JP6946299B2 - 生態系のままの微生物叢を保存するために凍結乾燥された組成物 - Google Patents
生態系のままの微生物叢を保存するために凍結乾燥された組成物 Download PDFInfo
- Publication number
- JP6946299B2 JP6946299B2 JP2018531508A JP2018531508A JP6946299B2 JP 6946299 B2 JP6946299 B2 JP 6946299B2 JP 2018531508 A JP2018531508 A JP 2018531508A JP 2018531508 A JP2018531508 A JP 2018531508A JP 6946299 B2 JP6946299 B2 JP 6946299B2
- Authority
- JP
- Japan
- Prior art keywords
- lyophilized
- mixture
- feces
- trehalose
- microbial flora
- 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
- 239000000203 mixture Substances 0.000 title claims description 136
- 230000000813 microbial effect Effects 0.000 title claims description 36
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 59
- 210000003608 fece Anatomy 0.000 claims description 54
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 50
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 50
- 239000002577 cryoprotective agent Substances 0.000 claims description 44
- 238000004108 freeze drying Methods 0.000 claims description 44
- 239000005913 Maltodextrin Substances 0.000 claims description 40
- 229920002774 Maltodextrin Polymers 0.000 claims description 40
- 229940035034 maltodextrin Drugs 0.000 claims description 40
- 239000002775 capsule Substances 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 34
- 239000012530 fluid Substances 0.000 claims description 33
- 244000005706 microflora Species 0.000 claims description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 230000002496 gastric effect Effects 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 208000027244 Dysbiosis Diseases 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 210000004211 gastric acid Anatomy 0.000 claims description 5
- 210000004051 gastric juice Anatomy 0.000 claims description 5
- 208000037384 Clostridium Infections Diseases 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 230000000306 recurrent effect Effects 0.000 claims description 3
- 229940127249 oral antibiotic Drugs 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- 206010009657 Clostridium difficile colitis Diseases 0.000 claims 1
- 206010054236 Clostridium difficile infection Diseases 0.000 claims 1
- 238000007865 diluting Methods 0.000 claims 1
- 239000000047 product Substances 0.000 description 52
- 241000894006 Bacteria Species 0.000 description 33
- 230000001580 bacterial effect Effects 0.000 description 33
- 238000002360 preparation method Methods 0.000 description 27
- 238000003860 storage Methods 0.000 description 24
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 21
- 230000002550 fecal effect Effects 0.000 description 21
- 230000035899 viability Effects 0.000 description 21
- 230000000694 effects Effects 0.000 description 18
- 239000000314 lubricant Substances 0.000 description 18
- 239000003085 diluting agent Substances 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000000463 material Substances 0.000 description 14
- 239000000523 sample Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000002207 metabolite Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 10
- 239000008119 colloidal silica Substances 0.000 description 10
- 238000002054 transplantation Methods 0.000 description 10
- 238000007710 freezing Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 241000193163 Clostridioides difficile Species 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 230000008014 freezing Effects 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000000968 intestinal effect Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 229910002012 Aerosil® Inorganic materials 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 244000005700 microbiome Species 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 235000021391 short chain fatty acids Nutrition 0.000 description 6
- 150000004666 short chain fatty acids Chemical class 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 239000000454 talc Substances 0.000 description 6
- 229910052623 talc Inorganic materials 0.000 description 6
- 241000606125 Bacteroides Species 0.000 description 5
- 241000736262 Microbiota Species 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 230000029142 excretion Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 241000186000 Bifidobacterium Species 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 4
- 208000004232 Enteritis Diseases 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 239000001506 calcium phosphate Substances 0.000 description 4
- 210000002421 cell wall Anatomy 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 238000007907 direct compression Methods 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 235000013336 milk Nutrition 0.000 description 4
- 239000008267 milk Substances 0.000 description 4
- 210000004080 milk Anatomy 0.000 description 4
- 230000003248 secreting effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 3
- 102000044503 Antimicrobial Peptides Human genes 0.000 description 3
- 108700042778 Antimicrobial Peptides Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 3
- 102000001109 Leukocyte L1 Antigen Complex Human genes 0.000 description 3
- 108010069316 Leukocyte L1 Antigen Complex Proteins 0.000 description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 3
- 208000001145 Metabolic Syndrome Diseases 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 3
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 3
- 229940038472 dicalcium phosphate Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 101150026046 iga gene Proteins 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 239000012466 permeate Substances 0.000 description 3
- 229920001282 polysaccharide Polymers 0.000 description 3
- 239000005017 polysaccharide Substances 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 231100000033 toxigenic Toxicity 0.000 description 3
- 230000001551 toxigenic effect Effects 0.000 description 3
- 239000011573 trace mineral Substances 0.000 description 3
- 235000013619 trace mineral Nutrition 0.000 description 3
- 241001515965 unidentified phage Species 0.000 description 3
- 241000193403 Clostridium Species 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 102000000541 Defensins Human genes 0.000 description 2
- 108010002069 Defensins Proteins 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000792859 Enema Species 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000186660 Lactobacillus Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920000715 Mucilage Polymers 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 239000001888 Peptone Substances 0.000 description 2
- 108010080698 Peptones Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 241000186569 [Clostridium] leptum Species 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000002528 anti-freeze Effects 0.000 description 2
- 208000029560 autism spectrum disease Diseases 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000002052 colonoscopy Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000002183 duodenal effect Effects 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940095399 enema Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 244000005709 gut microbiome Species 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000008011 inorganic excipient Substances 0.000 description 2
- 229940039696 lactobacillus Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 101150017059 pcd1 gene Proteins 0.000 description 2
- 235000019319 peptone Nutrition 0.000 description 2
- -1 polysaccharide carbohydrate compounds Chemical class 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 108010062877 Bacteriocins Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 description 1
- 208000012239 Developmental disease Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010013554 Diverticulum Diseases 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000605980 Faecalibacterium prausnitzii Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010017964 Gastrointestinal infection Diseases 0.000 description 1
- 206010031149 Osteitis Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 230000000735 allogeneic effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000011365 complex material Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005138 cryopreservation Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 238000009629 microbiological culture Methods 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910000150 monocalcium phosphate Inorganic materials 0.000 description 1
- 235000019691 monocalcium phosphate Nutrition 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 235000008935 nutritious Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000272 proprioceptive effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/04—Preserving or maintaining viable microorganisms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Mycology (AREA)
- Genetics & Genomics (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Rheumatology (AREA)
- Psychiatry (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Oil, Petroleum & Natural Gas (AREA)
Description
−高分子量を有し、かつ細胞外媒体中で保たれる、タンパク質及び多糖類のような分子であって、凍結段階の間に細胞からの水分流出を促進し、それにより細胞内の氷の結晶の形成を制限する、分子。細胞外媒体の粘度を増加させることにより、これらの分子は、結晶成長も低下させる。
−細胞壁を通過することが可能な分子、例えばアミノ酸及びオリゴ糖類。
−細胞壁及び細胞質膜を透過する分子、例えばDMSO及びグリセロール(Carvalho A.S. et al., 2004)。
−その物を−20℃〜−80℃の温度で冷凍する凍結(水は氷に変わる)。
−間隙にある遊離した氷を昇華させる段階である真空中での一次乾燥。
−乾燥物の表面に捉えられた水分子を脱離により抜き取る最終乾燥。
−全混合物の重量の0.1%〜1%、有利には0.5%の割合の疎水性コロイダルシリカと、
−全混合物の重量の0.1%〜1%、有利には0.5%の割合の親水性コロイダルシリカ、及び全混合物の重量の10%〜90%、有利には15%から75%の間、有利には25%から50%の間の割合のリン酸二カルシウムと、
−全混合物の重量の0.1%〜1%、有利には0.5%の割合のタルク、及び全混合物の重量の10%〜90%、有利には15%から75%の間の割合の微粉マルトデキストリンと、
から構成される。
−MIIE、特に糞便を採集する工程と、
−MIIEを、上記の凍結保護物質の混合物により、35/65から45/55までの範囲のM/T重量比で、好ましくは40/60のM/T重量比で希釈する工程と、
−先の工程で得られた混合物を凍結乾燥させ、凍結乾燥された組成物を得る工程と、
を含む、方法に関する。
−凍結乾燥された組成物を調製する工程と、
−凍結乾燥物を噴霧して、粉体形にする工程と、
−任意に、凍結乾燥物の流動を改善する1種以上の賦形剤を添加する工程と、
−胃液耐性カプセル剤の包被に、上記凍結乾燥された混合物を充填する工程と、
−上記カプセル剤をシールする工程と、
を含む、方法に関する。
1. 材料及び方法
1.1. 糞便試料採取
凍結乾燥条件の選択は、健康な無関係のボランティアによって提供され、かつ排泄直後にインキュベーション用の試料ポット内に備え付けられたGENbagAnaer(商標)システムの存在のもとに置かれた、3つの糞便の研究を基礎としている。試料は、排泄後に、1時間未満で研究所に直接送られた。各々の糞便の一部は、直接分析のためのコントロールとしてGENbagAnaer(商標)を用いて保管される。
この研究のために使用される凍結保護物質は、
−10%のグリセロール(G)、
−滅菌された脱脂粉乳の10%再構成物(L)、
−5%濃度のマルトデキストリン(M)、
−5%濃度のトレハロース(T5)及び10%濃度のトレハロース(T10)、
−6.7%濃度のマルトデキストリン及び10%濃度のトレハロースの混合物、又はそれらの40/60のM/T重量比の混合物(MT)、
−コントロールとしての9‰濃度のNaCl溶液(それは一般的に、新鮮な排泄物の希釈に使用される)、
である。
糞便を、凍結保護物質溶液で10倍希釈し、使い捨ての心棒を取り付けたUltraturrax(商標)型ホモジナイザーを使用して均質化した。懸濁された溶液を、本来の糞便試料300mgにつき3mlに相当する容量を有する凍結乾燥バイアルに入れた。
微生物学的研究の第1工程は、微生物叢の多様性及びその生存力の維持に対する種々の凍結保護物質の存在下での希釈の効果を試験するために凍結乾燥されていない希釈された糞便を分析することであった。この目的のために、10%の乳(L)、10%のグリセロール(G)、5%のマルトデキストリン(M)、5%のトレハロース(T)、10%のトレハロース(T10)、並びに6.7%のマルトデキストリン及び10%のトレハロースの混合物、すなわちそれらの40/60のM/T重量比の混合物(MT)で作製された特定量の希釈物を、糞便の凍結乾燥物の調製後に直ちに嫌気生活下に置き、そして微生物培養を直ちに行った。
2.1. 凍結乾燥前の微生物叢の多様性及び生存力に対する、種々の凍結保護物質の効果
様々な評価された凍結保護物質での、特にMT混合物での糞便希釈は、細菌量に対して大きな影響を及ぼさず、本来の糞便又は9%のNaClで希釈された糞便(新鮮な糞便でのFMTのために使用される調製物に相当する)と比較して、培養可能な微生物叢の種々の主要属の均衡に影響しなかった(図1)。微生物叢の主要な群は、生存したままである。
全細菌量を、凍結乾燥後の週の間に、又はMOで評価した。結果は、図2に表されている。試験された3種の凍結保護物質、すなわち5%のトレハロース溶液(T5)、10%のトレハロース溶液(T10)、並びに6.7%のマルトデキストリン及び10%のトレハロースの混合物(TM)は、凍結乾燥の間に、培養可能な細菌の全細菌量の90%より高い安定性を与えることが可能であり、この結果は、本来の糞便中、又は凍結乾燥前に9%のNaClで希釈された糞便中に存在する量と比較して約1logの損失に相当する。
上記のように試験された3種の凍結保護物質のうち、6.7%のマルトデキストリン及び10%のトレハロースの凍結保護物質混合物(又は40/60の重量比の混合物)は、糞便3について、或る特定の偏性嫌気性の属における約1log〜2logの減少にもかかわらず(図5)(示されていないが、その他の糞便については4logまで)、糞便中微生物叢を構成する主要属を生きた状態で維持するという最良の結果を与えるものである。それに対して、10%のグリセロール溶液は、好気性の属及び嫌気性の属の両方についてあまり保護作用を有さない(結果は示されていない)。
1. 材料及び方法
実施例1に記載される方法に従って、S4、S5、及びS6と呼ばれる3つの更なる糞便試料を、6.7%のマルトデキストリン及び10%のトレハロースの凍結保護物質混合物(又は40/60のM/T重量比の混合物)の存在下で希釈し、次いで凍結乾燥した。
2.1. 6ヶ月間の貯蔵後の凍結乾燥物における細菌生態系の安定性
2.1.1. 6ヶ月間の貯蔵後の凍結乾燥物における細菌の生存力及び多様性の分析
偏性嫌気性の個体群を、代表的な細菌群:ビフィドバクテリウム属の複数菌種及びバクテロイデス属の複数菌種の計数に基づき分析した。
糞便中微生物叢の特有の特徴の1つは、凍結乾燥法により影響され得る、極度の酸素感受性(EOS)細菌の存在である。
2.2.1. 凍結乾燥物中の代謝物の検出
細菌性代謝物、すなわち短鎖脂肪酸の産生を、72時間凍結乾燥物において、本来の糞便と比較して評価した。3種の分析された試料のうち、凍結乾燥は、発酵産物の保存をもたらし、その際、短鎖脂肪酸の濃度は、糞便試料に応じて、酢酸塩及びプロピオン酸塩の場合は2倍〜4倍増大し、酪酸塩の場合には2倍〜6倍増大した。細菌性代謝物は、揮発性であるが、凍結乾燥物中に存在する。その濃度の増大は、代謝物の濃縮をもたらす凍結乾燥の結果であると考えられる(図9)。
本来の糞便及び凍結乾燥物における抗クロストリジウム・ディフィシル効果を、1種の毒素原性菌株(菌株630)及び1種の非毒素原性菌株(菌株PCD1)を含む2種のクロストリジウム・ディフィシル菌株の存在下でin vitroで分析した。それらの菌株の増殖が阻止されると、接種領域の周りに青白い円が見られる。これは、接種円である。
1. 材料及び方法
1.1. 糞便の凍結乾燥物
健康な供与者からの4つの糞便を、実施例1に記載される方法により処理して、4種の糞便の凍結乾燥物:S4、S5、S6及びS7を得た。その際、S7は、実施例2と比べて追加的な糞便試料に相当する。
希釈剤
希釈剤の選択は、不活性な性質であること、そして特に特定の腸内効果が存在しないことに基づいている。
3種の流動性滑沢剤を選択した:タルク(Cooper社、フランス)、親水性コロイダルシリカ(Aerosil(商標)200 Pharma、Kraemer & Martin GmbH社、ドイツ、ザンクト−アウグスティン)、及び疎水性コロイダルシリカ(Aerosil(商標)R972、Degussa-Huls社、フランス、クールブヴォア)。
この試験は、欧州薬局方モノグラフ2.9.16に従って、まずは凍結乾燥物単独で行い、次いで0.5%で使用される流動性滑沢剤を入れた後に行い、そして必要に応じて、試験される希釈剤を75/25、50/50、及び25/75の重量比で入れた後に行った。これらの混合物は、手動で得られた。
0.95mLの大容量で比較的容易な摂取と両立可能なサイズ(23.3mm長)に関連して100番のカプセルを選択した。該カプセルに、カプセル充填剤及び良好な流動を特徴とする混合物を手動で充填した。
2.1. 凍結乾燥物の流動特性及び密度の研究
表1は、凍結乾燥物に対して実施した試験結果を示している。
表2は、各々の試料について製造されたカプセル剤の数、及び各々のカプセル中に組み込まれた凍結乾燥物の質量を示している。最初に実施された原物の理論質量は、最終列に報告される。
Claims (9)
- 凍結乾燥物の形で生態系のままの微生物叢を保存するための凍結保護物質の混合物の使用であって、
前記生態系のままの微生物叢は、糞便からなり、
前記凍結保護物質の混合物が、マルトデキストリン(M)及びトレハロース(T)を、35/65から45/55の間の範囲のM/T重量比で含むことを特徴とする、使用。 - 生態系のままの微生物叢と、凍結保護物質の混合物とを含む凍結乾燥された組成物であって、
前記生態系のままの微生物叢は、糞便からなり、
前記凍結保護物質の混合物は、35/65から45/55までの範囲のM/T重量比で使用されたマルトデキストリン及びトレハロースを含むことを特徴とする、凍結乾燥された組成物。 - (i)その糞便の重量割合が、凍結乾燥された組成物の15%〜35%に相当し、かつ凍結保護物質の混合物の重量割合が、凍結乾燥された組成物の85%〜65%に相当し、(ii)マルトデキストリン(M)及びトレハロース(T)が、40/60のM/T重量比で使用される、請求項2に記載の凍結乾燥された組成物。
- 請求項2又は3に記載の凍結乾燥された組成物を含む、胃液耐性カプセル剤。
- 前記凍結乾燥された組成物は、少なくとも1種の流動性賦形剤と混合されることを特徴とする、請求項4に記載の胃液耐性カプセル剤。
- ディスバイオシスを含む疾患又は障害の治療において使用するための、請求項2若しくは3に記載の凍結乾燥された組成物、又は請求項4若しくは5に記載の胃液耐性カプセル剤。
- 再発性クロストリジウム・ディフィシル感染症の場合の経口抗生物質治療のための代替として使用するための、請求項6に記載の凍結乾燥された組成物又は胃液耐性カプセル剤。
- 請求項4又は5に記載の胃液耐性カプセル剤の製造方法であって、
a. 糞便からなる生態系のままの微生物叢を採集する工程と、
b. 前記糞便からなる生態系のままの微生物叢を、マルトデキストリン及びトレハロースを35/65から45/65までの範囲のM/T重量比で含む凍結保護物質の混合物で希釈する工程と、
c. 工程bで得られた混合物を凍結乾燥する工程と、
d. 工程cにおいて得られた凍結乾燥物を噴霧して、粉体形にする工程と、
e. 任意に、該凍結乾燥物の流動を改善する1種以上の賦形剤を添加する工程と、
f. 胃液耐性カプセルの包被に、前記凍結乾燥された混合物を充填する工程と、
g. 該カプセルをシールする工程と、
を含む、方法。 - 前記凍結保護物質の混合物は、マルトデキストリン(M)及びトレハロース(T)の40/60のM/T重量比の混合物からなる、請求項8に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1562836A FR3045384B1 (fr) | 2015-12-18 | 2015-12-18 | Composition lyophilisee pour la conservation de microbiote dans son ecosysteme |
FR1562836 | 2015-12-18 | ||
PCT/EP2016/081603 WO2017103225A1 (fr) | 2015-12-18 | 2016-12-16 | Composition lyophilisee pour la conservation de microbiote dans son ecosysteme |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018537504A JP2018537504A (ja) | 2018-12-20 |
JP6946299B2 true JP6946299B2 (ja) | 2021-10-06 |
JP6946299B6 JP6946299B6 (ja) | 2021-11-17 |
Family
ID=55346090
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018531508A Active JP6946299B6 (ja) | 2015-12-18 | 2016-12-16 | 生態系のままの微生物叢を保存するために凍結乾燥された組成物 |
Country Status (14)
Country | Link |
---|---|
US (1) | US11110133B2 (ja) |
EP (1) | EP3389681B1 (ja) |
JP (1) | JP6946299B6 (ja) |
KR (1) | KR102445404B1 (ja) |
CN (1) | CN108472321B (ja) |
AU (1) | AU2016374580B2 (ja) |
CA (1) | CA3008315C (ja) |
DK (1) | DK3389681T3 (ja) |
ES (1) | ES2788646T3 (ja) |
FR (1) | FR3045384B1 (ja) |
HU (1) | HUE052404T2 (ja) |
IL (1) | IL260017B2 (ja) |
PT (1) | PT3389681T (ja) |
WO (1) | WO2017103225A1 (ja) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR3045383B1 (fr) * | 2015-12-18 | 2019-06-14 | Maat Pharma | Procede de lyophilisation d'un echantillon de microbiote fecal |
FR3067928B1 (fr) * | 2017-06-23 | 2020-02-28 | Fondation Mediterranee Infection | Procede de conservation d'un echantillon de bacteries |
CN110540941A (zh) * | 2019-07-16 | 2019-12-06 | 上海交通大学 | 一种从粪便中提取保存菌液的方法 |
WO2021076999A1 (en) * | 2019-10-18 | 2021-04-22 | Hubble Bioscience Inc. | Fecal-derived sterile postbiotic composition and method therefor |
EP3858363A1 (en) | 2020-01-28 | 2021-08-04 | Institut national de recherche pour l'agriculture, l'alimentation et l'environnement | Composition for treating intestinal or pulmonary diseases |
US11098377B1 (en) * | 2020-09-15 | 2021-08-24 | Nubiyota Llc | Systems and methods for characterizing compositions comprising bacterial populations |
CN113209039A (zh) * | 2021-04-22 | 2021-08-06 | 重庆晶云生物科技有限公司 | 一种肠菌胶囊及其制备方法 |
CN114181913A (zh) * | 2021-12-14 | 2022-03-15 | 厦门昶科生物工程有限公司 | 一种噬菌体冻干粉制剂及其生产方法 |
CN114404384A (zh) * | 2022-02-25 | 2022-04-29 | 北京富玛特生物科技有限公司 | 一种用于肠道菌群移植的口服胶囊及其制备方法 |
CN115404167A (zh) * | 2022-09-21 | 2022-11-29 | 上海承葛医药科技有限公司 | 一种适用于人体肠道菌群的冻存保护液 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007070052A2 (en) * | 2005-12-14 | 2007-06-21 | Oxthera, Inc. | Pharmaceutical compositions and methods for treating or preventing oxalate-related disease |
EP2104434A1 (en) * | 2006-09-19 | 2009-09-30 | Technion Research and Development Foundation Ltd. | Probiotic compositions and methods of making same |
EP3311825A1 (en) * | 2010-08-04 | 2018-04-25 | Thomas Julius Borody | Compositions for fecal floral transplantation and methods for making and using them |
WO2014152484A1 (en) * | 2013-03-14 | 2014-09-25 | Regents Of The University Of Minnesota | Freeze dried fecal microbiota for use in fecal microbial transplantation |
CN104244985A (zh) * | 2012-03-23 | 2014-12-24 | 先进生物营养公司 | 生物材料的稳定化组合物 |
FR3035328B1 (fr) | 2015-04-24 | 2019-08-23 | Maat Pharma | Procede de preparation d'un echantillon de microbiote fecal |
-
2015
- 2015-12-18 FR FR1562836A patent/FR3045384B1/fr active Active
-
2016
- 2016-12-16 US US16/062,302 patent/US11110133B2/en active Active
- 2016-12-16 CA CA3008315A patent/CA3008315C/fr active Active
- 2016-12-16 JP JP2018531508A patent/JP6946299B6/ja active Active
- 2016-12-16 DK DK16812752.0T patent/DK3389681T3/da active
- 2016-12-16 PT PT168127520T patent/PT3389681T/pt unknown
- 2016-12-16 KR KR1020187018184A patent/KR102445404B1/ko active IP Right Grant
- 2016-12-16 HU HUE16812752A patent/HUE052404T2/hu unknown
- 2016-12-16 EP EP16812752.0A patent/EP3389681B1/fr active Active
- 2016-12-16 AU AU2016374580A patent/AU2016374580B2/en active Active
- 2016-12-16 ES ES16812752T patent/ES2788646T3/es active Active
- 2016-12-16 WO PCT/EP2016/081603 patent/WO2017103225A1/fr active Application Filing
- 2016-12-16 CN CN201680073438.XA patent/CN108472321B/zh active Active
-
2018
- 2018-06-13 IL IL260017A patent/IL260017B2/en unknown
Also Published As
Publication number | Publication date |
---|---|
CA3008315C (fr) | 2022-09-13 |
FR3045384B1 (fr) | 2020-02-07 |
AU2016374580B2 (en) | 2023-06-08 |
HUE052404T2 (hu) | 2021-04-28 |
JP6946299B6 (ja) | 2021-11-17 |
FR3045384A1 (fr) | 2017-06-23 |
DK3389681T3 (da) | 2020-05-04 |
IL260017A (en) | 2018-07-31 |
ES2788646T3 (es) | 2020-10-22 |
US11110133B2 (en) | 2021-09-07 |
EP3389681B1 (fr) | 2020-02-05 |
CN108472321A (zh) | 2018-08-31 |
KR20180113981A (ko) | 2018-10-17 |
JP2018537504A (ja) | 2018-12-20 |
PT3389681T (pt) | 2020-05-08 |
WO2017103225A1 (fr) | 2017-06-22 |
KR102445404B1 (ko) | 2022-09-19 |
CN108472321B (zh) | 2022-04-15 |
US20190134110A1 (en) | 2019-05-09 |
EP3389681A1 (fr) | 2018-10-24 |
AU2016374580A1 (en) | 2018-07-19 |
IL260017B2 (en) | 2023-06-01 |
CA3008315A1 (fr) | 2017-06-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6946299B2 (ja) | 生態系のままの微生物叢を保存するために凍結乾燥された組成物 | |
JP6966591B2 (ja) | 便フローラを移植するための組成物、並びにそれを調製及び使用する方法、並びにそれを送達するためのデバイス | |
Tomás et al. | Encapsulation and subsequent freeze-drying of Lactobacillus reuteri CRL 1324 for its potential inclusion in vaginal probiotic formulations | |
AU2018272048B2 (en) | Lyophilized compositions comprising fecal microbe-based therapeutic agents and methods for making and using same | |
Wang et al. | Effects of a novel encapsulating technique on the temperature tolerance and anti-colitis activity of the probiotic bacterium Lactobacillus kefiranofaciens M1 | |
Torp et al. | Optimizing oral delivery of next generation probiotics | |
CN105008924B (zh) | 用于治疗和/或预防腹泻的益生菌菌株 | |
CN109789172A (zh) | 用于难辨梭菌治疗的组合物和方法 | |
Rakotonirina et al. | Fecal microbiota transplantation: a review on current formulations in Clostridioides difficile infection and future outlooks | |
RU2139070C1 (ru) | Способ получения аутопробиотика, содержащего живые бифидобактерии и лактобациллы | |
Popper et al. | Amoxicillin-clavulanic acid and ciprofloxacin-treated SPF mice as gnotobiotic model | |
RU2505304C2 (ru) | Способ получения аутопробиотика, содержащего живые бифидобактерии и лактобациллы | |
Di Pietro | Development of a protocol with concentrated bacteria for fecal microbiota transplantation and impact on the equine fecal microbiota after antibiotic-induced dysbiosis | |
Elebeedy et al. | The Healing Effect of Probiotics on Indomethacin Induced Gastric Ulcer in Rats | |
VOIDAROU | EDUCATION AND TITLES |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20191112 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20201208 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210304 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20210304 |
|
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: 20210831 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210915 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6946299 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R154 | Certificate of patent or utility model (reissue) |
Free format text: JAPANESE INTERMEDIATE CODE: R154 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313115 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |