JP5389471B2 - Nasal obstruction inhibitor - Google Patents

Description

  The present invention relates to a nasal congestion inhibitor that suppresses nasal congestion, a nasal congestion inhibitor in allergic rhinitis or a cold syndrome, and an improving agent that improves at least one of the symptoms of sleep disorder and snoring caused by nasal congestion. More specifically, a nasal congestion inhibitor, allergic rhinitis and / or cold syndrome, i.e., upper respiratory tract, effective in suppressing nasal obstruction of immediate and late phase reactions that are difficult to suppress with antihistamines The present invention relates to a nasal obstruction inhibitor that suppresses nasal obstruction caused by inflammation induced by viral infection of the nasal cavity, and a sleep disorder ameliorating agent and an agent for improving snoring caused by nasal obstruction.

Allergic rhinitis is a type I allergic disease characterized by the three major symptoms of sneezing, rhinorrhea, and nasal congestion. Immediate phase reaction that triggers sneezing, rhinorrhea, and nasal congestion immediately after antigen induction by pollen, etc. It is known to show a biphasic response of late phase reaction that induces nasal congestion in 4-24 hours. Traditionally, allergic rhinitis has been treated with antiallergic drugs that have antihistaminic activity as the main action, and sneezing and rhinorrhea in the immediate phase reaction are strongly suppressed. It is said that the effect on nasal congestion in the reaction is weak. From recent research results, “Nose Allergy Diagnosis Guidelines 2005 Edition”, Life Science Co., Ltd. (2006), page 16 (Non-patent Document 1) shows that histamine has little involvement in the onset of nasal congestion, and leukotriene ( LTs) and thromboxane A ₂ (TXA ₂ ) are described as being significantly involved. Further, pages 54 to 55 of Non-Patent Document 1 describe that oral LTs or TXA ₂ antagonists are currently used for the treatment of allergic rhinitis exhibiting nasal congestion in ethical drugs. However, only a few drugs can be used.

  On the other hand, vasoconstrictors such as pseudoephedrine are used for the suppression of nasal congestion caused by allergic rhinitis or cold in general drugs for the purpose of temporarily removing redness of the nasal mucosa. However, the therapy using a vasoconstrictor does not suppress inflammation itself but is merely a symptomatic therapy.

  In addition, nasal congestion is known to significantly deteriorate the quality of sleep. For example, in “Sleep Disorder Response and Treatment Guidelines”, Jiho Co., Ltd. (2006) (Non-patent Document 2), nasal congestion induces and increases snoring and sleep apnea syndrome that cause sleep disorders. It is described that it worsens. However, there is no safe drug that can be taken for a long time to improve sleep disorders caused by nasal congestion. Therefore, development of a safe and highly effective nasal congestion inhibitor is desired.

  In “Kampo Pharmacology”, Nanzan-do Co., Ltd. (1997) (Non-patent Document 3), Nantenjitsu (Minami Tenmi) is a sample of the white or red fruit of the barberry family Nandina Domestica. There is a description that Nantenjitsu contains an active ingredient of alkaloids and is generally used as a cough suppressant at a dose of about 5 to 10 g per day. Since Nantenjitsu has been used as a crude drug for many years and has a track record of use, drugs containing Nantenjitsu as an active ingredient are considered to be highly safe.

  Japanese Patent Application Laid-Open No. 2007-210909 (Patent Document 1) discloses an antiallergic agent, an antihistamine agent and an antiserotonin agent comprising Nantenji extract as an active ingredient, and Nanzenji extract is based on antihistamine and antiserotonin activity. It describes that it has excellent antiallergic action and can be used as an antiallergic agent.

  However, as described in Non-Patent Document 1, it is difficult to effectively suppress nasal congestion with an antihistamine or an antiallergic agent mainly having an antihistamine action.

  Japanese Patent Application Laid-Open No. 11-12187 (Patent Document 2) discloses an antipyretic analgesic / anti-inflammatory agent comprising a nonsteroidal anti-inflammatory agent such as ibuprofen and a Nanten extract as active ingredients. Japanese Laid-Open Patent Publication No. 2006-8540 (Patent Document 3) discloses a cold medicine containing a Nanten fruit extract and bromhexine hydrochloride, and Japanese Translation of PCT International Publication No. 2007-530620 (Patent Document 4) discloses meloxicam or a pharmaceutical thereof. A pharmaceutical composition comprising a top acceptable salt and a pharmaceutically active ingredient selected from antitussives, expectorants and anti-HI-histamines is disclosed, and Nantenjitsu is exemplified as an antitussive.

  However, it is not known at all that Nantenjitsu has a therapeutic effect on the nasal obstruction reaction induced in allergic rhinitis and cold syndrome, and an action to improve snoring and sleep disorders caused by nasal obstruction.

JP 2007-210909 A (claim, paragraph [0033]) Japanese Patent Laid-Open No. 11-12187 (Claims) JP 2006-8540 A (Claims) JP-T-2007-530620 (Claims)

Guidelines for Diagnosis of Nasal Allergy 2005, Life Science Co., Ltd. (2006), pages 16, 54-55 Sleep Disorder Response and Treatment Guidelines, Jiho Co., Ltd. (2006) Kampo Pharmacology, Nanzan-do Co., Ltd. (1997)

  Accordingly, an object of the present invention is to provide a nasal congestion inhibitor having an excellent therapeutic effect on the nasal congestion reaction.

  Another object of the present invention is to improve a nasal obstruction inhibitor capable of effectively suppressing nasal obstruction in at least one symptom of allergic rhinitis and cold syndrome, at least one symptom of sleep disorder and snoring caused by nasal obstruction. It is to provide an effective improver.

  Still another object of the present invention is to provide a highly safe nasal congestion inhibitor.

  As a result of diligent research to solve the above problems, the present inventor has found that a preparation containing Nantenjitsu as an active ingredient effectively suppresses a nasal obstruction reaction that is difficult to suppress with an antihistamine, Has a strong inhibitory action on both the immediate phase reaction and the late phase reaction, particularly in the nasal closed biphasic model, at least one of the immediate phase reaction and the late phase reaction of the nasal closed biphasic reaction It was found that nasal obstruction was significantly suppressed against (especially both reactions), and the present invention was completed.

  That is, the present invention relates to (1) a nasal congestion inhibitor containing Nantenjitsu as an active ingredient, (2) a nasal congestion inhibitor in allergic rhinitis containing Nantenjitsu as an active ingredient, and (3) a cold syndrome containing Nantenjitsu as an active ingredient. A nasal congestion inhibitor, (4) the nasal congestion inhibitor containing an extract of Nantenjitsu, and (5) the nasal congestion inhibitory action on at least one of the immediate phase reaction and the late phase reaction of the nasal congestion biphasic reaction A nasal obstruction inhibitor, (6) an agent for improving the symptoms of at least one of sleep disorders and snoring caused by nasal obstruction, comprising Nantenjitsu as an active ingredient.

  The nasal congestion inhibitor of the present invention contains Nantenjitsu as an active ingredient and has an excellent effect in suppressing nasal congestion. In particular, it effectively suppresses nasal congestion, which is difficult to suppress with antihistamines or antiallergic drugs that mainly have antihistamine action. Moreover, it has an inhibitory action on at least one of the immediate phase reaction and the late phase reaction (particularly both reactions) of the nasal closed biphasic reaction. Therefore, it is also useful as an agent for suppressing nasal congestion in allergic rhinitis or cold syndrome, and an improving agent for improving at least one symptom of sleep disorder and snoring caused by nasal congestion.

FIG. 1 is a graph showing the results of Test Example 1. FIG. 2 is a graph showing the results of dose dependency in Test Example 2. FIG. 3 is a graph showing the results of single administration and two consecutive administrations in Test Example 2. FIG. 4 is a graph showing the results of Test Example 3.

  The drug of the present invention contains Nantenjitsu as an active ingredient. Nanten may be either Nanten (Nandina Domestica) whose fruit color is red or Nanten (Nandina Domestica var. Leucocarpa) whose fruit color is white, and either red fruit and / or white fruit may be used. Nantenjitsu may be used in the form of a powder (herbal powder), but is usually used in the form of an extract (extracted extract, herbal extract). When used in the form of an extract (extracted extract), Nantenjitsu may be used for extraction as it is, or may be used for extraction in the form of powder, crushed material, cut product or cut product. Although undried Nantenjitsu may be used for extraction, it is usually extracted using dried Nantenjitsu.

  In addition, the passage slit diameter of the pulverized material of Nantenjitsu may be about 1 to 20 mm, preferably about 2 to 15 mm (for example, 5 to 10 mm). In the pulverization process of Nantenjitsu (raw drug substance), more finely pulverized or finely pulverized can efficiently extract more active ingredients. However, when finely pulverized or finely pulverized, the filter is often clogged in the filtration step after extraction, and the filtration efficiency decreases. In addition, it may be assumed that a special device such as centrifugal filtration, pressure filtration, or vacuum filtration is required instead of natural filtration. As described above, fine pulverization or fine pulverization of Nantenjitsu (raw drug substance) is easy to obtain a highly active extract, but is expensive in the extract production process. On the other hand, in the coarsely pulverized product, although the filtration efficiency can be improved, the extraction efficiency of the active ingredient is lowered. In the present invention, extraction efficiency and filtration efficiency of an active ingredient useful for suppressing nasal obstruction, even if it is a pulverized Nantenjitsu having an average diameter (or pulverization passage slit) of 5 to 15 mm, preferably about 7 to 13 mm, Both can be improved.

  Extraction solvents used for preparing the extract include water, lower alcohols (methanol, ethanol, propanol, isopropanol, butanol, etc.), polyhydric alcohols (ethylene glycol, propylene glycol, 1,3-butylene glycol, dipropylene glycol) ), Ethers (chain ethers such as ethyl ether and propyl ether, cyclic ethers such as dioxane and tetrahydrofuran), cellosolves, carbitols, esters (ethyl acetate, butyl acetate, etc.), ketones ( Acetone, ethyl methyl ketone, methyl isobutyl ketone, etc.), hydrocarbons (aliphatic hydrocarbons such as hexane, alicyclic hydrocarbons such as cyclohexane, aromatic hydrocarbons such as toluene), halogenated hydrocarbons Such as classes (such as methylene chloride) can be exemplified. These solvents may be used alone or in combination of two or more. In addition, physiological saline, phosphate buffer, phosphate buffered saline, etc. may be used, and supercritical fluids and subcritical fluids (supercritical fluids such as water, carbon dioxide, ethylene, propylene, methanol, ethanol, and ammonia). Fluid or subcritical fluid) may be used. Supercritical fluids and subcritical fluids can be used alone or in combination.

Among these extraction solvents, water, water-soluble organic solvents (C _1-4 lower alkanol, acetone, etc.) or a mixture thereof are often used from the viewpoint of usability and effect, and water and / or water-solubility is used. It is preferable to use a lower alkanol such as water and / or ethanol (for example, ethanol aqueous solution). When used as a mixed aqueous solution, the proportion of the water-soluble organic solvent (such as ethanol) may be about 5 to 80% (for example, 10 to 70%, particularly 20 to 50%) on a volume basis.

  The ratio of the extraction solvent with respect to Nantenjitsu is not particularly limited. For example, the solvent is 0.5 to 1000 parts by weight, preferably 1 to 500 parts by weight, more preferably 2 to 100 parts by weight (for example, 1 part by weight of dried Nantenjitsu (for example, It may be about 2 to 75 parts by weight, particularly 5 to 50 parts by weight.

  The extraction temperature is not particularly limited, and can be selected from the range of, for example, −30 ° C. to the boiling point of the solvent (for example, about 120 ° C.), and may be at a low temperature (for example, about −20 ° C. to 50 ° C.). The heating may be performed at about 120 ° C. or under heating. Further, the extraction may be performed at the reflux temperature of the solvent. Alternatively, extraction may be performed by immersion, or extraction may be performed while applying a shearing force (shearing force by a homogenizer, a stirrer, an ultrasonic generator, or the like).

  The extract of Nanjing with the solvent may be used as it is, or a dried product obtained by concentration, spray drying or the like may be dissolved again in a solvent (water or polar solvent). In addition, the extract (or extract) and the concentrated / dried product may be subjected to various treatments within a range that does not impair the physiological activity, for example, purification treatment (purification treatment such as decolorization, deodorization, and desalting), fractionation treatment (column It may be used after being subjected to a fractionation treatment by chromatography or the like. Furthermore, the extract of Nantenjitsu, the concentrated / dried product, and the processed product (purified and / or fractionated product) may be a lyophilized product, and the lyophilized product is dissolved in a solvent at the time of use. May be used. The extract (extract extract) is a liquid (viscous) containing the extract in a proportion of about 0.1 to 90% by mass (for example, 1 to 75% by mass, particularly 10 to 60% by mass) in terms of dry solid content. Liquid).

  The preparation of the present invention may be used alone as long as it contains Nantenjitsu as an active ingredient, and is combined with other active ingredients (for example, ingredients that are conventionally incorporated in allergic rhinitis drugs and cold medicines in general drugs). May be contained. The preparation of the present invention containing Nantenjitsu as an active ingredient may be administered in combination with other active ingredients. Such components include, for example, anti-inflammatory drugs, antipyretic drugs, analgesics, antihistamines, antiallergic drugs, anticholinergics, vasoconstrictors, bronchodilators, antitussives, expectorants, antiasthma drugs, antibacterial drugs Examples include drugs, antibiotics and vitamins.

  In the present invention, herbal medicine (nantenjitsu) is usually blended into the preparation in the form of herbal powder, herbal extract (extracted extract) and the like. The nasal obstruction inhibitor (or improving agent) of the present invention is prepared into an oral or parenteral preparation, and the oral preparation includes solid preparations such as tablets, pills, granules, powders, chewable tablets, capsules, Examples include syrups and liquids such as drinks, which are produced by conventional methods. For preparation of solid preparations, various carriers [for example, excipients (including sugars (including sugar alcohols), crystalline cellulose, light anhydrous silicic acid, etc.), binders (hydroxypropylcellulose, hydroxypropyl) Methyl cellulose, etc.), disintegrating agents (such as corn starch, croscarmellose sodium, crospovidone, etc.)] and lubricants (such as magnesium stearate) may be used. If necessary, a gastric polymer, an enteric polymer, an insoluble polymer and the like may be used. For the preparation of the liquid agent, a carrier (water, ethanol, etc.), a surfactant, a solubilizing agent, a buffering agent and the like can be used as necessary. Furthermore, the preparation of the present invention (nasal obstruction inhibitor or improving agent) may contain a preservative, a fragrance, a pigment, a sweetener, a flavoring agent, a refreshing agent, and the like.

  Examples of parenteral preparations include powders and liquids that can be administered to the nasal mucosa with sprays and the like.

  In the nasal obstruction inhibitor (or ameliorating agent) of the present invention, the effective amount of Nantenjitsu can be selected according to the degree of symptom, age, route of administration, etc. The amount is about 0.01 to 100 g, preferably about 0.1 to 50 g (for example, 0.5 to 25 g), and more preferably about 1 to 10 g (for example, 2 to 8 g). The nasal congestion inhibitor (or improving agent) of the present invention can be administered once or divided into 2 to 6 times per day.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

[Preparation 1 of extract of Nantenjitsu]
Nantenjitsu raw material (produced in Japan) was pulverized, 2 kg of a 3 mm crushed product that passed through a slit diameter of 3 mm was weighed, put into a stainless steel reflux vessel with a capacity of 20 L, and 20 L of 30 v / v% aqueous ethanol solution was added. The said container was set to the reflux apparatus, and reflux extraction was performed in the outer bath 90-100 degreeC for 1 hour. After standing to cool, the mixture was subjected to centrifugal filtration, and the filtrate was concentrated under reduced pressure to obtain 626 g of a soft extract (loss on drying: 41.04%).

[Preparation of extract of Nantenjitsu 2]
Nantentsu raw material (produced in Japan) was crushed, 2 kg of a 10 mm crushed product that passed through a slit of 10 mm was weighed and put into a stainless steel reflux vessel with a capacity of 20 L, and 20 L of 30 v / v% ethanol aqueous solution was added. The said container was set to the reflux apparatus, and reflux extraction was performed in the outer bath 90-100 degreeC for 1 hour. After allowing to cool, the mixture was subjected to centrifugal filtration, and the filtrate was concentrated under reduced pressure to obtain 855 g of a soft extract (loss on drying: 41.1%).

[Test Example 1]
Inhibitory action of Nantenjitsu extract on guinea pig nasal closure biphasic reaction (1) Positive control substance, test substance, sensitizer and inducer As a positive control substance, an antiallergic agent “ONON capsule 112.5 mg” having antileukotriene action ( Pranlukast 1 / 2H ₂ O (raw powder: purity 98% or more) extracted from Ono Pharmaceutical Co., Ltd. was used. The positive control substance was accurately weighed in a predetermined amount, placed in an agate mortar, pulverized with a pestle, and then dissolved in 0.5% (w / v) methylcellulose using water for injection (hereinafter referred to as water for injection). A (MC, 400 cp) aqueous solution was gradually added and suspended.

  A test sample (nantenjitsu) was prepared by accurately weighing a predetermined amount, adding water for injection, and stirring.

  On the other hand, as a sensitizer and inducer, ovalbumin [Ovalbumin (OVA)] (manufactured by Sigma-Aldrich Corporation) and aluminum hydroxide gel (Alum) (sold by Cosmo Bio Co., Ltd.) were used. The concentration was adjusted.

(2) Animals used Guinea pigs (Std: Hartley, clean) were used as animals used. Guinea pigs (weighing 297 to 355 g) were fed with solid feed RC4 (manufactured by Oriental Yeast Co., Ltd.) freely with drinking water (public tap water) for 7 days. No abnormalities were observed in all individuals during this breeding. Based on body weight, each group [control group (n = 10), pranlukast group (n = 8), Nantenjitsu group (n = 8)] was randomly assigned to each group and assigned an animal number.

(3) Administration The administered specimen was forcibly orally administered twice using a disposable syringe and a feeding tube. However, the positive control substance was administered once. The administration time was 1 hour and 4 hours before induction. The positive control substance was only one hour before induction.

(4) Induction of nasal obstruction reaction and measurement of nasal resistance (4-1) As a first sensitization (Day 0), a physiological saline solution containing 1 mg of OVA and 10 mg of Alum in 1 mL ((OVA 1 mg + Alum 10 mg) / mL) Was administered subcutaneously in the dorsal area of 1 mL per animal.

  (4-2) As a final sensitization (7 days later), 1 week after the first sensitization, 20 μL of 10 mg / mL OVA physiological saline solution was administered into both nasal cavities using a micropipette.

  (4-3) One week after the final sensitization, 10 μL each of 20 mg / mL OVA physiological saline solution was administered into both nasal cavities using a micropipette to induce an antigen-antibody reaction (guinea pig nasal closed biphasic reaction). .

  And the total respiratory function measuring system (Pulmos-I, manufactured by MIPS) at 4 time points before induction (OVA nasal nose) (or the day before induction, on the day of induction), 10 minutes after induction, 3 hours later and 5 hours later. Each time, nasal airway resistance (nRaw) of 100 breaths or more was measured. The average value of 100 breaths was defined as nRaw at each measurement time. In addition, about before induction | guidance | derivation, it measured on the day before induction | guidance | derivation and that day, and made the average value nRAW.

  Moreover, the increase value of nRaw after 10 minutes, 3 hours, and 5 hours after induction with respect to nRaw before induction was calculated by the following formula, and the inhibition against nasal closure reaction was evaluated.

nRaw increase value (cmH ₂ O · sec) = measured nRaw−nRaw before induction
The obtained results were displayed as an average value ± standard error, and statistical processing was performed. That is, the control group and the test substance group were tested by F test. When significant difference is found between groups (unequal variance), Aspin-Welch approximate test is performed. When no significant difference is found (equal variance), Student t-test is performed. It was. The significance level was 5% on both sides for both tests, and 5% and 1% were shown separately.

  The results are shown in FIG. 1 (in the figure, * indicates a significance level of 5% and ** indicates a significance level of 1%). The Nantenjitsu group significantly suppressed the immediate phase reaction and late phase reaction of nasal congestion relative to the control group. In addition, the degree of inhibition was as strong as that of pranlukast, a comparative drug.

[Test Example 2]
Dose Dependence of Nantenjitsu Extract on Guinea Pig Nasal Closed Biphasic Response In the same manner as in Test Example 1, positive control substances, test substances, sensitizers and inducers were prepared. In the same manner as in Test Example 1, guinea pigs (Std: Hartley strain, clean) were bred for 7 days. No abnormalities were observed in all individuals during this breeding. Randomized by stratification based on body weight [control (control) 2 consecutive administration group (n = 10), Nantenjitsu 2 continuous administration (2.5 g / kg: API conversion) group (n = 8), Nantenjitsu 2 Continuous administration (5g / kg: API conversion) group (n = 8), Nantenjitsu 2 continuous administration (10g / kg: API conversion) group (n = 8), Nantenjitsu single administration (10g / kg: API conversion) ) Group (n = 8)] and assigned animal numbers.

  The administered specimen was forcibly orally administered using a disposable syringe and a feeding tube. The number of administrations was a single administration or two consecutive administrations. The administration time was 1 hour before and 4 hours before induction. A single administration was performed only 1 hour before induction.

  A nasal congestion reaction was induced in the same manner as in Test Example 1. That is, as an initial sensitization (0 day), a physiological saline solution (OVA 1 mg + Alum 10 mg) / mL containing 1 mg of OVA and 10 mg of Alum in 1 mL was subcutaneously administered to the back of 1 mL per animal.

  As the final sensitization (7 days), one week after the first sensitization, 20 μL of 10 mg / mL OVA physiological saline solution was administered into both nasal cavities using a micropipette.

  One week after the final sensitization, 10 μL of 20 mg / mL OVA physiological saline solution was administered into both nasal cavities using a micropipette to induce an antigen-antibody reaction.

And, at the four measurement points before induction (OVA nasal nose) (the day before induction, the day of induction), 10 minutes after induction, 3 and 5 hours later, nasal resistance (nRaw) was measured in the same manner as in Test Example 1, The nRAW increase value (cmH ₂ O · sec) at each measurement point was calculated.

  The obtained results were displayed as an average value ± standard error, and statistical processing was carried out in the same manner as in Test Example 1. As a result, the results shown in FIGS. %, ** indicates a significance level of 1%).

  2 and 3, the dose of Nantenjitsu 2.5 to 10 g / kg (in terms of crude drug) showed a dose-dependent inhibitory effect on the nasal obstruction reaction (immediate phase reaction). In addition, a comparison between single administration and 2 consecutive administrations of Nantenjitsu 10 g / kg (in terms of drug substance) showed that the same inhibitory action was obtained, indicating that Nantenjitsu has an immediate effect on nasal obstruction. It was done.

  Therefore, the herbal medicine of Nantenjitsu has a powerful nasal obstruction inhibitory action comparable to that of high-dose pranlukast. In addition, Nantenjitsu's nasal obstruction inhibitory action is dose-dependent and easy to control. In addition, since the inhibitory action equivalent to that of double throwing is obtained, it has an immediate effect on the inhibitory action on the nasal closure reaction. From these results, it was shown that a nasal congestion inhibitor containing Nantenjitsu as an active ingredient is effective for treating allergic rhinitis, cold syndrome, and sleep disorders caused by nasal congestion.

[Test Example 3]
Efficacy of various Nantenjitsu extracts against guinea pig nasal closed biphasic reaction In the same manner as in Test Example 1, test substances, sensitizers and inducers were prepared. In the same manner as in Test Example 1, guinea pigs (Std: Hartley strain, clean) were bred for 7 days. No abnormalities were observed in all individuals during this breeding. Randomized by stratification based on body weight [control group (control) (n = 10), Nantenjitsu (3 mm crushed) (5 g / kg: API conversion) group (n = 8), Nantenjitsu (10 mm crushed) ( A distribution animal number was assigned to the group (n = 8)] (5 g / kg: API conversion). All drugs were administered as a single oral dose.

  The sample to be administered was forcibly orally administered using a disposable syringe and a feeding tube. The administration time was 1 hour before induction and a single administration.

  A nasal congestion reaction was induced in the same manner as in Test Example 1. That is, as an initial sensitization (0 day), a physiological saline solution (OVA 1 mg + Alum 10 mg) / mL containing 1 mg of OVA and 10 mg of Alum in 1 mL was subcutaneously administered to the back of 1 mL per animal.

  As the final sensitization (7 days), one week after the first sensitization, 20 μL of 10 mg / mL OVA physiological saline solution was administered into both nasal cavities using a micropipette.

  One week after the final sensitization, 10 μL of 20 mg / mL OVA physiological saline solution was administered into both nasal cavities using a micropipette to induce an antigen-antibody reaction.

And, at the four measurement points before induction (OVA nasal nose) (the day before induction, the day of induction), 10 minutes after induction, 3 and 5 hours later, nasal resistance (nRaw) was measured in the same manner as in Test Example 1, The nRAW increase value (cmH ₂ O · sec) at each measurement point was calculated. The late phase reaction is indicated by AUC: 3 to 5 hr.

  The obtained results were displayed as an average value ± standard error, and statistical processing was performed in the same manner as in Test Example 1. As a result, the results shown in FIG. 4 were obtained (in the figure, * represents a significance level of 5%, * * Indicates a significance level of 1%).

  From FIG. 4, both extracts of Nantenjitsu (3 mm crushed product) and Nantenjitsu (10 mm crushed product) significantly suppressed the immediate phase reaction (10 min) and late phase reaction (3-5 hr: AUC) of the nasal obstruction reaction. The effect was confirmed. In addition, since the degree of suppression was the same in both extracts, a highly active extract can be obtained even in a coarsely pulverized (10 mm crushed product) extract extract. Accordingly, it is possible to produce an inexpensive and highly active Nantenjitsu extract that is useful for suppressing nasal congestion.

Example 1
480 g of light anhydrous silicic acid (manufactured by WK F), 336 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), 720 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.), crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation) 1688.9 g of “PH101”) was charged into a vertical granulator (“FM-VG25 type” manufactured by Paulek Co., Ltd.), blade rotation number 200 rpm, cross screw rotation number 3000 rpm, 2181.6 g (1527 solid content) .1 g) and purified water were added and granulated. The obtained granulated product is wet-sized with a power mill (4 mmφ × 24 mm helical bone manufactured by Showa Chemical Machinery Co., Ltd.), and further with a fluidized bed dryer (“FD-5S type” manufactured by Pauleck Co., Ltd.). Drying was performed at an air supply temperature of 85 ° C. and an air volume of 2.5 m ³ / min to an exhaust temperature of 55 ° C. After drying, the particles were sized with a power mill (1.0 mmφ screen) to obtain a sized powder. 19.7 g of corn starch, 28.0 g of aspartame as a sweetener, 14 g of acesulfame potassium as a sweetener, 1.0 g of silicia oil as a fragrance adsorbent are added to 3960 g of the obtained sized powder, and a tumbler mixer (Showa) The mixture was mixed with “TM-15 type” manufactured by Chemical Machinery Co., Ltd. to obtain 2.1 g of powder (5000 mg as a raw drug of Nantenjitsu extract) per 3 capsules.

Example 2
480 g of light anhydrous silicic acid (manufactured by WK F), 336 g of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.), 720 g of corn starch (manufactured by Nippon Corn Starch Co., Ltd.), 240 g of crospovidone (manufactured by BASF), 1448.9 g of crystalline cellulose (“PH101” manufactured by Asahi Kasei Chemicals Co., Ltd.) was charged into a vertical granulator (“FM-VG25 type” manufactured by Paulek Co., Ltd.), blade rotation 200 rpm, cross screw rotation 3000 rpm, 2181.6 g of extract (1527.1 g as a solid content) and purified water were added and granulated. The obtained granulated product was wet-sized with a power mill (4 mmφ × 24 mm helical bone manufactured by Showa Chemical Machinery Co., Ltd.), and further fluidized bed granulator (“FD-5S type” manufactured by Pauleck Co., Ltd.) And dried at an air supply temperature of 85 ° C. and an air volume of 2.5 m ³ / min to an exhaust temperature of 55 ° C. After drying, the particles were sized with a power mill (1.5 mmφ screen) to obtain a sized powder. Add 216 g of crospovidone, 77 g of corn starch, 30.0 g of aspartame as a sweetener, 15 g of acesulfame potassium as a sweetener, 1.0 g of silicia as a fragrance adsorbent, and 21 g of magnesium stearate as an adsorbent for the fragrance. Then, using a tumbler mixer (“TM-15 type” manufactured by Showa Chemical Machinery Co., Ltd.) and using a rotary tablet press collect 19HUK (manufactured by Kikusui Seisakusho Co., Ltd.), 1 tablet 240 mg, 8. Tableting was performed with a 5 mmφ, 2-stage R punch with a tableting pressure of 9 KN / 杵 to obtain an uncoated tablet.

Example 3
The uncoated tablet obtained in Example 2 was pulverized and sieved with a roll granulator (manufactured by Nippon Granulator Co., Ltd.), and 2.16 g (5000 mg as the active ingredient of Nantenjitsu extract) of granules was obtained per 3 capsules. Obtained.

Example 4
2272.5 g of dried extract of Nantenjitsu (5000 mg as a crude drug), 150 g of light anhydrous silicic acid (manufactured by WKF), 180 g of hydroxypropylcellulose (Nippon Soda Co., Ltd.), corn starch (Nippon Cornstarch Co., Ltd.) 390g, Mannitol (manufactured by Merck) 240g, crystalline cellulose ("PH101" manufactured by Asahi Kasei Chemicals Co., Ltd.) 1087.5g was charged into a vertical granulator ("FM-VG25 type" manufactured by Paulec Co., Ltd.), blade rotation Purified water was added and granulated at several 200 rpm and a cross screw rotation of 3000 rpm. The obtained granulated product is wet-sized with a power mill (4 mmφ × 24 mm helical bone manufactured by Showa Chemical Machinery Co., Ltd.), and further with a fluidized bed dryer (“FD-5S type” manufactured by Pauleck Co., Ltd.). Drying was performed at an air supply temperature of 85 ° C. and an air volume of 2.5 m ³ / min to an exhaust temperature of 55 ° C. After drying, the particles were sized with a power mill (1.0 mmφ screen) to obtain a sized powder. To the obtained sized powder 2880 g, 89 g of corn starch, 10 g of aspartame 20 and 10 g of acesulfame potassium as sweeteners, a trace amount of 1-menthol and 1.0 g of silicia are added as fragrances, and a tumbler mixer (manufactured by Showa Chemical Machinery Co., Ltd.) TM-15 type ") to obtain 1.5 g of powder per 3 packages.

  The preparation of the present invention has at least one of a nasal obstruction reaction, particularly an immediate phase reaction and a late phase reaction, which is difficult to suppress with an antihistamine or an antiallergic agent mainly having an antihistamine action. It shows a high inhibitory effect on the reaction (particularly both reactions). Therefore, it is effective as a nasal congestion inhibitor in allergic rhinitis, cold syndrome, etc., and also effective in improving sleep disorders and / or snoring caused by nasal congestion. In addition, nasal congestion causes apnea syndrome during sleep, and sleep disorder also causes circulatory diseases such as depression, heart disease, and brain disease. Therefore, a preparation containing Nantenjitsu as an active ingredient is useful for the prevention and / or treatment of these diseases.

Claims (5)

A nasal congestion inhibitor comprising Nantenjitsu as an active ingredient, wherein the nasal congestion inhibitor suppresses nasal obstruction symptoms caused by at least a late phase reaction among an immediate phase reaction and a late phase reaction of a nasal biphasic reaction . A nasal obstruction inhibitor for allergic rhinitis containing Nantenjitsu as an active ingredient, which suppresses nasal obstruction symptoms caused by at least the late phase reaction of immediate phase reaction and late phase reaction of nasal obstruction Inhibitor . A nasal obstruction inhibitor for cold syndrome comprising Nantenjitsu as an active ingredient, which suppresses nasal obstruction symptoms caused by at least the late phase reaction of immediate phase reaction and late phase reaction of nasal obstruction Agent .   The nasal obstruction inhibitor according to any one of claims 1 to 3, comprising an extract of Nantenjitsu. An improving agent for improving at least one symptom of sleep disorder and snoring caused by nasal congestion, comprising Nantenjitsu as an active ingredient, and comprising at least a late phase of immediate phase reaction and late phase reaction of nasal congestion An improving agent for improving the above-mentioned symptoms caused by reaction .