MXPA00009341A - Utilization of natural and/or synthetic quinic acid and/or precursors thereof as insect repellents - Google Patents

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 OF THE SAME AS INSECT REPELLENTS DESCRIPTIVE MEMORY The present invention relates to an insect repellent against flying, crawling, biting and sucking insects, and other species of articulates (arthropods), such as termites and ticks (mites), as well as spiders (arachnids). Such insect repellents are commonly called repellents. Repellents are chemicals that have a repulsive effect on joints, particularly insects, which are harmful and annoying to humans and animals. Its use is of great practical importance in human and veterinary hygiene, where it protects man and animals against the attacks of blood-sucking insects, teethers or otherwise annoying arthropods. When repellents have to be applied directly to skin, coating or counter, it is necessary that they are well tolerated by the skin, non-toxic, particularly non-resorbable, that allow perspiration, safe in the light and perfect in the cosmetic aspect. In addition, the protection of the treated areas of the skin must be as wide as possible, that is, they must act against as many harmful and annoying insects as possible.

The practical use of repellents and their benefit is explained only by the fact that statistically every thirty seconds a person dies as a result of insert bites, and the number and degree of all other manifestations of attacks of inserts in man and animals remain unable to register in number. Therefore, only the transfer of dangerous diseases such as malaria, yellow fever, dengue fever and filariasis should be referred to as a causal factor for the benefit of the repellents. All repellents known to date have the common physical-chemical property of evaporating more or less rapidly at room temperature, while the intensity and duration of their protective effect depend essentially on two factors: 1. the more volatile a substance, the more intense wbe its protective effect, particularly just after application, however, the duration of its protection is proportionately shorter. In this regard, mention must be made in particular of essential oils and natural compounds comprising these oils, and it should be noted that in ancient times they were the only repellents available, such as garlic, pennyroyal oil and the juice of ripe tomatoes; essential oils citronella, bergamot, eucalyptus, lavender, clove, nutmeg, cinnamon and others. 2. The slower the evaporation at room temperature, the longer the protective effect. In relation to this, it should be taken into account that substances that do not evaporate to a sufficient degree can not establish a durable protective shield capable of altering the mechanism of attraction of parasites. These compounds are harmful although not totally unsuitable for use as repellents. Consequently, the following of the extremely extensive group of synthetic compounds that act as repellents, which are essentially part of the classes of compounds of amides, alcohols, esters and ethers have proven to be particularly effective and therefore have prevailed in the market: N, N-diethyl-m-toluamide (DEET), dimethyl phthalate (DMP) and ethyl ester of butylacetamidopropionic acid (BAP, 3535) and combinations thereof. Other compounds are not effective enough or involve massive toxicological risks and are only occasionally found in the market or are already completely extinguished. However, for some time past, medical experts and in particular dermatological experts have debated intensely about the tolerance and toxicological risks of the synthetic repellent active substances mentioned above, since, due to their molecular structure, are able to diffuse through the skin to be resorbed by it. Therefore, the objective of the present invention is to provide an effective insect repellent based on natural substances and substances identical to natural substances, which presents the lowest toxicological risk and has a high effectiveness over a long period. The objective is solved by the use of natural and / or synthetic quinic acid and / or precursors thereof. Preferably, the quinic acid is dissolved in at least one natural and / or identical to natural and / or synthetic toxicologically harmless and suitable vehicle. The natural and / or synthetic quinic acid and / or precursors thereof can be used for protection against crawling, biting, sucking and infectious parasites, particularly insects and related species. The active substance used in the present invention is quinic acid (1R, 3R, 4S, 5R) - (1, 3,4,5-tetrahydroxycyclohexane carbonic acid) with the structure: and the total formula C7H-? 2? 6. The molecular weight is 192.17. Preferably, the quinic acid is dissolved in a vehicle of natural or synthetic origin, preferably water. The amount of active ingredient that is preferred is 0.1 to 50% by weight of quinic acid in the vehicle.

An amount of from 5 to 30% by weight of quinic acid is particularly preferred. The vehicle used in the present invention may be a mixture of different vehicles. The use of a mixture of water with glycerol, alcohols or propane diols is particularly preferred. Particularly preferred is the use of a mixture of 0.1 to 50% by weight of quinic acid in 50 to 99.1% 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 vehicle. The quinic acid used is prepared by known methods (extraction and recrystallization) using its natural sources, quinic bark (Cortex Chinae), different species of quinone (rubiaceae), coffee beans, beets, prairie hay, white currants and blackberries, as well as blueberry leaves. Quinic acid can also be prepared synthetically and used. Precursors of quinic acid can also be used. A precursor that is preferred is its dehydrated form, shikimic acid (3,4,5-trihydroxy-1-cyclohexane carbonic acid). Hereinafter all these compounds will be designated quinic acid for reasons of simplicity. In 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, dissolved in a mixture of glycerol and water or 1, are used. 2-propylene glycol and water. In this case, the use of 5 to 30% quinic acid is particularly preferred. The mixing ratios of the different vehicles are like those mentioned above generally. In addition, the quinic acid can be used in the form of an emulsion, dispersion, lotion, cream, gel or solution. For the preparation of these types of applications, normal preparation methods can be used. Common substances and additives can also be used.

These substances and additives comprise solvents, solvent accelerators, emulsifiers, solubilizers, wetting agents, foam antifoaming agents, salt formers, pH regulators, gelatinizing agents, thickening agents, film-forming agents, binders, lubricants, strippers, coating agents. flow regulation, humectants, desiccants, fillers typically used, as well as auxiliary agents such as antioxidants, preservatives, odor correctors and coloring agents. The word "emulsion" includes all dispersed systems of two or more liquids not miscible with each other, whereby the emulsion components can be solid compounds at room temperature. These emulsions can be macro or microemulsions. Typically, water in oil or oil in water emulsions can be used. For the reduction of interfacial surface work (the work necessary for the emulsification) emulsifiers are used. The emulsifiers are usually surfactant compounds, typically with hydrophilic end groups. Typical examples thereof comprise: a) anionic emulsifiers, that is, emulsifiers with carboxylic, sulphonic, sulfate, phosphate, polyphosphate, lactate, citrate, tartrate, glucose or polyglucose end groups; b) cationic emulsifiers, that is, emulsifiers with end groups of amine salt or quaternary ammonium; c) amphoteric and zwitterionic emulsifiers, that is, emulsifiers with zwitterionic end groups or betaine end groups; as well as d) nonionic emulsifiers, that is, emulsifiers with alcohol, polyether, glycerol, pentaerythritol, sucrose, acetic acid and / or lactic acid residues as end groups. All emulsifiers also contain lipophilic end groups such as alkyl or alkenyl moieties, each of which are linear, branched or cyclic, as well as aryl or alkylaryl residues. Additional hydrophilic side groups such as hydroxyl, ester, sulfamide, amide, amine, polyamide, polyamine, ether, polyether, glycerol, sorbitol, pentaerythritol or sucrose groups may also be included. The word "gels" includes systems that are easily deformable in a stable manner and are rich in liquids of at least two components.

Normally these two components are a dispersed colloidal compound a) liquid and b) solid, such as gelatin, silicic acid, montmorillonites, bentonites, polysaccharides, polyacrylic acids, pectins, etc. In accordance with the present invention, a completely harmless active substance prepared from natural raw materials is used which can be formulated in equally harmless, cosmetically and pharmaceutically well-known solvents and completely toxicologically safe. Furthermore, the use according to the present invention offers, unlike all other compounds known hitherto, a completely new mechanism of action. This is not a mechanism based on a permanent evaporation cloud that extends over the skin and masks position receptors that are secreted from the skin, the effect of said mechanism being subject to variations depending on the circumstances. The use of quinic acid according to the present invention blocks a constant and permanent reaction with permanently produced or secreted precursors which are placed on the skin and are soluble in the repellent solvent, the formation of receptors on the skin, the coating or garments. that are on it regardless of the variations in the surrounding conditions. Such precursors are, for example, ammonia, lactic and butyric acid, carbon dioxide and certain amino acids (such as cystine and glutamine). In this way, it is not an evaporation cloud that masks these already formed receptors that keeps the parasites away, but their formation on the skin is easily avoided making the areas treated with it unattractive to destructive insects. The quinic acid used according to the present invention can not, because of its chemical and physical properties, penetrate into the skin. Consequently, there is no risk factor for health. The following examples will explain the invention. 1. Examples of formulations for the use of quinic acid according to the present invention TS (I) 10.00% by weight of quinic acid 20.00% by weight of water 70.0% by weight of 1, 2,3-propanetriol (glycerol) TS (II) 5.00% by weight of quinic acid 57.00% by weight of water 10.00% by weight of cetilestearyl-polyglucosides 28.00% by weight of glycerol TS (III) 2.00% by weight of quinic acid 3.00% by weight of glycerol 2.00% by weight of propane-1, -diol (1, 2-propylene glycol) 3.00% by weight of ethanol (ethyl alcohol) 90.00% by weight of Water 2. Application examples The repellents (I) and (II) were tested with two different people, while a commercial product was used as reference (KIK AKTIV-30% DEET).

Experiment The right forearm of a test person was treated over an area of approximately 250 cm2 with the respective test compound -TS (I) or (II). A quantity of 2 ml of the respective test compound was uniformly spread. The area of the treated forearm was sealed on both ends with an adhesive tape against insects and was provided with a short plastic tube. The untreated hand was covered with a thick glove and then served at the same time as a control for the bite activity of the laboratory animals. The left forearm was treated in the same way with a reference product (REF). About 300 to 400 insects of yellow fever (Aedes aegypti), almost exclusively small females, were used as laboratory animals in a breeding cage of 40x40x40 cm. For the test, the forearms and hands, successively, first the left one and then the right, were kept inside the cage with insects for 10 minutes. The number of insects that: a) tried to bite through the glove (positive control) b) flew closer to 3 cm towards the treated area, c) descended and remained perched on the treated area for more than two seconds, and d) They bit the treated area and sucked blood. 3. Results Test person (1) Test person (2) The number of insects that perched on the gloves was calculated since due to the high variable numbers an exact evaluation was impossible. The effectiveness of a compound is the result mainly of the relation of insects that rest on the glove and that are willing to bite, with the other values. The number of biting insects is the decisive factor for the period of effectiveness and with it in the tropics indirectly also for the risk of infection. The tested compounds ensure protection for more than 8 hours. As can be taken from parameters b) and c) there is a certain number of insects even with the use of the compounds used in accordance with the present invention that fly in the direction and land; however, they do not bite. A strong repellent effect can be attributed to all tested compounds, whereby the test product (I) showed the best effect. Particularly, the extremely low number of insects that flew towards and the fact that not a single insect perched allows the superior effect of the use of quinic acid according to the present invention having an amount of 10% of substance vis a vis the commercial reference compound having an amount of 30% active substance. Therefore, the advantage of preventing the formation of receptors directly on the skin as compared to the coverage of receptors is demonstrated particularly clearly.

Even the test product (II) with only one sixth of the active substance content of the reference results in a comparable effect. For the verification of these laboratory results an open field experiment was carried out with 20 test persons during a period of 5 days in a river prairie highly loaded with insects and blowfly. The preparation of the test persons was carried out in the same way as in the laboratory experiment. People who were tested with insects were exposed exclusively from sunset at temperatures of 18 to 28 ° C, relative humidity of 50 to 95% and wind speeds of less than 1 m / s, and people who were subjected to tests with blowfly were exposed exclusively during the day with the above conditions. For each experiment, groups of five test persons were formed of which one person served as an untreated control, two people were treated with the test product (I) and two people with the reference. The untreated control served as a measure for the desire of insects or bugs to bite and was exposed each time for one minute. The average values were calculated for all the experiments, which calculated the insects that perched on the gloves and the insects that perched on the remaining protective garment of the test persons were not taken into account.

Results of the test with insects, particularly Culex pipiens 1. Control untreated average during 1 minute of exposure 2. Average reference, exposure of 8 hours 10 minutes each, the numbers refer to 10 minutes 3. Average test product (I), exposure as in 2.

The comparison during an average test time of 10 minutes shows that an untreated person would have been bitten theoretically 420 times during that time, while both the reference and the TP (I) remained without bites. In a comparison of the reference and TP (I), it is again noticeable that the test product shows a much lower annoyance index (numbers of insects that fly towards and alight) and with this the result of laboratory experiments could to be verified.

Test results with blowflies, particularly Haematopoda pluvialis In this case, only biting numbers could be evaluated, since the blowflies fly towards an area in a stretch without a particular search flight, alight, bite, suck with speed vertiginous a drop of blood and start again.

Average bite of bugs in 1. control untreated during 1 minute of exposure: 2 2. reference against test product (I), 10 minutes exposure / hour, average of all test times This experiment carried out 12 times during a cross-check also shows that the effect of the test product used in accordance with the present invention lasts at least about two hours more than the effect of the commercial reference product. An open-field test was conducted to evaluate the effectiveness of the repellent effect against ticks as a typical representative of mites that are by far the most dangerous representatives of this genus. From a house for the protection of animals, three male shepherd dogs were provided, almost the same size and weight with three masters who took the dogs for a walk every day for four hours along an area that was known to be contaminated with ticks Consistently, on a daily basis each dog was marked with K (control), TP (I) and REF. The dog and its owner were each treated on the entire surface of their bodies with approximately 10 ml of test product (I) and reference. An untreated dog served in each case as a control whose masters, although they were inoculated against FSME, were treated with the reference to find the risk of a transfer of borreliosis by possible tick bites. After each four-hour walk daily, the test animals and their masters were examined carefully to verify the presence of ticks, and these were documented and collected in glasses marked and observed for another 72 hours.

Results 1. Control untreated - during five days of experiments 86 ticks, 68 of which of the genus /. rizinus and 18 of R. sanguineus -with which the respective stages (adults and larvae) were not differentiated- were found in the dogs. All ticks survived the subsequent 72 hours of observation.

A total of 24 ticks were found on the clothing items of the dogs' masters, so that, compared to the untreated dog, no tick could be found on the dog's owner's skin or embedded in it. The 24 ticks survived the time of subsequent observation as well. 2. Reference - a total of 6 ticks was found on the dog and 19 ticks (adults and larvae of 21 of L. ritinus and 4 of R. sanguineus) were found on the clothes of the dog owner, however, none of these They were on the skin or embedded in it. All ticks survived the subsequent 72 hours of observation. The repellent time (effect duration) of the reference product can therefore be given as 4 hours, which, however, the total of 6 ticks would surely have pierced the dog's skin with a decrease in the effect of the product, all time they survived the time of later observation. 3. Test product (I) - during the 5 full days of the experiment time, no tick was found on the dog. On the clothes of the dog owner (all wore a clear long-sleeved T-shirt and white linen pants) a total of 5 ticks of the genus / was found. rizinus, 3 of which did not survive the observation time. After 72 hours of observation time, the total of 110 ticks of the untreated control and the ticks of the test product (TP I) were immersed for 5 minutes in the test product (I) according to the instructions of the immersion test of ectoparasite analysis, and all were dead 24 hours later. The 25 ticks that survived the reference observation time were submerged as above in the reference product for 5 minutes and survived an additional 72 hours and then by immersion for 1 minute in TP (I) after an additional 24 hours were classified as being dead. That experiment showed that the test product (I) not only shows a period of protection against ticks that lasts at least 4 hours, but also that the ticks were killed reliably after having been put in contact with the product and that the latter is therefore superior to the normal market, accepted reference as to the absolute protective effect against tick bites. As support for the lethal effect that occurs surprisingly from the repellent used according to the invention, the following studies were carried out with different insects as follows: 1. test product (III) compared to a commercial insect repellent (reference) which comprises as an active substance according to the 0.05% tag of Bio Allethrin and 0. 25% Permethrin in an aqueous emulsion. Acrylic tubes with L = 50 cm, B = 30 cm, D = 25 cm, whose backgrounds were each painted with 1 ml of TB (lll) and REF, respectively, served as test containers. In both the containers treated with TB (III) and in the containers treated with REF, each 10 test insects were placed on the bottom and after 1 minute of contact time they were transferred to an untreated container and observed for another 48 hours. hours.

Test insects I. cockroaches (Blatella germanica) III. ants (Lasius niger) Results Both test insects that were contacted with TP (III) and those that were contacted with REF were all dead after 48 hours. An additional observation for 72 hours showed no resuscitation, so that the use of quinic acid according to the present invention shows an effect comparable to that of the commercially accepted reference product.

Claims (7)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of natural and / or synthetic quinic acid (1, 3,4,5-tetrahydroxycyclohexane carboxylic acid) and / or shikimic acid as parasite repellents against flying, crawling, biting, teasing and sucking insects.

2. The use as claimed in claim 1, wherein the quinic acid is also dissolved in at least one suitable vehicle.

3. The use as claimed in claim 2, wherein in addition 0.1 to 50% by weight of quinic acid are dissolved in 50 to 99.9% by weight of vehicle.

4. The use as claimed in any of claims 2 and 3, wherein the vehicle is also water.

5. The use as claimed in any of claims 2 to 4, wherein glycerol, alcohols or propanediols are also included.

6. The use as claimed in claim 5, wherein also comprise 0.1 to 50% by weight of quinic acid, 0.1 to 99.8% by weight of water and 0.1 to 99.8% by weight of an additional vehicle .

7. - The use as claimed in any of claims 1 to 6, in the form of emulsions, dispersions, lotions, creams, gels or solutions.