JP2009263270A - Nk1 receptor antagonist composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an NK1 receptor antagonist composition which has high safety permitting to use for medicines and has a sufficient therapeutic effect. <P>SOLUTION: The NK1 receptor antagonist composition uses arabitol as an active ingredient. The preferable content of the arabitol in the NK1 receptor antagonist composition is 0.01 to 30 mass%. The NK1 receptor antagonist composition may further be compounded with other materials as other components except the active ingredient, and used in various forms such as external preparations, internal preparations, foods, or drinks. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an NK1 receptor antagonist composition that is effective for the treatment or prevention of symptoms and diseases mediated by the NK1 receptor.

As is well known, common structure to the C-terminal amino acid sequence (Phe-X-Gly-Leu -Met-NH 2: SEQ ID NO: 1) peptide having are collectively referred to as tachykinin. The mammalian tachykinins to date, substance P (amino acid sequence: H-Arg-Pro-Lys -Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH 2: SEQ ID NO: 2), neurokinin A (amino acid sequence: H-His-Lys-Thr -Asp-Ser-Phe-Val-Gly-Leu-Met-NH 2: SEQ ID NO: 3) and neurokinin B (amino acid sequence: H-Asp-Met-His -Asp -Phe-Phe-Val-Gly- Leu-Met-NH 2: SEQ ID NO: 4) three have been identified. These three types of tachykinins are neuropeptides widely distributed in the living body. Among these three types of tachykinins, substance P whose physiological function has been studied in detail is substance P.

  Substance P is a neuropeptide consisting of 11 amino acids present in the mammalian body. This substance P is known to be involved in various pathological conditions such as asthma, inflammation, pain, psoriasis, migraine, movement disorders, cystitis, schizophrenia, vomiting, anxiety and the like because of its localization and function. (Non-Patent Document 1).

  And NK1 receptor (neurokinin 1 receptor) is identified as a receptor (receptor) which shows high affinity with substance P (Substance P) in the living body. That is, it has been found that substance P acts as an agonist (agonist) that interacts with the NK1 receptor to cause intracellular signal transduction. Furthermore, there exists an antagonist (antagonist) that can antagonize or block the binding between substance P, which is such an agonist, and the NK1 receptor. It is also known that there are a wide variety of disorders, symptoms or diseases that can be improved by such antagonists (antagonists).

  Examples of those symptoms or diseases include respiratory diseases (such as cough, asthma, airway hypersensitivity), skin diseases (such as contact dermatitis, atopic dermatitis, inflammation, redness, urticaria, eczema, psoriasis), Nervous inflammatory diseases (arthritis, migraine, nociception, etc.), CNS diseases (depression, mania, schizophrenia, stress-related disorders, obsessive-compulsive disorder, phobias, anxiety, alcoholism, psychoactive substance abuse, Parkinson Disease, movement disorders, psychosis, etc.), eating disorders (eg bulimia, bulimia, anorexia nervosa, eating behavior inhibition), pain (postoperative pain, chronic pain, neuropathic pain), pruritus Symptoms, vomiting, gastrointestinal disorders, kidney disorders, urological disorders, eye inflammation, allergic rhinitis, sleep disorders, premenstrual syndrome, obesity, headache, bladder disorders, genitourinary disorders, and the like.

  Various NK1 antagonists have been developed for the purpose of treating or preventing symptoms and diseases mediated by these NK1 receptors. For example, Non-Patent Document 2 describes clinical trial examples showing that an NK1 receptor antagonist is effective for diseases such as anxiety, depression, psychosis, schizophrenia, and vomiting. Non-Patent Document 3 describes clinical trial examples showing that NK1 receptor antagonists are effective as antiemetics.

  Based on such findings, various NK1 receptor antagonists have been developed and reported so far. Most of the reported NK1 receptor antagonists are peptidic analogs in which a part of the constituent amino acids of mammalian substance P is substituted with D-form (see Non-patent Document 4, Patent Document 1, etc.).

  As described above, the NK1 receptor antagonist that has been developed so far has been a peptide. With peptide type NK1 receptor antagonists, good pharmacokinetic properties cannot be obtained, and there is a limit to the expression of activity in vivo. Furthermore, the peptide-type NK1 receptor antagonist also has a problem that side effects due to antigenicity and agonistic action on humans occur.

  On the other hand, it has been reported that non-peptide NK1 receptor antagonists are currently under development (Non-patent Documents 5 and 2).

Takayanagi Kazunari, Cell membrane receptor, published by Nanzan-do, 1998 Kramer MS et al. , Science 281 (5383), 1640-1645 (1998). Gesztesi Z et al. , Anesthesiology 93 (4), 931-937 (2000). Zubrzycka M et al. , Endocrine Regulations, 34 (1), 13-18 (2000) Rost K et al. , Med Monattschr Pharm 29 (6), 200-205 (2006) Japanese Patent No. 2783520 JP 2006-89499 A

  As described above, most of the NK1 receptor antagonists that have been developed so far have been developed by derivatization in which a part of the amino acids constituting the mammalian endogenous substance P is substituted with D-amino acids or the like. is there. Since these conventional NK1 receptor antagonists are peptides, good pharmacokinetic properties cannot be obtained, and there is a limit to the expression of activity in vivo. In addition, these conventional NK1 receptor antagonists have problems with side effects due to antigenicity and agonistic action on humans. In contrast, non-peptide NK1 receptor antagonists are currently being developed. For example, (R. M. Snider et al., Science 251, 435-437 (1991)) discloses several non-peptide NK1 receptor antagonists (CP-96,345). However, these NK1 receptor antagonists have high selectivity for the NK1 receptor, but have a quinuclidine ring, and thus have a significant affinity for several ion channels, particularly L-type calcium channels. (M. Caeser et al., Br. J. Pharmacol. 109, 918-24 (1993)). Therefore, the non-peptide type NK1 receptor antagonist has not been put into practical use because there is a possibility of causing a side effect on the visceral vasculature. Thus, the present condition is that the NK1 receptor antagonist which is still safe and has a satisfactory therapeutic effect is not yet obtained.

  This invention is made | formed in view of the said conventional situation, The subject is providing the NK1 receptor antagonist composition which has the high safety | security which can be used for a pharmaceutical, and has a satisfactory therapeutic effect.

  The inventors have conducted intensive studies to solve the above problems, and have found that arabitol has an excellent NK1 receptor antagonistic action. That is, it has been found that arabitol is useful for treating or preventing NK1 receptor-mediated symptoms and diseases.

  The present invention has been made based on such knowledge. That is, the NK1 receptor antagonist composition according to the present invention is characterized by containing arabitol as an active ingredient.

Arabitol is a compound that is known to be abundant in lichens and mushrooms in nature, and has been confirmed to be safe. This arabitol is a hydrocarbon compound represented by the chemical formula C ₅ H ₁₂ O ₅ , and is represented by the following chemical structural formula (I), which is an optical isomer of D-arabitol, and the chemical structural formula (II). There is L-arabitol.

  Examples of arabitol used in the present invention include D-arabitol and L-arabitol, which are optical isomers as described above, and any one or a mixture thereof can be used. Among these, D-arabitol is preferable because of the degree of effects and availability. D-arabitol and L-arabitol can be purchased from, for example, Wako Pure Chemical Industries, Ltd.

  The compounding amount of arabitol in the NK1 receptor antagonist composition of the present invention is an effective amount. The blending amount of arabitol determined from such an effective amount is appropriately selected according to the usage, dosage form, age, sex and other conditions, symptoms, and degree of disease of the NK1 receptor antagonist composition of the present invention. The Usually, 0.01 to 30% by mass of the NK1 receptor antagonist composition is preferably blended. Preferably 0.1-10 mass% is mix | blended. The effect of this invention cannot be exhibited as a compounding quantity is less than 0.01 mass%. Moreover, even if it exceeds 30 mass%, an effect improvement is not seen and since it may become difficult to manufacture depending on a dosage form, it is better not to exceed 30 mass%. The dose is appropriately selected according to the age, sex and other conditions, symptoms, and degree of disease of the subject, but is usually 0.05 mg / kg to 500 mg / kg per day. The daily dose range is preferably 0.05 mg / kg to 100 mg / kg. For convenience, if desired, the total daily dose may be divided and administered in portions during the day. In particular, when used as an external preparation, it is usually preferable to blend 0.01 to 30% by mass. Preferably 0.1-10 mass% is mix | blended. The effect of this invention cannot be exhibited as a compounding quantity is less than 0.01 mass%. Moreover, even if it exceeds 30 mass%, an effect improvement is not seen, and since stability and manufacture may become difficult depending on prescription, it is better not to exceed 30 mass%.

  The NK1 receptor antagonist composition of the present invention can be selected from other ingredients other than arabitol, which is an active ingredient, so that external preparations, injections, pharmaceuticals as internal medicines, quasi-drugs, of course, cosmetics, foods It can be used in the form of a beverage or the like.

  When the NK1 receptor antagonist composition of the present invention is used as an external composition for skin, it is applied to whole body skin, scalp and the like. For example, external compositions such as creams, hand creams, emulsions, lotions, soaps, hand soaps, body soaps, bath preparations, athlete's foot drugs, acne treatment agents, antipruritics, eye drops, eye ointments, and skin cosmetics It can be prepared as hair cosmetics such as shampoo, rinse, tonic and hair restorer. In this case, the NK1 receptor antagonist composition of the present invention contains, as components other than arabitol, which is an active ingredient, known blending components according to the type and dosage form of the above-mentioned external preparation for skin, such as oil, water, Surfactants, moisturizers, lower alcohols, thickeners, chelating agents, dyes, preservatives, fragrances and the like can be appropriately blended. When used as an external preparation for the head, other components other than arabitol, which is an active ingredient, include, for example, oil components, ultraviolet absorbers, preservatives, moisturizers, surfactants, perfumes, water, alcohol Lubricants, thickeners, pigments, drugs and the like can be blended.

  When the NK1 receptor antagonist composition of the present invention is used as an internal preparation, as a component other than arabitol which is an active ingredient, first, a known compounding component such as an excipient (for example, lactose, sucrose, starch, Mannitol), disintegrants (eg calcium carbonate, carboxymethylcellulose calcium), binders (eg pregelatinized starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose) or lubricants (eg talc, stearic acid) Magnesium, polyethylene glycol 6000) is added. Thereafter, compression molding is performed. Then, if necessary, it can be made into an internal preparation by coating with a known method for the purpose of taste masking and sustainability. Examples of the coating agent include ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and Eudragit (trade name, methacrylic acid / acrylic acid copolymer manufactured by Rohm (Germany)). be able to.

  When the NK1 receptor antagonist composition of the present invention is used as an injection, as a component other than arabitol which is an active ingredient, a known compounding component, that is, a dispersant (for example, Tween 80 (Atlas Powder Co., Ltd.) Manufactured by the United States), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservatives (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol), isotonic agents (eg, Sodium chloride, glycerin, sorbitol, glucose, invert sugar) and the like. Next, arabitol together with these other ingredients is converted into an aqueous solvent (eg, distilled water, physiological saline, Ringer's solution, etc.) or an oily solvent (eg, vegetable oils such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol), etc. Dissolve, suspend or emulsify. Through these steps, an injection using the NK1 receptor antagonist composition can be produced. At this time, if necessary, additives such as a solubilizing agent (for example, sodium salicylate, sodium acetate), a stabilizer (for example, human serum albumin), a soothing agent (for example, benzalkonium chloride, procaine hydrochloride) are appropriately blended. be able to.

  When the NK1 receptor antagonist composition of the present invention is used as a food, it can be used as a health food, a functional food, a food for specified health use, or a disease by blending various food ingredients as components other than the active ingredient arabitol. It can be prepared in the form of consumer foods.

  Moreover, when using the NK1 receptor antagonist composition of this invention as a drink, it can prepare in the form of a drink by mix | blending various drinkable materials as components other than arabitol which is an active ingredient.

  The NK1 receptor antagonist composition according to the present invention can be prepared and used for foods taken daily or health foods or functional foods taken as supplements. By using the NK1 receptor antagonist composition for such foods and supplements, the NK1 receptor antagonist can be continuously ingested. As a result, functions such as symptoms mediated by the NK1 receptor, prevention, alleviation, and elimination of diseases can be realized in daily life without being particularly conscious of ingestion.

  In the NK1 receptor antagonist composition of the present invention, various foods can be used as health foods and functional foods realized by selecting various food materials as components other than arabitol which is an active ingredient. For the production of these health foods and functional foods, in addition to commonly used food materials and food additives, excipients, extenders, binders, disintegrants, lubricants, dispersants, preservatives, wetting agents Adjuvants such as dissolution aids, preservatives, stabilizers, capsule bases and the like can be used. Specific examples of these adjuvants include lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, calcium carbonate, methylcellulose, carboxymethylcellulose, or salts thereof. Gum arabic, polyethylene glycol, syrup, petrolatum, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, pullulan, carrageenan, dextrin, reduced palatinose, sorbitol, xylitol, stevia, synthetic sweetener, citrus Examples include acid, ascorbic acid, acidulant, baking soda, sucrose ester, hardened vegetable oil, potassium chloride, safflower oil, beeswax, soybean lecithin, and fragrance. Regarding the production of such health foods and functional foods, reference books for pharmaceutical preparations such as “Japanese Pharmacopoeia Manual (General Rules for Preparations)” (Yodogawa Shoten) can be referred to.

  Examples of the shape suitable for the health food and functional food include tablets, capsules, granules, powders, suspensions, and emulsions. If the manufacturing method of a tablet-like health food and a functional food is specifically illustrated, it will manufacture by compressing the thing which prepared the NK1 receptor antagonist composition of this invention in various food forms into a fixed shape, or water. Alternatively, a kneaded product moistened with a solvent such as alcohol may be formed into a fixed shape or cast into a fixed mold. If the manufacturing method of a capsule-like health food and a functional food is specifically illustrated, the formulation formed by preparing the NK1 receptor antagonist composition of the present invention may be liquid, suspension, paste, powder or granule. The capsules are filled in the form of, or encapsulated with a capsule base, and examples thereof include hard capsules and soft capsules.

  In addition, as foods that can be prepared from the NK1 receptor antagonist composition of the present invention, specifically, pudding, cookies, crackers, potato chips, biscuits, bread, cakes, Western confectionery such as chocolate, donuts, jelly, rice crackers, etc. , Yokan, Daifuku, Ohagi, other buns, Japanese confectionery such as castella, frozen confectionery (rice cakes), bread and confectionery such as chewing gum, noodles such as udon, buckwheat and kishimen, and fish meat such as kamaboko, ham and fish sausage Kneaded products, meat products such as ham, sausage, hamburger, corn beef, seasonings such as salt, pepper, miso, soy sauce, sauce, dressing, mayonnaise, ketchup, sweetener, pungent, Akashi-yaki, takoyaki, monja Teppanyaki food such as grilled, okonomiyaki, fried noodles, grilled udon, cheese, hard tie Dairy products such as yoghurt, natto, deep fried, tofu, konjac, dumplings, pickles, boiled, dumplings, shumai, croquettes, sandwiches, pizza, hamburgers, salads, and other powders (beef, pork, chicken) Livestock products, shrimp, scallops, sea bream, kelp, bonito marine products, vegetables / fruits, plants, yeast, algae, etc.) and oils and fragrances (vanilla, citrus fruits, etc.) Various foods such as powdered foods and drinks (instant coffee, instant tea, instant milk, instant soup, miso soup, etc.) can be mentioned, but are not particularly limited thereto.

  The NK1 receptor antagonist composition of the present invention can be taken continuously every day, particularly when used in the form of a beverage. Beverages are products that are continuously drunk. Therefore, beverages using the NK1 receptor antagonist composition can have functions such as prevention, reduction, and elimination of symptoms and diseases mediated by the NK1 receptor, in addition to the original function of healing thirst.

  As the types of beverages prepared from the NK1 receptor antagonist composition of the present invention, those of various compositions can be mentioned, and in the production of those beverages, sugars, flavors, Any fruit juice or food additive can be used. Regarding the production of beverages, existing reference books such as “Revised New Version Soft Drinks” (Kokai Co., Ltd.) can be referred to.

  In the case where the NK1 receptor antagonist composition of the present invention is in the form of a beverage, drink materials such as yogurt, apple, mandarin, and grape are specifically exemplified as beverage materials to be blended as components other than arabitol which is an active ingredient. , Fruit juice such as banana, pear, ume, watermelon, vegetable juice such as tomato, carrot, celery, cucumber, soft drink, milk, soy milk, coffee, cocoa, tea, green tea, barley tea, brown rice tea, sencha, gyokuro tea, roasted tea , Various herbal teas such as oolong tea, turmeric tea, puer tea, rooibos tea, rose tea, chrysanthemum tea, mint tea and jasmine tea, sports drinks, mineral water, and nutrition drinks).

  In the NK1 receptor antagonist composition of the present invention, since arabitol, which is an active ingredient, has an NK1 receptor antagonistic action, various symptoms or diseases mediated by NK1 receptor (for example, itching, pain, vomiting, cough, asthma) It is useful for the prevention and treatment of dermatitis (atopic dermatitis, contact dermatitis, urticaria, etc.), depression, hair loss, etc.). Moreover, since the NK1 receptor antagonist composition of the present invention contains arabitol, which is an active ingredient thereof, in food, it is clear that it is highly safe and has few side effects.

  Examples of the present invention will be described below. The following examples are preferred examples for explaining the present invention, and do not limit the present invention.

(Examples 1 and 2 and Comparative Examples 1 to 7)
In Examples 1 and 2 and Comparative Examples 1 to 7, arabitol, which is an active ingredient of the NK1 receptor antagonist composition of the present invention, has various symptoms or diseases (for example, itching, pain, vomiting, cough, asthma, skin It was confirmed that it antagonizes substance P in the prevention and treatment of inflammation (such as atopic dermatitis, contact dermatitis, urticaria, depression, hair loss, etc.). This activity was confirmed by the following assay.

[Performance Evaluation Test] NK1 Receptor Antagonism Assay (Reagent Preparation)
In this test, D-arabitol, L-arabitol, D-arabinose, maltotetriitol, maltitol, xylitol, ribitol, D-sorbitol, α-glycosylrutin were purchased from Wako Pure Chemical Industries, Ltd. Was diluted with physiological saline and used.

(Cloning of cDNA encoding human-derived NK1 receptor and production of animal cell expression vector)
To transiently express the cloned human NK1 receptor with HEK293, the human NK1 receptor cDNA was excised from pCDM8 (INVITROGEN) and the ampicillin resistance gene (nucleotides 1973 to 2964 from BLUESCRIPT SK +) was transformed into SacII. It was cloned into the expression vector pCDM9 derived by insertion into the site.

(Preparation of HEK293 expressing human NK1 receptor)
1 × 10 ⁵ HEK293 cells were seeded on a falcon dish (diameter 3.5 cm) using α-MEM medium (GIBCO) containing 10% fetal bovine serum, and overnight at 37 ° C. in a 5% CO ₂ incubator. Cultured. 20 μg of the expression vector was transfected using Transfection Reagent FuGENE6 (Roche) according to the method described in the attached instructions, and incubated at 37 ° C. for 3 days. And it assayed by the calcium imaging method.

(Preparation of nerve cells expressing NK1 receptor)
In accordance with the method of Renganathan et al. (Renganathan M et al., J Neurophysiol. 84 (2), 710-82 (2000)), neurons were dispersed and isolated from dorsal root ganglia of wild-type mice, and poly-L-lysine was isolated. Coated 24-well plates were seeded with 1 × 10 ⁵ cells. The culture conditions were 10% fetal bovine serum, 2 mM glutamine, 100 U / mL penicillin-streptomycin, 100 ng / mL NGF (manufactured by SIGMA), 5 μM cytosine arabinoside (manufactured by SIGMA) and 90% DMEM medium (manufactured by GIBCO). Among them, it was 5% CO ₂ and 37 ° C. After culturing for 1 to 3 weeks, it was subjected to the following calcium imaging analysis. By staining the nerve cells of the dorsal root ganglion derived from wild type mice with NK1 receptor antibody (manufactured by CHEMICON International), it was confirmed that half of the neurons were NK1 receptor positive.

(Calcium imaging measurement method)
Cells that transiently or constitutively express the NK1 receptor were measured using a high-resolution digital B / W cooled CCD camera (manufactured by Hamamatsu Photonics, trade name “ORCA”), and analyzed software (Hamamatsu Photonics). Image analysis was performed using a product name “AQUA COSMOS” manufactured by the company. In calcium labeling, “Fluo4-AM (trade name)” manufactured by Molecular Probes was used as a calcium-sensitive dye. 50 μg of “Fluo4-AM” was dissolved in 400 μL of DMSO (dimethyl sulfoxide), 4 μL of “Pronic F-127 (trade name)” of Molecular Probe was added and mixed, and then 4 mL of “OPTI” of GIBCO was added. -MEM (trade name) "was added.

  The calcium sensitive dye solution thus prepared was added to the cells and incubated at 37 ° C. for 60 minutes. Agonists, antagonists, and evaluation samples were prepared at a concentration 10 times the assay concentration, and analyzed by adding 1/10 volume of the cell supernatant at the time of analysis.

  All reagents and assay temperature were kept at 37 ° C. For transiently transfected cells, YFP reporter DNA fluorescence (490 nm excitation) was used to identify transfected cells.

  In the measurement, the initial fluorescence value was obtained by first imaging the cells in an untreated state. After 1 minute, the change in calcium fluorescence before and after the addition (2 to 5 minutes) was monitored at 1 second intervals for the evaluation sample having a desired concentration. Thereafter, substance P was added, and the intracellular calcium concentration change immediately after (2 to 5 minutes) was monitored as a change in fluorescence intensity at intervals of 1 second to determine the antagonist activity of the evaluation specimen.

(Calculation method of NK1 receptor antagonist activity)
The NK1 receptor antagonizing activity of the sample to be evaluated was determined according to the following formula (1). In addition, 15 cells expressing the NK1 receptor were selected for each measurement, and the fluorescence intensity change was recorded for each cell. For each cell, the antagonizing activity value of all the measured cells was averaged by the following formula (1) based on the antagonizing activity, and the antagonizing activity value of the evaluation sample was determined.

式（１）において、Ａ、Ｂ、Ｃは次の値を意味する。
Ａ： 評価サンプル添加前の初期値の細胞の蛍光強度
Ｂ： サブスタンスＰ（１００μＭ）添加後の細胞の最大蛍光強度
Ｃ： 評価サンプルで前処理し、次いで、サブスタンスＰ（１００μＭ）を添加した細胞の最大蛍光強度

In the formula (1), A, B, and C mean the following values.
A: Fluorescence intensity of cells at initial value before addition of evaluation sample B: Maximum fluorescence intensity of cells after addition of substance P (100 μM) C: of cells pretreated with evaluation sample and then added with substance P (100 μM) Maximum fluorescence intensity

(Evaluation criteria for evaluation specimens)
The effectiveness of the evaluation sample was determined by comparing the antagonizing activity value of the evaluation sample with the antagonizing activity of the reference substance SPANTIDE II (peptide analog of substance P). Evaluation criteria were set as follows.
Based on the antagonizing activity of SPANTIDE II set as a positive control, efficacy (（, ○, Δ, ×) was determined in four stages. The results are shown in Table 1. In addition, NK1 receptor antagonizing activity of SPANTIDE II was 65%.
A: An antagonizing activity of an evaluation sample is 80% or more, and a markedly superior performance than the positive control is judged as excellent (A). B: An antagonizing activity of the evaluation sample is 70% or more and less than 80%. Yes, those showing performance superior to that of the positive control were judged as effective (O). Δ: Antagonizing activity of the evaluation sample was 60% or more and less than 70%, and those showing the same performance as the positive control were somewhat. Effective (△) and judged ×: An antagonizing activity of the evaluation sample is less than 60%, and a performance that is lower than the positive control is judged as invalid (×)

  As is clear from Examples 1 and 2, arabitol was highly effective as an NK1 receptor antagonist. In particular, D-arabitol shown in Example 1 showed high effectiveness at a low concentration of 1 ppm, and then L-arabitol shown in Example 2 showed effectiveness. On the other hand, D-arabinose, maltotetriitol, maltitol, xylitol, ribitol, D-sorbitol, and α-glycosyl rutin of Comparative Examples 1 to 7 used for evaluation as other sugars have no NK1 receptor antagonist activity. There wasn't. From the above results, it was confirmed that arabitol has a very specific and excellent performance as an NK1 receptor antagonist.

(Examples 3 and 4 and Comparative Examples 8 to 11)
Hereinafter, Table 2 shows formulation examples in which the NK1 receptor antagonist composition of the present invention is specialized for an external preparation for skin. Moreover, in Comparative Examples 8-11 with respect to these Examples 3 and 4, arabitol was not added but another sugar was added. In the following Examples 3 and 4 and Comparative Examples 8 to 11, the other ingredients other than arabitol are the same.

＊1 ジメチルシリコン（商品名；KF96A−10cs：信越化学社製）
＊２ カルボキシビニルポリマー（商品名；カーボポール９８０：日光ケミカルズ社製）
＊３ クエン酸ナトリウムはｐＨ調整剤であり、適量とはｐＨを５．０に調整するのに必要な量である。

* 1 Dimethyl silicon (trade name; KF96A-10cs: manufactured by Shin-Etsu Chemical Co., Ltd.)
* 2 Carboxyvinyl polymer (trade name; Carbopol 980: Nikko Chemicals)
* 3 Sodium citrate is a pH adjuster, and the appropriate amount is the amount necessary to adjust the pH to 5.0.

(Fastness evaluation)
Take 6 grams of the topical skin preparation of Examples 3 and 4 described above (Table 2) to 6 people with chronic itching (2 men and 4 women) Applied. Similarly, 0.5 g of the external preparation for skin of Comparative Examples 8 to 11 was taken and applied once to a site where itching was felt. The application of the external preparation for skin in each case was carried out with the evaluation date shifted. The anti-fastness property was evaluated by applying the coating so that the evaluation date was shifted. After 30 minutes of application, sensory evaluation (3 points: remarkable effect, 2 points: effective, 1 point: neither can be said, 0 point: invalid) was obtained, and the average score of 6 persons was obtained. The antipruritic effect was determined according to The results are also shown in (Table 2).

(Criteria for antipruritic effect)
◎: Average point 2.4 points or more and 3.0 points or less ○: Average point 1.5 points or more and less than 2.4 points Δ: Average point 0.7 points or more and less than 1.5 points ×: Average point 0 points or more and 0 Less than 7 points

(Example 5 and Comparative Example 12)
Formulation examples in which the NK1 receptor antagonist composition of the present invention is specialized for internal liquids are shown in (Table 3). The total amount of the internal solution was 30 mL. Further, as Comparative Example 12 for Example 5, an internal liquid preparation containing the same components as Example 5 was prepared except that arabitol was not added.

(Fastness evaluation)
6 people with chronic itch (2 men, 4 women) were divided into 2 groups of 3 (1 man, 2 women) and each group received one oral solution of Example 5 An anchorage evaluation was performed. One hour after ingestion, sensory evaluation (3 points: marked effect, 2 points: effective, 1 point: cannot be said, 0 point: invalid) was performed. One week later, one oral solution of Comparative Example 12 was ingested to evaluate antistasis, and sensory evaluation was performed in the same manner. The other group was ingested with the internal solution of Comparative Example 12, and the same evaluation was performed except that the internal solution of Example 5 was ingested one week later. The average score of 6 persons for sensory evaluation was determined, and the antipruritic effect was determined according to the following criteria. The results are also shown in (Table 3).

(Criteria for antipruritic effect)
◎: Average point 2.4 points or more and 3.0 points or less ○: Average point 1.5 points or more and less than 2.4 points Δ: Average point 0.7 points or more and less than 1.5 points ×: Average point 0 points or more and 0 Less than 7 points

(Example 6 and Comparative Example 13)
The effect was confirmed using the NK1 receptor antagonist composition of the present invention as a tablet. Formulation examples and evaluation results are shown in (Table 4). The total amount of each tablet was 300 mg. As Comparative Example 13 for Example 6, a tablet containing the same components as Example 6 was prepared except that arabitol was not added.

(Fastness evaluation)
6 people with chronic itch (2 men, 4 women) were divided into 2 groups of 3 (1 man, 2 women), and each group received 1 tablet of Example 6. The anti-fastness was evaluated. One hour after ingestion, sensory evaluation (3 points: marked effect, 2 points: effective, 1 point: cannot be said, 0 point: invalid) was performed. One week later, one tablet of Comparative Example 13 was ingested by the same subject, and antistatic evaluation was performed, and sensory evaluation was performed in the same manner. In the other group, the tablet of Comparative Example 13 was given first, and the tablet of Example 6 was ingested one week later, and the same evaluation was performed. The average score of 6 persons for sensory evaluation was determined, and the antipruritic effect was determined according to the following criteria. The results are also shown in (Table 4).

(Criteria for antipruritic effect)
◎: Average point 2.4 points or more and 3.0 points or less ○: Average point 1.5 points or more and less than 2.4 points Δ: Average point 0.7 points or more and less than 1.5 points ×: Average point 0 points or more and 0 Less than 7 points

＊１卵殻カルシウム（商品名;TS-2:太陽化学株式会社製）

* 1 Eggshell calcium (trade name; TS-2: manufactured by Taiyo Chemical Co., Ltd.)

  As described above, the NK1 receptor antagonist composition according to the present invention has arabitol as an active ingredient, which has good NK1 antagonistic properties and high safety against living bodies. Therefore, the NK1 receptor antagonist composition according to the present invention is effective in the treatment of various symptoms and diseases mediated by the NK1 receptor. Further, the NK1 receptor antagonist composition according to the present invention can be easily prepared into a form such as an external preparation, an internal preparation, a food, and a drink by blending various materials as other components other than the active ingredient. Can be ingested easily on a daily basis.

Claims (5)

  An NK1 receptor antagonist composition comprising arabitol as an active ingredient.   The NK1 receptor antagonist composition according to claim 1, wherein the arabitol is D-arabitol.   The NK1 receptor antagonist composition according to claim 1 or 2, wherein the amount of the arabitol is 0.01 to 30% by mass.   2. It improves or prevents at least one symptom of atopic dermatitis, contact dermatitis, psoriasis or urticaria, asthma, itching, pain, cough, vomiting, mania symptoms, and hair loss. NK1 receptor antagonist composition of any one of -3.   The composition according to any one of claims 1 to 4, wherein the composition is configured as any one of an external preparation, an injection, an internal medicine, a cosmetic, a food, and a beverage by selecting other components than arabitol according to the use. The NK1 receptor antagonist composition according to any one of the above.