Analgesic composition

Abstract

To provide an analgesic composition.SOLUTION: An analgesic composition comprising limonene and geranyl acetate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an analgesic composition. [Background technology]

[0002] Pain can be broadly categorized into nociceptive pain, neuropathic pain, and psychogenic pain depending on its cause. Psychogenic pain is also called psychosocial pain and is not caused by physical abnormalities but rather by psychological causes. Furthermore, many psychogenic pains may involve complex causes (biological, psychological, social, and behavioral factors), such as stress and anxiety experienced in social life.

[0003] It is known that exposure to chronic stress reduces the skin pain threshold compared to healthy individuals, resulting in hyperalgesia, which makes people feel pain more intensely (Non-Patent Document 1). When intense pain continues, people tend to focus their attention on the pain, which leads to a decline in quality of life (QOL) and activities of daily living (ADL).

[0004] On the other hand, Japanese pepper is a deciduous shrub of the genus Zanthoxylum in the family Rutaceae. Japanese pepper has long been used as a spice and a raw material for traditional Chinese medicine. In traditional Chinese medicine, it is used to treat abdominal pain, diarrhea, vomiting, and to eliminate roundworms and pinworms. Japanese pepper essential oil is also produced. Japanese pepper essential oil contains multiple components. Regarding Japanese pepper, even when referring to the following prior art documents, it is not known that inhaling or suctioning the volatile components of Japanese pepper essential oil or the volatile components contained in Japanese pepper essential oil has a pain-relieving effect.

[0005] The volatile components contained in Zanthoxylum pepper essential oil are limonene and geranyl acetate. The combination of these two components is not known to have a pain-relieving effect. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent Application Publication No. 63-48208 [Patent Document 2] Patent Publication No. 2021-31458 [Non-patent literature]

[0007] [Non-Patent Document 1] Hiroki Ibe, Grant-in-Aid for Scientific Research Research Report, June 8, 2015 [Non-patent document 2] "Sansho" [online], Wakasa Seikatsu, [searched February 27, 2023], Internet<URL:https: / / himitsu.wakasa.jp / contents / japanese-pepper / > Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a novel analgesic composition. [Means for solving the problem]

[0009] As a result of extensive research, the present inventors have discovered that the coexistence of limonene and geranyl acetate, or the inhalation of the volatile components of Japanese pepper essential oil, has an excellent analgesic effect, and have completed the present invention.

[0010] That is, the present invention is as follows. [1] A pain-relieving composition containing limonene and geranyl acetate. [2] The composition according to [1] above, characterized in that the effect is obtained by inhaling or snorting. [3] A pain-relieving composition containing Zanthoxylum nigricans essential oil, characterized in that the effect is obtained by inhaling or suctioning the volatile components of the essential oil. [4] The composition according to any one of [1] to [3] above, which is an aromatic oil or an essential oil. [Effects of the Invention]

[0011] The present invention can provide an analgesic composition. The present invention can provide an analgesic composition preferably containing limonene and geranyl acetate. The present invention can also provide an analgesic composition preferably containing Zanthoxylum piperitum essential oil, the effect of which is obtained by inhaling or suctioning the volatile components of the essential oil. [Brief explanation of the drawings]

[0012] [Figure 1] Figure 1 shows the results of gas chromatography analysis of the components of Zanthoxylum persica (Zanthoxylum edulis) essential oil. (A) shows the chromatogram of the GC analysis. (B) shows the retention time (RT) and peak area (area) of each peak in the chromatogram. (C) shows the proportion of each component based on the area ratio of the chromatogram. [Figure 2] FIG. 2 is a graph showing the results of alleviating hyperalgesia by inhaling Japanese pepper aroma. [Figure 3] FIG. 3 is a graph showing the analgesic effect of inhaling limonene after inhaling geranyl acetate on chronic restraint stress (vCRS: vertical chronic restraint stress)-induced hyperalgesia. [Figure 4] FIG. 4 is a graph showing the analgesic effect of inhaling limonene followed by inhaling geranyl acetate on chronic restraint stress (vCRS)-induced hyperalgesia. [Figure 5] FIG. 5 is a graph showing the analgesic effect of simultaneous inhalation of geranyl acetate and limonene on chronic restraint stress (vCRS)-induced hyperalgesia. DETAILED DESCRIPTION OF THE INVENTION

[0013] composition In a first embodiment, the composition of the present invention is an analgesic composition containing limonene and geranyl acetate (also referred to herein as Composition 1 of the present invention). In a second aspect, the composition of the present invention is an analgesic composition (also referred to in this specification as Composition 2 of the present invention) that contains Zanthoxylum perforatum essential oil and whose effect is achieved by inhaling or suctioning the volatile components. In this specification, when simply referring to "the composition of the present invention," the "composition of the present invention" may refer to either composition 1 of the present invention or composition 2 of the present invention.

[0014] Limonene Composition 1 of the present invention contains limonene. Limonene is a monocyclic monoterpene hydrocarbon found mainly in the peels of citrus fruits. Limonene exists in d- and l-forms. The limonene contained in the composition of the present invention may be the d- or l-form, or a mixture of the d- and l-forms (e.g., racemic). The amount of limonene contained in composition 1 of the present invention is not particularly limited as long as limonene is contained, and may be, for example, 0.01 to 99.9 mass%, 0.1 to 90 mass%, 0.5 to 80 mass%, 1 to 70 mass%, 3 to 60 mass%, 5 to 40 mass%, or 5 to 20 mass%. The limonene content may be a value determined, for example, by gas chromatography analysis. Limonene in Composition 1 of the present invention may be chemically synthesized, isolated from a limonene-containing essential oil, or a limonene-containing essential oil. The essential oil may be used alone or in combination of two or more. Examples of limonene-containing essential oils include, but are not limited to, sweet orange, grapefruit, yuzu, mandarin, lemon, Japanese pepper, celery seed, dill, bergamot, fennel, lemon verbena, angelica root, neroli, frankincense, myrtle, Eucalyptus radiata, citronella, niaouli cineole, Eucalyptus globulus, cajeput, cypress, marjoram, lemongrass, rosewood, black pepper, myrrh, litsea asiatica, and tangerine. Commercially available limonene may be used, for example, "(+)-Limonene" (manufactured by Tokyo Chemical Industry Co., Ltd.).

[0015] The term "essential oil" as used herein is not particularly limited, but refers to volatile aromatic substances obtained from, for example, plant flowers, leaves, peels, fruits, roots, seeds, bark, resins, etc. Methods for obtaining essential oils from plants include, for example, pressing, solvent extraction, distillation (e.g., steam distillation, fractional distillation), supercritical fluid extraction, and low-temperature vacuum extraction.

[0016] Geranyl acetate Composition 1 of the present invention contains geranyl acetate, which is a monoterpene that exhibits a fragrant or fruity scent. The amount of geranyl acetate contained in Composition 1 of the present invention is not particularly limited as long as geranyl acetate is contained, and may be, for example, 0.01 to 99.9 mass%, 0.1 to 90 mass%, 1 to 80 mass%, 10 to 70 mass%, 20 to 60 mass%, or 25 to 55 mass%. The content of geranyl acetate may be a value determined by, for example, gas chromatography analysis. Geranyl acetate in Composition 1 of the present invention may be chemically synthesized, isolated from an essential oil containing geranyl acetate, or an essential oil containing geranyl acetate may be used. Examples of essential oils containing geranyl acetate include, but are not limited to, coriander, Ceylon citronella oil, palmarosa, lemongrass, Japanese pepper, ylang-ylang, and neroli. Commercially available geranyl acetate may be used, for example, "geranyl acetate" (manufactured by Tokyo Chemical Industry Co., Ltd.).

[0017] The mass ratio of limonene to geranyl acetate (limonene / geranyl acetate) contained in the composition of the present invention may be 0.01 / 99.9 to 99.9 / 0.01, 0.1 / 90 to 90 / 0.1, 0.5 / 80 to 80 / 1, 1 / 70 to 70 / 10, 3 / 60 to 60 / 20, or 5 / 60 to 40 / 20.

[0018] In one embodiment, the effect of Composition 1 of the present invention can be obtained by inhaling or suctioning. The analgesic effect of Composition 1 of the present invention includes cases other than those in which it is administered directly to the affected area (for example, administered into the body, such as the abdominal cavity).

[0019] In one embodiment, the volatile components of Composition 1 of the present invention are inhaled or inhaled and taken into the body. As long as the volatile components are inhaled or inhaled into the body, it is preferable that they are taken into the body via the respiratory tract, or that they are taken into the body without passing through the esophagus, regardless of the form of inhalation, whether through the nose (nasal) or the mouth (oral). Furthermore, Composition 1 of the present invention can also be inhaled or inhaled by placing a subject in an environment exposed to Composition 1 of the present invention. Subjects of Invention 1 of the present application include, for example, humans and non-human animals (e.g., rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.). The volatile components of Composition 1 of the present invention refer to components that can be vaporized (e.g., in a liquid state) or are vaporized (e.g., in a gaseous state) under conditions of room temperature and normal pressure.

[0020] In other embodiments, the composition 1 of the present invention may contain, in addition to limonene and geranyl acetate, essential oils or other components that can be contained in essential oils. The essential oils are not particularly limited as long as they achieve the effects of the present invention, but examples include Zanthoxylum persica (Zanthoxylum chinense) essential oil. The other components that can be contained in essential oils are not particularly limited as long as they achieve the effects of the present invention, but specific examples include geraniol, β-phellandrene, citronellal, etc. These essential oils and other components that can be contained in essential oils may be used alone or in combination of two or more. Furthermore, the other components that can be contained in essential oils may be chemically synthesized or isolated from essential oils. Specifically, composition 1 of the present invention may contain, for example, limonene (e.g., 1 to 60 mass%, 3 to 50 mass%, 5 to 40 mass%, based on all volatile components), geranyl acetate (e.g., 1 to 70 mass%, 20 to 60 mass%, 25 to 55 mass%, based on all volatile components), β-phellandrene (e.g., 1 to 30 mass%, 5 to 25 mass%, 10 to 23 mass%), citronellal (e.g., 0.1 to 20 mass%, 1 to 15 mass%, 3 to 9 mass%, based on all volatile components), geraniol (e.g., 0.1 to 20 mass%, 0.5 to 10 mass%, 1 to 6 mass%, based on all volatile components), etc. In one embodiment, composition 1 of the present invention may be a pain-relieving composition that contains at least one selected from limonene, geranyl acetate, and other components that can be contained in essential oils (e.g., pepper essential oil), and whose effect is achieved by inhaling or suctioning the volatile components.

[0021] Composition 1 of the present invention may or may not contain non-volatile components of Zanthoxylum piperitum essential oil. Examples of non-volatile components of Zanthoxylum piperitum essential oil include unsaturated fatty acid amides such as sanshool (boiling point of 400°C or higher) and sanshoamide (boiling point of 270°C or higher). Composition 1 of the present invention may contain, for example, 0 to 30% by mass of sanshool.

[0022] Analgesic composition The composition of the present invention has an analgesic effect. The analgesic effect is usually an effect of relieving pain, but may or may not include an effect of preventing pain. The target pain is not particularly limited, and may be one or more pains selected from nociceptive pain, neuropathic pain, psychogenic pain (psychosocial pain), etc. Psychogenic pain may be pain caused by stress (e.g., chronic stress), anxiety, etc. It may also be pain caused by hyperalgesia. It may also be either acute pain or chronic pain. In particular, the analgesic effect is preferably directed at pain caused by hyperalgesia due to chronic stress. The target of the analgesic effect of the composition of the present invention includes cases other than toothache. The analgesic effect (e.g., an analgesic effect against pain due to hyperalgesia, an effect of alleviating hyperalgesia) can be confirmed, for example, by measuring the mechanical sensory threshold in a von Frey test using mice. Furthermore, the analgesic effect (e.g., an analgesic effect against pain due to hyperalgesia) can be determined to be present when a significant difference or significant tendency is observed between the composition of the present invention and a non-composition of the present invention in a questionnaire survey of multiple people with pain regarding their pain state before and after inhalation or inhalation. Composition 1 of the present invention has an analgesic effect in the presence of limonene and geranyl acetate. Compared to the effects of limonene or geranyl acetate alone, the combination of the two components, limonene and geranyl acetate, has a superior analgesic effect. Furthermore, the analgesic effect of Composition 1 of the present invention is effective against all pain conditions except acute pain (e.g., oxidative stress-induced pain).

[0023] The period until the analgesic effect of the composition of the present invention appears is not particularly limited, but for example, the analgesic effect is exhibited 1 day, 1 week, 2 weeks, 3 weeks, 4 weeks, or 8 weeks after inhaling or suctioning the volatile components of Zanthoxylum persica (Japanese pepper) essential oil. The volatile components of Zanthoxylum persica (Japanese pepper) essential oil are preferably inhaled or suctioned intermittently or repeatedly (e.g., every 10 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 12 hours, or 1 day).

[0024] Zanthoxylum essential oil Composition 2 of the present invention contains Zanthoxylum piperitum essential oil. The "Zanthoxylum piperitum essential oil" in the present invention is not particularly limited as long as it is an essential oil obtained from a plant of the genus Zanthoxylum. Furthermore, it may be an essential oil obtained from a component derived from a plant of the genus Zanthoxylum (for example, a processed product of a plant of the genus Zanthoxylum) without using a plant of the genus Zanthoxylum directly as a raw material. Plants of the genus Zanthoxylum are divided into Zanthoxylum piperitum and its congener species. Examples of congener species of Zanthoxylum include Zanthoxylum simulans Hance., Zanthoxylum beecheyanum, Zanthoxylum americanum, Zanthoxylum simulana, Zanthoxylum schinifolium, Zanthoxylum ailanthoides, Zanthoxylum armatum, Zanthoxylum beecheyanum, Zanthoxylum nitidum, and the like. Examples of varieties of Japanese pepper include grape zanthoxylum, Asakura zanthoxylum (Zanthoxylum piperitum f. inerme), Yamaasakura zanthoxylum (Zanthoxylum piperitum f. brevispinum), Ryujin zanthoxylum (Zanthoxylum piperitum f. ovalifoliolatum), etc. Among these, it is preferable to use Japanese pepper, and it is particularly preferable to use grape zanthoxylum.

[0025] Zanthoxylum piperitum (Zanthoxylum piperitum) plants can be used as raw materials for Zanthoxylum piperitum essential oil. The parts used are not particularly limited, including, for example, fruit, seeds, leaves, and branches. However, fruit is preferred. The fruit may be immature (Zanthoxylum nigricans) or ripe, and may be dried or not. However, dried fruit is preferred, and ripe dried fruit is more preferred. Among dried fruits, either the peel or the seeds may be used, with the peel being preferred. The method for drying the fruit is not particularly limited, and known methods can be used. For example, hot air drying at approximately 60°C for 6 to 12 hours is preferred. When using the peel, it is preferable to remove the seeds after drying. In this disclosure, the term "about" is used to include, for example, slight deviations. Such ranges also include those within the experimental error (e.g., within ±10%, ±5%, ±2%, ±1%, ±0.1%, etc.) inherent in the standard method used to measure and / or quantify a given value or range. Therefore, it can be said that "about" is not necessarily unclear.

[0026] Zanthoxylum persica (Japanese pepper) essential oil can be produced using the above-mentioned raw materials by a known method for producing essential oils. For example, when dried Zanthoxylum persica (Japanese pepper) is used, it is preferable to include a step of pulverizing the dried Zanthoxylum persica (Japanese pepper). The pulverization step preferably includes one or more steps selected from a step of coarsely pulverizing the Zanthoxylum persica by dry pulverization (also referred to herein as step 1) and a step of finely pulverizing the Zanthoxylum persica (also referred to herein as step 2). When step 1 is included, the pulverization method is not particularly limited, but a method that can pulverize the Zanthoxylum persica in a short time while minimizing heat exposure is preferred. Specifically, pulverization using a hammer mill, pin mill, pulper, or the like is preferred. The pulverization particle size when coarsely pulverized in step 1 is preferably as large as possible to retain the oil vesicles in the Zanthoxylum persica (Japanese pepper). Specifically, the screen size is 0.3 mm to 5 mm, more preferably 0.5 mm to 3 mm. A screen size of 0.3 mm or more is preferred because it prevents the oil vesicles in the Zanthoxylum persica (Japanese pepper) from being destroyed, thereby minimizing the loss of essential oil. A screen size of 5 mm or less is preferred because it minimizes the risk of clogging in the subsequent step.

[0027] It is preferable to include step 2 after step 1. If step 2 is included, the grinding method is not particularly limited as long as it can finely grind the coarsely ground Japanese pepper peel. However, since this step is performed to actively destroy the Japanese pepper oil vesicles, it is preferable to add tap water or other water to pulverize the suspension, as this minimizes loss of essential oil. Specifically, for example, a colloid mill or homogenizer is preferable because it can grind liquid materials into fine particles. The finer the grinding particle size, the more preferable it is. Specifically, the gap size required to destroy Japanese pepper oil vesicles is preferably 0.1 mm to 1 mm, more preferably 0.1 mm to 0.5 mm, and particularly preferably 0.1 mm to 0.3 mm. A gap size smaller than 1 mm is preferable because it facilitates the destruction of oil vesicles, while a gap size of 0.1 mm or greater is preferable because it prevents a sudden rise in liquid temperature due to heat generation by the rotor and reduces the volatilization of essential oil.

[0028] It is preferable to include a step of separating the essential oil components of Japanese pepper (also referred to as step 3 in this specification) after steps 1 and 2. The method for step 3 is not particularly limited as long as it does not impair the effects of the present invention, and a wide variety of known methods can be used. For example, pressing, solvent extraction, distillation (e.g., steam distillation, fractional distillation), supercritical fluid extraction, low-temperature vacuum extraction, etc. can be used. When distillation is used, either atmospheric distillation or reduced-pressure distillation can be used. Among these, steam distillation is preferred because it does not contain phototoxic substances in the essential oil.

[0029] As the Japanese pepper essential oil, commercially available products may be used, for example, "FRAGRANT KISHU-WAKA Japanese pepper" (manufactured by Nakano BC Co., Ltd.).

[0030] The Japanese pepper essential oil contained in composition 2 of the present invention can be obtained, for example, by dry-pulverizing pitted dried Japanese pepper in a hammer mill (e.g., with a screen size of approximately 0.5 mm to 3 mm), then wet-pulverizing approximately 2 kg of the pulverized material suspended in tap water in a colloid mill with a gap size of approximately 0.1 mm to obtain a finely pulverized liquid. The resulting finely pulverized liquid is then added to an aroma distiller with water to make a final volume of approximately 40 L, and steam is directly heated into the distillation still at a gauge pressure of approximately 15 kg / h until the temperature reaches approximately 100°C. After approximately 100°C, steam is sent to the jacket at a flow rate of approximately 10 kg / h to indirectly heat the product, and atmospheric distillation is carried out for approximately 1 hour from the point when the product temperature reaches approximately 100°C.

[0031] Volatile components of Zanthoxylum pepper essential oil In composition 2 of the present invention, the "volatile components of pepper essential oil" refer to, for example, components that can evaporate from pepper essential oil (e.g., in a liquid state) or components that are vaporized (e.g., in a gaseous state) under conditions of room temperature and normal pressure. Specific examples include limonene (e.g., 1 to 60% by mass, 3 to 50% by mass, 5 to 40% by mass, based on the total volatile components of Zanthoxylum pepper essential oil), geranyl acetate (e.g., 1 to 70% by mass, 20 to 60% by mass, 25 to 55% by mass, based on the total volatile components of Zanthoxylum pepper essential oil), β-phellandrene (e.g., 1 to 30% by mass, 5 to 25% by mass, 10 to 23% by mass, based on the total volatile components of Zanthoxylum pepper essential oil), citronellal (e.g., 0.1 to 20% by mass, 1 to 15% by mass, 3 to 9% by mass, based on the total volatile components of Zanthoxylum pepper essential oil), and geraniol (e.g., 0.1 to 20% by mass, 0.5 to 10% by mass, 1 to 6% by mass, based on the total volatile components of Zanthoxylum pepper essential oil). Composition 2 of the present invention may or may not contain non-volatile components of Zanthoxylum pepper essential oil. Examples of non-volatile components of Zanthoxylum pepper essential oil include unsaturated fatty acid amides such as sanshool (boiling point of 400°C or higher) and sanshoamide (boiling point of 270°C or higher). Composition 2 of the present invention may contain, for example, 0 to 30% by mass of sanshool relative to the total volatile components of Zanthoxylum pepper essential oil. Composition 2 of the present invention may also contain no sanshool. Even if non-volatile components of Zanthoxylum pepper essential oil are contained in Composition 2 of the present invention, they will not volatilize and will not be inhaled or inhaled. The content ratio of each of the above components may be a value determined, for example, by gas chromatography analysis.

[0032] Composition 2 of the present invention exerts its effects through the volatile components of the pepper essential oil contained in the composition. The volatile components are inhaled or inhaled and taken into the body. If the volatile components are inhaled into the body, it does not matter whether they are inhaled or inhaled through the nose (intranasal) or the mouth (oral), but it is preferable that they are taken into the body via the respiratory tract, or that they are taken into the body without passing through the esophagus. Furthermore, composition 2 of the present invention can be taken into the body by inhaling or inhaling the volatile components, for example, by placing a subject in an environment exposed to composition 2 of the present invention. Subjects of the present invention 2 include, for example, humans and non-human animals (e.g., rats, mice, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.).

[0033] Composition 2 of the present invention may contain any component other than Zanthoxylum pepper essential oil, or may contain no components other than Zanthoxylum pepper essential oil and consist essentially of Zanthoxylum pepper essential oil. The phrase "consisting essentially of Zanthoxylum pepper essential oil" in composition 2 of the present invention means, for example, that composition 2 of the present invention contains 95% or more by mass of Zanthoxylum pepper essential oil. When components other than Zanthoxylum pepper essential oil are contained, the proportion of Zanthoxylum pepper essential oil relative to the total composition is not particularly limited as long as the effects of the present invention are achieved. For example, the proportion may be 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, 3% by mass or more, 10% by mass or more, 30% by mass or more, 50% by mass or more, 70% by mass or more, 80% by mass or more, or 90% by mass or more. It may also be 0.01% by mass or less, 0.1% by mass or less, 1% by mass or less, 5% by mass or less, 10% by mass or less, 30% by mass or less, 50% by mass or less, 70% by mass or less, 80% by mass or less, or 90% by mass or less. The components other than Zanthoxylum pepper essential oil are not particularly limited as long as they do not impair the effects of the present invention, and may contain one or more raw materials that can be used in pharmaceuticals, quasi-drugs, cosmetics, miscellaneous goods, etc. For example, other essential oils, carrier oils, ethanol, water, glycerin, etc.

[0034] A specific example of the composition of the present invention may be an aroma oil or essential oil. The term "aroma oil" as used herein is not particularly limited, and includes, for example, essential oils to which other components (carrier oils, fragrances other than essential oils, ethanol, non-volatile substances, etc.) have been added. Other forms are not particularly limited, but may include, for example, inhalants, patches, topical preparations, soaps, detergents, massage oils, creams, emulsions, cosmetic powders, body lotions, hair styling products, hair washes, body soaps, antiperspirants, shampoos, conditioners, lotions, massage creams, skin care oils, fabric softeners, spray products, air fresheners, perfumes, bath additives, etc. When components other than Japanese pepper are contained, the method of producing the form is not particularly limited, and the form may be produced by known methods. The composition of the present invention includes cases excluding one or more selected from bath additives, mouthwashes, gargles, spices, seasonings, condiments, and herbal medicines. The composition of the present invention also includes cases excluding foods and beverages, oral pharmaceuticals, and oral compositions. When the composition of the present invention is passed through the oral cavity, it is preferable that its volatile components are inhaled or sucked through the respiratory tract. The composition of the present invention or its description may include a statement that the composition of the present invention relieves pain, or that the effect (analgesic effect) is obtained by inhaling or suctioning the volatile components contained in the composition of the present invention.

[0035] The composition of the present invention may be used as is, or may be mixed with components other than the composition of the present invention. When mixed with components other than the composition of the present invention, the ratio of the composition of the present invention to the total mixture is not particularly limited as long as the effects of the present invention are achieved. For example, the ratio may be 0.0001% by mass or more, 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, 3% by mass or more, 10% by mass or more, 30% by mass or more, 50% by mass or more, 70% by mass or more, 80% by mass or more, or 90% by mass or more. Alternatively, the ratio may be 0.01% by mass or less, 0.1% by mass or less, 1% by mass or less, 5% by mass or less, 10% by mass or less, 30% by mass or less, 50% by mass or less, 70% by mass or less, 80% by mass or less, or 90% by mass or less. The components other than the composition of the present invention are not particularly limited as long as they do not impair the effects of the present invention. Specifically, for example, the composition of the present invention may be mixed with one or more plant-derived components (e.g., water-soluble, fat-soluble, or non-volatile components obtained from plant flowers, leaves, peels, fruits, roots, seeds, bark, resins, etc.), or raw materials usable in pharmaceuticals, quasi-drugs, cosmetics, miscellaneous goods, etc. For example, it may be mixed with other essential oils, carrier oils, ethanol, water, glycerin, etc. Specific examples include inhalants, patches, topical preparations, soaps, detergents, massage oils, creams, emulsions, cosmetic powders, body lotions, hair styling products, hair washes, body soaps, antiperspirants, shampoos, rinses, lotions, massage creams, skin care oils, essential oils, aroma oils, fabric softeners, spray products, fragrances, perfumes, bath additives, etc. In one embodiment, the composition of the present invention may contain sanshool. When a mixture containing the composition of the present invention is passed through the oral cavity, it is preferred that the volatile components of the composition of the present invention are inhaled or sucked through the respiratory tract.

[0036] Furthermore, methods for inhaling or inhaling the composition of the present invention include, for example, smelling the scent (aroma) of the composition of the present invention. There are no particular limitations as long as the volatile components can be inhaled or inhaled and the effects of the present invention can be achieved. For example, a method of volatilizing the composition of the present invention in a space and then inhaling or inhaling it can be used. The composition of the present invention may be applied directly to the skin or to a site other than the skin. For example, when used in the form of essential oils or aroma oils, known inhalation or inhalation methods used in aromatherapy and the like may be employed. Specific examples include inhalation or inhalation using a diffuser or aroma stone, bathing, compresses, aroma treatments, etc. Alternatively, the composition may be impregnated into tissue, cloth, or nonwoven fabric using a spray or the like, and the volatile components emitted therefrom may be inhaled or inhaled. The composition may also be impregnated into a mask or mask seal and worn for inhalation or inhalation. The composition may also be inhaled or inhaled using an inhaler such as a nebulizer. When applied to the oral cavity, the volatile components may be inhaled or inhaled via the respiratory tract.

[0037] In another embodiment, a pain-relieving composition containing an aromatic oil or essential oil from a plant of the genus Zanthoxylum is provided. The composition includes cases excluding one or more selected from bath additives, mouthwashes, gargles, spices, seasonings, condiments, and herbal medicines. The composition also includes cases excluding one or more selected from foods and beverages, oral pharmaceuticals, and oral compositions. When the composition is passed through the oral cavity, the volatile components are inhaled or drawn through the respiratory tract. The composition may be substantially free of sanshool or may contain 0 to 30% by mass of sanshool. The composition may also be one that exerts its effect by sniffing.

[0038] In another embodiment, there is provided a method for relieving pain, characterized by inhaling or snorting the volatile components of Japanese pepper essential oil, or limonene and geranyl acetate, and in yet another embodiment, there is provided a composition for respiratory absorption or an aromatic composition for relieving pain, comprising Japanese pepper essential oil, or limonene and geranyl acetate. [Example]

[0039] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples.

[0040] [Production of Zanthoxylum spp. essential oil] Grape-pulverized Japanese pepper was used as the Japanese pepper. Seeded dried Japanese pepper (JA Arida) was dry-pulverized using a hammer mill (HM-100, manufactured by LabNect Co., Ltd.). Next, 2 kg of the pulverized material suspended in tap water was wet-pulverized using a colloid mill (manufactured by Shinmaru Enterprises Co., Ltd.) with a gap size of 0.1 mm. This finely pulverized liquid was placed in an aroma distiller (manufactured by Motomura Manufacturing Co., Ltd.), and tap water was added to make a final volume of 40 L. Steam was directly pumped into the distillation still at a gauge pressure of 15 kg / h until the temperature reached 100 °C. After 100 °C, steam was pumped into the jacket at a gauge pressure of 10 kg / h for indirect heating. Once the product temperature reached 100 °C, atmospheric distillation was performed for 1 hour. The yield of essential oil obtained was 114 mL, representing a yield of 57 mL / kg per dry-pulverized material.

[0041] [Gas Chromatographic Analysis of Zanthoxylum spp. Essential Oil] Zanthoxylum pepper essential oil was diluted 50 times with acetone to prepare a sample, and the aroma components were measured by gas chromatography. Measurement conditions GC apparatus: GC-2014 (Shimadzu Corporation), column: DB-WAX 0.25 mm diameter x 30 m, film thickness 0.25 μm (Agilent Technologies), injection method: split (split ratio 50:1), injection port temperature: 250 °C, sample injection volume: 1 μL, column temperature: 40 °C (2 min) → 6 °C / min → 220 °C (13 min) Determination of limonene and geranyl acetate in pepper essential oil. The limonene standard (product name: (+)-Limonene, manufactured by Tokyo Chemical Industry Co., Ltd., product code: L0105) and the geranyl acetate standard (product name: Geranyl Acetate, manufactured by Tokyo Chemical Industry Co., Ltd., product code: G0028) were used. The limonene and geranyl acetate concentrations were adjusted with acetone to 20 ppm, 40 ppm, and 50 ppm, respectively, and 5 ppm, 10 ppm, and 20 ppm, respectively. GC was performed under the above measurement conditions, and calibration curves were created for limonene and geranyl acetate. These calibration curves were used to quantify the two components contained in Japanese pepper essential oil. The quantitative results indicated that limonene was present at 64,100 ppm and geranyl acetate at 506,900 ppm. The proportions of volatile components contained in Japanese pepper essential oil were calculated from the GC area ratios. The results are shown in Figure 1.

[0042] The results in Figure 1 show that volatile components of Japanese pepper essential oil include limonene (19%), geranyl acetate (49%), β-phellandrene (11%), citronellal (5%), and geraniol (4%).

[0043] [Generation of chronic restraint stress (vCRS) mice] After introducing inbred C57BL / 6 mice (8-9 weeks old), they were allowed to acclimate to the experimental environment (12-hour light / dark cycle, 23°C) for one week. To efficiently generate hyperalgesic mice in a short period of time, 9-10 week old mice were placed in a 50 mL centrifuge tube with ventilation holes, and the tube was held upright and subjected to chronic restraint stress for 6 hours per day for 10 days to generate chronic restraint stress (vCRS) mice. [Evaluation of hyperalgesia using the von Frey test] Next, the mechanical sensory threshold (Threshold (g)) of the mouse hind limbs was measured using the von Frey test on the day before (before) and at one-week intervals starting the day after 10 days of chronic restraint stress (vCRS). The von Frey test filaments were available in 10 diameters, ranging from small to large. When the tip of each filament was pressed against the sole of the mouse's paw, it exerted forces of 0.008, 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, 1.4, and 2 g, respectively. The filament force (g) exerted when the mouse swung its paw in response to the pain reflex was measured, and the pain response to mechanical stimulation of the hind limbs was evaluated. During the experiment, cages were changed, food was replenished, and water bottles were replaced every week. Body weight was measured for 10 days during chronic restraint stress (vCRS) and during the von Frey test. During chronic restraint stress (vCRS), a tendency for weight loss was observed due to stress. After that, weight tended to remain constant or gradually increase. None of the mice experienced a dramatic weight loss during the experiment, so it was determined that they were generally in good health.

[0044] <Experimental Example 1: Hyperalgesia induced by vCRS and the analgesic effect of inhaling Japanese pepper aroma> Twelve chronic restraint stress (vCRS) mice were generated using the method described above. One week after the end of vCRS (i.e., day 8 on the horizontal axis in Figure 2), six of the mice were inhaled with 150 μL of aroma stones adsorbed with Japanese pepper essential oil attached to a single-mouse cage. Pain responses to mechanical stimulation of the lower limbs were assessed using the von Frey test on the day before vCRS (before) and at one-week intervals from the day after the 10-day vCRS, from days 8 to 36. The von Frey test on day 8 was performed immediately before the aroma stone inhalation. In the control group, pain responses were similarly assessed without the aroma stones adsorbed with Japanese pepper essential oil attached to the mouse cage. In both groups, 10 days of chronic restraint stress (vCRS) significantly reduced the mechanical sensory threshold (Threshold (g)) from approximately 1.2-1.4 g (normal pain level) to approximately 0.4 g (indicating hyperalgesia). After vCRS, the animals were weighed, their cages were changed, and their food and water bottles were replaced every week, and the aroma stones were replaced every 3 days. The results are shown in Figure 2.

[0045] As shown in Figure 2, hyperalgesia caused by chronic restraint stress (vCRS) in the control group (n=6, black circles) did not recover in mechanical sensory threshold even after 30 days, and the hyperalgesic state persisted, whereas in the Japanese pepper aroma inhalation group (n=6, white circles), the mechanical sensory threshold (Threshold (g)) increased from 22 to 36 days, and hyperalgesia was alleviated. Hyperalgesia caused by chronic restraint stress was alleviated by inhaling Japanese pepper aroma, demonstrating that Japanese pepper aroma has an analgesic effect.

[0046] <Experimental Example 2: Analgesic effect of inhaling limonene after inhaling geranyl acetate> Five vCRS mice were generated using the method described above. One week after the end of vCRS (i.e., day 8 on the horizontal axis in Figure 3), five mice were placed in a single-mouse cage and allowed to inhale 83.0 μL of geranyl acetate (GA) (product name: Geranyl Acetate, Tokyo Chemical Industry Co., Ltd., product code: G0028) adsorbed onto an aroma stone. von Frey tests were performed weekly from day 8 to day 43, starting the day before vCRS and the day after the 10-day vCRS. The von Frey test on day 8 was performed immediately before the aroma stone inhalation. Furthermore, for three of the five mice (white circles), between days 43 and 64, aroma stones containing 11.9 μL of limonene (product name (+)-Limonene, manufactured by Tokyo Chemical Industry Co., Ltd., product code: L0105) were attached to the mouse cage and allowed to inhale. Meanwhile, two of the five mice (black circles) continued to inhale only geranyl acetate (GA) in the same manner. Both groups underwent von Frey tests every week between days 50 and 64. The proportions of limonene and geranyl acetate were 6.41% by mass and 50.69% by mass, respectively. The results are shown in Figure 3.

[0047] As shown in Figure 3, hyperalgesia induced by chronic restraint stress (vCRS) in rats treated with geranyl acetate (GA) alone did not recover or change in mechanical sensory threshold up to 43 days (n = 5). However, after 43 days, in the group inhaling limonene in addition to geranyl acetate (GA) (n = 3, open circles), the mechanical sensory threshold increased and almost completely recovered, demonstrating a clear analgesic effect. On the other hand, in the group receiving continued geranyl acetate (GA) alone (n = 2, filled circles), the hyperalgesic state was maintained. These results indicate that hyperalgesia induced by chronic restraint stress can be alleviated by inhaling limonene in addition to inhaling geranyl acetate, and that geranyl acetate and limonene have analgesic effects.

[0048] <Experimental Example 3: Analgesic effect of inhaling geranyl acetate after inhaling limonene> Eight vCRS mice were generated using the method described above. One week after the end of vCRS (i.e., day 8 on the horizontal axis in Figure 4), an aroma stone containing 11.9 μL of limonene (product name: (+)-Limonene, manufactured by Tokyo Chemical Industry Co., Ltd., product code: L0105) was attached to a single-mouse cage and allowed to inhale. Von Frey tests were performed weekly from days 8 to 43, starting the day before vCRS and the day after the 10-day vCRS. The von Frey test on day 8 was performed immediately before the aroma stone inhalation. Furthermore, between days 43 and 64, an aroma stone containing 83.0 μL of geranyl acetate (GA) (product name: Geranyl Acetate, manufactured by Tokyo Chemical Industry Co., Ltd., product code: G0028) was attached to the mouth cage and the animals were allowed to inhale the aroma stone, and von Frey tests were performed every week. The proportions of limonene and geranyl acetate were 6.41% by mass and 50.69% by mass, respectively. The results are shown in Figure 4.

[0049] As shown in Figure 4, the hyperalgesia caused by chronic restraint stress (vCRS) did not change until 43 days after administration of limonene alone, with no recovery of the mechanical sensory threshold (no statistically significant difference). However, after that, inhalation of geranyl acetate (GA) in addition to limonene increased the mechanical sensory threshold, resulting in a clear analgesic effect (n = 8). These results indicate that hyperalgesia induced by chronic restraint stress can be alleviated by inhaling geranyl acetate in addition to inhaling limonene, and that geranyl acetate and limonene have analgesic effects.

[0050] <Experimental Example 4: Analgesic effect by inhalation in the presence of geranyl acetate and limonene> Five vCRS mice were generated using the method described above. One week after the end of vCRS (i.e., day 8 on the horizontal axis in Figure 5), mice were placed in a single-mouse cage and allowed to inhale aroma stones containing 11.9 μL of limonene (product name: (+)-Limonene, Tokyo Chemical Industry Co., Ltd., product code: L0105) and 83.0 μL of geranyl acetate (GA) (product name: Geranyl Acetate, Tokyo Chemical Industry Co., Ltd., product code: G0028). Von Frey tests were performed weekly from day 8 to day 43, starting the day before vCRS and the day after the 10-day vCRS. The von Frey test on day 8 was performed immediately before the aroma stone inhalation. The proportions of limonene and geranyl acetate were 6.41 mass % and 50.69 mass %, respectively. The results are shown in Figure 5.

[0051] As shown in Figure 5, inhaling limonene and geranyl acetate (GA) increased the mechanical sensory threshold of the hyperalgesia induced by vCRS, returning it to the state before vCRS (n=5). These results indicate that hyperalgesia caused by chronic restraint stress can be alleviated by inhaling limonene and geranyl acetate, and that geranyl acetate and limonene have analgesic effects.

[0052] The results of the above experiments showed that inhaling both limonene and geranyl acetate had an analgesic effect on hyperalgesia caused by chronic restraint stress. Although the mechanism by which this effect is exerted is unclear, it is thought that the ingestion of both volatile components of limonene and geranyl acetate into the body exerts an effect that cannot be exerted by ingestion of either limonene or geranyl acetate alone. [Industrial Applicability]

[0053] The composition of the present invention is useful as a daily necessities, medicine, quasi-drug, etc., in that an analgesic effect can be obtained by inhaling or suctioning the volatile components.

Claims

1. An analgesic composition containing limonene and geranyl acetate.

2. 10. The composition of claim 1, wherein the composition is inhaled or inhaled to achieve its effect.

3. A pain-relieving composition containing Zanthoxylum esculentum, the effect of which is obtained by inhaling or suctioning the volatile components of said essential oil.

4. 4. The composition according to claim 1 or 3, which is an aromatic oil or an essential oil.

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