Agent for improving age-related olfactory impairment

Abstract

To provide an agent for improving age-related hyposmia that improves age-related hyposmia.SOLUTION: An agent for improving age-related hyposmia contains water particles, water vapor or a combination of them as an active ingredient, the agent to be administered by transnasal suction.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an agent for improving age-related olfactory decline.

Background Art

[0002] Olfactory function, like other senses such as vision and hearing, gradually declines with age. Age-related olfactory decline not only makes it difficult to detect and avoid dangerous odors such as food spoilage and gas leakage, but also significantly reduces the quality of life (QOL) in daily life, having adverse physical and mental effects.

[0003] After an odorant enters the nasal cavity, it dissolves in the olfactory mucus on the olfactory mucosa in the olfactory cleft and is recognized by olfactory receptors on olfactory nerve cells expressed in the olfactory epithelium. The olfactory receptor binds and activates the odorant, causing electrical excitation in the olfactory nerve cells. The odor is perceived when this electrical excitation is transmitted to the higher brain via neural connections. Factors contributing to olfactory decline include nasal congestion that blocks the passage of odorants to olfactory nerve cells, inflammation, post-infectious olfactory impairment where abnormalities occur in the olfactory tissue after infection, and central (nerve, brain) olfactory decline caused by disorders in the olfactory pathway within the skull. It has also been clarified that olfactory impairment appears as a prodromal symptom of neurodegenerative diseases represented by Alzheimer's disease and Parkinson's disease. In addition, various changes occur in the tissues of the olfactory system with aging, and it has been reported that these are involved in the cause of olfactory decline. Histological changes in the olfactory epithelium include the disappearance of olfactory nerve cells and basal cells that differentiate into olfactory nerve cells, and replacement with respiratory epithelial tissue (Non-Patent Document 1). In mice, it has been reported that the locations of olfactory epithelium degeneration also coincide with the histological degeneration locations of Bowman's glands that produce olfactory mucus in the lamina propria mucosae (Non-Patent Document 2).

[0004] However, for age-related olfactory decline, for example, although it has been reported in Non-Patent Document 3 that olfactory training, in which several odors are continuously smelled by elderly people to stimulate olfaction, can prevent olfactory decline, there is currently no known effective method for improving age-related olfactory decline in a short time.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present invention relates to providing an agent for improving age-related olfactory decline that improves age-related olfactory decline in a short time.

Means for Solving the Problems

[0007] The first step of smell perception is the dissolution of odorant substances into the olfactory mucus. Therefore, the present inventor focused on olfactory mucus secretion and conducted intensive studies. As a result, it was found that there is a significant negative correlation between age and the amount of olfactory mucus, and that olfactory mucus secretion decreases with aging, which is one of the causes of age-related olfactory decline. Then, the present inventor examined methods to increase the amount of olfactory mucus or promote the secretion of olfactory mucus in order to improve olfactory sensitivity. As a result, it was found that for elderly people, by inhaling water particles or water vapor into the nasal cavity before exposure to odors, olfactory sensitivity is improved based on an increase in the amount of olfactory mucus or promotion of olfactory mucus secretion, and olfactory decline can be improved.

[0008] That is, the present invention provides an agent for improving age-related olfactory decline, which contains water particles, water vapor, or a combination thereof as an active ingredient and is administered by nasal inhalation.

Effects of the Invention

[0009] According to the present invention, it is possible to improve the olfactory decline associated with aging by transnasal inhalation of water particles or water vapor.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0011] As shown in the following examples, when water particles or water vapor are inhaled into the nasal cavity of elderly people using a nebulizer or a vapor generator before exposure to an odor, the ability to identify the odor and the sensation intensity are improved, and the detection threshold is decreased (the detection threshold score is improved). The odor identification ability is the ability to distinguish the type of odor, the odor sensation intensity is the strength of perceiving the odor, and the odor detection threshold is the minimum concentration for perceiving the presence of the odor. When measuring the olfactory mucus volume of humans, the olfactory mucus volume decreased with aging, and there was a significant negative correlation between age and olfactory mucus volume (Figure 1). Also, there was a significant positive correlation between the average value of the olfactory sensation intensity evaluation value for odor substances and the olfactory mucus volume (Figure 2). These results indicate that olfactory mucus secretion decreases with aging, which is one of the causes of age-related olfactory decline. It has been proven by in vitro experiments using a nasal cavity model that water particles reach the olfactory cleft by inhaling water particles using a nebulizer (Visualization and Quantification of Nasal and Olfactory Deposition in a Sectional Adult Nasal Airway Cast, Pharm. Res, 2016 33:1527-1541). Therefore, it is considered that the inhaled water particles reach the olfactory cleft, mix with the olfactory mucus in the olfactory mucosa, and the amount of olfactory mucus increases. Also, it is known that the humidity in the nasal cavity increases according to the humidity of the inhaled air (The role of the nasal cavity and paranasal sinuses in biological defense, Japanese Journal of Chest Medicine, 1996, Vol. 55, November Supplement). Therefore, it is considered that the humidity in the nasal cavity increases by inhaling the water vapor generated from the vapor generator, the evaporation of the nasal mucus decreases, and the amount of olfactory mucus increases. From this, it has been found that nasal inhalation of water particles, water vapor, or a combination thereof before odor exposure increases the amount of olfactory mucus or promotes the secretion of olfactory mucus, and based on this, olfactory sensitivity is improved and olfactory decline can be ameliorated.

[0012] Accordingly, the present invention provides an ameliorating agent for age-related olfactory decline, which contains water particles, water vapor, or a combination thereof as an active ingredient and is administered by nasal inhalation. The present invention also provides the use of water particles, water vapor, or a combination thereof in the manufacture of an ameliorating agent for age-related olfactory decline administered by nasal inhalation. The present invention also provides the use of water particles, water vapor, or a combination thereof for ameliorating age-related olfactory decline by nasal inhalation. The present invention also provides a method for ameliorating age-related olfactory decline, which includes nasal inhalation of an effective amount of water particles, water vapor, or a combination thereof to a subject. Here, the use of water particles or water vapor in humans may be for therapeutic use or non-therapeutic use. "Non-therapeutic" means not including medical acts, that is, not including methods of operating on, treating, or diagnosing humans. More specifically, it is a concept that does not include methods in which a doctor, medical staff, or a person under the instruction of a doctor performs an operation, treatment, or diagnosis on a human.

[0013] In the present invention, "aging-related olfactory decline" means a decline in olfactory function associated with aging. Olfactory function includes the ability to identify different odors, the ability to detect the presence of an odor, the ability to perceive the intensity of an odor, and the ability to distinguish between different odors. In addition, "improvement" refers to an improvement in symptoms or conditions, the prevention or delay of the deterioration of symptoms or conditions, or the reversal, prevention, or delay of the progression of symptoms.

[0014] The types of odors perceived in the present invention are not particularly limited, and include the odors of generally known dangerous substances or toxic substances (e.g., gas flavorings, hydrogen sulfide, chlorine gas, putrefied substances, etc.); the scents of generally used fragrances (e.g., animal-derived fragrances such as musk, civet, castoreum, ambergris, etc.; essential oils derived from plants; plant-derived fragrances such as rose, jasmine, neroli, lavender, clove, peppermint, sandalwood, cinnamon, lemon, orange, bergamot, etc.); the odors of foods or their ingredients; malodors or unpleasant odors (e.g., body odor, axillary odor, bad breath, fecal odor, urine odor, tobacco odor, mold odor, musty odor, putrefaction odor, garbage odor, sewage odor, exhaust odor, duct odor, exhaust gas odor, etc.); and the odors of other odoriferous substances (e.g., cosmetics, pharmaceuticals, detergents, daily necessities, etc.).

[0015] As methods for evaluating olfactory function, in the case of humans, there are identification test methods by sensory evaluation (methods of answering the types of odors), threshold test methods (methods of determining the lowest concentration at which the presence of an odor can be detected), odor intensity tests (methods of answering the intensity of the perceived odor on various scales), odor preference tests (methods of answering the preference for the perceived odor on various scales), discrimination test methods (methods of selecting different odors), venous olfactory tests (e.g., the Alinamin test), etc. In these tests, commercially available test kits such as Open Essence (FUJIFILM Wako Pure Chemical Corporation), T&T Olfactometer (Daiichi Yakuhin Kogyo Co., Ltd.), Sniffin’ Sticks (registered trademark) (Burghart Medizintechnik), etc. may be used, or molecules presenting odors such as fragrances may be used alone or in combination and appropriately diluted.

[0016] In the present invention, the means for nasally inhaling water particles or water vapor is not particularly limited. For example, there are methods of inhaling using an inhaler capable of inhaling water particles such as a nebulizer, and methods of inhaling using a steam generator that generates heat by reacting with oxygen in the air and generates water vapor and can supply the warmed water vapor to the subject. As the nebulizer, an ultrasonic nebulizer, a mesh nebulizer, or a compressor nebulizer is preferably used. The particle diameter of the water particles is preferably less than 10 μm, more preferably 1 to 8 μm. Here, the particle diameter of the water particles is the effective diameter measured by the light scattering method.

[0017] As the steam generator, a known one having a water vapor generating body capable of generating water vapor can be used. For example, a steam generator including a bottomed cylindrical mask body having an opening capable of covering the nose of the subject at the end on the face contact side and a water vapor generating body capable of generating water vapor in the internal space of the mask body (Japanese Patent Application Laid-Open No. 2020-192309, Japanese Patent Application Laid-Open No. 2020-192310, etc.) can be mentioned. The water vapor generating body preferably contains an oxidizable metal, a carbon component, and water. The oxidizable metal is a metal that generates oxidation reaction heat by reacting with oxygen in the air, and steam is generated from water by such heat generation. Examples of the oxidizable metal include one or more powders or fibers selected from iron, aluminum, zinc, manganese, magnesium, and calcium. Examples of the carbon component include activated carbon, acetylene black, and graphite, which act as a water absorbent and have water retention ability, oxygen supply ability, and catalytic ability.

[0018] In the present invention, the effective amount of water particles or water vapor is not particularly limited as long as it can improve age-related olfactory decline by nasal inhalation, and can be appropriately adjusted according to the species and age of the subject, the original olfactory sensitivity, the nasal cavity shape, and the like. In the case of water particles, the spraying amount per minute is preferably 0.1 mL or more, more preferably 0.5 mL or more, preferably 2 mL or less, and more preferably 1.5 mL or less. In addition, the inhalation time of water particles per inhalation is preferably 1 minute or more, more preferably 2 minutes or more, and preferably 10 minutes or less, more preferably 7 minutes or less.

[0019] In the case of water vapor, the cumulative amount of water vapor generated and released within 10 minutes (water vapor generation amount in 10 minutes) starting from the start of water vapor generation is preferably 500 mg or more, more preferably 700 mg or more, still more preferably 900 mg or more, and preferably 2000 mg or less, more preferably 1700 mg or less, still more preferably 1400 mg or less. Here, the water vapor generation amount in 10 minutes is a numerical value measured as follows using the apparatus 30 shown in FIG. 4. The apparatus 30 shown in FIG. 4 includes a measurement chamber (volume 2.1 L) 31 made of aluminum, an inflow path 32 for allowing dehumidified air (humidity less than 2%, flow rate 2.1 L / min) to flow into the lower part of the measurement chamber 31, an outflow path 33 for allowing air to flow out from the upper part of the measurement chamber 31, an inlet temperature and humidity meter 34 and an inlet flow meter 35 provided in the inflow path 32, an outlet temperature and humidity meter 36 and an outlet flow meter 37 provided in the outflow path 33, and a thermometer (thermistor) 38 provided in the measurement chamber 31. As the thermometer 38, one with a temperature resolution of about 0.01 °C is used.

[0020] The surface temperature of the surface of the water vapor generator located on the skin side is measured by taking out the water vapor generator from the oxygen barrier bag at a measurement environmental temperature of 30 °C (30 ± 1 °C), placing it in the measurement chamber 31 with the surface located on the skin side of the water vapor generator, that is, the water vapor release surface facing upward, and placing the thermometer 38 with a metal sphere (4.5 g) on it for measurement. Also, in this state, dehumidified air is flowed from below, and the difference in absolute humidity before and after air flows into the measurement chamber 31 is obtained from the temperatures and humidities measured by the inlet temperature and humidity meter 34 and the outlet temperature and humidity meter 36. Furthermore, the amount of water vapor released by the water vapor generator is calculated from the flow rates measured by the inlet flow meter 35 and the outlet flow meter 37. Then, taking the time point when the water vapor generator is taken out from the oxygen barrier bag as the starting point, the total amount of water vapor measured until 10 minutes later is taken as the water vapor generation amount in 10 minutes. The inhalation time of water vapor per session is preferably 5 minutes or more, more preferably 7 minutes or more, and preferably 20 minutes or less, more preferably 15 minutes or less.

[0021] The agent for improving age-related olfactory decline of the present invention can be administered by nasal inhalation according to any suitable administration schedule. From the viewpoint of being able to immediately improve olfactory sensitivity, it is preferable to administer it to the subject before exposure to the odor. Specifically, it is preferably administered within 30 minutes before exposure to the odor, and more preferably within 10 minutes before exposure to the odor. Examples of administration before exposure to the odor include, for example, performing nasal inhalation of water particles, water vapor, or a combination thereof before cooking, before eating, before washing, and before cleaning. The administration period can be determined appropriately. For example, 1 day or more is preferable, 7 days or more is more preferable, and 30 days or more is even more preferable.

[0022] The application targets of the agent for improving age-related olfactory decline of the present invention include mammals that desire or require improvement of age-related olfactory decline. Examples of mammalian species include primates such as humans, chimpanzees, and monkeys, and rodents such as mice and rats. Primates are preferred, and humans are more preferred. Examples of humans who desire or require improvement of age-related olfactory decline include those whose sense of smell has declined due to aging (for example, the elderly).

Example

[0023] Example 1 1. Collection of olfactory mucus Thirty healthy men and women without self-reported nasal symptoms (aged from their 20s to 60s, 6 in each age group) were given topical anesthesia with lidocaine spray, and then medical sponges (sterilized Vency Sheets (registered trademark) XR, 0.7 cm × 0.7 cm, Kawamoto Sangyo) were inserted into four locations in the left and right olfactory clefts (OC) and inferior nasal meatus, and left standing for 5 minutes. After standing, the sponges were withdrawn and placed in 1.5 mL tubes, and immediately kept cold under dry ice. Subsequently, holes were made in the bottom of the tubes containing the sponges with a needle, and another 1.5 mL tube was placed below, and the sponges were squeezed with a high-speed centrifuge (10,000 r / min, 10 minutes) to collect olfactory mucus. The weight of the collected olfactory mucus was measured, and the average value of the mucus from the left and right olfactory clefts was taken as the olfactory mucus volume of each panel. As shown in Figure 1, when the olfactory mucus volume of each panel was plotted against age, a significant negative correlation was shown (r = -0.66, p < 0.0001, Spearman’s correlation).

[0024] 2. Measurement of Olfactory Sensitivity of the Olfactory Mucus Sampling Panel The above-mentioned 30 panelists were asked to smell six kinds of odor substances before and after collecting olfactory mucus, and were questioned about the sensory intensity of the odors. The odor substances used were p-cresol, p-cresyl acetate, cis-3-hexenol, cis-3-hexenyl acetate, isoborneol, and isobornyl acetate (all of the above, Tokyo Chemical Industry Co., Ltd.). Isoborneol and isobornyl acetate were prepared in a 1 v / v% solution, and the others were prepared in a 0.1 v / v% solution of mineral oil (Sigma-Aldrich). 1 mL of each of these odor solutions was placed in a glass vial and used as a test sample. Each panelist smelled the six kinds of odor solutions and selected one from the following 7 points: 1: Can't feel it, 2: Feel it faintly, 3: Feel it weakly, 4: Feel it moderately strongly, 5: Feel it strongly, 6: Feel it very strongly, 7: Feel it extremely strongly. As a result, as shown in Fig. 2, when the average value of the sensory intensity evaluation values for each odorant before olfactory mucus collection and the amount of olfactory mucus were plotted, a significant positive correlation was shown (r = 0.46, p < 0.01, Spearman’s correlation). From these results, it was shown that olfactory mucus secretion decreases with aging, suggesting that this is one of the causes of olfactory decline.

[0025] Example 2 Immediate change in the way of feeling odor by a nebulizer Five healthy men and women (in their 50s and 60s, Panels A to E) without self-reported nasal symptoms were subjected to three types of olfactory tests before and after using a nebulizer. As the nebulizer, an ultrasonic nebulizer NE-U07 (Omron Corporation, spray particle size: 1 to 8 μm, spray rate 1 mL / min) was used, and Milli Q water was sprayed for 5 minutes and then aspirated from the nasal cavity. The olfactory tests were of three types: (1-1) odor identification ability, (1-2) odor detection threshold, and (1-3) odor sensory intensity, and each test was carried out on separate days with a week interval.

[0026] 1-1. Odor identification ability test The odor identification ability was measured using open essences (FUJIFILM Wako Pure Chemical Corporation). The five panelists smelled 12 types of odors in order and selected the one that they thought corresponded to the odor from four choices (the answer was selected from six choices including odorless and don't know). From the first test, after an interval of more than one week, the same test was carried out after using the nebulizer. As shown in Table 1, compared with the first time, the number of correct answers increased in all panelists after using the nebulizer (p < 0.01, ratio paired t-test).

[0027]

Table 1

[0028] 1-2. Odor detection threshold test The detection threshold test was conducted for two types of odor substances. One was 2-phenylethyl alcohol (PEA, Tokyo Chemical Industry Co., Ltd.), and a 0.1 v / v% mineral oil solution was used as the highest concentration solution. Sequentially, 16 solutions diluted 2-fold with mineral oil were prepared. The other was Ambrettolide (Sigma-Aldrich), and an 8 v / v% mineral oil solution was used as the highest concentration solution. Similarly, 16 solutions with different concentrations were prepared. 1 mL of each of these odor solutions was placed in a glass vial and used as a test sample. The detection thresholds of PEA and Ambrettolide were measured on separate days with a week interval between each. In the test, first, the panelists were asked to smell the two weakest odor solutions and two blank solutions (mineral oil only), and then select the vial that they thought contained the odor solution. In the case of a correct answer, it was evaluated again at the same concentration, and the case where the correct answer was selected twice in a row was taken as the threshold score for 1 Run. In the case of an incorrect answer, the concentration of the odor solution was increased in order, and the test was carried out until a concentration at which two consecutive correct answers could be given was reached. For the 2nd Run, it was carried out starting from a solution 4 steps stronger than the concentration at which a correct answer was given in the 1st Run, and the solution was made weaker as long as two consecutive correct answers continued. Finally, the concentration at which two consecutive correct answers were given was taken as the threshold score for the 2nd Run. Next, starting from a solution 5 steps stronger than the score concentration of the 2nd Run, the test was carried out in the same manner as the 1st Run to obtain the score for the 3rd Run. For the 4th Run, starting from a solution 4 steps stronger than the score concentration of the 3rd Run, the test was carried out in the same manner as the 2nd Run. The score when smelling the weakest concentration was set as "15", the score when smelling only the strongest concentration was set as "0", and the score when not smelling the strongest concentration was also treated as "0". The average of the 4 Runs was taken as the threshold score. After the first detection threshold measurement, the nebulizer was continuously used, and the detection threshold test after use was conducted in the same manner. In the detection threshold test of Ambrettolide, since Panel A could distinguish the weakest concentration solution before using the nebulizer, the test was aborted. Also, since Panel E complained of fatigue during the detection threshold test after using the nebulizer, it was excluded from the analysis. The detection threshold scores of each panel were as shown in Table 2. Although there was no statistically significant difference, a tendency for the detection threshold scores to generally improve was shown by the use of the nebulizer.

[0029]

Table 2

[0030] 1 - 3. Odor sensation intensity For Panels B - E, the evaluation of the sensation intensity was conducted on mineral oil solutions (each containing 1 mL in a glass vial) of six odor substances: p - cresol (0.01 v / v%), acetyl - p - cresol (0.1 v / v%), cis - 3 - hexenol (0.01 v / v%), cis - 3 - hexenyl acetate (0.1 v / v%), isoborneol (1 v / v%), and isobornyl acetate (1 v / v%). (Panel A was not conducted due to scheduling reasons.) The evaluation criteria were the same as described above: 1: Not felt, 2: Slightly felt, 3: Weakly felt, 4: Somewhat strongly felt, 5: Strongly felt, 6: Very strongly felt, 7: Extremely strongly felt. One of these 7 levels was selected. The nebulizer was used continuously, and the evaluation of the sensation intensity was conducted again after use. The scores for each compound for each panel were as shown in Table 3. When comparing the sensation intensity scores before and after using the nebulizer for all evaluation values, the scores were significantly improved (p < 0.05, paired t - test).

[0031]

Table 3

[0032] Example 3. Immediate change in the way healthy seniors perceive odor by a vapor - generating device Ten healthy men and women (in their 50s and 60s) without self-perceived nasal symptoms were asked to use a commercially available steam-generating cup (Kao Corporation, steam generation amount 1080 mg / 10 min) that generates steam inside a cup covering the nose for 10 minutes. Before and after the use, the olfactory sensation intensity and preference for 10 types of odors were evaluated. p-Cresol (0.01 v / v%), acetyl-p-cresol (0.1 v / v%), cis-3-hexenol (0.01 v / v%), cis-3-hexenyl acetate (0.1 v / v%), isoborneol (0.1 v / v%), isobornyl acetate (1 v / v%), the scent of Melon (ingredients not disclosed, 10 ppm), the scent of Green Apple (ingredients not disclosed, 0.1 v / v%) in a mineral oil solution (1 mL each in a glass vial), as well as commercially available soy sauce (2 μL soaked into filter paper and placed in a glass vial), and a dashi pack (10 mg placed in a glass vial) were used. The olfactory sensation intensity was the same as the evaluation criteria in Example 1, and one was selected from the following 7 levels: 1: Not felt, 2: Slightly felt, 3: Weakly felt, 4: Somewhat strongly felt, 5: Strongly felt, 6: Very strongly felt, 7: Extremely strongly felt.

[0033] Regarding the preference, for the scent of Melon and the scent of Green Apple, one was selected from the following 7 levels: -3: Very unpleasant, -2: Unpleasant, -1: Slightly unpleasant, 0: Neither, 1: Slightly pleasant, 2: Pleasant, 3: Very pleasant, and the score was obtained. For the scent of soy sauce and the dashi pack, one was selected from the following 7 levels: -3: Very unappetizing, -2: Unappetizing, -1: Slightly unappetizing, 0: Neither, 1: Slightly appetizing, 2: Appetizing, 3: Very appetizing, and the score was obtained.

[0034] As a result, as shown in Figure 3, when comparing the scores before and after the use of the steam-generating device for all the olfactory sensation intensity evaluation results (N = 100) and preference evaluation results (N = 40), there was a significant tendency for the olfactory sensation intensity and a significant difference in the preference scores, with the scores improving (olfactory sensation intensity: p = 0.07, preference: p < 0.01, paired t-test).

Claims

1. An agent for improving presbyosmia, which has water particles, water vapor, or a combination thereof as an active ingredient and is administered by nasal inhalation, wherein the dose of the water particles is 0.1 to 2 mL as the spraying amount per minute, the dose of the water vapor is 500 to 2000 mg as the water vapor generation amount for 10 minutes, and the water particles, water vapor, or a combination thereof does not contain a drug for treating presbyosmia.

2. The agent for improving presbyosmia according to claim 1, which is administered before exposure to odor.

3. The agent for improving presbyosmia according to claim 1 or 2, which is administered using an inhaler or a vapor generator.

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