CA2028536A1 - Injectable parasiticidal composition - Google Patents

Injectable parasiticidal composition

Info

Publication number
CA2028536A1
CA2028536A1 CA002028536A CA2028536A CA2028536A1 CA 2028536 A1 CA2028536 A1 CA 2028536A1 CA 002028536 A CA002028536 A CA 002028536A CA 2028536 A CA2028536 A CA 2028536A CA 2028536 A1 CA2028536 A1 CA 2028536A1
Authority
CA
Canada
Prior art keywords
hydrogen
substituted
halogen
composition according
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002028536A
Other languages
French (fr)
Inventor
Walter Oechslein
Jean-Claude Gehret
Ernst Hess
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Geigy AG filed Critical Ciba Geigy AG
Publication of CA2028536A1 publication Critical patent/CA2028536A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)

Abstract

AP/5-17812/+

Injectable parasiticidal composition Abstract Parenterally injectable compositions for controlling parasites, which compositions contain from 0.1 to 10 % of a benzoylphenylurea as active ingredient, from 0.1 to 60 % of a 1-substituted azacycloalkan-2-one, from 2 to 90 % of a physiologically tolerable surfactant or mixture of surfactants and, if appropriate, as stabilising component, from 0.05 to 1 % of an acid or a buffer mixture and ad 100 % of a physiologically tolerable hydrophilic solvent or mixture of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic solvents.

Description

AP/5-17812/+

Iniectable Parasiticidal composition The present invention relates to a composition for controlling parasites harmful to animals, which composition is parenterally injectable and contains at least one sparingly soluble benzoylphenylurea as active ingredient.

Injectable formulations are often the most favourable forrn of administration because even small arnounts of active ingredient can be dosed very accurately, they are easy to administer and they cause negligible distress to the animals to be treated, especially relatively large productive livestock, such as, for example, cattle, sheep, horses and donkeys. When, however, sparingly soluble substances, such as, especially, benzoyl-phenylureas, are used in the form of injectable formulations, problems occur in producing an effective plasma level, that is to say, an even distribution of a sufficient arnount of active ingredient in the plasma, because the injected material is influenced by the tissue fluid and, for example, the physico-chemical propenies of the material can thus be so changed that a considerable proponion of the injected material crystallises very rapidly and, as a result, remains at the site of injection or very close thereto. For example, benzoylureas, such as N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chloro-phenyl]-N'-[2,6-difluorobenzoyl]-urea, can be dissolved in dimethyl sulfoxide and N-methylpyrrolidone (approximately 35 %; here and hereinafter, percentages are weight-per-volume percentages). Although those solutions are water-miscible, they have the disadvantage that, when injected parenterally, a considerable amount of the injected material is precipitated on contact with the tissue fluid, remains at the site of injection and therefore contributes nothing to the achievement of as high a plasma level as possible.
The use of such solutions is therefore uneconomical and, especially in the case of animals that are later to be slaughtered and used as food for animals or especially humans, is possible only to a limited extent owing to the local concentration of injected material.

Surprisingly, it has now been found that, by the addition of l-substitnted azacycloalkan-2-ones, it is possible to produce parenterally injectable formulations of sparingly soluble benzoylphenylureas with which a very markedly increased bioavailability is achieved. As a result, the high level of activity known ~ se of this class 20~3~
of compound can be exploited even in this accurately dosable form of administration. The composidons according to the invention differ from conventional compositions in advantageous manner in that the injected material is better distributed in the plasma and therefore considerably less mate~ial has to be injected to achieve an effec~ of the same intensity as in the case of conventional compositions, or in that, when the same amounts of active ingredient are used, it is possible with the compositions according to the invention to maintain a high plasma level over a distinctly longer period of time than in the case of conventional compositions.

The present invention accordingly relates to a composition for controlling parasites, which composition is parenterally injectable and contains (a) from 0.1 to 10 %, preferably from 0.5 to 7 % and especially from 1 to 5 %, of at least one benzoylphenylurea as active ingredient, (b) from 0.1 to 60 %, preferably from 0.1 to 50 %, especially from Q5 to 10 %, of a l-substituted azacycloaLIcan-2-one, (c) from 2 to 90 %, preferably from 40 to 85 %, of a physiologically tolerable surfactant or mixture of surfactants, (d) if appropriate, as stabilising component, from 0.05 to 1 % of an acid or a buffer mixture and ~e) ad 100 % of a physiologically tolerable hydrophilic solvent or mixture of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic solvents.

The above information is to be understood as meaning that component e) is alwayspresent, that is to say, the sum of components a), b), c) and d) cannot be 100 %.

Advantageously, the type and amount of solvent is chosen first in accordance with the type and amount of active ingredient and later, if necessary, further solvent is added to the total mixture ad 100 %. The solvent used to make up the amount may be that used to dissolve the active ingredient or may be a different solvent. The term "solvent" is also used here to mean "mixture of solvents".

"Parenterally injectable" is to be understood within the scope of this invention as meaning that the composition containing the dissolved active ingredient can be introduced into the body subcutaneously, intramuscularly or intravenously, for example under the skin, into the muscle tissue or into the blood vessels, by means of a cannula (injection syringe, 202~S3G

infusion, etc.), by-passing the gastro-intestinal tract.

Intramuscular and, especially, subcutaneous administration are preferred within the scope of the present invention. According to the invention, it is possible to formulate and administer any sparingly soluble benzoylphenylurea.

The preparation and mode of action of benzoylureas have already been described in numerous publications, for example in PCT Patent Application WO 86/03941 and European Patent Applications EP-0,079,311 and EP-0,179,022.

A group of benzoylphenylureas preferred within the scope of the present invention consists of compounds of formula I

R3 ~ COt X ~ CO--N--R7 (I) R4 Rs wherein each of Rl, R2, R3 and Rs, independently of the others, is hydrogen, halogen, Cl-C6aL~cyl, Cl-C6haloalkyl, Cl-C6aL~coxy, Cl-C6haloaL~coxy or Cl-C6aLlcylthio;
R4 is hydrogen, halogen, Cl-C6aLkyl, Cl-C6haloaLIcyl, Cl-C6aL~oxy, Cl-C6haloaLIcoxy, Cl-C6aL~cylthio or NHR'; wherein R' is hydrogen, R8CO- or RgNHCO-, wherein R8 is a Cl-C4aLkyl that is unsubstituted or mono- to tri-substituted by the same or different subsdtuents from the group halogen, Cl-C4aLlcoxy, Cl-C4acyloxy and -COOG, wherein G
is hydrogen, an aL~cali metal cadon or an aLkaline-earth metal cadon, and Rg is a Cl-C4-aL~cyl or phenyl group that is unsubsdtuted or mono- to tri-substituted by halogen;
X is -NH- or I e y~; wherein Y~ is an inorganic or organic cation;
R6 is hydrogen or Cl-C6a~yl; and R7 is an unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, the substituents being selected from the series halogen, especially fluorine or chlorine, alkyl, haloaL~cyl, aL~oxy, haloalkoxy, alkylthio, haloaL~cylthio, aL~cenyl, haloaLIcenyl, alkynyl, haloaLtcynyl, alkylsulfinyl, aL~cylsulfonyl, haloalkylsulfinyl, haloaL~ylsulfonyl, aL~cylamino, dialkylamino and benzyl and also phenoxy or pyridyloxy, -``` 20~3~

each of which last two substituents is substituted by substituents from the group consisting of halogen, haloaLkyl, haloalkoxy and nitro, it being possible, in the case where R7 is substituted phenyl, for cyano, N'-n-propyl-N'-phenylureido, an -O-CF2-CF2-O- bridge connecting two adjacent carbon atoms of the phenyl ring to one another, or phenoxy that is substituted by an -O-CF2-CF2-O- bridge connecting two adjacent carbon atoms of the phenyl ring to one another, also to be present as substituent (a phenyl ring that is substituted by an -O-CF2-CF2-O- bridge connecting two adjacent ring carbon atoms to one another forms a 2,2,3,3-tetrafluoro-1,4-benzodioxane radical with said bridge).

ALtcyl as substituent or as part of a substituent is, insofar as the number of carbon atoms is not defined, preferably unbranched or branched Cl-C6aLlcyl, especially Cl-C4alkyl and preferably methyl.

AL~cenyl and aLIcynyl as substituents or parts of substituents have preferably from 3 to 5 carbon atoms, the multiple bond generally being separated from the rest of the molecule by at least one carbon atom not participating in the multiple bond.

Halogen is to be understood as being fluorine, chlorine, bromine or iodine, but especially fluorine or chlorine.

In connection with R7, substituents at the ring or ring system are especially aL~yl, haloaL~cyl, aLIcylthio, aLI~oxy and haloaLIcoxy groups which may be straight-chained or branched and preferably have from 1 to 4 carbon atoms. Examples of such groups are, inter alia, methyl, -CF3, methoxy, methylthio, -OCF3, ethyl, ethoxy, n-propyl, -CF2-CHF-CF3, n-propoxy, -OCF2-CHF-CF3, isopropyl, isopropoxy, n-butyl, n-butoxy, n-pentyl, n-pentyloxy, n-hexyl and n-hexyloxy.

Prominence should be given to compounds of formula I wherein each of Rl, R2, R3 and Rs, independently of the others, is hydrogen, halogen, Cl-C6aL~cyl, Cl-C6haloaL~cyl, Cl-C6aL~oxy, Cl-C6haloaLIcoxy or Cl-C6aL~cylthio;
R4 is hydrogen, halogen, Cl-C6aLIcyl, Cl-C6haloaLkyl, Cl-C6aL~coxy, Cl-C6haloaLkoxy, Cl-C6aL~cylthio or NHR'; wherein R' is hydrogen, R8Ca or RgNHCO-, wherein R8 is a Cl-C4aLIcyl that is unsubstituted or mono- to tri-substituted by the same or different substituents from the group halogen, Cl-C4aLlcoxy, Cl-C4acyloxy and -COOG, wherein G
is hydrogen, an aLIcali metal cation or an aLlcaline-earth metal cation, and Rg is a Cl-C4-aL~yl or phenyl group that is unsubstituted or mono- to tri-substituted by halogen;

2~28~3~

X is -NH- or - IN~ Y~; wherein y~E3 is an inorganic or organic cation;
R6 is hydrogen or Cl-C6alkyl; and R7 is an unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, the substituents being selected from the series halogen, especially fluorine or chlorine, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkylsul~myl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, alkylamino, dialkylamino and benzyl and also phenoxy or pyridyloxy, each of which last two substituents is substituted by halogen, haloalkyl, haloalkoxy or by nitro.

Especially preferred are representatives of formula I wherein each of Rl and Rs, independently of the other, is hydrogen, fluorine, chlorine, methoxy or methylthio, especially fluorine;
R3 is hydrogen or fluorine and R4 is hydrogen or NH2;
R2 is hydrogen, fluorine or chlorine, especially hydrogen;
X is -NH- or - IN~ Y~; wherein Y~ is Na~3, K~ or tetraalkylammonium. such as (n-C4Hg)4N~3, (CH3)4N~3, (C2Hs)4N~or n-CI6H33-N~33(CH3)3, but especially -NH-;
R6 is hydrogen or Cl-C3alkyl, preferably hydrogen, and R7 is unsubstituted or, preferably, substituted phenyl, the phenyl radical preferably being substituted by one or two halogen atoms, especially fluorine or chlorine, and, additionally, either by Cl-C6haloalkoxy, especially Cl-C3halo-alkoxy, or by 2-pyridyloxy, the 2-pyridyloxy radical for its part being preferably substituted by CF3 and halogen, especially CF3 and fluorine or chlorine.

A further group of preferred benzoylphenylureas within the scope of formula 1 consists of the following compounds of formula II

F R~O
~ CONHCONH~ N (II) `: 2 ~ 3 ~

wherein R4 is hydrogen or NH2;
Rlo is hydrogen, halogen or methyl; and Rll is hydrogen or halogen.

A preferred sub-group is i~ormed by compounds of formula II wherein R4 is hydrogen or NH2;
Rlo is hydrogen, fluorine, chlorine or bromine; and Rll is hydrogen, fluorine, chlorine or bromine.

Especially preferred representatives of formula II are those wherein R4 is hydrogen or NH2;
Rlo is 4-fluoro, 4-chloro, 4-bromo or 4-methyl; and Rll is chlo~ine.

The compounds in the following Table are especially preferred individual representatives of compounds of formula II:

2028~36 Table 1: Preferred benzovl~henvlureas of formula II
O
Compound no. R R~o R,, m.p. [ C]
1.1 H 4-CH3 Cl 178- 179 1.2 H 4-Br Cl 198-200 1.3 H 4-CH3 H 188-189 1.4 H 4-F Cl 174-177 1.5 H 4-CI Cl 185-189 1.6 H 4-F H 185-188 1.7 H 4-CI H 185- 188 - 1.8 H H Cl 172-173 1.9 H H H 186-188 1.10 H 4-Br H
1.11 H H Br 1.12 H H I
1.13 H 4-Br Br 1.14 H 4-CH3 F
1.15 H S-CH3 H
1.16 H S-CH3 Cl 1.17 H S-CH3 F
1.18 H 6-CH3 Cl 1.19 H 6-F Cl 1.20 H 6-Cl Cl 1.21 H 6-CI F
1.22 H 6-CI H
1.23 H H F
1.24 NH2 4-C~ Cl 181-182 Preferred embodiments of the present invention contain as active ingredient one of the benzoylphenylureas listed below, which list is not, however, exhaustive.

~ CONHCONH~
F

Cl ~< ~ .
(~ CONHCONH~ OCF3 202~53~

CONHCONH ~ ~o,8F2 F Cl CONHCONH ~ OCF2CHFCI
. . .
F Cl F Cl F ~ CONHCONH ~ OCF2CHFCI
F Cl F Cl CONHCONH ~ OCF2CHFCI

FF Cl CONHCONH ~ CF3 F Cl CONHCONH~OCF2CHFBr F Cl CONHCONH ~ ~ 8F2 2~ 3~

F F Cl CONHCONH ~ ,CHa F Cl F Cl CONHCONH ~ ocF2cHF2 F Cl Cl CONHCONH ~ NHCON

Cl C3H7(n) ~CONHCONH~O~CF2CFC12 F Cl CONHCONH ~ OCF2CHFCF3 F Cl Cl CONHCONH

Cl Cl CONHCONH ~

r) 3 ~

CONHCONH~N\~

F

CONHCONH ~ N

N
CONHCONH

CONHCONH ~ Cl Cl F O ~ CF3 N

CONHCONH ~ Cl Cl F O ~ -CF3 Cl Cl CONHCONH- ~ O ~ CN

F
CONHCONH ~ Cl Cl F O ~ CF3 2~28~6 -CONHCONH ~ Cl Cl CONCONH ~ Na~

Cl CONCONH ~ OCF3 K~

CONCONH ~ o' (n-C4Hg)4N~

F Cl CONCONH ~ OCF2CHFCI (C2H5)4 F Cl F Cl CONHCONH ~ OCF2CHFCF3 F Cl F Cl CONCONH ~ OCF2CHFCI ~n-C4H9)4 F Cl 2~2~)~36 CONCONH- ~ CF3 K0 F Cl CONCONH ~ OCF2CHFBr (n-C4Hg)4N~
F Cl F Cl F ~ CONCONH ~ OCF2CHFCF3 (n-C4Hg)4N~
F Cl Cl Cl CONCONH ~ ~ NO2 Na~

F Cl O-CF2 CONCONH ~ O ~ o~ (n~C4Hs)4 FF Cl CONCONH ~ o~ (CH3)4N~

F F Cl CONCONH ~ CH2CH2CH3 F Cl ~028536 F Cl CONCONH ~ OcF2cHF2 Na~
F Cl Cl CONCONH ~ NHCON ~ (CH3)4N0 . ` Cl C3H7(n Cl Cl CONCONH { ~ O ~ CF2CFcl2 K~
F Cl F Cl F ~ CONHCONH ~ OcF2cHFcF3 F Cl F Cl CONCONH ~ OCF2CHFCF3 (n-C4Hg)4N
F Cl Cl Cl CONCONH ~ OCF2CHFCF3 (C2Hs)4 Cl Cl CONCONH ~ (n-C4Hg)4N~

Cl Cl CONCONH ~ (n-C4Hg)4N~
Cl F

~ CONCONH ~ N (CH3)4N0 .` F
F

CONCONH ~ N N~

Cl e ~ CONCONH ~ ~ K~

Especially preferred are formulations according to the invention that contain N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl]-N'-[2,6-difluorobenzoyl]-urea or N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl]-N'-[2,6-difluoro-3-aminobenzoyl]-urea as active ingredient.

Within the scope of the present invention, l-substituted azacycloalkan-2-ones shall be understood as being compounds of formula III

(C~ -R
C (III) wherein n is an integer from 2 to 7 and R is a C6-Cl5alkyl which may be interrupted by an oxygen atom. R is preferably an unbranched C10-Cl4alkyl, especially n-dodecyl. Of the l-substituted azacycloalkan-2-ones, 1-n-dodecylazacycloheptan-2-one (Azone(~)) and l-n-dodecylazacyclopentan-2-one are especially preferred.

202~36 The use of l-substituted azacycloaLkan-2-ones, including azone (Azone~), as penetration enhancers in transdermal systems (penetration into and through the skin after topical administration) is known, for example, from US 4 557 934 and the corresponding patent publication EP 0 129 284. Those references describe the carrier function of l-substituted azacycloalkan-2-ones, which amounts to an improved penetration of the skin batTier in the case of certain active ingredients. Japanese Patent Applications JP 63-002 923 and JP
61-263 914 disclose azone as a formulation auxiliary in preparations for controlling tumours.

Within the scope of the present invention, suitable physiologically tolerable surfactants are especially non-ionic surfactants.

Within the scope of the present invention, suitable physiologically tolerable surfactants are especially non-ionic surfactants having a molecular weight of less than 20,000, preferably less than S,OOû, that belong to the group defined below:

(1) Polyethoxylated triglycerides, (2) polyethoxylated hydroxystearic acid esters, (3) polyethoxylated sorbitan fatty acid esters, (4) sorbitan fatty acid esters, (5) poly-ethoxylated methyl glucoside sesquistearates, (6) fatty acid sugar esters, (7) polyethoxylated fatty alcohol ethers, (8) polyethoxylated fatty acid esters, (9)polyethoxylated fatty acid amines and (10) polyethoxy/polypropoxy block polymers[preferably block polymers having HLB values (HLB: hydrophilic-lipophilic balance) of -12-20].

Of the polyethoxylated triglycerides, hydroxystearic acid esters, sorbitan fatty acid esters, methyl glucoside sesquistearates, fatty alcohol ethers, fatty acid esters and fatty acid amines, mention may be made especially of those having from 2 to 100, especially from 10 to 40 and, more especially, 10, 20 or 40 ethylene oxide units.

Of the polyethoxy/polypropoxy block polymers, those having an ethylene oxide content of from 20 to 80 % should be given prominence.

Especially suitable representatives of the group listed above are (EO = number of ethylene oxide units):

2028~3~

(1) Polyethoxylated castor oil (EO 40), commercially available under the name CREMOPHOR~ EL (BASF AG);

Polyethoxylated, hydrogenated castor oil (EO 40, EO 60), commercially available under the name CREMOPHOR(~' RH 40, RH60, (BASF AG);

(2) Polyethoxylated 12-hydroxystearic acid ester (EO lS), commercially available under the name SOLUTOL(~) HS 15 (BASF);
(3) Polyethoxylated sorbitan monolaurate (EO 20), commercially available under the name IWEEN~ 20 (ICI);

Polyethoxylated sorbitan monopalmitate (EO 20), commercially available under the name IWEEN~) 40 (ICI);

Polyethoxylated sorbitan monostearate (EO 20), commercially available under the name TWEEN(~ 60 (ICI);

Polyethoxylated sorbitan monooleate (EO 20), commercially available under the name TWEEN~' 80 (ICI);

Polyethoxylated sorbitan tristearate (EO 20), commercially availablG under the name TWEEN(~ 65 (ICI);

Polyethoxylated sorbitan trioleate (EO 20), commercially available under the name TWEEN~3' 85 (ICI);
(4) Sorbitan monolaurate, cornmercially available under the name SPAN~) 20 (IC3~;

Sorbitan monopalmitate, commercially available under the name SPAN~) 40 (ICl);

Sorbitan monostearate, commercially available under the name SPAN(~ 60 (ICI);

Sorbitan monooleate, commercially available under the name SPAN~ 80 (ICI);

Sorbitan tristearate, commercially available under the name SPAN~ 65 (ICI);

2~28~3~

Sorbitan trioleate, commercially available under the name SPAN(~) 85 (ICI);

(S) Polyethoxylated methyl glucoside sesquistearate (EO 20), commercially available under the name GLUCAMATE(~ SSE-20 (Amerchol Corp.);

(6) 12-hydroxysteaTin saccharose ester, saccharose monolaurate, saccharose monomyristate, saccharose monopalrnitate, saccharose monooleate, saccharose monostearate, saccharose distearate saccharose dioleate, saccharose dipalmitate, Saccharose mono-/di-/tri-palmitate/stearate products are comrnercially available, for example under the names CRODESTA~ DKS F10, F20, F50, F70, F110, F140~ F160 (Croda Chemicals Ltd.);

Saccharose monococoate, commercially available under the name CRODESTA@) SL40 (Croda Chemicals Ltd.);

(7) Polyethoxylated oleyl alcohol ether (EO 2), commercially available under the names AMEROXOL~' OE-2 (Amerchol Europe) and Brij 92 (Atlas Chemie/ICI);

Polyethoxylated oleyl alcohol ether (EO 10), commercially available under the names AMEROXOL(~ OE- lû (Amerchol Europe) and Brij 96 (Atlas Chemie/ICI);

Polyethoxylated oleyl alcohol ether (EO 20), commercially available under the names AMEROXOL~' OE-20 (Amerchol Europe) and Brij 98 (Atlas ChemietICI);

(8) Polyethoxylated stearate (EO 8, EO 20, EO 30, EO 40*, EO 50, EO 100), comr,nercially available under the names Myrj~) 45, 49, 51, (52,52C,52S)*, 53, 59 (ICI~;

2~2~3~ `

Polyethoxylated l~urate (in the form of dilaurate) (EO 5, EO 10), commercially available under the name Pegosperse~ 200-DL (Glyco Inc.);

Polyethoxylated cocoate (EO 7), commercially available under the name CETIOL(3' HE (Henkel Corp.);

(9) Polyethoxylated tallow fatty amine (EO 10), commercially available under the name GENAMIN(~) T100 (Hoechst AG);

(10) Ethylene oxide/propylene oxide block polymer having a molecular weight of approximately 16,000 and an ethylene oxide content of 80 %, cornmercially available under the narne PLURONIC~' F-108 (BASF Wyandotte Corp.);

Ethylene oxide/propylene oxide block polymer having a molecular weight of approximately 4500 and an ethylene oxide content of 50 %, commercially available under the narne PLURONIC~) P-85 (BASF Wyandotte Corp.);

Ethylene oxide/propylene oxide block polymer having a molecular weight of approximately 1450 and an ethylene oxide content of 20 %, commercially available under the name PLURONIC~) L-42 (BASF Wyandotte Corp.);

Ethylene oxide/propylene oxide block polymer having a molecular weight of approximately 2900 and an ethylene oxide content of 40 %, commercially available under the names SYNPERONIC/~3) PE L 64 (ICI) and Pluronic L 64 (BASF Wyandotte Corp.).

The above trade names for surfactants are to be understood as being only examples and not limitations.

Within the scope of the present invention, the following surfactants (A to F) and mixtures of surfactants (X to Z) have proved to be especially suitable:
A) Polyethoxylated castor oil (EO 40);
B) Polyethoxylated hydrogenated castor oil (EO 40);
C) Polyethoxylated 12-hydroxystearic acid ester (EO 15);
D) Polyethoxylated oleyl alcohol ether (EO 10);

2~2~36 E) Polyethoxylated laurate (in the form of dilaurate; molecular weight 200, 400, EO 5, EO 10);
F) Ethylene oxide/propylene oxide block polymer (molecular weight 2900, ethyleneoxide content 40 %);
X) Mixture of A) and B), preferably in the ratio A:B = 2:1 to 1:2, especially 1:1;
Y) Mixture of C) and E), preferably in the ratio of C:E = 2: 1 to 1 :2, especially 1: 1;
Z) Mixture of A) and E), preferably in the ratio of A:E = 3:1 to 1:2, especially 1:1 to ' . ' 1.5:1 Non-ionic surfactants, such as can be used within the scope of the present invention, are known from standard works of the relevant literature. The following may be mentioned as examples of such standard works:

Ash, M. and I., Encyclopedia of Sllrfactants, Chemical Publishing Co. Inc., New York, N.Y. (Vol. I, 1980; Vol. II,1981; Vol. III, 1981; Vol. IV, 1985);

1986 International McCutcheon's Emulsifiers & Detergents, The Manufacturing Confectioner Publishing Co., Glen Rock, NJ, USA;

Stache, H., Tensid-Taschenbuch, Carl Hanser Verlag, Munich, Vienna, 1981.

Within the scope of the present invention, suitable physiologically tolerable hydrophilic solvents are those belonging to the group listed below:

a) MonohydroxyaLlcyl groups having from 2 to 10 carbon atoms, b) acyclic saturated polyols, c) dimethyl sulfoxide, d) glycerol formal, e) 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (solketal), f) tetrahydrofurfuryl alcohol (polyethoxy) ether (glycofurol), g) water and h) N-methylpyrrolidone.

There may be mentioned as examples of representatives of sub-group a): ethanol, l-propanol, 2-propanol, 2-butanol, tert.-butyl alcohol, l-hexanol, 1-heptanol,2-heptanol, l-octanol, 2-octanol, l-nonanol and l-decanol.

Examples of representatives of sub-group b) are especially polyols having from 2 to 6, pref~rably 3 or 4, carbon atoms and 2 or 3 hydroxy groups, such as 1,2-propanediol, glycerol, 1,2-butanediol, 1,3-butanediol and corresponding polyols etherified by lower 2028~36 alkyl groups, especially methyl groups, such as, for example,1,2-propanediol-1-methyl ether, and, in addition, polyethylene glycols having an average molar mass in the range of from 200 to 600, such as, for example, polyethylene glycol 300 (commercially available, for example, under the name PLURIOL E300, BASF).

Suitable lipophilic solvents are especially esters of carboxylic acids, for example ethyl acetate, n-propyl acetate and n-butyl acetate, and liquid waxes, such as, for example, isopropyl myristate, isopropyl palmitate, lauric acid hexyl ester and ethyl oleate.

In the case of mixtures of hydrophilic and lipophilic solvents, the proportion of lipophilic solvent is advantageously from 0.1 to 30 %, based on the total amount of solvent.

Within the scope of the present invention it is possible to use any surfactant and solvent normally suitable for administration in veterinary medicine.

Acids suitable as stabilising component within the scope of this invention are especially organic acids having from 3 to 6 carbon atoms. Examples of suitable acids are CitIiC acid, ascorbic acid, lactic acid, malic acid and tartaric acid.

Suitable as stabilising buffer mixtures are physiologically tolerable buffer mixtures customarily used in human medicine or in veterinary medicine.

The preferred embodiments of the injectable parasiticidal compositions according to the invention include, for example, the following compositions:

(A) From 0.1 to 10 % of a benzoylphenylurea, ~rom 0.5 to l0 % of a 1-substitutedazacycloaLtcan-2-one, from 2 to 90 % of a surfactant or rnixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent;

(B) From 0.5 to 7 % of a benzoylphenylurea, from 0.5 to l0 % of a 1-substituted azacycloaL~can-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent;

(C) From 1 to S % of a benzoylphenylurea, from 0.5 to 10 % of a 1-subsdtuted azacycloaLkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent;

2028~36 (D) From 0.1 to lO % of a benzoylphenylurea, from 0.1 to 50 % of a 1-substitutedazacycloaLtcan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent;

(E) From 0.5 to 7 % of a benzoylphenylurea, from 0.1 to 50 % of a 1-substituted azacycloaL~an-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent;

(F) From 1 to 5 % of a benzoylphenylurea, from 0.1 to 50 % of a 1-substituted azacycloaLkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent;

(G) From 0.1 to lO % of a benzoylphenylurea, from 0.1 to 60 % of a 1-substitutedazacycloaLkan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent;

(H) From 0.5 to 7 % of a benzoylphenylurea, from 0.1 to 60 % of a 1-substituted azacycloaLIcan-2-one, from 2 to 90 % of a surfactant or mixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent;

(I) From 1 to 5 % of a benzoylphenylurea, from 0.1 to 60 % of a 1-substituted azacycloaLIcan-2-one, from 2 to 90 % of a surfactant or rnixture of surfactants, from 0.05 to 1 % of a stabiliser and ad 100 % of solvent.

Within the combinations (A) to (I), specific embodiments that are especially preferred are those wherein the active ingredient is N-L3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)~-chlorophenyl]-N'-[2,6-difluorobenzoyl]-urea or N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl]-N'-[2,6-difluoro-3-aminobenzoyl]-urea.

Also especially preferred within the combinations (A) to (I) are those wherein the 1-substituted azacycloaL~an-2-one is n-dodecylazacycloheptan-2-one or n-dodecyl-azacyclopentan-2-one.

The present invention relates also to a process for the preparation of an injectable composition for controlling parasites in and on productive livestock and domestic animals, which composition is parenterally injectable and contains from 0.1 to 10 % of a benzoylphenylurea as active ingredient, from 0.1 to 60 % of a l-substituted azacyclo-alkan-2-one, from 2 to 90 % of a physiologically tolerable surfactant or mixture of surfactants and, if appropriate, as stabilising component, from 0.05 to 1 % of an acid or a buffer mixture and ad 100 % of a physiologically tolerable hydrophilic solvent or mixture of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic solvents, which process comprises dissolving the benzoylphenylurea in a hydrophilic solvent and mixing the solution with the surfactant and the l-substituted azacycloalkan-2-one, and, if appropriate, with the lipophilic solvent and, if appropriate, with a stabiliser, making up the batch with a solvent and sterile-filtering the resulting final mixture through a filter and then subjecting it to heat sterilisation.

The injectable compositions according to the invention are effective against a large number of parasites, especially against ectoparasites in and on domestic animals and productive livestock, such as insects of the orders Homoptera, Heteroptera, Diptera, Thysanoptera, Or~hoptera, Anoplura, Siphonaptera, Psocoptera and Hymenoptera and also arachnida of the order Acarina, especially the sub-order Ixodida (ticks). The compositions according to the invention also exhibit a good anthelmintic action. They are suitable for controlling parasitic nematodes, for example of the orders Rhabditida, Ascaridida, Spirurida and Trichocephalida, or for controlling cestodes of the orders Cyclophyllidae and Pseudophillidae or for controlling trematodes of the order Digenea in domestic animals and productive livestock.

Domestic animals and productive livestock are to be understood as being, for example, catde, sheep, goats, horses, pigs, cats and dogs.

The particular advantage of the compositions according to the invention resides in the fact that they can be used systemically by administering them locally and thus spreading them through the whole animal via the blood plasma and tissue fluid.

The present invention accordingly relates also to a method for the systemic controi of parasites in and on productive livestock and domestic animals, which comprises the prophylactic or curative parenteral injection of the composition according to ~he invention into the animal.

In addition, the present invention relates to the use of l-substituted azacycloalkan-2-ones 2028~'~6 in benzoylphenylurea-based veterinary medicinal preparations for controlling endo- and ecto-parasites.

Examples Formulation of compositions according to the invention Example F-l:
N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl]-N' -[2,6-difluoro-benzoyl]-urea 2.5 g polyethoxylated castor oil (EO 40) 40.0 g dimethyl sulfoxide 20.0 g lauric acid hexyl ester 5.0 g n-dodecylazacycloheptan-2-one 5.0 g n-propyl acetate ad100 ml Exarnple F-2 N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl]-N'-[2,6-difluoro-benzoyl]-urea 2.5 g polyethoxylated castor oil (EO 40) 40.0 g dimethyl sulfoxide 20.0 g lauric acid hexyl ester S.0 g n-dodecylazacycloheptan-2-one 10.0 g n-propyl acetate ad100 ml Example F-3:
N-[3-(3-chloro-S-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl]-N ' -[2,6-difluoro-3-aminobenzoyl]-urea 2.5 g polyethoxylated castor oil (EO 40) 40.0 g dimethyl sulfoxide 20.0 g lauric acid hexyl ester S.0 g n-dodecylazacycloheptan-2-one S.0 g n-propyl acetate ad100 ml 2028~36 Example F-4:
N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl] -N ' -[2,6-difluoro-3-aminobenzoyl]-urea 2.5 g polyethoxylated castor oil (EO 40) 40.0 g dimethyl sulfoxide 20.0 g lauric acid hexyl ester 5.0 g n-dodecylazacycloheptan-2-one 10.0 g n-propyl acetate ad100 ml Example F-5:
N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl]-N' -[2,6-difluoro-benzoyl]-urea - 2.5 g polyethoxylated castor oil (EO 40) 40.0 g PEG-200dilaurate 42.5 g citric acid 0.25 g n-dodecylazacycloheptan-2-one 5;0 g N-methylpyrrolidone ad100 ml Biolo icalExample Bioavailabilitv (plasma concentration) In order to investigate bioavailability in vivo, formulations F-1 to F-5 according to the invention are each administered once subcutaneously to each of 4 cattle of from 200 to 300 kg body weight (BW) at a dose of 1 mg/kg BW. For comparison purposes, the control group, consisting of 4 cattle, receives the active ingredient in the following formulation:

N-[3-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-4-chlorophenyl]-N'-[2,6-difluoro-benzoyl]-urea 2.5 g polyethoxylated castor oil (EO 40) 40.0 g PEG-200dilaurate 42.5 g N-methylpyrrolidone ad1ûO ml The plasma samples taken after specific intervals of time are analysed. Whereas the formulations according to the invention achieve plasma concentrations in the Iange of 20'~8~36 from 50 to 100 ppb after 24 hours, the concentration of the active ingredient in the case of the formulation not according to the invention is below that range by at least a factor of two.

Claims (20)

1. A composition for controlling parasites that attack productive livestock and domestic animals, which composition is parenterally injectable and contains from 0.1 to 10 % of a benzoylphenylurea as active ingredient, from 0.1 to 60 % of a 1-substituted azacycloalkan-2-one, from 2 to 90 % of a physiologically tolerable surfactant or mixture of surfactants and, if appropriate, as stabilising component, from 0.05 to 1 % of an acid or a buffer mixture and ad 100 % of a physiologically tolerable hydrophilic solvent or mixture of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic solvents.
2. A composition according to claim 1, which contains compounds of formula I
(I) wherein each of R1, R2, R3 and R5, independently of the others, is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy or C1-C6alkylthio;
R4 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylthio or NHR'; wherein R' is hydrogen, R8CO- or R9NHCO-, wherein R8 is a C1-C4alkyl that is unsubstituted or mono- to tri-substituted by the same or different substituents from the group halogen, C1-C4alkoxy, C1-C4acyloxy and -COOG, wherein G
is hydrogen, an alkali metal cation or an alkaline-earth metal cation, and R9 is a C1-C4-alkyl or phenyl group that is unsubstituted or mono- to tri-substituted by halogen;
X is -NH- or -??Y?; wherein Y? is an inorganic or organic cation;
R6 is hydrogen or C1-C6alkyl; and R7 is an unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, the substituents being selected from the series halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkyl-sulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, alkylamino, dialkylamino and benzyl and also phenoxy or pyridyloxy, each of which last two substituents is substituted by substituents from the group consisting of halogen, haloalkyl, haloalkoxy and nitro, it being possible, in the case where R7 is substituted phenyl, for cyano, N'-n-propyl-N'-phenylureido, an -O-CF2-CF2-O- bridge connecting two adjacent carbon atoms of the phenyl ring to one another, or phenoxy that is substituted by an -O-CF2-CF2-O- bridge connecting two adjacent carbon atoms of the phenyl ring to one another, also to be present as substituent.
3. A composition according to claim 2, wherein each of R1, R2, R3 and R5, independently of the others, is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy or C1-C6alkylthio;
R4 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkylthio or NHR'; wherein R' is hydrogen, R8CO- or R9NHCO-, wherein R8 is a C1-C4alkyl that is unsubstituted or mono- to tri-substituted by the same or different substituents from the group halogen, C1-C4alkoxy, C1-C4acyloxy and -COOG, wherein G
is hydrogen, an alkali metal cation or an alkaline-earth metal cation, and R9 is a Cl-C4-alkyl or phenyl group that is unsubstituted or mono- to tri-substituted by halogen;
X is -NH- or -??Y?; wherein Y? is an inorganic or organic cation;
R6 is hydrogen or C1-C6alkyl; and R7 is an unsubstituted or substituted phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, the substituents being selected from the series halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkyl-sulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, alkylamino, dialkylamino and benzyl and also phenoxy or pyridyloxy, each of which last two substituents is substituted by halogen, haloalkyl, haloalkoxy or by nitro.
4. A composition according to claim 2, wherein each of R1 and R5, independently of the other, is hydrogen, fluorine, chlorine, methoxy or methylthio;
R3 is hydrogen or fluorine and R4 is hydrogen or NH2;
R2 is hydrogen, fluorine or chlorine;
X is -NH- or -??Y?; wherein Y? is Na?, K? or tetraalkylammonium, such as (n-C4H9)4N?, (CH3)4N?, (C2H5)4N?
or n-C16H33-N?(CH3)3;
R6 is hydrogen or C1-C3alkyl, and R7 is unsubstituted phenyl or phenyl substituted by one or two halogen atoms and, additionally, by C1-C6haloalkoxy or by 2-pyridyloxy, the 2-pyridyloxy radical for its part being substituted by CF3 and halogen.
5. A composition according to claim 1, which contains compounds of formula II

(II) wherein R4 is hydrogen or NH2;
R10 is hydrogen, halogen or methyl; and R11 is hydrogen or halogen.
6. A composition according to claim 5, wherein R4 is hydrogen or NH2;
R10 is hydrogen, fluorine, chlorine or bromine; and R11 is hydrogen, fluorine, chlorine or bromine.
7. A composition according to claim 5, wherein R4 is hydrogen or NH2;
R10 is 4-fluoro, 4-chloro, 4-bromo or 4-methyl; and R11 is chlorine.
8. A composition according to claim 1, which contains N-[3-(3-chloro-5-trifluoromethyl-pyridyl-2-oxy)-4-chlorophenyl]-N'-[2,6-difluorobenzoyl]-urea as active ingredient.
9. A composition according to claim 1, which contains N-[3-(3-chloro-5-trifluoromethyl-pyridyl-2-oxy)-4-chlorophenyl]-N'-[2,6-difluoro-3-aminobenzoyl]-urea as active ingredient.
10. A composition according to claim 1, wherein the 1-substituted azacycloalkan-2-one is a compound of formula III

(III) wherein n is an integer from 2 to 7 and R is a C6-C15alkyl which may be interrupted by an oxygen atom.
11. A composition according to claim 1 that contains n-dodecylazacycloheptan-2-one.
12. A composition according to claim 1 that contains n-dodecylazacyclopentan-2-one.
13. A composition according to claim 8 that contains n-dodecylazacycloheptan-2-one.
14. A composition according to claim 8 that contains n-dodecylazacyclopentan-2-one.
15. A composition according to claim 1 that contains dimethyl sulfoxide as hydrophilic solvent.
16. A composition according to claim 1 that contains N-methylpyrrolidone as hydrophilic solvent.
17. A composition according to claim 1 that contains a lipophilic solvent from the group consisting of esters of carboxylic acids and liquid waxes.
18. A composition according to claim 1 that contains as stabilising component an acid selected from the group consisting of citric acid, ascorbic acid, lactic acid, malic acid and tartaric acid.
19. A process for the preparation of a composition for controlling parasites that attack productive livestock and domestic animals, which composition is parenterally injectable and contains from 0.1 to 10 % of a benzoylphenylurea as active ingredient, from 0.1 to 60 % of a 1-substituted azacycloalkan-2-one, from 2 to 90 % of a physiologically tolerable surfactant or mixture of surfactants and, if appropriate, as stabilising component, from 0.05 to 1 % of an acid or a buffer mixture and ad 100 % of a physiologically tolerable hydrophilic solvent or mixture of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic solvents, which process comprises dissolving the benzoyl-phenylurea hydrophilic solvent and mixing the solution with the surfactant and the 1-substituted azacycloalkan-2-one, and, if appropriate, with the lipophilic solvent and, if appropriate, with a stabiliser, making up the batch with a solvent and sterile-filtering the resulting final mixture through a filter and then subjecting it to heat sterilisation.
20. A method of controlling parasites that attack productive livestock and domestic animals, which method comprises injecting parenterally into the host organism attacked by parasites a composition containing from 0.1 to 10 % of a benzoylphenylurea as active ingredient, from 0.1 to 60 % of a 1-substituted azacycloalkan-2-one, from 2 to 90 % of a physiologically tolerable surfactant or mixture of surfactants and, if appropriate, as stabilising component, from 0.05 to 1 % of an acid or a buffer mixture and ad 100 % of a physiologically tolerable hydrophilic solvent or mixture of solvents or a mixture of physiologically tolerable hydrophilic and lipophilic solvents.
CA002028536A 1989-10-27 1990-10-25 Injectable parasiticidal composition Abandoned CA2028536A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH3898/89-4 1989-10-27
CH389889 1989-10-27

Publications (1)

Publication Number Publication Date
CA2028536A1 true CA2028536A1 (en) 1991-04-28

Family

ID=4265876

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002028536A Abandoned CA2028536A1 (en) 1989-10-27 1990-10-25 Injectable parasiticidal composition

Country Status (8)

Country Link
EP (1) EP0425443A1 (en)
JP (1) JPH03161438A (en)
KR (1) KR910007521A (en)
AP (1) AP217A (en)
AU (1) AU632862B2 (en)
CA (1) CA2028536A1 (en)
IE (1) IE903877A1 (en)
ZA (1) ZA908597B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU631259B2 (en) * 1989-12-18 1992-11-19 Ciba-Geigy Ag Formulations of benzoylphenyl ureas for combating ectoparasites
US5290794A (en) * 1992-10-27 1994-03-01 Warner Lambert Co. Soluble calcium lactate antibacterial complexes as non-irritating parenteral forms
IT1290845B1 (en) * 1996-12-12 1998-12-14 Isagro Spa COMPOSITIONS FOR THE SYSTEMIC CONTROL OF PARASITES OF HOT BLOOD ANIMALS
TW480153B (en) 1997-11-20 2002-03-21 Sumitomo Chemical Co Method to control animal ecto-parasites
US7517880B2 (en) 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
US6239112B1 (en) * 1998-07-09 2001-05-29 Merial, Inc. Water miscible macrolide solutions
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
ME00275B (en) 1999-01-13 2011-02-10 Bayer Corp ?-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7235576B1 (en) 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
WO2003068229A1 (en) 2002-02-11 2003-08-21 Bayer Pharmaceuticals Corporation Pyridine, quinoline, and isoquinoline n-oxides as kinase inhibitors
ATE529406T1 (en) 2002-02-11 2011-11-15 Bayer Healthcare Llc ARYL UREAS AS KINASE INHIBITORS
DE602004010407T2 (en) 2003-07-23 2008-10-16 Bayer Pharmaceuticals Corp., West Haven FLUORO-SUBSTITUTED OMEGA-CARBOXYARYLDIPHENYL-UREA FOR THE TREATMENT AND PREVENTION OF DISEASES AND SUFFERING

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2928485A1 (en) * 1979-07-14 1981-01-29 Bayer Ag USE OF UREA DERIVATIVES AS A MEDICINAL PRODUCT IN THE TREATMENT OF FATTY METABOLISM DISORDERS
DE3217619A1 (en) * 1982-05-11 1983-11-17 Bayer Ag, 5090 Leverkusen 2,4-DIHALOGENBENZOYL (THIO) UREA, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PEST CONTROL
DE3217620A1 (en) * 1982-05-11 1983-11-17 Bayer Ag, 5090 Leverkusen 2,5-DIHALOGENBENZOYL (THIO) UREA, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PEST CONTROL
EP0142667B1 (en) * 1983-09-22 1989-02-01 BASF Aktiengesellschaft N-benzoyl-n'-alkoxyphenyl ureas and their use in combating insects and acaridae
EP0331382B1 (en) * 1988-02-29 1992-09-09 Pfizer Inc. Transdermal flux enhancing compositions

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR

Also Published As

Publication number Publication date
AU6499890A (en) 1991-05-02
AU632862B2 (en) 1993-01-14
IE903877A1 (en) 1991-05-08
JPH03161438A (en) 1991-07-11
EP0425443A1 (en) 1991-05-02
AP217A (en) 1992-09-10
KR910007521A (en) 1991-05-30
AP9000216A0 (en) 1990-10-31
ZA908597B (en) 1991-07-31

Similar Documents

Publication Publication Date Title
CA2028536A1 (en) Injectable parasiticidal composition
US5177110A (en) Injectable parasiticidal composition
EP0546018B1 (en) Pharmaceutical composition of florfenicol
US10688111B2 (en) Liquid formulations of compounds active at sulfonylurea receptors
EP0812591B1 (en) Injectable compositions containing Nimesulide
BR122019001738B1 (en) parasiticidal compositions comprising an isoxazoline active agent and uses thereof
Davidson et al. A topical nitric oxide-generating therapy for cutaneous leishmaniasis
JP7578752B2 (en) Injectable isoxazoline pharmaceutical compositions and their use against parasitic infestations - Patents.com
KR100482269B1 (en) Injectable Anaesthetic Agent Comprising 2,6-Diisopropylphenol as an Active Ingredient and Preparation Method thereof
BR122023023401A2 (en) INJECTABLE PHARMACEUTICAL COMPOSITION, USES OF AN ISOXAZOLINE COMPOUND AND KIT COMPRISING SAID COMPOUND
EP1551390B1 (en) Formulation comprising avermectins / milbemycins and levamisole in a pyrrolidone solvent
KR920001773B1 (en) A process for the preparation of an injectable solution containing anthracycline glycoside
IE58016B1 (en) Pour-on formulation for the control of parasites
JPH03169812A (en) Triacetin-containing sustainably active prescribed medicinal agent for injection application
EP0353526B1 (en) Agent against fish parasites containing triazinedione derivatives
KR20090104015A (en) Drugs for parasite control in animals
US3228834A (en) Pharmaceutical diluent compositions
HU229293B1 (en) Aqueous based pharmaceutical formulations of water-soluble prodrugs of propofol
EP1713466B1 (en) Antiparasitic composition containing an organic amine salt of closantel
CN1822880B (en) Parasiticidal composition
ES2241269T3 (en) SULFUROPENTAFLUOROFENILPIRAZOLES FOR THE CONTROL OF INFESTATIONS BY ECTOPARASITOS.
FR2607702A1 (en) INJECTABLE SOLUTIONS READY FOR USE CONTAINING ANTI-TUMOR AGENT ANTHRACYCLINE-GLUCOSIDE
KR100514009B1 (en) 1,2,4-benzotriazine oxides formulations
CA2839491A1 (en) Anti-parasitic composition comprising a macrocyclic lactone and levamisole and method of treatment of parasitic infestation
AU2005336458B2 (en) Anthelmintic formulations

Legal Events

Date Code Title Description
FZDE Dead