EP1065926A1

EP1065926A1 - Utilization of natural and/or synthetic quinic acid and/or precursors thereof as insect repellents

Info

Publication number: EP1065926A1
Application number: EP99916865A
Authority: EP
Inventors: Franz Bencsits
Original assignee: Biolink Technologies AG
Current assignee: Biolink Technologies AG
Priority date: 1998-03-24
Filing date: 1999-03-22
Publication date: 2001-01-10
Also published as: DE19812927C1; WO1999048363A1; BR9909152A; NO20004708D0; KR20010034611A; CA2325372A1; NO20004708L; AU746660B2; AU3520399A; CN1298279A; JP2002507549A

Abstract

The invention relates to the utilization of natural and/or synthetic quinic acid (1,3,4,5-tetrahydroxycyclohexane carboxylic acid) and/or precursors thereof as insect repellents.

Description

Use of natural and / or synthetic

Quinic acid and / or precursors thereof as a pest repellent

The present invention relates to a pest repellent against flying, crawling, stinging, biting and sucking insects and other related types of arthropods (arthropods), such as mites and ticks (Acarina), and arachnids (Arachnida). Such pest repellents are generally also called repellents.

Repellents are chemical substances that have a repulsive effect on arthropods affecting humans and animals, particularly insects. Their use is of great practical importance in human and veterinary hygiene, where they protect humans and animals from infestation with blood-sucking, biting or other troublesome arthropods. In the case of repellents to be applied directly to the skin, fur or clothing, it is necessary that they are skin-friendly, non-toxic, in particular non-absorbable, sweat and light-fast and cosmetically perfect. In addition, the protection of the treated areas should last as long as possible and the spectrum of activity of the repellents should be as broad as possible, i.e. they should work against as many pests and nuisances as possible.

The practical application of repellents and their benefits can easily be explained solely from the fact that, statistically speaking, a human being dies from the consequences of a mosquito bite every thirty seconds worldwide and the number and extent of all other sequelae of pest attacks on humans and animals are inconceivable stay. Therefore, only the transmission of dangerous diseases such as malaria, yellow fever, dengue and filariasis should be referred to as a causal factor for the benefits of repellents. All of the repellents known to date have the chemical-physical property evaporate more or less quickly at room temperature, whereby two factors are effective for the intensity and duration of their protective action:

1. The more volatile a substance is, the more intense its protective effect is particularly shortly after application, but the shorter its duration of protection. In particular, reference should be made here to the class of essential oils and the natural substances containing these oils, such as were available as sole repellents in earlier times, e.g. Extracts from garlic, pennyroyal oil and the juice of ripe tomatoes or the essential oils citronella, bergamot, eucalyptus, lavender, clove, nutmeg, cinnamon and much more.

2. The slower the evaporation takes place at room temperature, the longer the protective effect. It should be noted, however, that substances that do not evaporate sufficiently do not form a permanent protective shield that interferes with the locking mechanism of the nuisance. These substances are poorly or not at all suitable as repellents.

From the extremely extensive group of synthetic substances with a repellent effect, which can essentially be assigned to the classes of amides, alcohols, esters and ethers, the following have proven to be particularly effective and are therefore preferred on the market: N, N-diethyl -m-toluamide (DEET), dimethyl phthalate (DMP) and ethyl butylacetamido-propionate (BAP, 3535) and combinations thereof. Others are not effective enough or because of massive toxicological risks they can only be found on the market in isolated cases or have already completely disappeared. However, discussions in medical and especially dermatological circles about the tolerance and the toxicological risks of the above-mentioned synthetic repellant active substances have been intensifying since their molecular structure means that they are able to diffuse through the skin or can be absorbed by it. Accordingly, the present invention has for its object to provide an effective pest repellent based on natural and πatuπdeπter raw materials with the lowest toxicological risk, which also has a high effectiveness over a long period of time. This object is achieved by the use of natural and / or synthetic Quinic acid and / or precursors dissolved thereof. Quinic acid is preferably dissolved in at least one suitable, toxicologically acceptable, natural and / or natural and / or synthetic carrier

Natural and / or synthetic quinic acid and / or precursors thereof can be used in humans and animals to ward off creeping, flying, stinging, sucking and disease-carrying diseases, in particular insects and related species

The active ingredient used according to the invention is quinic acid (1 R, 3R, 4S, 5R) - (1, 3, 4,5-tetrahydroxycyclohexane carboxylic acid) with the

Structure. ^ CCH and the sumπfomnel CH ₁₂ 0 ₆

;-O

The molecular weight is 192.17

The quinic acid is preferably dissolved in a suitable carrier of natural or synthetic origin, preferably water. The preferred active ingredient content is 0.1 to 50% by weight of quinic acid in the carrier. A content of 5 to 30% by weight of quinic acid is particularly preferred

The carrier used according to the invention can also be a mixture of different carriers. The use of a mixture of water with glycols, alcohols or propanediols is preferred. The use of a mixture of 0.1 to 50% by weight of quinic acid in 50 to 99 is particularly preferred , 1% by weight of a mixture of 0.1 to 99 9% by weight of water and 0 1 to 99.9% by weight of the other carrier The quinic acid used is produced by the known processes (leaching and recrystallization) from its natural occurrence in Chinese bark (Cortex Chinae), various types of Chinona (Rubiaceae), coffee beans, sugar beets, meadow hay, gooseberries and blackberries as well as bilberry and cranberry leaves . Quinic acid can also be synthetically produced and used. Precursors of quinic acid can also be used. A preferred precursor is its dehydrated form, the shikimic acid (3, 4, 5-trihydroxy-1-cyclohexane carboxylic acid). In the following, all these substances are called quinic acid for the sake of simplicity.

In further preferred embodiments, 0.1 to 50% by weight of quinic acid and 50 to 99.9% by weight of water, or 0.1 to 50% by weight of quinic acid, are dissolved in a mixture of glycerol and water or from 1 , 2-propylene glycol and water. Here too, the use of 5 to 30% by weight of quinic acid is particularly preferred. The mixing ratios of the different carriers are as stated above.

Quinic acid can also be used in the form of an emulsion, dispersion, lotion, cream, gel or solution. The generally customary preparation methods can be used to produce these forms of use. The usual raw materials and additives can also be used. These base materials and additives include the commonly used solvents, solution accelerators, emulsifiers, solvents, wetting agents, anti-foaming agents, salt formers, buffers, gel formers, thickeners, film formers, binders, lubricants, anti-adhesives, flow regulators, humectants or drying agents, fillers and auxiliaries such as antioxidants - tien, preservatives, odor correctors and colorants.

The term emulsion encompasses all disperse systems composed of two or more immiscible liquids, the emulsion partners also being able to be present as solid substances at room temperature. These emulsions can be macro or micro emulsions. Typically, water-in-oil or oil-in-water emulsions are used. To reduce the interfacial work (work to be done on emulsifying), emulsifiers are used. Emulsifiers are usually surface-active substances _, typically with hydrophilic end groups. Typical examples include:

a) anionic emulsifiers, i.e. Emulsifiers with carboxylate, sulfonate, sulfate, phosphate, polyphosphate, lactate, citrate, tartrate, glucose or polyglucose end groups;

b) cationic emulsifiers, i.e. Emulsifiers with amine salt or quaternary ammonium end groups;

c) amphoteric and zwitterionic emulsifiers, i.e. Emulsifiers with zwitterionic end groups or betaine end groups; such as

d) non-ionic emulsifiers, i.e. Emulsifiers with alcohol, polyether, glyceri, sorbitol, pentaerythritol, sucrose, acetic acid and / or lactic acid residues as the end group.

All emulsifiers also contain lipophilic end groups such as alkyl or alkenyl residues, each straight-chain, branched or cyclic, and aryl or alkylaryl residues.

Furthermore, hydrophilic side groups such as hydroxyl, ester, sulfamide, amide, amine, polyamide, polyamine, ether, polyether, glycerol, sorbitol, pentaerythritol or sucrose groups can be included.

The term gels encompasses dimensionally stable, easily deformable, liquid-rich systems consisting of at least 2 components. These two components are usually a) a liquid and b) a solid, colloidally distributed substance, such as gelatin, silica, montmorillonite, bentonite, polysaccharides, polyacrylic acid, pectins etc.

According to the invention, a completely harmless active ingredient, which is produced directly from natural raw materials and is just as harmless, cosmetically and pharmaceutically 6

well-known and toxicologically fully secured solvents and preparations can be formulated.

In addition, in contrast to all other previously known substances, the use according to the invention offers a completely new mode of action. This is not based on a permanent evaporation cloud lying over the skin, which covers the locating receptors for nuisances that are secreted from the skin and is therefore naturally subject to fluctuations in effect that correspond to circumstances. The use of quinic acid according to the invention blocks the formation of receptors on the skin, the fur or overlying clothing independently in a constant, permanent reaction with the starting materials on the skin and also soluble in the solvent of the pesticide, which are permanently formed or released by the body of fluctuations in environmental conditions. These starting materials are, for example, ammonia, lactic and butyric acid, carbon dioxide and certain amino acids (such as cystine and glutamine). So there is no evaporation bell covering these already formed receptors, which prevents nuisances, but their emergence on the skin is prevented and the areas treated with it are thus unattractive for pests.

Because of its chemical and physical properties, the quinic acid used according to the invention is unable to penetrate the skin. Nor is it a risk factor for health.

The following examples illustrate the invention.

1. Examples of formulations for the use of quinic acid according to the invention

TS (I) 10.00% by weight quinic acid 20.00% by weight water 70.00% by weight 1, 2, 3-propanetriol (glycerol) S (II) 5.00% by weight quinic acid

57.00% by weight of water

10.00% by weight of cetylstearyl polyglycosides

28.00 wt% glycerin

S (III) 2.00% by weight quinic acid

3.00% by weight glycerin

2.00% by weight propane-1,2-diol (1,2-propylene glycol)

3.00% by weight of ethanol (ethyl alcohol)

90.00% by weight of water

2. Examples of use

The pest repellants (I) and (II) were tested on two different people, a product from the market serving as reference (KIK AKTIV - 30% DEET).

Attempt:

The right forearm of a test subject was treated on an area of approximately 250 cm ² with the corresponding test substance - TS (I) or (II). An amount of 2 ml of the corresponding test substance was distributed evenly. The treated forearm area was sealed at both ends with a mosquito-proof adhesive tape and a short plastic tube. The untreated hand was covered with a thick glove and thus also served as a control for the pricking activity of the test animals. The left forearm was also treated with reference product (REF). About 300 to 400 yellow fever mosquitoes (Aedes aegypti), almost exclusively females, were used as experimental animals in a breeding cage of 40x40x40 cm.

For the test, the forearms and the hand were held one after the other, first the left, then the right, hourly in the mosquito cage and the number of mosquitoes recorded for 10 minutes (a) tried to pierce the glove (positive control),

(b) flew to the treated area closer than 3 cm,

(c) remained on the treated area for more than 2 seconds and

(d) stab the treated area and suck blood.

3. Results: Test person (1)

Time after expos. - End of flight on approaching end of flight Number of applications Duration glove (a) mosquitoes (b) mosquitoes (c) bites (d) TS (I) REF TS (I) REF TS (I) REF TS (I) REF

1 hour 10 min 100 100 0 0 0 0 0 0

2 hours 10 min 100 100 0 0 0 0 0 0

3 hours 10 minutes 100 100 0 0 0 0 0 0

4 hours 10 minutes 100 100 0 2 0 0 0 0

5 hours 10 minutes 100 100 0 4 0 1 0 0

6 hours 10 minutes 100 100 2 12 0 7 0 0

7 hours 10 minutes 100 100 1 10 0 3 0 0

8 hours 10 minutes 100 100 8 0 3 0 0 ¹

Test person (2)

Time after expos. - End of flight on approaching end of flight Number of applications Duration Glove (a) Mosquitoes (b) Mosquitoes (c) Bites (d) TS (II) REF TS (II) REF TS (II) REF TS (II) REF

1 hour 10 min 100 100 0 0 0 0 0 0

2 hours 10 min 100 100 0 0 0 0 0 0

3 hours 10 minutes 100 100 0 0 0 0 0 0

4 hours 10 minutes 100 100 5 3 1 1 0 0

5 hours 10 minutes 100 100 8 8 2 1 0 0

6 hours 10 minutes 100 100 14 10 6 7 0 0

7 h 10 min 100 100 10 12 4 2 0 0

8 h 10 min 100 100 8 10 4 6 0 0

The sitting mosquitoes on the gloves were estimated because an exact count is not possible due to the changing numbers.

The effectiveness of a substance results above all from the ratio of the mosquitoes stuck on the glove to the other values.

The number of biting mosquitoes is the decisive factor for the duration of the effect and thus indirectly in the tropics for the risk of infection. The tested substances guarantee protection for over 8 hours. As can be seen from parameters b) and c), there is a certain number of mosquitoes flying and settling down when using the substances used according to the invention; however, these do not sting. A strong repellent effect can therefore be attributed to all tested substances, whereby TEST PRODUCT (I) showed the most effective wrinkle. In particular the extremely low number of mosquitoes approaching and the fact that not a single mosquito has been dismantled shows the superior effect of the use of quinic acid according to the invention with an active substance content of 10% compared to the commercially available reference product with 30% active substance content. The advantage of the prevention of formation of zeptors directly on the skin compared to the coverage of the receptors is particularly clearly shown.

Even TEST PRODUCT (II) with only one sixth of the active substance content of the reference still has a comparable effect.

To check these laboratory results, a field test was carried out with 20 test subjects over a period of 5 days in a floodplain heavily contaminated with mosquitoes and brakes.

The preparation of the test subjects was carried out immediately after the laboratory test. The subjects of the tests against mosquitoes were exposed only from sunset at temperatures of 18 to 28 ° C, relative humidity of 50 to 95% and wind speeds below 1 m / s. The subjects in the brake tests only during the day under the above conditions.

Groups of five subjects were formed for each experiment, of which 1 subject served as an untreated control, 2 subjects were treated with TEST PRODUCT (i) and 2 subjects with REFERENCE. The untreated control served as a unit of measurement for the mosquitoes 'or brakes' reluctance to sting or bite and was only exposed for 1 minute each.

Average values were formed from all tests, the sitting mosquitoes on the gloves being estimated and sitting mosquitoes on the remaining protective clothing of the test subjects being disregarded.

TESTING RESULTS, mosquitoes, mainly Culex pipiens

1. Average untreated control over 1 min. exposition

Sitting on flying mosquitoes Sitting mosquitoes Number of glove stitches

5 42 42 42 11

Average REFERENCE, exposure 8 hours for 10 minutes, numbers related to 10 minutes

Sitting on flying mosquitoes Sitting mosquitoes Number of glove stitches

120 17 6 0

3. Average TEST PRODUCT (I), exposure as 2.

Sitting on flying mosquitoes Sitting mosquitoes Number of glove stitches

130 4 0 0

The comparison over an average test time of 10 minutes shows that an untreated person would have been stabbed 420 times during this time, while both REFERENCE and TP (I) remained without a stab.

What is striking in the comparison of REF and TP (I) is again that the TEST PRODUCT had a much lower nuisance rate (number of mosquitoes approaching and settling down) and was thus able to confirm the results of the laboratory tests.

TEST RESULTS BRAKES, mainly Haematopoda pluvialis

Only the number of bites could be evaluated here, since brakes approach, sit, bite, suck a drop of blood in a flash without a special search flight and fly off again.

Average bites from brakes

1. untreated control over 1 min. Exposure: 2nd 2. REFERENCE against TEST PRODUCT (I), 10 min. Exposure time / hour, average of all test times

0 brake bites at

Time after application REF. TP (l)

1. hours 0.0 0.0

2. hours 0.0 0.0

3. hours 0.1 0.0

4. hours 1.0 0.0

5. hours 2.0 0.1

6. hours 3.0 1.0

This test carried out 12 times in the cross test also shows that the test product according to the invention has an effect duration which is at least two hours longer than that of the commercially available reference product.

A five-day field test was carried out to test the effectiveness of the repellant activity against ticks, as a typical representative of the Acarinae, which is also the most dangerous representative of this genus for humans and animals. Three sheep dogs, male, of approximately the same size and weight, with three dog handlers were provided by an animal shelter, each of whom led the animals for four hours a day in a known tick-contaminated area. 1 dog was marked daily with K (control), TP (I) and REF. Dog and the associated guide were treated with the entire body of the body with approx. 10 ml TEST PRODUCT (I) and REFERENCE. An untreated dog served as a control, whose guide, although vaccinated against TBE, was treated with REFERENCE in order to counter the risk of transmission of Lyme disease through possible tick bites.

After each four-hour exit, the test animals and their guides were carefully examined for the presence of ticks, documented and collected in labeled glasses and followed up for 72 hours. Results:

1. untreated control - a total of 86 ticks were found in the dog on the five test days, including 68 of the genus L. ricinus and 18 R. sanguineus, the individual stages (adults and nymphs) not being distinguished. All ticks survived the 72 hour follow-up.

A total of 24 ticks were found on the dog handler's clothing. In contrast to the untreated dog, no tick was found on the skin or drilled. The 24 ticks also survived the follow-up period.

2. REFERENCE - a total of 6 ticks were found on the dog, 19 ticks on the handler's clothing (adults and nymphs of the 21st ritinus and 4 R.sanguineus), but none were on the skin or drilled. All ticks survived 72 hours of follow-up. The repellency time (duration of action) of the reference product can therefore be given as 4 hours, although the total of 6 ticks on the dog's fur would have drilled in if the effectiveness of the product had deteriorated, since they survived the follow-up period.

3. TEST PRODUCT (I) - not a single tick was found on the dog in the 5-day test period.

A total of 5 ticks of the genus l.rizinus were found on the dog handler's clothing (all long-sleeved, light shirt and linen trousers in white), of which 3 ticks did not survive the observation.

After the 72-hour follow-up period, a total of 110 ticks from the untreated control and the ticks from test product (TP I) were immersed in the TEST PRODUCT (I) for 5 minutes in accordance with the requirements of the immersion test for ectoparasite screening and were all dead 24 hours later Ticks that survived the follow-up after REFERENCE were, as above, 5 min. in the Reference product dipped and survived another 72 hours and was then dipped for 1 min. in TP (I) classified as dead after a further 24 hours.

This test showed that TESTPRODUKT (I) not only has a protection period against ticks of at least 4 hours, but also reliably kills them when they come into contact with the product and is therefore superior to the market-recognized reference in absolute protection against tick bites.

To ensure the surprisingly mortal effect of the pesticide according to the invention, the following screenings were carried out with various insects as follows:

1. TEST PRODUCT (III) compared to one

2. commercial insect control agent (REFERENCE), containing as active ingredient It. Label 0.05% organic allethrin and 0.25% permethriπ in aqueous emulsion.

Acrylic tubs with L = 50 cm, W = 30 cm, D = 25 cm served as test containers, the bottoms of which were coated with 1 ml of TB (III) and REF. 10 test insects were placed on the floor in each of the containers treated with TB (III) and in the containers treated with REF and, after a contact time of 1 minute, transferred to untreated containers and followed up for 48 hours.

Test insects:

I. Cockroaches (Blatella germanica)

II. Ants (Lasius niger)

Results:

Both the test insects brought into contact with TP (III) and with the REF were all dead after 48 hours. A further follow-up over 72 hours did not result in any resuscitation, so that the use of Chinese acids according to the invention has an effect comparable to the commercially available, recognized reference product.

Claims

claims

1. The use of natural and / or synthetic quinic acid (1, 3, 4, 5- Tetrahydroxycyclohexancarbonsäure) and / or precursors thereof weir medium as Schadlingsab _¬.

2. Use according to claim 1, characterized in that the quinic acid is dissolved in at least one suitable carrier.

3. Use according to claim 2, characterized in that 0.1 to 50 wt .-% quinic acid is dissolved in 50 to 99.9 wt .-% carrier.

4. Use according to at least one of claims 2 and 3, characterized in that the carrier is water.

5. Use according to at least one of claims 2 to 4, characterized in that glycerol, alcohols or propanediols are contained as further carriers.

6. Use according to claim 5, characterized in that 0.1 to 50 wt .-% quinic acid, 0.1 to 99.8 wt .-% water and 0.1 to 99.8 wt .-% of a further carrier are.

7. Use according to at least one of claims 1 to 6, in the form of emulsions, dispersions, lotions, creams, gels or solutions.

8. Use according to at least one of claims 1 to 7, for defense against flying, creeping, stinging, biting and sucking pests and nuisances.