1 ~, 40% v/v
butyldioxitol, 10~ v/v Shellsol AB, 5.4~ w/v glycolic
acid 70%, and aqua dest. ad 100%.
Formulation 49: 11.8% w/v levamisole hydrochloride, 40~ v/v trihydroxy-
hexane, 10~ w/v Aqualose LL100~, and aqua dest. ad 100~.
Formulation 50: 10~ w/v levamisole base, 5% acetic acid, 50~ v/v butyldi-
oxitol, and aqua dest: ad 100~.
Formulation 51: 11.8% w/v levamisole hydrochloride, 10% w/v Aqualose
LL10 ~, 50~ v/v butyldioxitol, and aqua dest. ad 100~.
Formulation 52: 11.8~ w/v levamisole hydrochloride, 50~ v/v Polysolvan
~, and aqua dest. ad 1003.
Formulation 53: 11.8~ w/v levamisole hydrochloride, 10% w/v Aqualose
LL10 ~, 50% v/v 2-propanol, and aqua dest. ad 1003.
Formulation 54: 11.8% w/v levamisole hydrochloride, 10~ v/v ethanol, 20%
w/v Aqualose A ~, and aqua dest. ad 100%.
Formulation 55: 11.8~ w/v levamisole hydrochloride, 30% v/v 2-(2-butoxy-
ethoxy)ethanol, 10% v/v N-methylpyrrolidone, 10~ w/v
Aqualose LL10 ~, and aqua dest. ad 100%.
Formulation 56: 11.8% w/v levamisole hydrochloride, 10~ w/v Aqualose
LL100~, 40% v/v 2-methyl-2,4-pentanediol, and aqua
dest. ad 1003.
Example VI
~rtificially infected sheep were treated by applying a formulation
along the backline. Faeces were examined by routine Mc.Master technique,
described in J. Counc. Sci. Industr. Res. Austr. 12, 50 (1939), before
treatment and 7 days after treatment.
~2S~ 39
4 Weeks before treatment the sheep were artiflcially infected with
L3-larvae of dirferent worm species.
Prior to treatment sheep were weighed and the tested formulations
were applied along the backline in such a quantity that 10 mg of leva-
misole/kg of body weight was administered.
Irritation-scores were noted on day 7 and day 14 after treatment.
None of the formulations caused any detectable irritation.
Table 1: ~ Efficacy of a number of formulations 7 days after treatment.
Formulations No. % Efficacy
1 93
3 100
100
7 96
8 100
14 100
29 95
100
31 100
33 100
100
39 190
44 92
46 100
48 100
100
51 91
53 93
