JPH0436201A - Production of synthetic capsaicins and microcapsule pharmaceutical preparation thereof in the same bath - Google Patents

Abstract

PURPOSE:To obtain a safe and readily handleable preparation with hardly any irritation by condensing an acid halide with vanillylamine in a solvent, the dispersing the resultant capsaicins in water in a reaction bath thereof and subsequently converting the dispersion into oil-in-water type microcapsules. CONSTITUTION:A compound expressed by formula I (R is 4-12C alkyl, alkenyl or alkynyl; Hal is halogen), e.g. pelargonic acid chloride is condensed with vanillylamine or a salt thereof in a solvent, as necessary, in the presence of an acid binder to provide a compound expressed by formula II, e.g. N-(4- hydroxy-2-methoxybenzyl)-nonanamide, which is then directly dispersed in water in a reaction bath thereof and further subjected to an oil-in-water type polymerization method such as an interfacial polymerization method or in-situ polymerization method to afford a microcapsule pharmaceutical preparation of capsaicins. Thereby, the objective preparation with hardly any irritation can be obtained by starting from raw materials with hardly any irritation, without any contact of workers engaged in production thereof in spite of the strong irritating property of capsaicins.

Description

[Detailed Description of the Invention] [Industrial Application Field] Kabsaicin is known as a pungent component of chili peppers.
It can be used as an ingredient in patches, or as a repellent to prevent rodents and other animals from eating or biting it due to its strong pungent taste and irritant properties, and it can also be put in the mouth by children. It is known that it can be applied to an unbroken object to prevent it from being licked or chewed.

However, due to its properties, bepsaicin has strong irritation and pungency to the human body, especially to the mucous membranes, and in some cases, contact with or inhalation of even a small amount can cause rashes and sneezing, or if it gets into the eyes, it can cause temporary blindness. In addition, if it adheres to the human body or clothing, it leaves a strong pungent taste and is extremely difficult to handle. The present invention synthesizes these cabsaicins in a sealed state and makes them into microcapsules that are less irritating.Since the form is safe and easy to handle, it can be mixed into various paints and resins, for example. Microcapsules are easier to use and have long-lasting efficacy, which is a feature of microcapsules. By treating equipment, building structures, etc., trees, etc., it is expected to be used in a variety of fields, such as as a preventive agent against feeding damage by animals and school buildings, and as a long-lasting patch. Therefore, it plays a large role in industry.

[Conventional technology]

As mentioned above, bebsaicin has a strong irritant and pungent taste, which makes it extremely difficult not only during the manufacturing process, but also in all handling situations such as weighing, packaging, and removing it after synthesis. Extreme care was also required when processing. For example, it is stated in the literature that the synthesis of cabsaicins was carried out in a completely closed system (Hiroo Ueda, Perfume No. 129, 41-46, October 1982).

[Invention or problem to be solved]

Kabsaicin has been recognized to be useful as a patch and as a repellent ingredient for animals such as rats, but due to its strong irritant properties, extremely careful handling is required, so it is difficult to produce it industrially. In particular, it required a considerable amount of equipment from the standpoint of safety and health, and it had to be quite complicated to operate. In view of these points, the present invention uses raw materials that are less irritating, is manufactured without giving workers involved in the production an opportunity to come into contact with highly irritating cabsaicin, and when taken out as a product, it is already less irritating. The challenge was to make it into a pharmaceutical form.

[Means to solve the problem]

As a result of intensive research to solve the above-mentioned problems, the inventors found that
Producing turnip saicin using less irritating raw materials,
We succeeded in producing microcapsules of mildly irritating kabsaicin in a ~ bath without directly contacting the highly irritating kabsaicin drug substance by directly feeding the raw materials necessary for microencapsulation into this reactor. However, the present invention was achieved.

That is, kabsaicin represented by formula (1) (wherein R represents an alkyl group, alkenyl group, or alkynyl group of 04 to C12) is combined with formula (n) and R-C-Hal (TI) (formula During,
R represents a C2-C1□ alkyl group, alkenyl group or alkynyl group, and Hal represents a halogen atom. ) is obtained by condensing vanillylamine or its salt in a solvent, if necessary in the presence of an acid binder, and then raw materials necessary for microencapsulation such as an encapsulating agent are directly added to the reaction mixture. When the oil-in-water type microcapsules are produced by introducing the microcapsules into the microcapsules, it is possible to obtain microcapsules of kabsaicin which are safe for manufacturing workers, are bulky, and are easy to handle.

Solvents used in the condensation reaction include water, aromatic hydrocarbons such as benzene, toluene, and xylene, hexane, heptane,
Aliphatic hydrocarbons such as petroleum benzene, halogenated hydrocarbons such as dichloroform and dichloromethane, ethers such as diethyl ether, tetrahydrofuran, and dioxane, and phthalate esters, adipate esters, phosphate esters, maleate esters, etc. The main examples include solvents used as plasticizers for resins, and these include two or more types (
For example, it can also be used as a mixed solvent of water and Hensen, etc.). An acid binder is not necessary when using 2 equivalents or more of hanylylamine with respect to the compound of formula (II), or
When an equivalent amount of hanylylamine is used, one equivalent or more of the acid binder is removed, and when a hydrochloride, hydrobromide or other salt of hanylylamine is used, the salt is removed, and the formula (I
In order to condense with the compound [) and complete the reaction, one or more acid binders in an amount of 2 equivalents or more relative to the salt are required. Examples of acid binders include bases such as alkali metal hydroxides (NaOH, KOH, etc.), alkaline earth metal hydroxides (Ca(OH)2, Mg(OH)2, etc.), alkali metal hydrides (NaH, etc.), and alkalis. Metal Alcolade (N
aOCJs, etc.), alkali metal oxides (Na20, K2
O, etc.), alkali metal carbonates (K2CO*, Na2C
L, etc.), sodium amide, triethylamine, N.

Examples include aliphatic and aromatic tertiary amines such as N-dialkylaniline and pyridine, and silver oxide can also be used. Further, when a reaction is carried out in a two-phase system by mixing water and a water-insoluble solvent, it is also possible to use a phase transfer catalyst such as tetra-n-butylammonium or triethylbenzylammonium chloride.

The above condensation reaction can usually be carried out at a temperature between room temperature and the boiling point of the solvent.

Also, are there any raw materials represented by compound (n) in the formula that can be purchased as reagents? If desired, the compound represented by can be easily obtained by reacting it with an excess of thionyl chloride, phosphorus trichloride, phosphorus tribromide, etc. in a condensation solvent as described above. Therefore, the present invention uses the compound of formula (I [I) as a starting material to produce the compound of formula (n), then performs a condensation reaction to produce the compound of formula (I), and finally microencapsulates. It is also possible to perform all three steps in one bath.

Examples of the kabsaicins of formula (I) of the present invention include N-
(4-Hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide (Cabsain), N
-(4-hydroxy-3-methoxybenzyl)-8-methylnonanamide (dihydrocabsaicin), N-(4-
Hydroxy-3=methoxybenzyl)-7-methyloctanamide (nordihydrocabsaicin), N-(4-hydroxy-3-methoxybenzyl)-9-methyldecanamide (homodihydrocabsaicin), N-(4-hydroxy -3-methoxybenzyl)-9-methyldec-trans-7-enamide (homo kabsaicin), N-(4-
Examples include hydroxy-3-methoxybenzyl)-nonanamide. After obtaining crude kabsaicin in the solvent, microencapsulation was performed as it was in the reactor, or if necessary, water and an insoluble or poorly soluble solvent were added to the reactor and stirred for a while. After that, microencapsulation is performed after adding a purification operation to remove the aqueous layer, or the solvent used in the reaction is distilled off by vacuum distillation etc. before encapsulation, and the residue obtained is microencapsulated and stimulated. To obtain microcapsules of cabsaicin having almost no irritation by encapsulating the strongly toxic cabsaicin in the capsule.

The reaction vessel used in the present invention is equipped with a stirrer whose rotation speed can be varied from low to high speed in order to carry out the process from synthesis to microencapsulation in one bath, and the contents can be heated with a jacket, an immersion heater, etc., and a stopper is provided at the bottom. It is necessary to have an outlet with a In addition, since vacuum distillation may be required in some cases, it is convenient to have a reaction bath that can perform vacuum distillation.

When producing the raw material of kabsaicin, a solvent with a higher specific gravity than water is used, and when post-processing is performed such as washing with water, the target substance will be in the lower layer. For this reason, it is desirable to place a storage tank for the target material connected to the discharge port. After draining the aqueous layer, the target product may be returned from the storage tank to the reaction vessel and subjected to the microencapsulation process. Of course, these series of operations are performed in a closed system. In this encapsulation, it is necessary to carefully consider the encapsulation conditions in order to efficiently encapsulate most of the kabsaicins, and in some cases, it is necessary to carefully consider the encapsulation conditions. It can also be produced by a chemical method. Also, as for the average particle size of the microcapsules, should we consider the encapsulation conditions and select the optimal diameter for the application?
It is about 50 μm and easy to manufacture. The microencapsulation of the present invention is an interfacial polymerization method in which water-insoluble or sparingly soluble kabsaicin is dispersed in water, and a core substance containing kabsaicin and a water-insoluble polymer film are formed on the surface of the dispersed particles. It may be formed by an oil-in-water type polymerization method such as or in-5 intu polymerization method, or is not limited to these two methods as long as it is an oil-in-water type polymerization method.

The case of interfacial polymerization method will be explained.

Oil-soluble film agent A is dissolved in the synthesized hydrophobic core substance containing cabsaicins, water and auxiliary substances such as dispersants are added thereto, and the mixture is stirred under predetermined stirring conditions to form the hydrophobic core substance and the hydrophobic core substance in the aqueous phase. A system is prepared in which a solution of oil-soluble film agent A is dispersed with a desired particle size. While stirring this system, an aqueous solution of water-soluble membrane agent B is added to cause both membrane agents to react at the interface of the dispersed particles, forming a polymer membrane that is insoluble in both the core substance and water, thereby encapsulating the hydrophobic core substance. (1-stage encapsulation method). In order to obtain microcapsules containing less free kabsaicin compounds, the following multi-stage encapsulation can be performed. In other words, a solution of oil-soluble film agent C in a solvent that is difficult to be miscible with water and has high solubility for kabsaicins is added to the microencapsulated system either as it is or pre-dispersed in water, and then stirred under predetermined stirring conditions. The water-soluble membrane agent is reacted under the following temperature conditions to form a polymer membrane again at the interface of the dispersed particles (two-stage encapsulation method). By repeating this operation in multiple stages, free kabsaicin is efficiently incorporated into the solvent serving as the core material, and microcapsules with extremely low free kabsaicin are produced (multi-stage encapsulation method). The oil-soluble film agent A used here may be the same as C, and the water-soluble film agent B may be the same as or different from D, and examples thereof include the following.

Examples of oil-soluble film agents include polyvalent isocyanate, polyvalent carboxylic acid chloride, polyvalent sulfonic acid chloride, etc., such as hexamethylene diisocyanate, trimethylhexamethylene diisocyanate, isophorone diisocyanate, phenylene diisocyanate, toluene diisocyanate, xylylene diisocyanate, naphthalene diisocyanate. , polymethylene polyphenylisocyanate, sebacic acid dichloride, adipic acid dichloride,
Acelaic acid dichloride, terephthalic acid dichloride, trimesic acid dichloride, pensene sulfonyl dichloride, etc. On the other hand, water-soluble membrane materials include polyvalent amines, polyvalent hydroxy compounds, etc., such as ethylenediamine, hexamethylenediamine, phenylenediamine, diethylenetriamine, triethylene. Examples include tetramine, piperazine, ethylene glycol, butanediol, hexanediol, polyethylene glycol, etc.

The In 5 itu polymerization method will be explained.

In the in-5-itu polymerization method, the membrane material is dissolved in either a hydrophobic core substance containing the active ingredient or an aqueous phase, the hydrophobic core substance is dispersed in the aqueous phase, and the core substance and water are mixed at the interface of the dispersed particles. This is a method of manufacturing microcapsules by forming an insoluble polymer film on both phases, and is different from interfacial polymerization. In the case of the method of the present invention, after a suspension of microcapsules of kabsaicins synthesized in the aqueous phase is created by this polymerization method, (
(1-stage encapsulation method), in this system: ■ disperse a hydrophobic core substance in which the oil-soluble film material E is dissolved in a solvent that has high solubility and is difficult to miscible with water; After dispersing a solvent that has high solubility and is difficult to be miscible with water, water-soluble membrane material F is added to this system as it is or dissolved in water to make it insoluble in both the core substance and the water phase at the interface of the dispersed particles. (two-stage encapsulation method). By repeating this operation in multiple stages, the free active ingredient is efficiently incorporated into the solvent serving as the core substance, and microcapsules containing a small amount of free kabsaicins are produced (multi-stage encapsulation method). Examples of the membrane materials E and F include the following.

As the oil-soluble membrane material E, a radical polymerized material such as acrylic ester, methacrylate ester, vinyl acetate, styrene, divinylbenzene, or ethylene dimethacrylate is used, and as the water-soluble membrane material F, urea/formalin, It is preferable to form a capsule membrane by a polyaddition reaction such as melamine/formalin or phenol/formalin.

The type and amount of membrane material used in the method of the present invention are selected depending on the type of core material and the intended use of the microcapsule. In addition, the method of the present invention uses interfacial polymerization method and In 5i
Multi-stage encapsulation may be performed by combining tu polymerization methods. In addition, if solid microcapsules such as powder are required depending on the application, the manufactured suspension microcapsules are dried using a spray dryer or multi-stage hot air dryer to remove moisture and easily evaporate. If a solvent is encapsulated in the capsule, the solvent can be removed to obtain a dry preparation.

Next, microcapsules≠ There are dispersants for dispersing the hydrophobic core substance in the aqueous phase as essential auxiliaries, but specific examples include gum arabic, sodium alginate, locust bean gum, and xanthan gum Normally, the suspension composition at the time of microencapsulation of natural polysaccharides, semi-synthetic polysaccharides such as carboxymethylcellulose and methylcellulose, and synthetic polymers such as polyvinyl alcohol, etc., is 0. 01-10.0%, preferably 0.1-3.0%.

In addition, polyoxyethylene alkyl ether, polyoxystylene alkyl allyl ether, alkylphenyl condensate ether, polyoxyethylene alkyl ester, polyoxyethylene alkylamino ether, polyoxyethylene alkylamide, polyoxyethyne polyoxypropylene One or more surfactants such as block polymer, polyoxyethylene vegetable oil ether, sorbitan fatty acid ester, and polyoxyethylene sorbitan fatty acid ester are used in an amount of usually 10% or less, preferably 3% or less. In addition, when dissolving cabsaicin with a solvent to use it as a capsule core substance, for example, ethers such as butyl ether, ethyl vinyl ether, etc.
Aliphatic and aromatic hydrocarbons such as heptane and xylene,
Plasticizers mainly for resins such as halogenated hydrocarbons such as dichloromethane and trichloroethane, mineral oils such as machine oil, vegetable oils, phthalate esters, adipate esters, phosphate esters, maleate esters, and low-molecular epoxy compounds. One or more kinds of solvents such as those used as solvents are used. Other auxiliary agents that may be added to the core material and/or aqueous phase include a fungicide, a specific gravity adjuster, and depending on the active ingredient, a decomposition inhibitor and a pH adjuster.

〔Effect of the invention〕

As a result of producing kabsaicin according to the present invention, it is possible to produce microcapsules that are synthesized from kabsaicin, which has a strong irritant effect even in trace amounts, or from raw materials with almost no irritant properties, and have very little free kabsaicin in the same bath. It was possible to obtain a safe and easy-to-handle formulation with minimal irritation without having to be directly touched by workers involved in manufacturing.

〔Example〕

The present invention will be explained below with reference to Examples (parts represent parts by weight).

Example 1 4-Hydroxy-3-methoxybenzylamine hydrochloride 5
8.5 parts of benzene, 200 parts of benzene, and 200 parts of benzene were placed in a reactor having a three-one motor with variable rotation speed and an outlet with a stopper at the bottom and stirred. 58 parts of potassium carbonate are added thereto, and further 54 parts of pelargonic acid chloride are added dropwise at room temperature. If stirring is continued for 3 hours, the reaction will be completed. After stopping stirring and allowing the mixture to stand for 30 minutes, the lower aqueous layer is discharged from the bottom. Next, by almost completely removing the solvent by distillation under reduced pressure, a composition of N-(4-hydroxy-3-methoxyhensyl)-nonanamide can be obtained. A very small amount was collected and the purity of N-(4-hydroxy-3-methoxyhensyl)-nonanamide was determined by high performance liquid chromatography (hereinafter referred to as HPLC) to be 92.1%. The irritation to mucous membranes was severe. In this reactor, 85.6 parts of dioctyl phthalate, 25.7 parts of Millionate 3040 (manufactured by Nippon Polyurethane Co., Ltd.), and Nucalgen D-
Add 5.1 parts of 230 (manufactured by Takemoto Yushi Co., Ltd.) and stir, then add 284 parts of a 1% aqueous solution of gum arabic, and after stirring, add 650
Stir at rpm for 10 minutes to obtain a dispersion. Next, stir 2
The speed was lowered to 50 rpm, and an aqueous solution made by adding water to 4.3 parts each of ethylenediamine and diethylenetriamine to make 42.8 parts was gradually dropped into the system.
The reaction was carried out at °C for 2 hours to obtain a suspended first-stage microcapsule. ) was 1.5%).

Depending on the purpose, the agent as it is may be usable with considerably less irritation, or a second stage of microencapsulation was performed as follows to further reduce the free component ratio and reduce irritation. That is, in a reactor of the same type prepared separately, 85.6 parts of dioctyl phthalate and 3 parts of millionate were added.
04017.1 part and Nucalgen D-2303,4
Adjust the mixture of parts.

To this was added 171 parts of a 1% aqueous solution of gum arabic, and the mixture was stirred at a rotation speed of 65 rpm for 10 minutes to obtain a dispersion. This dispersion is added to the suspended first stage microcapsules and stirred at 250 ml for 15 minutes. Furthermore, water was added to 4.3 parts each of ethylenediamine and diethylenetriamine to make 4.
2.8 parts of the solution was gradually added dropwise and reacted at 60°C for 2 hours to perform the second encapsulation, resulting in a suspension containing 9% N-(4-hydroxy-3-methoxybenzyl)-nonanamide. 850 parts of microcapsule formulation were obtained. The free component rate of this product was 0.2%, and the irritation was extremely low. Dioctyl phthalate used for this microcapsulation is a solvent, Millionate 3040 is an oil-soluble membrane material, ethylenediamine and diethylenetriamine are water-soluble membrane materials, and Nucalgen D-230 and gum arabic are dispersants. In addition, the free component rate is 500 mg of sample.
was added to 500 TIL of distilled water, shaken for 30 minutes, the shaken liquid was filtered with a membrane filter (0.2 μm), and N-(4-hydroxy-3-methoxyhensyl)-nonanamide in the filtrate was analyzed by HPLC. It was quantified and divided by the quantified value before encapsulation to give a percentage (the free component ratio in the following examples was also measured in the same manner).

Example 2 Using the same container as in Example 1, 4-hydroxy-3-
methoxybenzylamine 4.7 parts diethyl ether 2
5.7 parts of 8-methylnon-trans-6-enoitsuccinic acid chloride and 0.2 parts of pyridine are added to 5 parts of the solution, and the mixture is stirred at room temperature for 4 hours.

Add 10 parts of water to this, stir for 5 minutes, and leave to stand for 5 minutes.
Drain the lower water layer. When the ether is almost completely removed under reduced pressure, a composition of (E)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-ninamide can be obtained. Collect a very small amount of N-(4
The purity of -hydroxy-3methoxyhensyl)-8-methylnon-6-ninamide was determined by HPLC.9
It was 0.5%, and the irritation to the skin, especially the mucous membranes, was as strong as the component of Example 1. Into this reactor were placed 21.5 parts of dimethyl phthalate, 3.0 parts of sebacic acid dichloride, 3.0 parts of Millionate MR-400 (manufactured by Nippon Polyurethane Co., Ltd.), and 0.1 part of Emulgen 910 (manufactured by Kao Soap Co., Ltd.) and stirred. to obtain a homogeneous mixture. Furthermore, Gohsenol GH-17 (manufactured by Nippon Gosei Kagaku Co., Ltd.)
Add 50.0 parts of a 1.5% aqueous solution of
Stir at m for 10 minutes to obtain a dispersion. Next, stir at 25 or
An aqueous solution made by adding water to 1.0 parts of sodium hydroxide, 1.0 parts of ethylenediamine, and 1.0 parts of diethylenetriamine to make 13.9 parts was gradually added dropwise to this system, and after the dropwise addition, the liquid temperature was lowered to 60%. ``N
A suspended microcapsule containing 7.5% of -(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-ninamide was obtained. The free component rate of this product is 0
．． It was as low as 6%, and the irritation was significantly reduced, resulting in a formulation that could be easily handled. In addition, dibutyl phthalate used for this microcapsulation is a solvent, sebacic acid cucoride and Millionate MR-400 are oil-soluble membrane materials, sodium hydroxide, ethylenecyamine, and diethylene triamine are water-soluble membrane materials, and Emulgen 9]0 and Gohsenol GH-17 is a dispersant.

Example 3 N-(4-
A synthetic reaction of hydroxo-3-methoxybenzyl)nonanamide is carried out. Stirring was stopped, and after standing for 30 minutes, the lower aqueous layer was discharged from the bottom. A small amount of the dioctyl adipate solution in the reactor was collected and the purity of N-(4-hydroxy-3-methoxybenzyl)-nonanamide was determined by HPLC to be 30.3%, indicating that it is irritating to the skin and mucous membranes. was as strong as in Example 1. In this reactor were added Millionate MR-20042, 8 parts, and
y'' :/ 8.8 parts of D-410 (manufactured by Takemoto Yushi Co., Ltd.) was added and stirred, and further 455 parts of a 2% aqueous solution of gum arabic was added and stirred for 10 minutes at a stirring speed of 650 rpm to obtain a dispersion system.Next. The stirring was lowered to 25 rpm, and an aqueous solution of 8.6 parts each of ethylenediamine and diethylenetriamine and 85.6 parts of water was gradually added dropwise to the system.
After the dropwise addition, the temperature of the solution was raised to 60° C. and the mixture was reacted for 2 hours, followed by encapsulation to obtain 850 parts of suspended microcapsules containing 9% N-(4-hydroxy-3-methoxybenzyl)-nonanamide. The free component ratio of this product was 0.9%, and the irritation was significantly reduced.

Example 4 71.2 parts of cyclohexane and 100 parts of dioctyl phthalate were added in place of 200 parts of benzene in Example 1,
A synthesis reaction of N-(4-hydroxy-3-methoxybenzyl)-nonanamide was carried out in the same manner, stirring was stopped,
After standing still for 30 minutes, drain the lower aqueous layer from the bottom. A small amount of the solution in the reactor was sampled, and the purity of N-(4-hydroxy-3-methoxybenzyl)-nonanamide was determined by HPLC to be 30.6%, and the irritation to the skin and mucous membranes was as low as that of Example 3. It was just as intense as 1. Into this reactor were placed 8 parts of Millione MR-20022 and 8.5 parts of New Calgen D-225 (manufactured by Takemoto Yushi Co., Ltd.) and stirred, followed by 45 parts of a 1.5% aqueous solution of Gohsenol GH-17.
5 parts were added and stirred for 10 minutes at a stirring speed of 650 rpm to obtain a dispersion system. Next, the stirring was lowered to 250 rpm, and one drop of an aqueous solution prepared by adding water to 8.6 parts each of ethylenediamine and diethylenetriamine to make 85.6 parts was gradually added dropwise to the system. time reaction,
Encapsulation was performed to obtain 850 parts of suspended microcapsules containing 9% N-(4-hydroxy-3-methoxybenzyl)-nonanamide. The free component rate of this product is 0.
9%, and the irritation was significantly reduced.

This product was further dried with a spray dryer to almost completely remove water and cyclohexane, resulting in approximately 30% N-
250 parts of powdered microcapsules containing (4-hydroxy-3-methoxybenzyl)-nonanamide were obtained.

The free component rate of this product was 1.0%, and the irritation was low.

Test Examples Powdered microcapsules of Example 4 and N-(4
N-(4-hydroxy-3-methoxybenzyl)-nonanamide compound was added to vinyl compound 5E-24 (manufactured by Mitsui Toatsu Chemical Co., Ltd.).
- After adding 0.2% as nonanamide, heat and mix at 180°C for 10 minutes using a hot rolling roll machine (NS-105 (J) W type manufactured by Nishimura Koki Co., Ltd.) to form a polyvinyl chloride sheet with a thickness of 1 mm. A test was conducted to investigate the effect of N-(4-hydroxy-3-methoxybenzyl)-nonanamide on polyvinyl chloride sheets to prevent rats from building school buildings.

Note that the untreated area is a sheet made of only vinyl compound.

Test method Cut each sheet to 75 x 150 mm, fold it in half, put two solid samples for rats in it, and staple it on three sides to use it as a test sample. This sample was placed in a breeding cage containing 34 rats weighing approximately 300 g and left overnight, and the area of the sheet covered by the rats was examined.

Each cage contained one sample of each sample, and three cages were tested.

The microcapsule formulation of Example 4 was easy to handle with almost no irritation during measuring, mixing, etc. and sheet processing under high heat, whereas the synthetic product only had a slight amount of irritation on the hands. It was also very irritating, and the strong spiciness lingered for a long time. Additionally, it had a strong pungent odor during processing, making it extremely difficult to handle. The sheet made from the microcapsule formulation of Example 4 had a better effect on preventing rats from building school buildings. The above results also confirmed the usefulness of the production method of the present invention.

Patent applicant: Nippon Kayaku Co., Ltd.

Claims (1)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R represents an alkyl group, an alkenyl group, or an alkynyl group of C_4 to C_1_2.) , formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R represents an alkyl group, alkenyl group, or alkynyl group of C_4 to C_1_2, and Hal represents a halogen atom.) and vanillylamine or The salt is obtained by condensation in a solvent, optionally in the presence of an acid binder, and then directly dispersed in water in the reaction bath,
A method for producing capsaicin and its microcapsules in the same bath, characterized by carrying out oil-in-water microencapsulation.