JP5405793B2 - Preventive or therapeutic agent for nonspecific hypersensitivity of mucous membrane - Google Patents
Preventive or therapeutic agent for nonspecific hypersensitivity of mucous membrane Download PDFInfo
- Publication number
- JP5405793B2 JP5405793B2 JP2008263107A JP2008263107A JP5405793B2 JP 5405793 B2 JP5405793 B2 JP 5405793B2 JP 2008263107 A JP2008263107 A JP 2008263107A JP 2008263107 A JP2008263107 A JP 2008263107A JP 5405793 B2 JP5405793 B2 JP 5405793B2
- Authority
- JP
- Japan
- Prior art keywords
- hypersensitivity
- mucosa
- bacterium
- nasal
- nonspecific
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000026935 allergic disease Diseases 0.000 title claims description 129
- 206010020751 Hypersensitivity Diseases 0.000 title claims description 120
- 230000009610 hypersensitivity Effects 0.000 title claims description 109
- 239000003814 drug Substances 0.000 title claims description 42
- 229940124597 therapeutic agent Drugs 0.000 title claims description 36
- 230000003449 preventive effect Effects 0.000 title description 30
- 210000004400 mucous membrane Anatomy 0.000 title description 20
- 241000894006 Bacteria Species 0.000 claims description 126
- 210000004877 mucosa Anatomy 0.000 claims description 38
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 36
- 201000010105 allergic rhinitis Diseases 0.000 claims description 36
- 230000001684 chronic effect Effects 0.000 claims description 29
- 210000002850 nasal mucosa Anatomy 0.000 claims description 29
- 230000000813 microbial effect Effects 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000000427 antigen Substances 0.000 claims description 10
- 108091007433 antigens Proteins 0.000 claims description 10
- 102000036639 antigens Human genes 0.000 claims description 10
- 241000186016 Bifidobacterium bifidum Species 0.000 claims description 8
- 229940002008 bifidobacterium bifidum Drugs 0.000 claims description 8
- 231100000749 chronicity Toxicity 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 230000000069 prophylactic effect Effects 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 6
- 239000000428 dust Substances 0.000 claims description 5
- 230000000638 stimulation Effects 0.000 claims 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 82
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 58
- 210000004027 cell Anatomy 0.000 description 57
- 239000004310 lactic acid Substances 0.000 description 41
- 235000014655 lactic acid Nutrition 0.000 description 41
- 241000186000 Bifidobacterium Species 0.000 description 40
- 239000000047 product Substances 0.000 description 32
- 239000007788 liquid Substances 0.000 description 21
- 230000001580 bacterial effect Effects 0.000 description 20
- 241000218645 Cedrus Species 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 239000007921 spray Substances 0.000 description 13
- 239000007789 gas Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000001694 spray drying Methods 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 210000002345 respiratory system Anatomy 0.000 description 9
- 241000700199 Cavia porcellus Species 0.000 description 8
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 8
- 230000007815 allergy Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 241000194033 Enterococcus Species 0.000 description 7
- 239000013566 allergen Substances 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 6
- 206010070834 Sensitisation Diseases 0.000 description 6
- 241000194017 Streptococcus Species 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- 230000008313 sensitization Effects 0.000 description 6
- 241000700198 Cavia Species 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 210000002200 mouth mucosa Anatomy 0.000 description 5
- 210000001331 nose Anatomy 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 230000000172 allergic effect Effects 0.000 description 4
- 230000003266 anti-allergic effect Effects 0.000 description 4
- 239000000043 antiallergic agent Substances 0.000 description 4
- -1 cysteinyl leukotrienes Chemical class 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229960001340 histamine Drugs 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 206010039083 rhinitis Diseases 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 241001608472 Bifidobacterium longum Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 240000001046 Lactobacillus acidophilus Species 0.000 description 3
- 235000013956 Lactobacillus acidophilus Nutrition 0.000 description 3
- 241000186606 Lactobacillus gasseri Species 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 3
- 208000036071 Rhinorrhea Diseases 0.000 description 3
- 206010039101 Rhinorrhoea Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229940039695 lactobacillus acidophilus Drugs 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 210000003928 nasal cavity Anatomy 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 206010041232 sneezing Diseases 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000186015 Bifidobacterium longum subsp. infantis Species 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 206010015993 Eyelid oedema Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 206010023644 Lacrimation increased Diseases 0.000 description 2
- 240000001929 Lactobacillus brevis Species 0.000 description 2
- 241000186673 Lactobacillus delbrueckii Species 0.000 description 2
- 206010028735 Nasal congestion Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 208000030961 allergic reaction Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 229940009291 bifidobacterium longum Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 210000005056 cell body Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012228 culture supernatant Substances 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 210000000744 eyelid Anatomy 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 230000007803 itching Effects 0.000 description 2
- 230000004317 lacrimation Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000193749 Bacillus coagulans Species 0.000 description 1
- 241000012248 Bacillus toyonensis Species 0.000 description 1
- 241000186012 Bifidobacterium breve Species 0.000 description 1
- 241000186148 Bifidobacterium pseudolongum Species 0.000 description 1
- 241001468229 Bifidobacterium thermophilum Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 241000193171 Clostridium butyricum Species 0.000 description 1
- 240000005109 Cryptomeria japonica Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010015237 Erythema of eyelid Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 244000199866 Lactobacillus casei Species 0.000 description 1
- 241000186840 Lactobacillus fermentum Species 0.000 description 1
- 240000002605 Lactobacillus helveticus Species 0.000 description 1
- 241001468157 Lactobacillus johnsonii Species 0.000 description 1
- 241000186605 Lactobacillus paracasei Species 0.000 description 1
- 240000006024 Lactobacillus plantarum Species 0.000 description 1
- 241000186604 Lactobacillus reuteri Species 0.000 description 1
- 241000218588 Lactobacillus rhamnosus Species 0.000 description 1
- 241000186869 Lactobacillus salivarius Species 0.000 description 1
- 241000194036 Lactococcus Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 244000172809 Leuconostoc cremoris Species 0.000 description 1
- 241000192130 Leuconostoc mesenteroides Species 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- MXRIRQGCELJRSN-UHFFFAOYSA-N O.O.O.[Al] Chemical compound O.O.O.[Al] MXRIRQGCELJRSN-UHFFFAOYSA-N 0.000 description 1
- 241000192134 Oenococcus oeni Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241000191998 Pediococcus acidilactici Species 0.000 description 1
- 241000191996 Pediococcus pentosaceus Species 0.000 description 1
- 239000001888 Peptone Substances 0.000 description 1
- 108010080698 Peptones Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 244000057717 Streptococcus lactis Species 0.000 description 1
- 235000014897 Streptococcus lactis Nutrition 0.000 description 1
- 241000194020 Streptococcus thermophilus Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 241000500332 Tetragenococcus halophilus Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229940054340 bacillus coagulans Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940004120 bifidobacterium infantis Drugs 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000005178 buccal mucosa Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010981 drying operation Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000005081 epithelial layer Anatomy 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000005722 itchiness Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000005037 parasympathetic nerve Anatomy 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000004202 respiratory function Effects 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 238000009531 respiratory rate measurement Methods 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
Images
Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
本発明は、アレルギー物質への繰返し暴露等によりアレルギーが重症化及び／又は慢性化等して過敏症となった粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療剤、及びアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤に関する。 The present invention relates to a prophylactic or therapeutic agent for nonspecific hypersensitivity of mucous membranes (excluding lower respiratory tract mucous membranes) in which allergies become severe and / or chronic due to repeated exposure to allergic substances, etc., And a preventive or therapeutic agent for nasal hypersensitivity due to aggravation and / or chronicity of allergic rhinitis.
アレルギー疾患は、外部からの抗原（アレルゲン）に対し免疫反応が起こる疾患であり、作用機序により大きくＩ〜ＩＶ型に分類されている。代表的なアレルギー疾患であるアレルギー性鼻炎は、鼻粘膜のＩ型アレルギー疾患であり、花粉、ハウスダスト等の様々なアレルゲンによって引き起こされ、発作型反復性のくしゃみ、水性鼻漏、鼻閉を３主徴とする。 Allergic diseases are diseases in which an immune reaction occurs against an external antigen (allergen), and are broadly classified into types I to IV depending on the mechanism of action. Allergic rhinitis, which is a typical allergic disease, is a type I allergic disease of the nasal mucosa and is caused by various allergens such as pollen and house dust, and can cause seizure type recurrent sneezing, aqueous rhinorrhea, and nasal congestion. The main feature.
アレルギー性鼻炎の症状とは、粘液層に捕捉された抗原が以下のごとく処理される結果最終的に発現する症状である。すなわち、抗原は鼻粘膜に吸収された後、マクロファージなどの抗原提示細胞により処理され、これをＴ細胞が認識することによりinterleukin-4などのcytokinesを産生し、これらがＢ細胞に作用してＩｇＥ抗体が産生される。ＩｇＥ抗体は鼻粘膜の肥満細胞膜上に結合して感作状態が成立し、ある期間の後再び侵入した抗原がＩｇＥ抗体に結合することによりhistamine、cysteinyl leukotrienes(CysLTs）などの化学伝達物質（chemical mediators）が遊離され、これらが組織を攻撃することによりアレルギーが発症する。 The allergic rhinitis symptom is a symptom that finally appears as a result of the antigen trapped in the mucus layer being processed as follows. That is, after the antigen is absorbed into the nasal mucosa, it is processed by antigen-presenting cells such as macrophages, which are recognized by T cells to produce cytokines such as interleukin-4, which act on B cells to act on IgE. Antibodies are produced. IgE antibodies bind to mast cell membranes on the nasal mucosa to establish a sensitized state, and antigens that have re-entered after a certain period of time bind to IgE antibodies to bind chemical agents such as histamine and cysteinyl leukotrienes (CysLTs). mediators) are released and allergies develop when they attack the tissue.
近年、アレルギー疾患の患者数が急増し、しかもその症状は慢性化及び重症化している。さらに、このアレルギー疾患に罹患する患者の中には、繰り返し特定のアレルゲンに暴露されることにより、アレルゲンに対する即時性及び遅発性の反応性が増強され、それ以外の抗原や刺激に対しても過剰反応を示す状態（非特異的過敏性亢進）となることが知られている。例えば、アレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性においては、鼻粘膜が抗原等の特異的刺激だけでなく、化学的刺激、塵埃、冷気等の非特異的刺激に対しても過剰反応する状態となっており、鼻粘膜の非特異的過敏性亢進が起こっている。重症及び／又は慢性症状に特徴的な鼻過敏性は、histamineなどを点鼻投与することにより評価されており、アレルギー性鼻炎患者は健常者に比して１０００倍以上低濃度から反応性を示す。 In recent years, the number of patients with allergic diseases has increased rapidly, and the symptoms have become chronic and severe. In addition, some patients suffering from this allergic disease have increased immediate and delayed reactivity to allergens by repeated exposure to specific allergens, as well as other antigens and stimuli. It is known that a state of excessive reaction (nonspecific hypersensitivity) is obtained. For example, in nasal hypersensitivity due to severe and / or chronic allergic rhinitis, the nasal mucosa not only with specific stimuli such as antigens but also with nonspecific stimuli such as chemical stimuli, dust, and cold air. It is in an overreactive state, and nonspecific hypersensitivity of the nasal mucosa occurs. Nasal hypersensitivity, characteristic of severe and / or chronic symptoms, has been evaluated by nasal administration of histamine and the like, and allergic rhinitis patients are more responsive than normal subjects at a concentration lower than 1000 times. .
粘膜の非特異的過敏性亢進は、繰り返し暴露される特定のアレルゲンのみならず、他のアレルゲンによっても引き起こされるため、原因（アレルゲン）の除去ができない。このため対処法として、このアレルギー反応を抑制する物質の投与が行われている。粘膜の非特異的過敏性亢進を抑制するために、蜂蜜を有効成分とするアレルギー性過敏症抑制剤（特許文献１）、及び上気道過敏症の予防・治療剤（特許文献２）が考案されている。 Non-specific hypersensitivity of the mucosa is caused not only by specific allergens that are repeatedly exposed, but also by other allergens, so the cause (allergen) cannot be removed. Therefore, as a countermeasure, a substance that suppresses this allergic reaction is administered. In order to suppress non-specific hypersensitivity of the mucous membrane, an allergic hypersensitivity inhibitor (Patent Document 1) containing honey as an active ingredient and an agent for preventing and treating upper airway hypersensitivity (Patent Document 2) were devised. ing.
さらに、アレルギー疾患や、その重症化及び／又は慢性化による粘膜の非特異的過敏性亢進を発症すると、医薬品を長期にわたり服用する必要がある。このため、薬剤の長期服用による副作用の危険性が問題となり、副作用が少なく安全性が高い医薬品又は飲食品の開発が望まれている。 Furthermore, if an allergic disease or non-specific hypersensitivity of the mucosa due to its seriousness and / or chronicity develops, it is necessary to take a medicine for a long time. For this reason, there is a problem of the risk of side effects due to long-term use of drugs, and development of pharmaceuticals or foods and drinks with low side effects and high safety is desired.
Ｉ型アレルギー疾患に対しては、乳酸菌が抗アレルギー作用を有することが知られており、副作用が少ない抗アレルギー剤として利用されている。例えば、特許文献３には、ヒトの腸内細菌群より分離された乳酸菌を含有するヒスタミン遊離抑制効果を有するＩ型アレルギー抑制剤が開示されている。 For type I allergic diseases, lactic acid bacteria are known to have antiallergic action and are used as antiallergic agents with few side effects. For example, Patent Document 3 discloses a type I allergy inhibitor having a histamine release inhibitory effect containing lactic acid bacteria isolated from human intestinal bacteria.
特許文献４には、乳酸菌を有効成分として含む抗アレルギー剤が開示されている。特許文献５及び６には、乳酸菌を含む抗アレルギー用組成物が開示されている。特許文献７には、新規微生物でアレルギーを処置することが開示されている。特許文献８には、新規微生物を含むアレルギー関連疾患を処置する組成物が開示されている。特許文献９には、有胞子乳酸菌を有効成分とする抗アレルギー剤が開示されている。特許文献１０には、Ｉ型アレルギーの改善に有効なケフィア様炭酸含有ヨーグルトが開示されている。特許文献１１には、抗アレルギーの乳酸菌が開示されている。
これらの乳酸菌を用いた抗アレルギー剤は、Ｉ型アレルギー疾患には有効であるものの、アレルギー疾患の重症化等により発症する粘膜の非特異的過敏性亢進については、治療効果及び安全性が高い薬剤は未だ開発されていない。
本発明は、上記現状に鑑み、粘膜の非特異的過敏性亢進やアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性における非特異的過敏性を抑制することができる、安全性が高い粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療剤、及びアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤を提供することを目的とする。 In view of the above situation, the present invention can suppress nonspecific hypersensitivity in nasal hypersensitivity due to nonspecific hypersensitivity of mucous membranes and severe and / or chronic allergic rhinitis. An object of the present invention is to provide a preventive or therapeutic agent for nonspecific hypersensitivity of mucous membranes (excluding lower respiratory tract mucosa), and a prophylactic or therapeutic agent for nasal hypersensitivity due to severe and / or chronic allergic rhinitis. .
本発明者らは、有用菌であるビフィズス菌、乳酸菌及び酪酸菌のアレルギー疾患への作用について鋭意研究を重ねた結果、従来の乳酸菌の抗アレルギー作用によるアレルギー性鼻炎への効果は、くしゃみ、鼻閉及び鼻漏等の症状を抑制するものであるが、ビフィズス菌、乳酸菌及び酪酸菌はこのような作用のみならず、アレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏症等のアレルギー性疾患の重症化及び／又は慢性化による非特異的過敏性亢進にも効果を示すこと、さらに、アレルギー性疾患（アレルギー性鼻炎等）と関係しない鼻等の粘膜の非特異的過敏性亢進にも効果を示すことを見出した。乳酸菌がアレルギー性鼻炎に対して抗アレルギー作用を示すことは知られていたが、粘膜の非特異的過敏性の抑制に有効であることの報告は、これまで一切なされておらず新規な知見である。また、ビフィズス菌、乳酸菌及び酪酸菌は、鼻粘膜の非特異的過敏性の抑制に特に有効であることや、中でも、アレルギー性鼻炎の重症化及び／又は慢性化による鼻粘膜の非特異的過敏性の抑制に有効であることを見出した。さらに、アレルギー性鼻炎が慢性化した患者では、粘膜の不可逆的肥厚が認められるが、ビフィズス菌、乳酸菌及び酪酸菌は、鼻腔内の好酸球浸潤をも抑制することを見出し、これにより粘膜肥厚の抑制にも有効であることに想到した。
本発明者らは、上記知見に基づきさらに研究を重ね、本発明を完成するに至った。
As a result of intensive studies on the effects of useful bacteria, bifidobacteria, lactic acid bacteria and butyric acid bacteria on allergic diseases, the effects of conventional lactic acid bacteria on allergic rhinitis are sneezing, nose Although it suppresses symptoms such as closure and rhinorrhea, bifidobacteria, lactic acid bacteria and butyric acid bacteria not only have such effects, but also allergic properties such as nasal hypersensitivity due to severe and / or chronic allergic rhinitis It is effective for non-specific hypersensitivity due to disease severity and / or chronicity, and non-specific hypersensitivity of the mucous membrane of the nose that is not related to allergic diseases (allergic rhinitis, etc.) It has been found to show an effect. Although it was known that lactic acid bacteria have an antiallergic action against allergic rhinitis, it has never been reported that it is effective in suppressing mucosal nonspecific hypersensitivity. is there. In addition, bifidobacteria, lactic acid bacteria and butyric acid bacteria are particularly effective in suppressing nonspecific hypersensitivity of the nasal mucosa, and in particular, nonspecific hypersensitivity of the nasal mucosa due to severe and / or chronic allergic rhinitis. It was found to be effective in suppressing sex. In addition, irreversible thickening of the mucosa is observed in patients with chronic allergic rhinitis. It is thought that it is effective also for suppression of the above.
The present inventors have further studied based on the above findings and have completed the present invention.
すなわち、本発明は、以下の（１）〜（１０）に関する。
（１）ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を含むことを特徴とする粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療剤。
（２）粘膜が、鼻粘膜である前記（１）に記載の非特異的過敏性亢進の予防又は治療剤。
（３）非特異的過敏性亢進が、アレルギー性鼻炎の重症化及び／又は慢性化によるものである前記（２）に記載の非特異的過敏性亢進の予防又は治療剤。
（４）菌が、乾燥物である前記（１）〜（３）のいずれか一項に記載の非特異的過敏性亢進の予防又は治療剤。
（５）菌が、シングルミクロンの菌体乾燥物である前記（１）〜（３）のいずれか一項に記載の非特異的過敏性亢進の予防又は治療剤。
（６）菌が、生菌である前記（１）〜（５）のいずれか一項に記載の非特異的過敏性亢進の予防又は治療剤。
（７）菌が、死菌である前記（１）〜（３）のいずれか一項に記載の非特異的過敏性亢進の予防又は治療剤。
（８）菌が、菌体の処理物である前記（１）〜（３）のいずれか一項に記載の非特異的過敏性亢進の予防又は治療剤。
（９）ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を含むことを特徴とするアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤。
That is, the present invention relates to the following (1) to (10).
(1) A prophylactic or therapeutic agent for nonspecific hypersensitivity of mucous membranes (excluding lower respiratory tract mucous membranes), comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria.
(2) The preventive or therapeutic agent for nonspecific hypersensitivity according to (1), wherein the mucosa is a nasal mucosa.
(3) The agent for preventing or treating nonspecific hypersensitivity as described in (2) above, wherein the nonspecific hypersensitivity is caused by the severe and / or chronic allergic rhinitis.
(4) The preventive or therapeutic agent for nonspecific hypersensitivity according to any one of (1) to (3), wherein the bacterium is a dried product.
(5) The agent for preventing or treating nonspecific hypersensitivity according to any one of (1) to (3) above, wherein the bacterium is a single-micron dried microbial cell product.
(6) The preventive or therapeutic agent for nonspecific hypersensitivity according to any one of (1) to (5), wherein the bacterium is a living bacterium.
(7) The preventive or therapeutic agent for nonspecific hypersensitivity according to any one of (1) to (3), wherein the bacterium is a dead bacterium.
(8) The agent for preventing or treating nonspecific hypersensitivity according to any one of (1) to (3), wherein the bacterium is a processed product of the microbial cell.
(9) A preventive or therapeutic agent for nasal hypersensitivity due to aggravation and / or chronicity of allergic rhinitis, comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria.
本発明はまた、以下の抑制方法、使用等に関する。
ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を含む組成物を哺乳類に投与する粘膜（下気道粘膜を除く）の非特異的過敏性亢進の抑制又は治療方法。
ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を含む組成物を哺乳類に投与するアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の抑制又は治療方法。
The present invention also relates to the following suppression method, use and the like.
A method for suppressing or treating nonspecific hypersensitivity of mucosa (excluding lower respiratory tract mucosa), wherein a composition containing at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria is administered to mammals.
A method for suppressing or treating nasal hypersensitivity caused by severe and / or chronic allergic rhinitis, comprising administering to a mammal a composition comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria.
粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療のための、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌。
アレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療のための、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌。
粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療剤を製造するための、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌の使用。
アレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤を製造するための、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌の使用。
At least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, and butyric acid bacteria, for the prevention or treatment of nonspecific hypersensitivity of the mucosa (excluding the lower respiratory tract mucosa).
At least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, and butyric acid bacteria, for preventing or treating nasal hypersensitivity due to severe and / or chronic allergic rhinitis.
Use of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, and butyric acid bacteria, for producing a preventive or therapeutic agent for nonspecific hypersensitivity of mucous membranes (excluding lower airway mucosa).
Use of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, and butyric acid bacteria, for producing an agent for preventing or treating nasal hypersensitivity caused by allergic rhinitis becoming severe and / or chronic.
本発明の粘膜の非特異的過敏性亢進の予防又は治療剤、及びアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤は、アレルギー疾患の重症化及び／又は慢性化による粘膜の非特異的過敏性を効果的に予防又は治療することができ、しかも安全性が高いものである。本発明の粘膜の非特異的過敏性亢進の予防又は治療剤はさらに、アレルギー性鼻炎等のアレルギー性疾患に関係しない鼻等の粘膜の非特異的過敏性亢進の予防又は治療にも有効である。本発明で用いるビフィズス菌、乳酸菌及び酪酸菌は腸内細菌であり、副作用がほとんどない安全な菌体であり、経口投与によっても粘膜の非特異的過敏性亢進に対する予防及び治療効果を発揮できることから、医薬品とした場合に投与しやすいだけでなく、食品として日常的に摂取することができるものである。 The preventive or therapeutic agent for non-specific hypersensitivity of the mucous membrane of the present invention and the preventive or therapeutic agent for nasal hypersensitivity due to the severe and / or chronic allergic rhinitis are allergic and / or chronic allergic diseases. It is possible to effectively prevent or treat non-specific hypersensitivity of mucous membranes, and to have high safety. The preventive or therapeutic agent for nonspecific hypersensitivity of the mucosa of the present invention is further effective for the prevention or treatment of nonspecific hypersensitivity of the mucous membrane of the nose which is not related to allergic diseases such as allergic rhinitis. . Bifidobacteria, lactic acid bacteria, and butyric acid bacteria used in the present invention are enteric bacteria, are safe cells with few side effects, and can exhibit preventive and therapeutic effects on nonspecific hypersensitivity of mucous membranes even by oral administration. In addition to being easy to administer as a pharmaceutical product, it can be taken daily as a food.
本発明の粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療剤、及びアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤（以下、これらを単に本発明の予防又は治療剤ともいう）は、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を含むものである。 Preventive or therapeutic agent for nonspecific hypersensitivity of mucosa (except lower airway mucosa) of the present invention, and preventive or therapeutic agent for nasal hypersensitivity due to severe and / or chronic allergic rhinitis (hereinafter referred to as these) The simple preventive or therapeutic agent of the present invention includes at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria.
本発明における「粘膜」は、下気道粘膜以外の粘膜であり、鼻粘膜、口腔粘膜、眼球粘膜、眼瞼粘膜等の眼粘膜、胃粘膜、頬側粘膜、腸管粘膜等の消化器粘膜等が挙げられる。本発明の予防又は治療剤は、鼻粘膜、口腔粘膜、眼粘膜等の非特異的過敏性亢進の予防又は治療に好適であり、鼻粘膜、口腔粘膜にさらに好適であり、鼻粘膜に特に好適である。本発明の予防又は治療剤はまた、鼻粘膜の非特異的過敏性亢進の合併症として口腔粘膜、眼粘膜等において非特異的過敏性亢進が起きている場合にも有効なものである。 "Mucosa" in the present invention is a mucosa other than the lower respiratory tract mucosa, and includes nasal mucosa, oral mucosa, ocular mucosa, ocular mucosa such as eyelid mucosa, gastric mucosa, buccal mucosa, digestive mucosa such as intestinal mucosa and the like. It is done. The preventive or therapeutic agent of the present invention is suitable for the prevention or treatment of nonspecific hypersensitivity such as nasal mucosa, oral mucosa and ocular mucosa, more suitable for nasal mucosa and oral mucosa, and particularly suitable for nasal mucosa. It is. The preventive or therapeutic agent of the present invention is also effective when nonspecific hypersensitivity occurs in the oral mucosa, ocular mucosa and the like as a complication of nonspecific hypersensitivity of the nasal mucosa.
本明細書中、「粘膜の非特異的過敏性」とは、特定の抗原等の特異的刺激だけでなく、化学的刺激、塵埃、冷気等の不特定の、又は非特異的な刺激に対して粘膜が過剰に反応することをいう。この反応には、鼻粘膜の場合、くしゃみ、鼻閉、鼻漏、粘膜肥厚等が挙げられ、眼球粘膜の場合、かゆみ（そう痒感）、眼球結膜の充血、流涙、眼刺激、眼脂、光がまぶしい等が挙げられ、眼瞼粘膜の場合、かゆみ、瞼の腫れ、眼瞼浮腫、眼瞼縁の発赤、流涙等が挙げられ、口腔粘膜の場合、舌やのどの痛み・かゆみ・不快感、唇・舌・のどの腫脹（はれる）等が挙げられ、消化器粘膜の場合、腹痛、便通異常、悪心（気分が悪くむかむかした感じ）、嘔吐等が挙げられる。本発明における粘膜の非特異的過敏性亢進には、アレルギー疾患の重症化及び／又は慢性化が原因となるものと、そのような原因疾患によらないものとが含まれる。鼻粘膜の非特異的過敏性についていえば、過敏性非感染性鼻炎に分類される複合型鼻炎（鼻過敏症）のうち、アレルギー性鼻炎の重症化及び／又は慢性化によるものの他、非アレルギー性鼻炎（血管運動性（本態性）鼻炎及び好酸球増多性鼻炎）による鼻粘膜の非特異的過敏性亢進も含まれる。なお、アレルギー反応が重症化及び／又は慢性化しておらず、非特異的過敏性が亢進していない鼻アレルギー等のアレルギー疾患は、本発明における「粘膜の非特異的過敏性亢進」には含まれない。 In this specification, “non-specific hypersensitivity of mucous membrane” means not only specific stimuli such as specific antigens, but also unspecific or non-specific stimuli such as chemical stimuli, dust and cold. This means that the mucous membrane reacts excessively. This reaction includes sneezing, nasal congestion, rhinorrhea, mucosal thickening, etc. in the case of nasal mucosa. In the case of ocular mucosa, itching (pruritus), redness of the eyeball conjunctiva, lacrimation, eye irritation, eye oil In the case of eyelid mucosa, itching, swelling of eyelids, eyelid edema, redness of eyelid margin, lacrimation, etc. In the case of oral mucosa, pain / itchiness / discomfort in the tongue and throat , Swelling of the lips, tongue, throat, etc. In the case of digestive mucosa, abdominal pain, bowel movement abnormalities, nausea (feeling unpleasant and tingling), vomiting and the like. The mucosal nonspecific hypersensitivity in the present invention includes those caused by the allergic disease becoming severe and / or chronic and those not caused by such causative disease. Regarding non-specific hypersensitivity of the nasal mucosa, complex rhinitis (nasal hypersensitivity) classified as hypersensitivity non-infectious rhinitis is due to the severity and / or chronicity of allergic rhinitis and non-allergy Nonspecific hypersensitivity of the nasal mucosa due to rhinitis (vasomotor (essential) rhinitis and eosinophilia) is also included. In addition, allergic diseases such as nasal allergies in which allergic reactions are not severe and / or chronic and nonspecific hypersensitivity is not enhanced are included in the “enhanced nonspecific hypersensitivity of mucosa” in the present invention. I can't.
本明細書中、「アレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性」とは、上記「粘膜の非特異的過敏性亢進」のうち、アレルギー性鼻炎の重症化及び／又は慢性化により鼻粘膜が非特異的過敏性亢進となった状態を意味する。なお、本明細書中、「鼻過敏性」には、外部からの非特異的抗原との抗体反応だけでなく、内部の（１）知覚過敏、神経過敏等の知覚系過敏性亢進、（２）腺細胞、血管平滑筋細胞、内皮細胞そのものの過敏性を含めた遠心路系の過敏性、（３）腺や血管の数、量の増加、（４）鼻粘膜上皮層のバリヤーの機能障害、（５）鼻粘膜を支配する副交感神経過緊張、交感神経の低下によるものも含まれる。
本発明の粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療剤は、アレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤として、特に好適である。
In the present specification, “nasal hypersensitivity due to severe and / or chronic allergic rhinitis” means that allergic rhinitis becomes severe and / or chronic among the above-mentioned “non-specific hypersensitivity of mucosa” Means that the nasal mucosa has become nonspecific hypersensitivity. In the present specification, “nasal hypersensitivity” includes not only an external antibody reaction with a nonspecific antigen, but also internal (1) hypersensitivity such as hypersensitivity and hypersensitivity, (2 ) Hypersensitivity of the centrifuge system including glandular cells, vascular smooth muscle cells, and hypersensitivity of endothelial cells themselves, (3) Increased number and amount of glands and blood vessels, (4) Impaired barrier function of nasal mucosal epithelial layer, (5) Parasympathetic nerve overtension governing the nasal mucosa and those caused by sympathetic nerve lowering are also included.
The preventive or therapeutic agent for non-specific hypersensitivity of the mucosa (except the lower respiratory tract mucosa) of the present invention is particularly suitable as a preventive or therapeutic agent for nasal hypersensitivity due to severe and / or chronic allergic rhinitis. is there.
本発明において、「予防」には発症を抑制する又は遅延させることが含まれる。「治療」には、症状又は疾病を完全に治癒させることの他、症状を緩和することも含まれる。 In the present invention, “prevention” includes suppressing or delaying the onset. “Treatment” includes alleviating symptoms as well as completely curing the symptoms or illness.
本発明に使用される菌は、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌であって、具体的には例えば、Bifidobacterium bifidum、B. longum、 B. breve、B. adolescentis、B. infantis、B.pseudolongum、B.thermophilum等のビフィズス菌；例えば、Lactobacillus acidophilus、L. casei、L. gasseri、L. plantarum、L. delbrueckii subsp bulgaricus、L. delbrueckii subsp lactis、L. fermentum、L. helveticus、L. johnsonii、L. paracasei subsp. paracasei、L. reuteri、L. rhamnosus、L. salivarius、L. brevis等の乳酸桿菌；例えば、Leuconostoc mesenteroides、Streptococcus(Enterococcus) faecalis、Streptococcus(Enterococcus) faecium、 Streptococcus(Enterococcus) hirae、Streptococcus thermophilus、 Lactococcus lactis、L. cremoris、Tetragenococcus halophilus、Pediococcus acidilactici、P. pentosaceus、Oenococcus oeni等の乳酸球菌；例えば、Bacillus coagulans等の有胞子性乳酸菌； Bacillus toyoi、B．licheniformis、Clostridium butyricum等の酪酸菌；その他の有用菌が挙げられる。
これらの菌体は、例えばＡＴＣＣ又はＩＦＯなどの機関や財団法人 日本ビフィズス菌センターなどから容易に入手することができる。また、市販されているものを適宜使用することもできる。
The bacterium used in the present invention is at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, and butyric acid bacterium. Specifically, for example, Bifidobacterium bifidum, B. longum, B. breve, B. Bifidobacteria such as adolescentis, B. infantis, B. pseudolongum, B. thermophilum; for example, Lactobacillus acidophilus, L. casei, L. gasseri, L. plantarum, L. delbrueckii subsp bulgaricus, L. delbrueckii subsp lactis, L. fermentum L. helveticus, L. johnsonii, L. paracasei subsp. Paracasei, L. reuteri, L. rhamnosus, L. salivarius, L. brevis, etc .; for example, Leuconostoc mesenteroides, Streptococcus (Enterococcus) faecalis, Stroctocuscus (Enterococcus) ) Lactococcus such as faecium, Streptococcus (Enterococcus) hirae, Streptococcus thermophilus, Lactococcus lactis, L. cremoris, Tetragenococcus halophilus, Pediococcus acidilactici, P. pentosaceus, Oenococcus oeni, etc .; for example, Bacillus coagulans Bacillus toyoi, B. Examples include butyric acid bacteria such as licheniformis and Clostridium butyricum; and other useful bacteria.
These cells can be easily obtained from, for example, an organization such as ATCC or IFO or the Japan Bifidobacteria Center. Moreover, what is marketed can also be used suitably.
本発明で使用する菌としては、ビフィズス菌が好ましく、Bifidobacterium bifidum、Bifidobacterium longum、Bifidobacterium infantis、Bifidobacterium breveがより好ましく、Bifidobacterium bifidum、Bifidobacterium longumがさらに好ましい。複数の菌を組み合わせて使用する場合には、ビフィズス菌と乳酸菌との組み合わせが好ましく、Bifidobacterium bifidumと、（ｉ）Lactobacillus acidophilus、（ｉｉ）Lactobacillus gasseri、（ｉｉｉ）Streptococcus(Enterococcus) faecalis、又は（ｉｖ）Streptococcus(Enterococcus) faeciumの（ｉ）〜（ｉｖ）のいずれかとの組み合わせが好ましく、中でも、Bifidobacterium bifidum G9-1と、（ｉ）Lactobacillus acidophilus、（ｉｉ）Lactobacillus gasseri、（ｉｉｉ）Streptococcus(Enterococcus) faecalis、又は（ｉｖ）Streptococcus(Enterococcus) faeciumの（ｉ）〜（ｉｖ）のいずれかとの組み合わせがより好ましい。ビフィズス菌と乳酸菌とを組み合わせて用いる場合の配合比率は特に限定されない。 Bacteria used in the present invention are preferably bifidobacteria, more preferably Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium infantis, and Bifidobacterium breve, and more preferably Bifidobacterium bifidum and Bifidobacterium longum. When a plurality of bacteria are used in combination, a combination of bifidobacteria and lactic acid bacteria is preferable, and Bifidobacterium bifidum, (i) Lactobacillus acidophilus, (ii) Lactobacillus gasseri, (iii) Streptococcus (Enterococcus) faecalis, or (iv) ) Streptococcus (Enterococcus) The combination of faecium with any of (i) to (iv) is preferred, among which Bifidobacterium bifidum G9-1, (i) Lactobacillus acidophilus, (ii) Lactobacillus gasseri, (iii) Streptococcus (Enterococcus) A combination of faecalis or (iv) Streptococcus (Enterococcus) faecium with any one of (i) to (iv) is more preferred. The blending ratio when using a combination of bifidobacteria and lactic acid bacteria is not particularly limited.
上記菌体は、公知の条件又はそれに準じる条件で培養することにより得ることができる。例えば、ビフィズス菌や乳酸菌の場合、グルコ−ス、酵母エキス、及びペプトン等を含む液体培地で前記ビフィズス菌や乳酸菌の１種又は２種以上を通常約２５〜４５℃程度で約４〜７２時間程度、好気又は嫌気培養し、培養液から菌体を集菌し、洗浄し、湿菌体を得る。 The said microbial cell can be obtained by culture | cultivating on well-known conditions or the conditions according to it. For example, in the case of bifidobacteria and lactic acid bacteria, one or more of the bifidobacteria and lactic acid bacteria are usually used at about 25 to 45 ° C. for about 4 to 72 hours in a liquid medium containing glucose, yeast extract, peptone and the like. Cultivate aerobic or anaerobically, collect cells from the culture, wash and obtain wet cells.
本発明において用いるビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌としては、生菌が好ましいが、菌の処理物を用いてもよい。菌の処理物とは、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌に何らかの処理を加えたものをいい、その処理は特に限定されない。該処理物として具体的には、該菌体の超音波などによる破砕液、該菌体の培養液又は培養上清、それらを濾過ないし遠心分離など固液分離手段によって分離した固体残渣などが挙げられる。また、細胞壁を酵素又は機械的手段により除去した処理液、トリクロロ酢酸処理又は塩析処理などして得られるタンパク質複合体（タンパク質、リポタンパク質、糖タンパク質など）やペプチド複合体（ペプチド、糖ペプチド等）なども該処理物として挙げられる。さらに、これらの濃縮物、これらの希釈物又はこれらの乾燥物なども該処理物に含まれる。また、該菌体の超音波などによる破砕液、該細胞の培養液又は培養上清などに対し、例えば各種クロマトグラフィーによる分離などの処理をさらに加えたものも本発明における該処理物に含まれる。ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌の死菌体も本発明における該処理物に含まれる。前記死菌体は、例えば、酵素処理、約１００℃程度の熱をかける加熱処理、抗生物質などの薬物による処理、ホルマリンなどの化学物質による処理、γ線などの放射線による処理などにより得ることができる。 The at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium and butyric acid bacterium used in the present invention is preferably a living bacterium, but a processed product of the bacterium may be used. The treated product of the bacterium refers to a product obtained by adding some treatment to at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, and butyric acid bacterium, and the treatment is not particularly limited. Specific examples of the treated product include a disruption solution of the microbial cells by ultrasonic waves, a culture solution or a culture supernatant of the microbial cells, and a solid residue obtained by separating them by solid-liquid separation means such as filtration or centrifugation. It is done. In addition, treatment solutions obtained by removing cell walls with enzymes or mechanical means, protein complexes (proteins, lipoproteins, glycoproteins, etc.) and peptide complexes (peptides, glycopeptides, etc.) obtained by trichloroacetic acid treatment or salting-out treatment, etc. ) Etc. are also mentioned as the treated product. Furthermore, these concentrates, these dilutions, or these dried products are also included in the treated product. In addition, the treated product in the present invention includes those obtained by further adding, for example, various chromatographic separations to the disrupted solution of the bacterial cells by ultrasonic waves, the cell culture solution or the culture supernatant. . A dead cell of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium and butyric acid bacterium is also included in the treated product in the present invention. The dead cells can be obtained by, for example, enzyme treatment, heat treatment at about 100 ° C., treatment with drugs such as antibiotics, treatment with chemicals such as formalin, treatment with radiation such as γ rays. it can.
本発明において使用される菌は、乾燥物（菌体乾燥物）であってもよく、菌体乾燥物としては、シングルミクロンの菌体乾燥物が好ましい。菌体乾燥物とは、通常は乾燥された個々の菌体又は乾燥された菌体の集合物をいう。また、シングルミクロンとは、小数第１位を四捨五入して１〜１０μｍをいう。本発明に使用されるビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌として、シングルミクロンの菌体乾燥物を使用すると、製剤中の生菌率が上がるため、粘膜の非特異的過敏性亢進の予防及び治療効果が高くなる。 The bacterium used in the present invention may be a dried product (bacterial cell dried product), and the microbial cell dried product is preferably a single micron dried cell product. The dried microbial cell usually refers to a dried individual microbial cell or a collection of dried microbial cells. Single micron means 1-10 μm by rounding off the first decimal place. When a single micron dried microbial cell product is used as at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, and butyric acid bacterium used in the present invention, the viable cell rate in the preparation increases, so Preventive and therapeutic effects of specific hypersensitivity increase.
菌体乾燥物の好ましい製造方法について説明する。上記菌体を溶媒に分散して菌体液とする。溶媒は、当業界で用いられる公知の溶媒を用いてよいが、水が好ましい。また、所望によりエタノールを加えてよい。エタノールを加えることによって、最初にエタノールが気化し、ついで水が気化するから、段階的な乾燥が可能となる。さらに、菌体液は、懸濁液であってもよい。溶媒は上記で示したものと同じでよい。また、懸濁させる際、懸濁剤、例えばアルギン酸ナトリウム等を使用してもよい。
また、上記菌体液には、さらに保護剤、賦形剤、結合剤、崩壊剤、又は静電気防止剤など当業界で一般に用いられている添加剤を通常の配合割合で添加してもよい。
A preferred method for producing a dried microbial cell product will be described. The said microbial cell is disperse | distributed to a solvent and it is set as a microbial cell liquid. As the solvent, a known solvent used in the art may be used, but water is preferable. If desired, ethanol may be added. By adding ethanol, ethanol is vaporized first, and then water is vaporized, so that stepwise drying is possible. Further, the bacterial cell liquid may be a suspension. The solvent may be the same as shown above. When suspending, a suspending agent such as sodium alginate may be used.
Moreover, you may add the additive generally used in this industry, such as a protective agent, an excipient | filler, a binder, a disintegrating agent, or an antistatic agent, to the said microbial cell liquid by a normal compounding ratio.
上記菌体液を、菌体乾燥物を製造するために噴霧乾燥装置による乾燥操作に付する。噴霧乾燥装置は、シングルミクロンの噴霧液滴を形成できる微粒化装置を備えた噴霧乾燥装置が好ましい。非常に粒径の小さな噴霧液滴にすると、噴霧液滴の単位質量あたりの表面積が大きくなり、乾燥温風との接触が効率よく行われるため、生産性が向上する。
ここでシングルミクロンの液滴とは、噴霧液滴の粒径が小数第１位を四捨五入して１〜１０μｍであるものをいう。
The bacterial cell liquid is subjected to a drying operation by a spray dryer in order to produce a dried bacterial cell product. The spray drying apparatus is preferably a spray drying apparatus equipped with a atomizing apparatus capable of forming single micron spray droplets. When spray droplets having a very small particle diameter are used, the surface area per unit mass of the spray droplets is increased, and contact with dry hot air is efficiently performed, so that productivity is improved.
Here, the droplet of single micron means that the particle size of the spray droplet is 1 to 10 μm rounded to the first decimal place.
噴霧乾燥装置には、微粒化装置が、例えばロータリーアトマイザー（回転円盤）、加圧ノズル、又は圧縮気体の力を利用した２流体ノズルや４流体ノズルである噴霧乾燥装置が挙げられる。
本発明においては、シングルミクロンの噴霧液滴を形成できるものであれば、上記形式のいずれの噴霧乾燥装置であってもよいが、４流体ノズルを有する噴霧乾燥装置を使用するのが好ましい。
Examples of the spray drying device include a spray drying device in which the atomization device is, for example, a rotary atomizer (rotary disk), a pressurized nozzle, or a two-fluid nozzle or a four-fluid nozzle using the force of compressed gas.
In the present invention, any spray drying apparatus of the above type may be used as long as it can form single micron spray droplets, but it is preferable to use a spray drying apparatus having a four-fluid nozzle.
４流体ノズルを有する噴霧乾燥装置では、４流体ノズルの構造としては、気体流路と液体流路とを１系統として、これを２系統ノズルエッジにおいて対称に設けたもので、ノズルエッジに流体流動面となる斜面を構成している。
また、ノズルエッジの先端の衝突焦点に向かって、両サイドから圧縮気体と液体を一点に集合させる外部混合方式の装置がよい。この方式であれば、ノズル詰まりがなく長時間噴霧することが可能となる。
In a spray drying apparatus having a four-fluid nozzle, the four-fluid nozzle has a gas flow channel and a liquid flow channel as one system, which are provided symmetrically at the two-system nozzle edge. It constitutes the slope that becomes the surface.
Also, an external mixing type apparatus that gathers compressed gas and liquid from one side toward the collision focus at the tip of the nozzle edge is preferable. With this method, it is possible to spray for a long time without nozzle clogging.
４流路ノズルを有する噴霧乾燥装置について図１を用いてさらに詳しく説明する。４流路ノズルのノズルエッジにおいて、液体流路３又は４から湧き出るように出た菌体液が、気体流路１又は２から出た高速気体流により流体流動面５で薄く引き伸ばされ、引き伸ばされた液体はノズルエッジ先端の衝突焦点６で発生する衝撃波で微粒化させることにより、シングルミクロンの噴霧液滴７を形成する。
A spray drying apparatus having a four-channel nozzle will be described in more detail with reference to FIG. At the nozzle edge of the four-channel nozzle, the bacterial cell liquid that springed out from the
圧縮気体としては、例えば、空気、炭酸ガス、窒素ガス又はアルゴンガス等の不活性ガス等を用いることができる。とくに、酸化されやすいもの等を噴霧乾燥させる場合は、炭酸ガス、窒素ガス又はアルゴンガス等の不活性ガスを用いるのが好ましい。
圧縮気体の圧力としては、約１〜１５ｋｇ重／ｃｍ２、好ましくは約３〜８ｋｇ重／ｃｍ２である。
ノズルにおける気体量は、ノズルエッジ１ｍｍあたり、約１〜１００Ｌ／分、好ましくは約１０〜２０Ｌ／分である。
As the compressed gas, for example, an inert gas such as air, carbon dioxide, nitrogen gas, or argon gas can be used. In particular, when spray-drying a material that is easily oxidized, it is preferable to use an inert gas such as carbon dioxide, nitrogen gas, or argon gas.
The pressure of the compressed gas, about 1~15kg heavy / cm 2, preferably about 3~8kg heavy / cm 2.
The amount of gas in the nozzle is about 1 to 100 L / min, preferably about 10 to 20 L / min per 1 mm of the nozzle edge.
その後、乾燥室において、その噴霧液滴に乾燥温風を接触させることで水分を蒸発させ菌体乾燥物を得る。
乾燥室の入り口温度は、約２〜４００℃、好ましくは約５〜２５０℃、より好ましくは約５〜１５０℃である。入り口温度が約２００〜４００℃の高温であっても、水分の蒸発による気化熱により乾燥室内の温度はそれほど高くならず、また、乾燥室内の滞留時間を短くすることにより、生菌の死滅や損傷をある程度抑えることができる。
出口温度は、約０〜１２０℃、好ましくは約５〜９０℃、より好ましくは約５〜７０℃である。
Thereafter, in the drying chamber, the spray droplets are brought into contact with dry hot air to evaporate the water and obtain a dried bacterial cell product.
The inlet temperature of the drying chamber is about 2 to 400 ° C, preferably about 5 to 250 ° C, more preferably about 5 to 150 ° C. Even if the inlet temperature is about 200 to 400 ° C., the temperature in the drying chamber is not so high due to the heat of vaporization due to the evaporation of moisture, and the residence time in the drying chamber is shortened to Damage can be suppressed to some extent.
The outlet temperature is about 0-120 ° C, preferably about 5-90 ° C, more preferably about 5-70 ° C.
４流路ノズルを有する噴霧乾燥装置では、液体流路が２流路あるので、異なった２種の菌体液又は菌体液と他の溶液若しくは懸濁液をそれぞれの液体流路から、同時に噴霧することにより、これらが混合された菌体乾燥物を製造できる。
例えば、異なった２種類の菌体の菌体液を同時に噴霧することにより、該２種の菌体を含有する菌体乾燥物が得られる。
In the spray drying apparatus having a four-channel nozzle, since there are two liquid channels, two different types of bacterial cell liquids or bacterial cell liquids and other solutions or suspensions are sprayed simultaneously from the respective liquid channels. Thus, a dried microbial cell product in which these are mixed can be produced.
For example, by simultaneously spraying two different types of bacterial cell solutions, a dried bacterial cell product containing the two types of bacterial cells can be obtained.
上記のように菌体乾燥物の粒径を小さくすることにより、生菌率が上がり、生菌率の多い製剤を提供できるという利点がある。
すなわち、シングルミクロンの菌体乾燥物を得るためにはシングルミクロンの噴霧液滴を噴霧するのが好ましい。噴霧液滴の粒径を小さくすると、噴霧液滴の単位質量あたりの表面積が大きくなるので、乾燥温風との接触が効率よく行われ、乾燥温風の熱による菌体の死滅又は損傷を極力抑えることができる。その結果として、生菌率が上がり生菌数の多い菌体乾燥物が得られる。
By reducing the particle size of the dried bacterial cell as described above, there is an advantage that the viable cell rate is increased and a preparation having a high viable cell rate can be provided.
That is, it is preferable to spray single micron spray droplets in order to obtain a single micron dried cell. When the particle size of the spray droplets is reduced, the surface area per unit mass of the spray droplets increases, so that contact with the dry hot air is performed efficiently, and killing or damaging the cells due to the heat of the dry hot air as much as possible. Can be suppressed. As a result, the viable cell rate is increased and a dried cell body having a large number of viable cells is obtained.
本発明において、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌の製剤中の生菌数は、製剤の一日投与量として、約１０５ＣＦＵ以上、好ましくは約１×１０７ＣＦＵ以上含むことが好ましい。
ここで、製剤中の生菌数の測定は菌体によって異なるが、例えば日本薬局方外医薬品規格に記載のされたそれぞれの菌体の定量方法により容易に測定できる。
In the present invention, the number of viable bacteria in the preparation of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria is about 10 5 CFU or more, preferably about 1 ×, as a daily dose of the preparation. It is preferable to contain 10 7 CFU or more.
Here, the measurement of the number of viable bacteria in the preparation varies depending on the bacterial cells, but can be easily measured by, for example, each bacterial cell quantification method described in the Japanese Pharmacopoeia Standards for Drugs.
本発明の非特異的過敏性亢進の予防又は治療剤、及びアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤は、上記菌又はその処理物と、他の成分とを混合することにより容易に製造される。他の成分は、本発明の効果を奏する限り特に限定されない。本発明にかかる非特異的過敏性亢進の予防又は治療剤、及びアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤は、医薬品や食品組成物の形態として用いることができる。医薬品の場合には、経口投与に適しており、内服剤とすることが好ましい。内服剤の剤型としては、例えば、錠剤、散剤、顆粒剤、丸剤、チュアブル剤、トローチ剤、液剤等が挙げられる。中でも、錠剤又は散剤が好ましい。 The preventive or therapeutic agent for nonspecific hypersensitivity of the present invention, and the preventive or therapeutic agent for nasal hypersensitivity due to the severity and / or chronicity of allergic rhinitis are the above-mentioned bacteria or a processed product thereof, and other components. It is easily manufactured by mixing. Other components are not particularly limited as long as the effects of the present invention are exhibited. The preventive or therapeutic agent for nonspecific hypersensitivity according to the present invention and the preventive or therapeutic agent for nasal hypersensitivity due to severe and / or chronic allergic rhinitis may be used as a form of a pharmaceutical or a food composition. it can. In the case of a pharmaceutical, it is suitable for oral administration and is preferably an internal preparation. Examples of the dosage form of the internal preparation include tablets, powders, granules, pills, chewable agents, troches, and liquids. Among these, tablets or powders are preferable.
本発明にかかる非特異的過敏性亢進の予防又は治療剤、及びアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤は、上述したように錠剤、散剤、顆粒剤、丸剤、チュアブル剤、トローチ剤、液剤等の薬剤の形態に加工されてもよい。かかる薬剤の加工方法は、公知の製剤方法に従ってよい。 As described above, the preventive or therapeutic agent for nonspecific hypersensitivity according to the present invention and the preventive or therapeutic agent for nasal hypersensitivity due to severe and / or chronic allergic rhinitis are tablets, powders, granules, It may be processed into pharmaceutical forms such as pills, chewables, troches, and liquids. Such drug processing methods may be in accordance with known pharmaceutical methods.
例えば、錠剤を製造する場合は、公知の打錠機を用いるとよい。該打錠機としては、例えば単発式打錠機又はロータリー型打錠機等が挙げられる。また、賦形剤（例えば、乳糖、デンプン、結晶セルロース又はリン酸ナトリウム等）、結合剤（例えば、デンプン、ゼラチン、カルメロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルピロリドン等）、崩壊剤（例えばデンプン、カルメロースナトリウム等）、滑沢剤（例えばタルク、ステアリン酸マグネシウム、ステアリン酸カルシウム、マクロゴール、ショ糖脂肪酸エステル等）等、当業界で使用される公知の添加剤等を含有していてもよい。 For example, when manufacturing a tablet, it is good to use a well-known tableting machine. Examples of the tableting machine include a single-shot tableting machine and a rotary tableting machine. In addition, excipients (eg, lactose, starch, crystalline cellulose, sodium phosphate, etc.), binders (eg, starch, gelatin, carmellose sodium, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), disintegration Contains known additives used in the industry, such as agents (eg starch, carmellose sodium), lubricants (eg talc, magnesium stearate, calcium stearate, macrogol, sucrose fatty acid ester, etc.) It may be.
また、例えば、散剤又は顆粒剤の製造方法としては、公知の方法に従ってよく、例えば上記菌体乾燥物をそのまま使用してもよい。丸剤、チュアブル剤又はトローチ剤の製造方法は、公知の方法に従って行われてよく、例えば錠剤を製造するのと同じ手段で作ることができる。 In addition, for example, as a method for producing a powder or granule, a known method may be used. For example, the above-mentioned dried bacterial cell may be used as it is. Pills, chewables or lozenges can be produced according to known methods, for example, by the same means as for producing tablets.
本発明の予防又は治療剤の投与量としては、例えば、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を１日あたり約１０５ＣＦＵ以上とすることが好ましく、約１０７ＣＦＵ以上とすることがより好ましい。この量を、１日１回〜３回に分けて投与する。ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌の１日あたりの投与量の上限は、約１０１２ＣＦＵであることが好ましい。 The dose of the preventive or therapeutic agent of the present invention is preferably about 10 5 CFU or more per day, for example, at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria, More preferably, it is 7 CFU or more. This amount is administered once to 3 times a day. The upper limit of the daily dose of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria is preferably about 10 12 CFU.
本発明の予防又は治療剤の投与対象としては、粘膜（下気道粘膜を除く）の非特異的過敏性が亢進した個体が好適な対象であり、鼻粘膜の非特異的過敏性が亢進した個体がより好適であり、アレルギー性鼻炎の重症化及び／又は慢性化により鼻粘膜の非特異的過敏性が亢進した個体、すなわちアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性を発症した個体がさらに好適な対象である。また、個体としてはヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル等の哺乳類が好ましく、特にヒトが好ましい。 The subject of administration of the preventive or therapeutic agent of the present invention is preferably an individual with increased nonspecific hypersensitivity of the mucosa (excluding the lower respiratory mucosa), and an individual with increased nonspecific hypersensitivity of the nasal mucosa Is more suitable and has developed non-specific hypersensitivity of the nasal mucosa due to severe and / or chronic allergic rhinitis, that is, developed nasal hypersensitivity due to severe and / or chronic allergic rhinitis Individuals are more suitable subjects. Further, as an individual, mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys and the like are preferable, and humans are particularly preferable.
ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を哺乳類（好ましくはヒト）に投与することにより、粘膜（下気道粘膜を除く）の非特異的過敏性を抑制又は治療することができる。 By administering to mammals (preferably humans) at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria, nonspecific hypersensitivity of the mucosa (except the lower respiratory tract mucosa) is suppressed or treated. be able to.
本発明は、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を含む組成物を哺乳類に投与する粘膜（下気道粘膜を除く）の非特異的過敏性亢進の抑制又は治療方法、及び、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌を含む組成物を哺乳類に投与するアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の抑制又は治療方法も包含する。 The present invention suppresses or treats nonspecific hypersensitivity of mucous membranes (excluding lower airway mucosa) administered to a mammal with a composition containing at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria Method and suppression or treatment of nasal hypersensitivity caused by severe and / or chronic allergic rhinitis by administering to mammals a composition comprising at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria Methods are also encompassed.
本発明は、粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療のための、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌；アレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療のための、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌；粘膜（下気道粘膜を除く）の非特異的過敏性亢進の予防又は治療剤を製造するための、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌の使用；及び、アレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性の予防又は治療剤を製造するための、ビフィズス菌、乳酸菌及び酪酸菌からなる群より選ばれる少なくとも１種の菌の使用も包含する。 The present invention relates to at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria, and butyric acid bacteria for preventing or treating nonspecific hypersensitivity of mucous membranes (excluding lower airway mucosa); At least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria for prevention or treatment of nasal hypersensitivity due to severe and / or chronicity; non-specific mucosa (except lower airway mucosa) Use of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacterium, and butyric acid bacterium for the manufacture of a prophylactic or therapeutic agent for hypersensitivity; and the nose due to severe and / or chronic allergic rhinitis The use of at least one bacterium selected from the group consisting of bifidobacteria, lactic acid bacteria and butyric acid bacteria for producing a prophylactic or therapeutic agent for hypersensitivity is also included.
以下実施例を示してさらに詳しく説明を行うが、本発明はこれによりなんら制限されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
実施例１
１．菌（ＢＢＧ９−１：Bifidobacterium bifidum G9-1）の調製方法
ＢＢＧ９−１の菌体乾燥物の調製は以下のように行った。すなわち、ＢＢＧ９−１の凍結保存菌株を３７℃で２４時間静置培養後、ビフィズス菌試験用液体培地（１）（日本薬局方外医薬品規格「ビフィズス菌」の項に記載）にこの培養菌液をビフィズス菌試験用液体培地（１）１００に対して１の割合（容量比）で接種し、３７℃で１８時間静置培養した。得られた培養菌液を遠心分離し、水で３回洗浄後、適量の水を加え、湿菌体１ｋｇに対し、グルタミン酸塩０．１ｋｇ及びデキストリン０．５ｋｇの割合で加えて噴霧乾燥装置にて菌体乾燥物とした。これにより生菌数２．２×１０１１ＣＦＵ／ｇの菌体乾燥物を得た。
Example 1
1. Preparation Method of Bacteria (BBG9-1: Bifidobacterium bifidum G9-1) The dry product of BBG9-1 was prepared as follows. That is, after the BBG9-1 cryopreserved strain was allowed to stand at 37 ° C. for 24 hours, the cultured bacterial solution was added to the liquid medium for bifidobacteria test (1) (described in the section of the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacteria”). Was inoculated at a ratio (volume ratio) of 1 with respect to the liquid medium for bifidobacteria test (1) 100, followed by stationary culture at 37 ° C for 18 hours. The obtained culture solution is centrifuged, washed three times with water, an appropriate amount of water is added, and 0.1 kg of glutamate and 0.5 kg of dextrin are added to 1 kg of wet cells, and the mixture is added to the spray drying apparatus. The cells were dried. As a result, a dried microbial cell product having a viable cell count of 2.2 × 10 11 CFU / g was obtained.
２．菌体乾燥物中の生菌数の測定
日本薬局方外医薬品規格「ビフィズス菌」の項に記載されているビフィズス菌の定量法に準じて測定した。すなわち、菌体乾燥物５ｇを精密に量り、希釈液（２）３０ｍＬ中に加え、強く振り混ぜ、更に同希釈液を加えて正確に５０ｍＬとし、よく振り混ぜ、この菌液１ｍＬを正確に量り、別に正確に分注した同希釈液９ｍＬ中に加える操作（１０倍希釈法）を繰り返し、１ｍＬ中の生菌数が２０〜２００個となるよう希釈した。この液１ｍＬをペトリ皿にとり、ここに５０℃に保ったビフィズス菌試験用カンテン培地を２０ｍＬ加えてすばやく混和し、固化させた。これを３７℃で４８〜７２時間嫌気培養し、出現したコロニー数と希釈倍率から菌体乾燥物中の生菌数を求めた。
2. Measurement of the number of viable bacteria in the dried microbial cell body The measurement was performed according to the method for quantifying bifidobacteria described in the section of the Japanese Pharmacopoeia Pharmaceutical Standards “Bifidobacteria”. That is, weigh accurately 5 g of the dried bacterial cell product, add it to 30 mL of diluent (2), shake vigorously, add the same diluent to make exactly 50 mL, shake well, and accurately measure 1 mL of this bacterial solution. Then, the operation (10-fold dilution method) of addition into 9 mL of the same diluted solution that was accurately dispensed was repeated, and diluted so that the number of viable bacteria in 1 mL was 20 to 200. 1 mL of this solution was placed in a Petri dish, and 20 mL of an agar medium for bifidobacteria test maintained at 50 ° C. was added thereto and quickly mixed to solidify. This was anaerobically cultured at 37 ° C. for 48 to 72 hours, and the number of viable bacteria in the dried microbial cell was determined from the number of colonies that appeared and the dilution rate.
３．モデル動物の作製方法
非特異的過敏性亢進のモデル動物は、Nobe et al., Jpn. J. Pharmacol. 75, 243-251 (1997)、Nobe et al., Inflamm. res. 47 (1998) 369-374、及びMizutani et al., Jpn. J. Pharmacol. 86, 170-182 (2001)に記載の方法に基づいて作製した。以下に、モデル動物の作製方法を記載する。
3. Method for preparing model animals Model animals with nonspecific hypersensitivity are Nobe et al., Jpn. J. Pharmacol. 75, 243-251 (1997), Nobe et al., Inflamm. Res. 47 (1998) 369 -374, and Mizutani et al., Jpn. J. Pharmacol. 86, 170-182 (2001). Below, the production method of a model animal is described.
３．1 非特異的過敏性亢進のモデル動物の構築
（１）水酸化アルミニウム（Ａｌ（ＯＨ）３）を含むスギ花粉抽出液の調製
スギ花粉を１００ｍｇ／ｍＬにてリン酸緩衝生理食塩水（ＰＢＳ）に加え、１８時間４℃にて懸濁したのち、１７００×ｇ、１５分間遠心分離を行い上澄を回収し、タンパク濃度が２００μｇ／ｍＬとなるようにＰＢＳで希釈した。
3.1 Construction of a model animal for nonspecific hypersensitivity (1) Preparation of cedar pollen extract containing aluminum hydroxide (Al (OH) 3 ) Sugi pollen at 100 mg / mL in phosphate buffered saline ( After suspending at 4 ° C. for 18 hours, the supernatant was collected by centrifugation at 1700 × g for 15 minutes, and diluted with PBS to a protein concentration of 200 μg / mL.
２００ｍｇ／ｍＬのＡｌ（ＯＨ）３水溶液を調製し、この水溶液１ｍＬに塩化ナトリウム９ｍｇを加え、さらに上記の希釈したスギ花粉抽出液１ｍＬを氷中で攪拌しながら滴下し、Ａｌ（ＯＨ）３を含むスギ花粉抽出液を調製した。 A 200 mg / mL aqueous solution of Al (OH) 3 was prepared, 9 mg of sodium chloride was added to 1 mL of this aqueous solution, and 1 mL of the above diluted cedar pollen extract was added dropwise with stirring in ice, and Al (OH) 3 was added. A cedar pollen extract containing was prepared.
（２）モルモットへのスギ花粉による感作
（１）で調製したスギ花粉抽出液をモルモットの鼻腔内に、１日２回、３μＬずつ滴下し、７日間連続して投与した（０週〜第１週）。さらに最終感作１週間後より、１週間に１回の割合で、スギ花粉をモルモットの片鼻に約１．８ｍｇずつ、すなわち両鼻孔で約３．６ｍｇ吸入させて反応惹起を行った。このスギ花粉吸入によりモルモットにアレルギー性鼻炎を発症させることができる。さらに、スギ花粉による反復反応惹起を繰り返すと、反応惹起４回目（第５週）以降で惹起後３０分〜２時間（即時性）ならびに惹起後４〜６時間（遅発性）にそれぞれ鼻腔抵抗の上昇のピークが再現性よく観察された。また、ヒスタミンを鼻腔に投与しても濃度依存的な鼻腔抵抗の上昇が見られ、非感作群に対して１０００倍以上の低濃度から反応性を示すようになった。このような二相性のアレルギー反応を示すモルモットを、非特異的過敏性亢進のモデル動物として使用した。
(2) Sensitization of cedar pollen to guinea pigs The cedar pollen extract prepared in (1) was dropped into the nasal cavity of the guinea pig twice a day at a dose of 3 μL and administered continuously for 7 days (from
４．モデル動物に対するＢＢＧ９−１の効果
上記１．で調製したＢＢＧ９−１の菌体乾燥物は、モデル動物に投与する直前に０．０５ｍｇ／ｍＬにて、生理食塩水に懸濁し、モデル動物に投与した。実験は以下の３つのモルモット群を用いて行なった。
モルモット群Ａ（ｎ＝１３）：スギ花粉による反応惹起を行なわず、スギ花粉による感作を行なう１週間前〜スギ花粉による反復反応惹起期間中にわたって６回（１日１回を、６日）／週にて、上記１．で調製したＢＢＧ９−１の菌体乾燥物の代わりに、１回あたり生理食塩水を１ｍＬ／個体、経口投与するグループ。
モルモット群Ｂ（ｎ＝１１）：上記３．（２）で作製したモデル動物に、スギ花粉による感作を行なう１週間前〜スギ花粉による反復反応惹期間中にわたって６回（１日１回を、６日）／週にて、上記１．で調製したＢＢＧ９−１の菌体乾燥物を１回あたり０．０５ｍｇ／１ｍＬ／個体、経口投与するグループ。
モルモット群Ｃ（ｎ＝１２）：上記３．（２）で作製したモデル動物に、スギ花粉による感作を行なう１週間前〜スギ花粉による反復反応惹期間中にわたって６回（１日１回を、６日）／週にて、上記１．で調製したＢＢＧ９−１の菌体乾燥物の代わりに、１回あたり生理食塩水を１ｍＬ／個体、経口投与するグループ。
4). Effect of BBG9-1 on model animals The BBG9-1 dried product prepared in (1) was suspended in physiological saline at 0.05 mg / mL immediately before administration to the model animal, and then administered to the model animal. The experiment was conducted using the following three guinea pig groups.
Guinea pig group A (n = 13): 1 week before sensitization with cedar pollen without inducing reaction with cedar pollen to 6 times (once a day for 6 days) during the period of initiating repeated reaction with cedar pollen Per week. A group in which 1 mL / individual physiological saline is orally administered per time instead of the dried BBG9-1 cell product prepared in 1.
Guinea pig group B (n = 11): From 1 week before the sensitization with cedar pollen to the model animal prepared in (2) to the repetitive reaction induction period with cedar pollen at 6 times (once a day, 6 days) / week. The group which orally administers 0.05 mg / 1mL / individual BBG9-1 dried substance prepared by 1 time.
Guinea pig group C (n = 12): From 1 week before the sensitization with cedar pollen to the model animal prepared in (2) to the repetitive reaction induction period with cedar pollen at 6 times (once a day, 6 days) / week. A group in which 1 mL / individual physiological saline is orally administered per time instead of the dried BBG9-1 cell product prepared in 1.
反応惹起１６回目（１７週）の反応惹起を行なった後、４８時間後にロイコトリエンＤ４（ＬＴＤ４）を点鼻投与し、呼吸機能の経時的変化を、two-chambered double-flow plethysmograph法を利用した多機能呼吸測定装置（Ｐｕｌｍｏｓ−Ｉ，Ｍ.Ｉ.Ｐ.Ｓ.）を用い、鼻腔抵抗（ｓＲａｗ）を指標として、その変化をモニターした。結果を図２に示す。 After initiating the reaction for the 16th time (17 weeks), leukotriene D 4 (LTD 4 ) is administered nasally 48 hours later, and changes in respiratory function over time are measured using the two-chambered double-flow plethysmograph method. Using the multifunctional respiratory measurement device (Pulmos-I, M.I.P.S.), the change was monitored using nasal resistance (sRaw) as an index. The results are shown in FIG.
５．結果
鼻粘膜の非特異的過敏性を呈さない群Ａ（灰色）では、ＬＴＤ４の投与量を上げても鼻腔抵抗が変化しないのに対して、鼻粘膜の非特異的過敏性が亢進した群Ｃ（白）ではＬＴＤ４の投与により鼻腔抵抗が増大した。一方、鼻粘膜の非特異的過敏性が亢進したモルモットに上記で調製したＢＢＧ９−１を投与した群Ｂ（黒）は、群Ａとほぼ同様の結果を示し、投与したＢＢＧ９−１により、ＬＴＤ４の投与による鼻粘膜の非特異的過敏性が有意に抑制されることが分かった。
5. Results In group A (gray) which does not exhibit nonspecific hypersensitivity of nasal mucosa, nasal resistance does not change even when the dose of LTD 4 is increased, whereas nonspecific hypersensitivity of nasal mucosa is enhanced In C (white), nasal resistance was increased by LTD 4 administration. On the other hand, group B (black) in which BBG9-1 prepared above was administered to guinea pigs with increased nonspecific hypersensitivity of the nasal mucosa showed almost the same results as group A, and the BBG9-1 administered showed LTD. It was found that nonspecific hypersensitivity of the nasal mucosa by administration of 4 was significantly suppressed.
本発明により、粘膜（下気道粘膜を除く）の非特異的過敏性亢進、及びアレルギー性鼻炎の重症化及び／又は慢性化による鼻過敏性を効果的に予防又は治療することができる。 According to the present invention, nonspecific hypersensitivity of mucous membranes (excluding lower respiratory tract mucosa) and nasal hypersensitivity due to severe and / or chronic allergic rhinitis can be effectively prevented or treated.
１、２ 圧縮気体が供給される気体流路
３、４ 被乾燥体を含む液体が供給される液体流路
５ 流体流動面
６ 衝突焦点
７ 噴霧液滴
DESCRIPTION OF SYMBOLS 1, 2 Gas flow path to which compressed gas is supplied 3, 4 Liquid flow path to which the liquid containing the to-be-dried body is supplied
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008263107A JP5405793B2 (en) | 2008-10-09 | 2008-10-09 | Preventive or therapeutic agent for nonspecific hypersensitivity of mucous membrane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008263107A JP5405793B2 (en) | 2008-10-09 | 2008-10-09 | Preventive or therapeutic agent for nonspecific hypersensitivity of mucous membrane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2010090073A JP2010090073A (en) | 2010-04-22 |
| JP5405793B2 true JP5405793B2 (en) | 2014-02-05 |
Family
ID=42253172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008263107A Active JP5405793B2 (en) | 2008-10-09 | 2008-10-09 | Preventive or therapeutic agent for nonspecific hypersensitivity of mucous membrane |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP5405793B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5769710B2 (en) * | 2010-07-22 | 2015-08-26 | ビオフェルミン製薬株式会社 | Lipid metabolism improving agent, lipid metabolism improving agent, anti-obesity agent and anti-obesity agent |
| JP6616100B2 (en) * | 2015-05-15 | 2019-12-04 | フロイント産業株式会社 | Process for producing powdered composition containing dead cells of lactic acid bacteria and / or bifidobacteria |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4123375B2 (en) * | 2004-01-29 | 2008-07-23 | ソニー株式会社 | Optical disc and optical disc recording / reproducing apparatus |
| JP2006143677A (en) * | 2004-11-22 | 2006-06-08 | Ace Bio Product Kk | Anti-allergic material |
-
2008
- 2008-10-09 JP JP2008263107A patent/JP5405793B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2010090073A (en) | 2010-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102211832B1 (en) | Composition containing nicotinic acid and/or nicotinamide and/or tryptophan for positively influencing the intestinal microbiota | |
| Bodera et al. | Immunomodulatory effect of probiotic bacteria | |
| JP6637725B2 (en) | Preventive and / or therapeutic agent for viral infection | |
| JP4942831B2 (en) | Antiallergic composition | |
| JP2003535903A (en) | Immunotherapy or treatment of bacterial or viral infections on mucosal surfaces using probiotics, and compositions therefor | |
| CN112877233B (en) | Lactobacillus helveticus strain and application thereof | |
| KR20200024133A (en) | Enteric-selective blockade for the treatment and prevention of autism and related disorders | |
| CN114728027A (en) | Bacterial strains, compositions thereof and use thereof for the treatment of gastrointestinal disorders | |
| US20200171106A1 (en) | Composition comprising bacterial strains belonging to the species lactobacillus salivarius for the treatment of parkinson's disease | |
| JP2003514869A (en) | Compositions and methods for the treatment of allergic diseases | |
| EP3079704B1 (en) | A pharmaceutical composition containing combinations of nicotinamide and 5-aminosalicylic acid for beneficially influencing the intestinal microbiota and/or treating gastrointestinal inflammation | |
| Sanap et al. | Probiotics, their health benefits and applications for development of human health: a review | |
| CN110643541B (en) | Lactobacillus casei capable of adjusting Th2/Th1 balance of allergic asthma and application thereof | |
| JP5681533B2 (en) | Gastrointestinal pain prevention or alleviation agent | |
| AU2021229110B2 (en) | Lactobacillus Helveticus strain and composition containing same for prevention or treatment of inflammatory diseases | |
| JP2009057346A (en) | Composition for regulating immune balance | |
| JP5405793B2 (en) | Preventive or therapeutic agent for nonspecific hypersensitivity of mucous membrane | |
| US20170273326A1 (en) | Lactic acid bacteria-containing composition | |
| KR20210005717A (en) | Probiotic Bifidobacterium Brevet Strains and Compositions Containing the Strains | |
| US20220387526A1 (en) | Uremic toxin reducing agent | |
| CN113893353A (en) | Method for improving survival rate of intestinal probiotics in oral delivery process | |
| JP5631721B2 (en) | Gastrointestinal hypersensitizer | |
| JP2001158743A (en) | Lactobacillus-containing composition, medicament and food | |
| JP6442219B2 (en) | Oral immune function regulating composition | |
| JP6402016B2 (en) | Nerve function improving agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20110603 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20130402 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130530 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20131029 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20131031 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 5405793 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
| S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |