JP5730980B2 - Insect repellent for internal use - Google Patents

Description

  The present invention relates to the use of an agent for repelling insects that is safe for internal use and a pharmaceutical composition containing the agent for repelling insects.

Mosquito bites cause not only discomfort with redness and itching, but also diseases such as Japanese encephalitis, West Nile fever, malaria, dengue fever, and filariasis, and are still a serious threat, especially in tropical and subtropical regions. ing. In other areas, it is well known from information from various media that it has become irrelevant due to local infection due to overseas travel boom, invasion from imported crops, expansion of habitat due to global warming, etc. It has become.
In addition to mosquitoes, there are many other diseases that are transmitted by fleas, flies, ticks, lice, and the like. In addition, those that do not directly affect health but that damage clothing by eating fiber keratin are also serious pests for us.

To date, many insect repellent sprays applied to skin and clothes containing diet (DEET, diethyl toluamide) have been used. Diet seems to have been used for over 40 years and there are no reports of serious health hazards, but there are strict conditions for use for safety, such as prevention of accidental ingestion, avoiding inhalation, and limiting to infants ( For example, refer nonpatent literature 1).
Furthermore, this technique has drawbacks such as being troublesome to apply because it has a large area to be applied, and being unable to be used on the face.

  In addition, a method of causing an insecticidal and bactericidal component of insects such as mosquitoes to exist in the space so as to have a certain concentration or more has been put into practical use for a long time with mosquito coils and camphors. Recently, synthetic pyrethroids and diets synthesized from active ingredients contained in insecticides have been used. However, this technique is limited to indoor use and has a drawback that it is difficult to use for outdoor activities.

  On the other hand, for consumers who hesitate to use such chemical substances, insect repellent technology using natural fragrances and essential oils has been put to practical use (see Patent Documents 1 to 4). However, none of these are based on internal use. Furthermore, among natural fragrances and essential oil components, citronellol, which is a non-aromatic monoterpene compound, is disclosed together with specific data on the contrary. Further, geraniol and linalool, which are the compounds, are also described as attractants although there is no disclosure of specific data (see Patent Document 5). Not all ingredients have an effective insect repellent effect.

  Thus, there are no reports of attempts to repel insects by taking a pest repellent component. Moreover, there are no reports of successful insect repellent by internal use in the present state of the art.

JP-A-3-285993 JP-A-7-112907 JP 11-269909 A JP 2003-138290 A JP-A-10-117657

Notification of the Director of Safety Measures, Ministry of Health, Labor and Welfare on August 24, 2005, No. 0824003

  Regardless of whether it is a chemically synthesized product or a natural ingredient, there is a subconscious that pest repellents are inherently dangerous (poisonous or harmful), so far, take repellents to get a repellent effect There was no room for the idea itself to be born. Even if such an idea is made, it will be dismissed as a dangerous and reckless idea from the viewpoint of those skilled in the art. This is supported by the fact that no reports or practical applications have been made so far.

  However, if the present inventors can provide a compound having an excellent insect repellent effect by internal use, it becomes a useful technique for human beings, and it is also useful if administered to pets or livestock that mediate pathogens. I started to study to challenge this taboo.

  The present inventors searched whether there are any known or unknown pest repellent components that have no safety problems even when taken, and orally ingest them to prevent pest repellents. We have been conducting intensive research for many years to see if the effect is manifested.

  Whether or not the insect repellent effect is achieved by oral administration may be evaluated by whether or not the insect repellent component is released on the human body surface after being absorbed in the digestive tract. There is a strong risk of human experimentation against this. Therefore, the present inventors have recognized the need to newly construct a new animal experiment system using animals.

  And as a result of intensive studies from various directions, the present inventors have found for the first time that the body odor of animals can be evaluated by urine odor, and that specific volatile components in urine change with age. As a result of further investigation by paying attention to this new knowledge, the present inventors realized a body odor having an insect repellent effect if an insect repellent component is orally administered to an animal and the component is excreted without being metabolized in urine. For the first time, he realized that he was able to establish a new animal experiment system for screening for orally administered insect repellents.

  That is, this system evaluates the effect of a test substance on body odor by orally ingesting the test substance into a test animal (animals that do not sweat, such as mice) and measuring the amount of the test substance in the urine. It is a new system. By using this system, it can be confirmed that the test substance administered orally is released on the surface of the human body without human experimentation.In other words, the body odor with insect repellent and insect repellent effect can be realized by internal use. Can be confirmed.

  In the course of further research, the inventors have succeeded in constructing another animal experiment system. That is, the test substance is orally ingested by an animal without body hair (for example, a hairless mouse), placed in a container together with a blood-sucking insect (for example, an adult female mosquito), and the total number of bloodsucking and landing at a predetermined time, and / or actually It was also found that the actual insect repellent and insect repellent action of the components taken internally can be evaluated by a test method for examining the number of blood sucked in the mouth.

  The present invention also newly provides a new animal experiment system for confirming such an internal insect repellent component. By using this system, it is possible not only to confirm the possibility of taking a known external insect repellent component, but also to develop a new internal repellent component.

Using the novel system according to the present invention, the insect repellent effect by oral administration of many insect repellent components was examined.
As a result, surprisingly, even with the same non-aromatic monoterpene compound, limonene, citral and citronellyloxyacetaldehyde exhibit an insect repellent effect by oral administration, but geraniol cannot be expected to have this effect. I found. In particular, it has been found that citral and citronellyloxyacetaldehyde exhibit an excellent effect by a small amount of oral administration, and the present invention has been completed.

  That is, this invention includes the following aspects, for example.

(1) An oral repellent pharmaceutical agent containing only citronellyloxyacetaldehyde as an active ingredient.
(2) The internal insect repellent pharmaceutical agent according to (1), characterized in that it is taken at an active ingredient amount of 0.1 to 0.5 mg / Kg per dose.

(3) The target pests are mosquitoes (Acaeca, Anopheles acaensis, etc.), flies (a house fly, abalone fly, black fly, amber flies, aerial fly, a fruit fly, etc.), a buyo (ayutsutomebuyu, umabuyu, ashimadayu), abu (Yeosobiabu, Kinirobu, Gomabubu, Beef Ab, Akaushi Abu, etc.), Fleas (Hitfish, Catfish, etc.), Tick (Yamanite, Tanegata, Mite, Mites, Tsutsugamushi), L Matsukareha, Iraga, etc.), fiber pests (Iga, Koiga, Hime Marutsu Shimushi, Himekatsuobushi, etc.), stink bugs (Spottle turtles, leafhoppers, bed bugs, etc.), ants (Ohari, Akamiari, Himeari, Azumaozazu, etc.), bees Wasps, Kiirosuzumebachi, lid Mont wasp, Yellow paper wasp, Nihonmitsubachi, Honeybee, Komaruhanabachi, for internal use insect pharmaceutical agent according to at least one selected from the carpenter bees etc.), characterized by (1) or (2).
(4) For humans, for pets (dogs, cats, rabbits, other mammals, birds, reptiles, etc., animals kept by humans for pets), livestock (cow, pigs, chickens, sheep, goats, (1) to (3), an insect repellent for internal use, characterized in that it is for use by humans such as horses.

(5) An insect repellent for internal use containing only citronellyloxyacetaldehyde as an active ingredient.
(6) The oral repellent for internal use according to (5), characterized in that it is taken in an amount of 0.1 to 0.5 mg / Kg of active ingredient per dose.
(7) The insect repellent for internal use according to (5) or (6), wherein the aroma of citronellyloxyacetaldehyde is not volatilized until reaching the digestive organs.
(8) The target pests are mosquitoes (Acaeca, Anopheles, Amanita, etc.), flies (a housefly, a mosquito fly, a fly), a fly, a fly, a fruit fly, a flyfish (Aokitsumegebuyu, Umabuyu, Ashimadayu, etc.), abu (Yeosobiabu, Kinirobu, Gomabubu, Beef Ab, Akaushi Abu, etc.), Fleas (Hitfish, Catfish, etc.), Tick (Yamanite, Tanegata, Mite, Mites, Tsutsugamushi), L Matsukareha, Iraga, etc.), fiber pests (Iga, Koiga, Hime Marutsu Shimushi, Himekatsuobushi, etc.), stink bugs (Spottle turtles, leafhoppers, bed bugs, etc.), ants (Ohari, Akamiari, Himeari, Azumaozazu, etc.), bees (5) to (7), characterized in that it is at least one selected from hornets, killer whales, phthalmon wasps, wasps, Japanese bees, honey bees, bumblebees, wasps, etc. Insect repellent taken.
(9) For humans, for pets (dogs, cats, rabbits, other mammals, birds, reptiles, etc., animals kept by humans for the purpose of pets), livestock (cattle, pigs, chickens, sheep, goats, The insect repellent for internal use according to any one of (5) to (8), wherein the insect repellent is for use by humans such as horses.

(10) A method for repelling humans or animals other than humans, characterized by taking or ingesting the agent according to any one of (1) to (9).
(11) Addition of citronellyloxyacetaldehyde as an active ingredient in an amount of 30 to 100 ppm, preferably 50 ppm to inhibit or counteract the insect repellent action and / or the ingredient having an insect attracting action (for example, citronellol, tetrahydro A method for producing an insect-repellent food or drink characterized by not containing geraniol, nerol, geraniol, etc.).

(12) A method of using an insect repellent food or drink characterized by comprising the following steps (consisting of the following steps):
(A) administering the agent according to any one of (5) to (8);
(B) After adsorbing the natural sweat or spontaneously evaporated sweat from the body surface while wearing the clothes;
(C) Wear the clothing to repel insects or store the clothing to protect the clothing itself from fiber pests.
(13) A mosquito accretion repellent and / or a blood sucking repellent characterized by comprising citronellyloxyacetaldehyde as an active ingredient.

The limonene, citral and citronellyloxyacetaldehyde of the present invention are useful because they have an insect repellent effect and are safe to be taken internally. A pharmaceutical composition, supplement or food or drink containing citral as an active ingredient is particularly useful because it exhibits an excellent pest repellent effect.
According to the present invention, there is no need for devices such as mosquito coils, mosquito traps, insect repellent sprays, etc., and there is no need to use the devices, and insects can be obtained by a simple method of ingesting a safe insect repellent. The remarkable effect that the awning can be achieved is achieved.

  The active ingredient compound according to the present invention is (a) a substance that is safe when taken orally and has excellent insect-proofing and insect-repelling properties, and (b) a substance that is released from sweat glands after being absorbed into the body. (C) In addition, it is effective even with a small dose, and is effective as well as lasting (in other words, it is effective immediately when taken, and also has a long period of insect repellent and insect repellent properties) It has characteristics and properties such as (substance), (d) and a substance that does not interfere with social life (a substance that has a pest repellent effect and is not unpleasant to humans).

  Compounds having these characteristics and properties have not been known in the past, and active compound compounds do not have a certain directionality or common characteristics, and there are many compounds that are not effective even with similar compounds. It is necessary to confirm the effect of each, and as a result of repeated trial and error, the present invention has finally been completed. Accordingly, an insect repellent for internal use containing such a compound as an active ingredient is not only novel but also cannot be easily inferred, and sufficiently satisfies patent requirements.

  In addition, the present invention has succeeded in developing a novel screening method. If a compound is screened by this screening method and the properties (a) to (d) are confirmed for the obtained compound, the object can be obtained. An internal insect repellent (an internal insect repellent compound) can be selected and obtained.

  In the present invention, insect repellent means broadly preventing harmful insects from causing harm to humans and animals (including pets and livestock), and does not cause harmful insects. In addition to this, there are further examples of eradicating pests (at least one action of insect repellent, repellent, insect repellent action).

The vertical axis represents the peak intensity of each component, the horizontal axis represents the number of days elapsed from the start of the test, and the graph compares each component in the urine of a mouse administered with the test substance.

Non-aromatic terpene compounds, limonene and citral used in the present invention are listed in the food additive list, and citronellyloxyacetaldehyde has a track record as a food additive.
In the present invention, the amount of limonene, citral and citronellyloxyacetaldehyde used is within the range of safe amounts for oral intake described in, for example, the Food Additives Official Document.

  The dose or intake of limonene, citral and citronellyloxyacetaldehyde per dose varies depending on the age, but is usually 0.05 mg / Kg or more, and preferably 0.1 mg to 2 mg / Kg. In particular, when only citral or citronellyloxyacetaldehyde is used as an active ingredient, 0.1 mg to 0.5 mg / Kg is particularly preferable. And usually this is taken or ingested 1 to 3 times a day.

  In the present invention, when the dose or intake of limonene, citral and citronellyloxyacetaldehyde is extremely large (for example, 100 mg / Kg or more, further 200 mg / Kg or more, etc.), an effective insecticidal effect Is not preferred because it cannot be obtained. The present invention is also very characteristic in that the dose or intake of the active ingredient is not proportional to the insect repellent effect (the effect cannot be obtained in a concentration-dependent manner), for example, 5 mg / Kg or less, further 1 mg / Kg or less. The insect repellent is most effective in a relatively low dose range.

Insect repellent compounds for internal use such as limonene according to the present invention (and / or internal insect repellents containing such compounds as active ingredients) are pharmaceuticals, quasi-drugs (for example, Regain (Daiichi Sankyo Healthcare Co., Ltd. products) ), Etc.), supplements, foods and beverages and the like.
In addition, the insect repellent for internal use such as limonene according to the present invention is not only intended for humans but also for humans for the purpose of pets such as dogs, cats, rabbits, other mammals, birds and reptiles. The effect is also exerted on animals (pets) and animals (domestic animals) kept for human use such as cows, pigs, chickens, sheep, goats and horses. The target animal is not limited to animals that sweat, but can also be applied to animals that do not sweat, such as dogs and mice, and may or may not have body hair.

  When the compound of the present invention is used as a composition, when the dosage form is a liquid or semi-solid preparation, the content of limonene, citral or citronellyloxyacetaldehyde, or the total content thereof is determined by taking the above dose or intake once. What is necessary is just to add so that it may be contained as a quantity.

In particular, when the compound of the present invention is used in a composition as a supplement or food / drink (including not only for humans but also pet food, livestock feed, etc.), a fragrance component and / or an active component having an insect attracting action It is important not to contain a component that inhibits or cancels the insect repellent action (for example, citronellol, tetrahydrogeraniol, nerol, geraniol described in Patent Document 5).
Some natural fragrances and essential oils contain limonene, citral, and the like, but also other fragrance ingredients such as citronellol. Therefore, such a configuration is not preferable because the insect repellent effect of the active ingredient is inhibited or offset. Since the supplement or food and drink according to the present invention does not contain a fragrance component having an insect attracting action and / or a component that inhibits and cancels the insect repellent action of the active ingredient, it exhibits a remarkable insect repellent effect, and Supplements or foods and beverages using the compounds of the present invention can be clearly distinguished from natural fragrances and essential oils, and supplements and foods and beverages using these.

  Further, when the compound of the present invention is used particularly for supplements and foods and drinks, for example, the active ingredient is added after microencapsulation by a conventional method or inclusion by a known inclusion compound such as cyclodextrin, etc. It is preferable to make the active ingredient not exhibiting the function of the perfume by the time (a state where the aroma is not volatilized until reaching the digestive organs). Thereby, the supplement or food and drink according to the present invention has almost no decrease due to volatilization of the active ingredient even if it is not a sealed product, and the supplement or food and drink using the compound of the present invention uses the active ingredient as a fragrance. It is clearly distinguishable from the supplements and foods and drinks used. Further, the aroma of the active ingredient may be completely inhibited by using a sufficient amount of other perfume ingredients in combination, and the above-described configuration (a state where the active ingredient has not exhibited the function of the perfume by the time of eating) may be achieved.

Specific forms (dosage forms) of the composition of the present invention are solid preparations, semi-solid preparations, or liquids. For example, tablets, chewable tablets, granules, powders (including fine granules), capsules, liquids Etc. In producing a preparation using the composition of the present invention, pharmaceutical additives suitable for each dosage form, other food additives, base materials, etc. are used as appropriate, and ordinary methods described in the Japanese Pharmacopoeia and the like And can be manufactured.
For example, when the dosage form of the composition of the present invention is a tablet, those described in the examples of the present invention are used as excipients, hydroxypropylcellulose, polyvinyl alcohol, etc. are used as binders, and magnesium stearate is used as a lubricant. , Talc, etc. can be used.

  Further, when the dosage form of the composition of the present invention is a powder or a capsule, those described in the Examples of the present invention can be used as excipients, and hydroxypropyl cellulose, polyvinyl alcohol, etc. can be used as binders. . In addition, in each form (dosage form), if necessary, disintegrants such as crospovidone, low-substituted hydroxypropylcellulose, carmellose, surfactants such as polysorbate, adsorbents such as calcium silicate and light anhydrous silicic acid, Coloring agents such as iron sesquioxide and caramel, stabilizers such as sodium benzoate, pH regulators, and other food additives can be blended.

Even when the dosage form of the composition when the compound of the present invention is used as a composition is a food, it can be produced by a known production facility or the like.
For example, the compound of the present invention can be produced according to a conventional method as appropriate by using it in combination with other foods or food ingredients. The dosage form may be selected as appropriate, but it may be solid (powder, granule, etc.), paste, liquid, suspension or emulsified liquid. For example, sweeteners, acidulants, vitamins and other drinks You may formulate in an insect repellent drink using the various components normally used for pharmaceutical manufacture. In this case, it is important not to include a fragrance component having an insect attracting action and / or a component that inhibits or offsets the insect repellent action of the active ingredient. Moreover, even if what was formulated into the pharmaceutical composition or the supplement dosage form is used as a food-drinks composition, there is no problem. In addition, in the manufacture of insect-repellent foods and drinks containing citronellyloxyacetaldehyde as an active ingredient, the amount of the ingredient is preferably 30 to 100 ppm, preferably 30 to 50 ppm.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

(Example 1) Tablet (1) Ingredients The ingredients of this tablet are shown in Table 1 below.

(Table 1)
In 1 tablet (mg) (mg)
――――――――――――――――――――――――――――――
Limonene or citral 30-
Citronellyloxyacetaldehyde-20
Talc 30 30
Magnesium stearate 10 10
Hydroxypropyl cellulose 5 5
Crystalline cellulose 250 250
Corn starch 150 150
Lactose appropriate amount appropriate amount
――――――――――――――――――――――――――――――

(2) Manufacturing method Take the above ingredients and the amount, and manufacture tablets according to the section of “General Tablets” “Tablet”.

(Example 2) Granule (1) component The components of this granule are shown in Table 2 below.

(Table 2)
In 1 package (mg) (mg)
――――――――――――――――――――――――――――――
Limonene or citral 30-
Citronellyloxyacetaldehyde-20
Corn starch 350 350
Hydroxypropylcellulose 50 50
Lactose appropriate amount appropriate amount
――――――――――――――――――――――――――――――

(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”.

Example 3 Capsule (1) Component The components of this capsule are shown in Table 3 below.

(Table 3)
In 1-2 capsules (mg) (mg)
――――――――――――――――――――――――――――――
Limonene or citral 30-
Citronellyloxyacetaldehyde-20
Corn starch 350 350
Hydroxypropylcellulose 50 50
Lactose appropriate amount appropriate amount
――――――――――――――――――――――――――――――

(2) Manufacturing method After taking the above components and quantities and preparing a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granules”, it is filled into capsules to produce hard capsules.

(Example 4) Liquid agent (1) component The component of this liquid agent is shown in Table 4 below.

(Table 4)
In 100 mL (mg) (mg)
――――――――――――――――――――――――――――――
Limonene or citral 30-
Citronellyloxyacetaldehyde-20
Sodium benzoate 70 70
Polyvinyl alcohol 60 60
Sucrose 900 900
Purified water balance remainder
――――――――――――――――――――――――――――――

(2) Manufacturing method The above ingredients and quantities are taken and a liquid preparation is produced according to the section “General preparation preparations” “Liquid preparation”.

(Test Example 1) Insect repellent effect test 1
The insecticidal effect test for the test substance is shown below.

(1) Test substances Linalool, citronellal, limonene and geraniol were purchased from Sigma-Aldrich. The test substance was prepared and prepared as an aroma mix containing 7.5 μg of each of these. The dose volume was 0.2 mL / Kg in all cases.

(2) Animals A 6-week-old BALB / c male mouse was purchased from Nippon Charles River Co., Ltd., and was controlled in a rat breeding room controlled at a temperature of 20 to 26 ° C., a humidity of 30 to 70%, and an illumination time of 7:00 to 19:00. Five rats were placed in each ratchet bracket taper cage, and they were preliminarily raised for about one week by freely ingesting feed (F-2 for breeding mice and rats, manufactured by Funabashi Farm) and tap water through a water filter. On the day of the test, the animals were visually observed for their health and confirmed to be good, and their body weight was measured. The animals were randomly divided into 5 groups per group.

The present inventors have continued research on the relationship between the animal's age and body odor for many years, and found that the animal's body odor can be evaluated by urine odor, and that specific volatile components in urine change with age.
Based on this result, the present inventors have found that if an insect repellent component is orally administered to an animal and the component is excreted without being metabolized in urine, a body odor having an insect repellent effect can be realized.
Furthermore, the present inventors can realize an oral insect repellent that is harmless to the human body if a substance having an insect repellent and insect repellent effect is orally ingested and the substance is released from the surface of the human body without being metabolized. I noticed.

  Since the verification of this idea may conflict with Article 32 of the Patent Law, it must be verified by animal testing. Therefore, the present inventors have come to the conclusion that the presence or absence of body odor having an insect repellent / repellent effect can be evaluated by orally ingesting a test substance into a test animal and measuring the amount of the test substance in the urine. It came.

  That is, the present invention also relates to a novel screening method for an orally administered insect repellent (component) by orally ingesting a test substance into a test animal and measuring the amount of the test substance in the urine. In this screening method, a test substance in urine, that is, a test substance dissolved in urine and / or a test substance volatilized from urine is measured. In the present example, the test substance volatilized from urine was measured.

  The method for measuring the test substance released from urine is not particularly limited. First, sample extraction methods include solid-state extraction methods such as conventional solvent extraction methods and solid-phase extraction methods, as well as solid preparation methods. The phase micro extraction method (Solid Phase Micro Extraction: SPME) can be advantageously used, and the method using the SPME in the head space (HS-SPME) is particularly suitable for sampling of volatile substances.

  SPME is coated with an adsorbent on the part corresponding to the needle of the syringe, and after adsorbing the headspace gas, it can be directly thermally desorbed by a measuring instrument such as a gas chromatograph, and is simple and highly reproducible. As described above, SPME integrates sampling, extraction, concentration, and sample injection functions into a single small instrument, and has a feature that it can be performed without using a solvent. The test substance in the sample can be directly extracted and concentrated with an extraction fiber, which is a very useful instrument, and a commercially available product can be used as appropriate.

  After extracting the sample as described above, the components are measured. As a measuring method, conventional methods such as gas chromatography (GC), GC / mass spectrometry (GC-MS), hydrogen ion flame detector-GC, HPLC (high performance liquid chromatography), and capillary electrophoresis are appropriately used. . SPME and HS-SPME can be routinely used in combination with GC such as GC or GC / MS.

  In this example, mouse urine was analyzed by measuring a sample extracted by HS-SPME with a hydrogen ion flame detector-gas chromatography.

  The test was conducted as follows. First, the test substance was orally administered from 4 to 5 pm on the test start day. On the second day and thereafter, it was orally administered once a day around 5 pm.

  Urine was collected as a body odor substance. A specimen was collected by a headspace solid-phase microextraction method and analyzed by a chemical analysis method using a hydrogen ion flame detector-gas chromatography.

In the HS-SPME method, a 10 ml sample is taken into a 20 ml headspace vial, 5 μl of 0.1% cyclohexanol is added as an internal standard substance, and the aromatic components in the headspace are adsorbed on the SPME fiber at 35 ° C. for 10 minutes. The amount of volatile components was measured. Detailed conditions are as follows.
SPME fiber: Superco DVB / Carboxen / PDMS
Analyzing device: Hewlett Packard 5890 (with Restek Stabilwax column)
Analysis conditions: carrier gas: helium; flow rate: 2.4 ml / min; vaporization chamber temperature: 230 ° C;
Column temperature: 5 minutes at 40 ° C, then increase to 240 ° C by 5 ° C per minute

  The peak intensity of each component in urine was determined by subtracting the pre-dose value and the post-dose peak value.

(4) Test results The results obtained are shown in FIG. In addition, a value is an average value of 5 animals per group.
From FIG. 1, it was recognized that a body odor having an insecticidal effect can be realized by ingesting limonene, citronellal and linalool. However, even with the same non-aromatic monoterpene compound, it was not recognized that body odor having an insecticidal effect could be realized by ingesting geraniol.

(Test Example 2) Insect repellent effect test 2
(1) Test substance Limonene, citronellyloxyacetaldehyde, citral, linalool and citronellal were purchased from Sigma-Aldrich. These stock solutions diluted with purified water to a concentration of 50 ppm, 500 ppm and 5000 ppm were used as test substances. In all cases, the dose was 0.2 mL / test animal.

(2) Test animal An unblood-sucking female mosquito (Human striped mosquito) was used as a blood-sucking pest, and an animal (hairless mouse male) with exposed skin was used as the blood-sucking animal.

(3) Test method One hour after oral administration of the test drug, the hairless mouse is placed in a transparent acrylic container (300 mm x 300 mm x 300 mm) with nylon goose sleeves containing 20 adult human blood suckers that are not blood-sucked. The number of mosquitoes on the mouse was measured every 30 seconds for 5 minutes [total number of accretion (administration of test drug)]. In addition, the number of mosquitoes that actually sucked blood for 5 minutes [total blood sucking number (test drug administration)] was measured.
For comparison of the effects of the test drug, the [total number of accretion (non-administration)] and the actual [total blood absorption (non-administration)] when the test drug was not administered were measured for each test drug.
The test was performed under the conditions of 24.2 ± 1 ° C. and 55 ± 3% RH (relative humidity). The accretion evasion rate and blood sucking evasion rate were calculated by the following equations.

Accretion avoidance rate (%) = [1−total accretion number (test drug administration) / total accretion number (non-administration)] × 100
Blood absorption repellent rate (%) = [1-total number of blood absorption (test drug administration) / total number of blood absorption (non-administration)] × 100

(4) Test results Tables 5 and 6 show the accretion avoidance rate and blood sucking avoidance rate of each test drug. The numerical value is an average value of test results obtained three times.
Table 5 shows that citral and limonene have a repellent effect on both the total number of mosquitoes and the number of blood sucked at any dose (concentration), and in particular, citral has an excellent insect repellent effect. Moreover, about citral and citronellyloxyacetaldehyde, the negative dose dependence was recognized, and it was recognized that the insect-repellent effect which was excellent was expressed, so that the dose was low. On the other hand, from Table 6, a positive dose dependency was observed for linalool and citronellal, and an insect attracting action was observed at a low dose (for example, about 0.5 mg / Kg).

(Table 5)
Test substance Concentration ppm Accretion repellent rate% Blood absorption repellent rate%
―――――――――――――――――――――――――――――――
50 25.4 25.4
Limonene 500 25.9 20.1
5000 20.4 20.6
―――――――――――――――――――――――――――――――
Citronellyl 50 40.2 71.0
Oxyacetate 500-36.7-1.3
Aldehyde 5000-65.1-32.8
―――――――――――――――――――――――――――――――
50 73.5 82.1
Citral 500 61.0 69.6
5000 41.5 22.6
―――――――――――――――――――――――――――――――

(Table 6)
Test substance Concentration ppm Accretion repellent rate% Blood absorption repellent rate%
―――――――――――――――――――――――――――――――
50-39.0-9.4
Linalool 500 34.8 42.4
5000 20.6 35.7
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50 -20.8 6.3
Citronellal 500 6.2 14.9
5000 28.9 31.6
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  The limonene, citral, and citronellyloxyacetaldehyde of the present invention exhibit pest repellent effects by internal use, and citral is particularly useful because it has an excellent insect repellent effect and is safe to use.

Claims (8)

An insect repellent pharmaceutical agent for internal use that contains citronellyloxyacetaldehyde alone as an active ingredient and is taken in an amount of 0.1 to 0.5 mg / Kg of active ingredient at a time .   The target pest is at least one selected from mosquitoes, flies, gnats, flies, fleas, ticks, lice, cockroaches, moths, fiber pests, stink bugs, ants, and bees. Insect repellent medicine.   It is any one for humans, pets, and livestock, The insect repellent pharmaceutical agent for internal use of Claim 1 or 2 characterized by the above-mentioned. Only citronellyloxyacetaldehyde is used as an active ingredient, and it is ingested in an amount of 0.1 to 0.5 mg / Kg of active ingredient at a time. Inhibits and offsets the insect repellent action of the active ingredient and the active ingredient. An insect repellent for internal use , characterized in that it does not contain any ingredients to be used.   The insect repellent for internal use according to claim 4, wherein the aroma of citronellyloxyacetaldehyde is not volatilized until it reaches the digestive organs.   The target pest is at least one selected from mosquitoes, flies, gnats, flies, fleas, ticks, lice, cockroaches, moths, fiber pests, stink bugs, ants, and bees. An insect repellent for internal use.   The insect repellent for internal use according to any one of claims 4 to 6, wherein the repellent is for human use, pet use, or livestock use. Insects for animals other than humans, characterized by taking or ingesting an insect repellent for internal use containing only citronellyloxyacetaldehyde as an active ingredient at an active ingredient amount of 0.1 to 0.5 mg / Kg per dose How to avoid.

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