EP1253824A2

EP1253824A2 - Fluid insecticidal formulations for treatment of parasitic insect larvae by dermal application

Info

Publication number: EP1253824A2
Application number: EP00990645A
Authority: EP
Inventors: Kirkor Sirinyan; Dorothee Stanneck
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1999-12-16
Filing date: 2000-12-05
Publication date: 2002-11-06
Also published as: WO2001043545A3; HUP0203738A2; BR0016413A; AR026960A1; US20030109496A1; CN1411335A; AU3006101A; JP2003516943A; WO2001043545A2; DE19960775A1; CA2391802A1

Abstract

The invention relates to the use of polysiloxanes, comprising at least one quaternary ammonium group as adjuncts in formulations containing larvicidal and/or ovicidal active ingredients and agents which contain a) a larvicidal and/or ovicidal active ingredient and b) a polysiloxane derivative, with at least one quaternary ammonium group per molecule and optionally further adjuncts and vehicles.

Description

Insecticidal liquid formulations that can be applied dermally to combat parasitic insect larvae

The present invention relates to the use of polysiloxanes containing at least one quaternary ammonium group for the preparation of new, storage-stable. Skin-compatible, dermally applicable liquid formulations of larvicidal and / or ovicidal active ingredients for controlling parasitic insect larvae on animals.

In the manufacture of active ingredient formulations in the field of pharmacy and veterinary medicine, the problem of inadequate solubility of the active ingredients and, associated therewith, also a lack of storage stability of the finished formulations frequently arises, and in particular in the case of aqueous formulations

When used, it is partially water-soluble, larvicidal and / or ovicidal

Active substances in the form of liquid formulations that can be applied dermally, it is therefore necessary to prepare homogeneous solutions based on organic solvents and insecticidal active substances. For this purpose, the active compounds are usually dissolved in organic solvents such as isopropanol, 2-butoxyethyl acetate, ethylene glycol diacetate and, if appropriate, mixed with other additives. The preparation of such formulations is described in US Pat. No. 4,874,753, EP-A 137 627 and GB-A 2 135 886 described. The disadvantages of the said systems when using larvicidal and / or ovicidal active ingredients are that in many cases they lead to skin irritation and, furthermore, in the usual spot on primary packaging, they still have a relatively narrow long-term stability and thus meet the basic requirements of the official pharmaceutical regulations Long-term stability behavior does not meet

It is desirable to replace these formulations with those which are outstandingly skin-friendly and toxicologically harmless, and which also have a very good long-term effect of several weeks and their Characterize long-term stability of several years in all climate zones in the conventional spot on primary packaging.

In order to remedy the said disadvantage of the known formulations, for example, it is proposed in the patents AU-A 627 847, EP-A 413 610

Active ingredients in high-boiling solvents such as monopropylene glycol, which also contain natural, skin-compatible oils such as pine oil, sunflower oil or soybean oil. Furthermore, it can be seen from the patent specification WO 91/13545 that well-effective, skin-compatible liquid formulations can be produced by aliphatic said substances in amounts of> 50%

Solvents such as 2- (2-butoxyethoxy) ethanol or 2- (2-methoxy-ethoxy) ethanol dissolves. The disadvantage of these formulations is that they require the use of larger amounts of active ingredient and also lead to skin irritation in sensitive animal breeds. In order to achieve an acceptable biological effect through the use of small amounts of active substance, the use of is described in US Pat. No. 5,466,458

Emulsions based on the said active ingredients with long-chain, aliphatic amines or alcohols such as hexadecan-1-ol, 1-octadecylamine are proposed. The disadvantage of using the long-chain amines is that they degrade the active substances in question over time. In most cases, the formulations based on long-chain alcohols do not have a sufficient long-term effect.

The object of the present invention is therefore to provide a skin-friendly and environmentally compatible, user-friendly formulation which is excellently stable in the conventional spot on primary packaging materials in accordance with the pharmaceutical guidelines and is highly effective against parasitic insect larvae on the basis of larvicidal and / or ovicidal active ingredients.

From EP-A 0 017 121, 0 017 122, 0 282 720, 0 294 642, 0 166 122 and 0 164 668 a multitude of polysiloxanes with terminal quaternary amino groups and their use as so-called "conditioners" in shampoo and hair care products are known , Surprisingly, the aforementioned objects are now achieved by the agents according to the invention using the above-mentioned polysiloxanes. Clear solutions or emulsions with high storage stability result.

Furthermore, the use of these polysiloxanes according to the invention surprisingly achieves improved tolerance and an activity-increasing, synergistic effect.

The present invention accordingly relates to the use of polysiloxanes containing at least one quaternary ammonium group as formulation auxiliaries in formulations of larvicidal and / or ovicidal active substances.

The present application also relates to new compositions containing

a) a larvicidal and / or ovicidal active ingredient and

b) a polysiloxane derivative containing at least one quaternary ammonium group per molecule,

and, if appropriate, further auxiliaries and carriers.

The agents according to the invention are particularly suitable for the production of spot on and pour on s for use in combating parasites on animals.

Larvicidal and / or ovicidal active ingredients based on juvenile hormones and fluorobenzoyl ureas can be used to prepare the liquid formulations according to the invention, juvenile hormones with activity against flea larvae being particularly preferred. Juvenile hormones with anti-parasitic effect

Insect larvae are known (see GB-A 2 140 010, DE-OS 37 00 881, DE-OS 38 25 172). The larvicidal and / or ovicidal activity of fluorobenzoylureas is also known and can be found in the literature (see, for example, EP-A 343 110, DE-OS 38 27 133, EP-A 230 400, EP-A 255 803).

The following active ingredients are particularly suitable:

Juvenile hormones and juvenile hormone-like substances such as:

Substituted diaryl ethers such as:

Benzoyl ureas such as:

The use of pyriproxyfen should be particularly emphasized:

The amounts of active ingredient can be varied widely between 0.1-15%. Amounts in the range 0.1-7.5% are preferred. Quantities of 0.1-5% are particularly preferably used. Quantities in the range of 0.2-2.0% are very particularly preferably used for the production of the new formulations according to the invention. Percentages relate to percent by weight.

Of course, further active ingredients can be used as combination partners in the agents according to the invention.

Combination active ingredients which may be mentioned are the insecticides used in the field of controlling ectoparasitic insects, such as nicotinyl and, in particular, chloronicotinyl insecticides, N-phenylpyrazoles, carbamates, phosphoric and phosphonic acid esters, growth inhibitors or mixtures of these active ingredients with one another and their mixtures with synergists. For the purposes of this application, synergists are understood to mean compounds which themselves do not have the desired activity, but which, as a mixing partner, increase the

Effectiveness of the actual active ingredients lead.

Examples of chloronicotinyl insecticides are compounds of the formulas (I), (II) and (III):

in which

n represents 1 or 2,

m represents 0, 1 or 2,

Subst. Stands for one of the substituents listed above, in particular for halogen, very particularly for chlorine, and

A, Z, X and E have the meanings given above.

The following connections are specifically mentioned:

imidacloprid

AKD1022

1 - I

CH ₂ -N _{^ ^} NH

S .. ^ .NHH /

Y ϊl CH ^{a ~} i NN

\

I NO, NO,

The connections are particularly noteworthy

The connections are also particularly emphasized

Substituted phenyl and naphthyl carbamates may be mentioned as carbamates.

The following compounds may be mentioned as phenylpyrazoles:

May be mentioned:

2-Osobutylphenyl N-methylcarbamate,

4-dimethylamino-3-methyl-phenyl-N-methylcarbamate, 2-isopropoxy-phenyl-N-methylcarbamate,

1-naphthyl-N-methyl carbamate, m-tolyl-N-methyl carbamate,

3,4-xylyl-N-methylcarbamate,

3,5-xylyl-N-methyl carbamate, 2- [1,3-dioxolan-2-yl] phenyl-N-methyl carbamate.

The compounds with the common names Phoxim, Fenitrothion, Dichlorvos, Trichlorfon and Malathion may be mentioned as preferred phosphoric acid esters.

Juvenile hormones and juvenile hormone-like substances such as:

Substituted diaryl ethers such as:

Benzoyl ureas such as:

Triazines such as:

NH-R ¹

(Continuation)

The amounts of the combination active ingredients can be varied widely between 0.1 to 12.5%, the amounts in the range 0.1 to 10.0% being particularly preferred and the amounts in the range 0.5 to 7.5% being particularly preferred , Percentages are to be understood here as percentages by weight.

Piperonyl butoxide and sesame oil are preferred as synergists for these compounds. These synergists are described, for example, in patent specification EP-413 610.

The selected formulation aids based on polydimethylsiloxanes with cationic quaternary amine groups of the formula

R '= different organic residues,

are known polymeric or oligomeric compounds. Examples, but not restrictive, are those in EP-A 0 017 121, p. 2, lines 11 to p. 3, line 3, EP-A 0 017 122, p. 2, lines 11 to p. 3, Line 13, EP-A 0 166 122, page 4, line 31 to page 7 whole, EP-A 0 294 642, page 5, line 10 to page 8, line 51, EP-A 282 720, page 6, line 10 to page 14, line 54 and the polysiloxanes described in EP-A 0 164 668 on page 4, line 31 to page 8, line 3.

Polysiloxanes with both mono- and polyquaternary amine groups can be used to prepare the agents according to the invention. Of course, said polydimethylsiloxanes can have further functional groups such as carboxylic acid, amine, hydroxyl, carboxylic ester groups. The most particularly preferred functional groups are hydroxyl and carboxylic acid groups. Their viscosity can be varied widely in the range from 200 to 17,500 mm ² s ^~ l (at 25 ° C), measured in accordance with DIN 53 019 as a 50% aqueous solution, with a viscosity in the range from 250 to 10,000 mm ² s ^" l (at 25 ° C) particularly, and which are particularly preferred with a viscosity in the range from 250 to 1 350 mm ² s ^~ l (at 25 ° C).

Polysiloxanes of the formula (V) are very particularly preferred

R = long-chain alkyl radical,

which are sold by the Goldschmidt company under the trade name ABIL®.

The amounts of polydimethylsiloxane used can be varied widely between 0.1-15%; the amounts in the range 0.1-5% are preferred. Amounts between 0.1 and 2.5% are particularly preferred. The amounts in the range 0.25-2.5% are used with very particular preference for the production of the formulations according to the invention. The percentages are to be understood as percentages by weight.

Aliphatic polyethers such as diethylene glycol monomethyl ether, dipropylene glycol monopropyl ether; cyclic carbonates such as propylene carbonate, ethylene carbonate, aliphatic and aromatic alcohols such as ethanol, isopropanol; Acetates such as benzyl acetate, benzyl benzoate or mixtures thereof are used with one another.

Aliphatic polyethers, in particular diethylene glycol monomethyl ether, dipropylene glycol monopropyl ether or diethylene glycol monomethyl ether, are particularly preferred as solvents. Dipropylene glycol monopropyl ether is used with particular preference for the production of the new liquid formulations. Possibly mixtures of the abovementioned solvents can also be used.

In the formulation according to the invention, the organic solvent content is 2.5 to 99.8% by weight, preferably 60 to 99.0% by weight, particularly preferably 60 to 93.7% by weight, very particularly preferably 65 -90% by weight and especially 75-83% by weight.

The proportion of water in the new formulations can be varied widely by 0-95% by weight, 0-30% by weight being preferred, being particularly preferred

7.5-30% by weight, very particularly preferred are 7.5-25% by weight and in particular 12.5-17.5% by weight.

In addition, the formulations according to the invention can contain customary auxiliaries such as antioxidants or odor masking agents.

Stabilizers and antioxidants that may be mentioned are sulfites or metabisulfites such as potassium metabisulfite; organic acids such as citric acid; ascorbic acid; Phenols, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, the organic acids citric acid and malic acid being preferred. Very particularly preferred stabilizers are citric acid and butylated hydroxytoluene. Their proportion can be varied widely in the range 0.05 to 2.5% by weight, quantities in the range 0.075-0.15% by weight being particularly preferred.

Odor masking agents are e.g. Mixtures of organic fatty acid esters. They are preferably present in the formulations according to the invention in 0.1 to 2% by weight.

Surprisingly, the liquid formulations according to the invention are distinguished by an excellent storage stability of several years in all climatic zones, skin, user and environmental compatibility. Surprisingly, they are ideal for filling and dispensing in normally storage-critical "single dose polypropylene plastic tubes" with a wall thickness of 300-500 μm and a filling volume of 1.0 to 4.0 ml.

The liquid formulations according to the invention also show an unexpected synergistic, i.e. Effect-increasing effect, for example when using pyriproxyfen as an active ingredient.

The agents according to the invention are environmentally friendly and user-friendly due to their very low toxicity.

With favorable warm-blood toxicity, the agents according to the invention are suitable for combating parasitic insects which occur in animal husbandry and animal breeding in domestic and farm animals as well as zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive types of pests.

The pests include:

From the order of the anoplura e.g. Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp .; from the order of the Mallophaga e.g. Trimenopon spp., Menopon spp., Eomenacanthus spp., Menacanthus spp., Trichodectes spp., Felicola spp., Damalinea spp.,

Bovicola spp; from the order of the Diptera e.g. Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fan- nia spp., Glossina spp., Lucilia spp., Calliphora spp ., Auchmeromyia spp., Cordylobia spp., Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfartia spp.,

Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypoderma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp ..

From the order of the Siphonaptera e.g. Ctenocephalides spp., Echidnophaga spp.,

Ceratophyllus spp .. The effect against fleas and ticks should be particularly emphasized.

Ixodes spec, Rhipicephalus spec, Dermacentor spec, Haemaphysalis spec, Boophilus spec; Hyalomma spec mentioned.

Livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, and birds such as Chickens, geese, turkeys, ducks.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

The pets include dogs and cats.

The use in cats and dogs is particularly emphasized.

The application can be prophylactic as well as therapeutic.

To produce the formulation according to the invention, the desired constituents are mixed with one another in appropriate amounts, e.g. through the use of conventional stirred tanks or other suitable devices.

If the ingredients require it, it can also be used under a protective atmosphere or others

Methods of oxygen exclusion are worked.

The following examples are intended to explain the invention: example 1

A homogeneous spot on formulation (100 g) consisting of

1.00 g pyriproxyfen (2- [l-methyl-2- (4-phenoxyphenoxy) ethoxy] pyridine (PPF)

82.00 g diethylene glycol monoethyl ether

15.00 g water

2.00 g Abil Quat 3272 (1)

Abil Quat 3272, 50% product - is a polydimethylsiloxane with diquaternary

Ammonium group and the viscosity range of 1000 +/- 200 [mm ² .sl] at 25 ° C from Goldschmidt AG, D-4300 Essen.

Example 2

A homogeneous spot on formulation (100 g) consisting of

1.00 g of pyriproxyfen (2- [1-methyl-2- (4-phenoxyphenoxy) ethoxy] pyridine

82.00 g dipropylene glycol monomethyl ether 15.00 g water

2.00 g Abil Quat 3272 (1)

Abil Quat 3272, 50% product - is a polydimethylsiloxane with a diquaternary ammonium group and a viscosity range of 1000 +/- 200 [mm ² .sl] at 25 ° C from Goldschmidt AG, D-4300 Essen. Example 3

A homogeneous spot on formulation (100 g) consisting of

1.00 g pyriproxyfen (2- [l-methyl-2- (4-phenoxyphenoxy) ethoxy] pyridine

82.00 g dipropylene glycol monomethyl ether

15.00 g water

2.00 g Abil Quat 3274 (2)

(2) Abil Quat 3274 is a 50% polydimethylsiloxane solution with a diquatera

Ammonium g ppe and the viscosity range of 5000 - 15000 [mm ² .sl] at 25 ° C from Goldschmidt AG, D-4300 Essen.

Example 4

A homogeneous spot on formulation (100 g) consisting of

1.00 g of pyriproxyfen (2- [1-methyl-2- (4-phenoxyphenoxy) ethoxy] pyridine

82.00 g diethylene glycol monoethyl ether 15.00 g water

2.00 g Abil Quat 3274 (2)

(2) Abil Quat 3274 is a 50% polydimetylsiloxane solution with a diquaternary ammonium group and a viscosity range of 5000 - 15000 [mm ² .sl] at 25 ° C from Goldschmidt AG, D-4300 Essen. Counterexample 1

A homogeneous spot on formulation (100 g) consisting of

1.00 g pyriproxyfen (2- [l-methyl-2- (4-phenoxyphenoxy) ethoxy] pyridine

99.00 g diethylene glycol monoethyl ether

Counterexample 2

A homogeneous spot on formulation (100 g) consisting of

1.00 g of pyriproxyfen (2- [1-methyl-2- (4-phenoxyphenoxy) ethoxy] pyridine 99.00 g of dipropylene glycol monomethyl ether

Studies on the effectiveness of the spot-on formulations according to Examples 1-

4 on fleas on cats

The studies were conducted to demonstrate the effectiveness of the 1% pyriproxyfen solutions according to the flea sterilization examples in cats.

20 flea-fixed cats were divided into 2 groups of 10 cats. One group received 0.1 ml / kg pyriproxyfen spot on 1% as a spot on in the neck, the other group served as an untreated control. The cats were reinfested at weekly intervals and falling flea eggs were collected over a period of 24 hours. These eggs were at 85% rel. Humidity and 28 ° C incubated and observed for the development of fleas over a period of 30 days.

Furthermore, 20 cats each were divided into 2 groups of 10 cats. One G ppe each received 0.1 ml / kg pyriproxyfen spot on 1% as spot on in the neck, the other

Gmppe served as an untreated control. At weekly intervals over the The cats were placed on fleece blankets for 6 hours each for a period of 4 weeks. The blankets were sprinkled with floating egg at 85% rel. Humidity and 28 ° C and observed for the development of fleas over a period of 30 days.

The development of adult fleas from eggs of the treatment group was suppressed by at least 95% over a period of 7 weeks compared to the control group. The effectiveness on day 56 is p.appl. 92%.

The development of adult fleas to be treated on blankets after contact

Cats were 95% or more suppressed over a 17 day period.

Studies on the effectiveness of the spot-on formulations according to Examples 1-4 on fleas in dogs

The studies were carried out to demonstrate the effectiveness of the 1% pyriproxyfen solutions according to the examples for sterilizing fleas in dogs.

20 flea-fixed dogs were divided into 2 groups of 10 dogs. A

Group received 0.04 ml / kg pyriproxyfen spot on 1% solutions according to Examples 1-4 as spot on in the neck, the other group served as an untreated control. The dogs were reinfested at weekly intervals over a period of 11 weeks and falling flea eggs were collected over a period of 24 hours. These eggs were at 85% rel. Humidity and 28 ° C incubated and observed for the development of fleas over a period of 30 days.

Furthermore, the dogs were placed on fleece blankets for 6 hours at weekly intervals over a period of 4 weeks. The blankets were sprinkled with floating egg, at 85% rel. Humidity and 28 ° C and incubated on the

Development of fleas was observed over a period of 30 days. Over a period of 10 weeks, the development of adult fleas from Eiem of the treatment group was 100% suppressed.

The development of adult fleas to be treated on blankets after contact

Dogs were 100% suppressed over the entire 24 day test period.

Determination of the long-term stability behavior

For this purpose, the conventional PP spot on tubes with an average wall thickness of approx. 350 μm were filled with 0.4 ml spot on solution and stored for 6 months at 40 ° C and 75% relative humidity. The results of these studies are shown in Table 1.

Tab. 1: Long-term stability behavior of the spot on solutions

Table 1 shows that Formulations 1-4 meet the stability requirements of the drug guidelines. The formulation bars listed in counterexamples 1-2 are unfortunately not stable in storage. The respective amounts of active substance decrease> 10% during storage.

The toxicological properties of the respective formulations are shown in Table 2.

Tab. 2: The toxicological properties of the spot on solutions

The table shows that the new spot-on formulas have excellent target animal and environmental compatibility as well as user safety.

Claims

claims

1. Use of polysiloxanes containing at least one quaternary ammonium group as formulation auxiliaries in formulations of larvicidal and / or ovicidal active substances.

2. Means containing

a) a larvicidal and / or ovicidal active ingredient and

b) a polysiloxane derivative with at least one quaternary ammonium group per molecule,

optionally other auxiliaries and carriers.

3. "Single-can" polypropylene plastic tub, characterized in that they are filled with an agent according to claim 2.