TW202140051A - Solid dosage forms with improved disintegration profiles - Google Patents

Solid dosage forms with improved disintegration profiles Download PDF

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TW202140051A
TW202140051A TW110101737A TW110101737A TW202140051A TW 202140051 A TW202140051 A TW 202140051A TW 110101737 A TW110101737 A TW 110101737A TW 110101737 A TW110101737 A TW 110101737A TW 202140051 A TW202140051 A TW 202140051A
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bacteria
solid dosage
dosage form
total mass
mev
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TW110101737A
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賽易德 艾爾塔夫
陸建男
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美商艾弗洛生物科技股份有限公司
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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61P35/00—Antineoplastic 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

Abstract

Methods and compositions related to improved solid dosage forms that facilitate the oral delivery of bacteria or agents of bacterial origin are provided herein.

Description

具有改善的崩散譜之固體劑型Solid dosage form with improved disintegration spectrum

藥物產品的固體劑型的配方可能對其活性藥物成分的生體可用率產生重大影響。為改善生體可用率，可以在固體劑型中包括崩散劑。但是，有許多潛在崩散劑可供選擇，每種都有其自身特性。由於固體配製物崩散過程係複雜的且未被充分理解，因此任何特定的崩散劑促進特定固體劑型的崩散的有效性係不可預測的。結果，即使添加崩散劑，藥物產品的許多固體劑型的崩散速率仍保持緩慢，從而不利地影響活性成分的生體可用率。The formulation of the solid dosage form of a pharmaceutical product may have a significant impact on the bioavailability of its active pharmaceutical ingredients. In order to improve the bioavailability, disintegrating powder can be included in the solid dosage form. However, there are many potential disintegrating powders to choose from, each with its own characteristics. Since the disintegration process of solid formulations is complex and not fully understood, the effectiveness of any particular disintegrant to promote the disintegration of a particular solid dosage form is unpredictable. As a result, even if a disintegrant is added, the disintegration rate of many solid dosage forms of the drug product remains slow, thereby adversely affecting the bioavailability of the active ingredient.

本揭露部分地基於發現某些改善的固體劑型，該固體劑型促進細菌和細菌來源的試劑（例如組分）（例如，微生物胞外囊泡或mEV）之口服遞送。例如，在某些實施方式中，本文揭露的固體劑型包括崩散劑的某些組合和/或量，其導致組成物的崩散時間與常規的固體劑型（例如，包含常規量的崩散劑的固體劑型）相比減少（例如，2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍）。在某些實施方式中，與具有常規固體劑型的藥物產品相比，本文提供的固體劑型導致治療功效和/或生理作用的增加。The present disclosure is based in part on the discovery of certain improved solid dosage forms that facilitate the oral delivery of bacteria and bacteria-derived agents (such as components) (eg, microbial extracellular vesicles or mEV). For example, in certain embodiments, the solid dosage forms disclosed herein include certain combinations and/or amounts of disintegrating agents, which result in the composition’s disintegration time being comparable to conventional solid dosage forms (e.g., solids containing conventional amounts of disintegrating agents). Dosage form) compared to reduce (for example, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times). In certain embodiments, the solid dosage forms provided herein result in increased therapeutic efficacy and/or physiological effects compared to pharmaceutical products having conventional solid dosage forms.

在某些方面，本文提供了藥物組成物的固體劑型。在某些實施方式中，固體劑型包含藥劑（例如細菌和/或細菌來源的試劑（例如mEV），包含細菌和/或細菌來源的試劑（例如mEV）的粉末）和一種或多種崩散劑（例如，一種、兩種或三種崩散劑）。在某些實施方式中，固體劑型包含藥劑（例如細菌和/或細菌來源的試劑（例如mEV），包含細菌和/或細菌來源的試劑（例如mEV）的粉末）和三種崩散劑。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%或25%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的45%、40%、35%、30%或25%。在一些實施方式中，一種或多種崩散劑的總質量係藥物組成物總質量的至少30%、至少35%、至少40%、至少45%或至少50%。在一些實施方式中，一種或多種崩散劑的總質量不超過藥物組成物總質量的70%、65%、60%或55%。在一些實施方式中，一種或多種崩散劑包括低取代的羥丙基纖維素（L-HPC，例如LH-B1）、交聯羧甲基纖維素鈉（例如，Ac-Di-Sol、Ac-Di-Sol SD-711）、和/或交聚維酮（PVPP，例如科利當（Kollidon），例如科利當CL-F）。In certain aspects, solid dosage forms of pharmaceutical compositions are provided herein. In some embodiments, the solid dosage form contains a pharmaceutical agent (such as bacteria and/or bacteria-derived reagents (such as mEV), powders containing bacteria and/or bacterial-derived reagents (such as mEV)) and one or more disintegrating agents (such as , One, two or three disintegrating powders). In some embodiments, the solid dosage form includes an agent (for example, a bacterial and/or bacterial-derived agent (for example, mEV), a powder including a bacterial and/or bacterial-derived agent (for example, mEV)) and three disintegrating agents. In some embodiments, the total mass of the drug is at least 5%, 10%, 15%, 20%, or 25% of the total mass of the drug composition. In some embodiments, the total mass of the medicament does not exceed 45%, 40%, 35%, 30%, or 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrants is at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrating powders does not exceed 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition. In some embodiments, one or more disintegrants include low-substituted hydroxypropyl cellulose (L-HPC, for example LH-B1), croscarmellose sodium (for example, Ac-Di-Sol, Ac- Di-Sol SD-711), and/or crospovidone (PVPP, such as Kollidon, such as Kollidon CL-F).

在某些實施方式中，本文提供的固體劑型包含L-HPC。在一些實施方式中，L-HPC係LH-B1級。在某些實施方式中，L-HPC總質量係藥物組成物總質量的至少22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量不超過藥物組成物總質量的22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量係藥物組成物總質量的約22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量係藥物組成物總質量的約29%至約35%。在某些實施方式中，L-HPC（LH-B1）總質量係藥物組成物總質量的約32%。In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is LH-B1 grade. In some embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC is about 29% to about 35% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of L-HPC (LH-B1) is about 32% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）。在一些實施方式中，Ac-Di-Sol係SD-711級。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量不超過藥物組成物總質量的1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的約1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的約3%至約9%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol、Ac-Di-Sol SD-711）總質量係藥物組成物總質量的約6%。In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, Ac-Di-Sol). In some embodiments, Ac-Di-Sol is grade SD-711. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4% of the total mass of the pharmaceutical composition. %, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is about 3% to about 9% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol, Ac-Di-Sol SD-711) is about 6% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聚維酮（PVPP，例如，科利當，例如，科利當CL-F）。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聯維酮總質量係藥物組成物總質量的約12%至約18%。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的約15%。In certain embodiments, the solid dosage forms provided herein comprise crospovidone (PVPP, for example, Coledon, for example, Coledon CL-F). In some embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crosvidone is about 12% to about 18% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition.

在一些實施方式中，本文提供的固體劑型包含：(i) 藥劑，其具有的藥劑總質量係藥物組成物總質量的至少5%且不超過藥物組成物總質量的35%，(ii) L-HPC（例如，LH-B1級的L-HPC），其具有的L-HPC總質量係藥物組成物總質量的至少22%（例如，至少22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、或42%）且不超過藥物組成物總質量的42%（例如，不超過22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、或42%）；(iii) 交聯羧甲基纖維素鈉（例如，Ac-Di-Sol，SD-711級的Ac-Di-Sol），其具有的交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的至少0.01%（例如，至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、或16%）且不超過藥物組成物總質量的16%（例如，不超過1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、或16%）；以及 (iv) 交聚維酮，其具有的交聚維酮總質量係藥物組成物總質量的至少5%（例如，至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）且不超過藥物組成物總質量的25%（例如，不超過5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）。在某些實施方式中，L-HPC總質量加上交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量加上交聚維酮總質量係藥物組成物總質量的至少35%、40%、45%或50%。在一些實施方式中，固體劑型包含：L-HPC總質量係藥物組成物總質量的約32%；交聯羧甲基纖維素鈉（例如Ac-Di-Sol）總質量係藥物組成物總質量的約6%；交聚維酮總質量係藥物組成物總質量的約15%。In some embodiments, the solid dosage form provided herein includes: (i) a medicament, the total mass of which is at least 5% of the total mass of the pharmaceutical composition and no more than 35% of the total mass of the pharmaceutical composition, (ii) L -HPC (for example, L-HPC of LH-B1 level), which has a total mass of L-HPC that is at least 22% (for example, at least 22%, 23%, 24%, 25%, 26%) of the total mass of the pharmaceutical composition %, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% ) And not more than 42% of the total mass of the pharmaceutical composition (for example, not more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%); (iii) croscarmellose sodium (for example, Ac-Di- Sol, SD-711 grade Ac-Di-Sol), the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is at least 0.01% of the total mass of the pharmaceutical composition (for example, at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% , Or 16%) and not more than 16% of the total mass of the pharmaceutical composition (for example, not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% , 11%, 12%, 13%, 14%, 15%, or 16%); and (iv) crospovidone, which has a total mass of crospovidone that is at least 5% of the total mass of the pharmaceutical composition ( For example, at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% , 21%, 22%, 23%, 24%, or 25%) and not more than 25% of the total mass of the pharmaceutical composition (for example, not more than 5%, 6%, 7%, 8%, 9%, 10% , 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In some embodiments, the total mass of L-HPC plus the total mass of croscarmellose sodium (for example, Ac-Di-Sol) plus the total mass of crospovidone is at least 35 percent of the total mass of the pharmaceutical composition. %, 40%, 45% or 50%. In some embodiments, the solid dosage form comprises: the total mass of L-HPC is about 32% of the total mass of the pharmaceutical composition; the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is the total mass of the pharmaceutical composition The total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型還包含甘露醇。在一些實施方式中，甘露醇係甘露醇SD200。在某些實施方式中，甘露醇總質量係藥物組成物總質量的至少10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，甘露醇總質量不超過藥物組成物總質量的10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%或40%。在某些實施方式中，甘露醇總質量係藥物組成物總質量的約10%、11%、12%、13%、14%、15%、15.5%、16%、16.5%、17%、17.5%、18%、18.5%、19%、19.5%、20%、20.5%、21%、21.5%、22%、22.5%、23%、23.5%、24%、24.5%、25%、25.5%、26%、26.5%、27%、27.5%、28%、28.5%、29%、29.5%、30%、30.5%、31%、31.5%、32%、32.5%、33%、33.5%、34%、34.5%、35%、35.5%、36%、36.5%、37%、37.5%、38%、38.5%、39%、39.5%或40%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約17%至約23%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約20%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約19.5%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約32%至約40%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約36.5%。In certain embodiments, the solid dosage forms provided herein further comprise mannitol. In some embodiments, the mannitol is mannitol SD200. In some embodiments, the total mass of mannitol is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% of the total mass of the pharmaceutical composition. %, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of mannitol does not exceed 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% of the total mass of the pharmaceutical composition. %, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40%. In some embodiments, the total mass of mannitol is about 10%, 11%, 12%, 13%, 14%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5 of the total mass of the pharmaceutical composition. %, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34% , 34.5%, 35%, 35.5%, 36%, 36.5%, 37%, 37.5%, 38%, 38.5%, 39%, 39.5% or 40%. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 17% to about 23% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 20% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 19.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 32% to about 40% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 36.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含硬脂酸鎂。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約0.01%、0.1%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、10%或11%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1.5%。In certain embodiments, the solid dosage forms provided herein comprise magnesium stearate. In some embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition. , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In some embodiments, the total mass of magnesium stearate is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含膠體二氧化矽（colloidal silica）（也稱為膠體二氧化矽（colloidal silicon dioxide））。在一些實施方式中，膠體二氧化矽係Aerosil 200。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，總膠體二氧化矽質量係藥物組成物總質量的約0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，膠體二氧化矽（例如Aerosil 200）總質量係藥物組成物總質量的約1%。In certain embodiments, the solid dosage forms provided herein comprise colloidal silica (also known as colloidal silicon dioxide). In some embodiments, the colloidal silica is Aerosil 200. In some embodiments, the total mass of colloidal silica is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition. , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition. , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of colloidal silica (such as Aerosil 200) is about 1% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約20%甘露醇（例如甘露醇SD200）；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮（例如PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200）。In certain embodiments, the solid dosage form provided herein contains about 25% of the agent (for example, powder containing bacteria and/or agents of bacterial origin (for example, mEV)); about 20% of mannitol (for example, mannitol SD200); about 32% % L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone (such as PVPP); about 1% magnesium stearate; and about 1% colloidal silica (such as Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約8%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約36.5%甘露醇；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage form provided herein contains about 8% pharmaceutical agent (e.g., powder containing bacteria and/or bacteria-derived agent (e.g. mEV)); about 36.5% mannitol; about 32% L-HPC (e.g. L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone; about 1.5% magnesium stearate; and about 1 % Colloidal silica (such as Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約19.5%甘露醇；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage form provided herein contains about 25% pharmaceutical agent (e.g., powder containing bacteria and/or bacteria-derived agents (e.g. mEV)); about 19.5% mannitol; about 32% L-HPC (e.g. L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone; about 1.5% magnesium stearate; and about 1 % Colloidal silica (such as Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約19.5%甘露醇（例如甘露醇SD200）；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮（例如PVPP）；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200）。In certain embodiments, the solid dosage form provided herein contains about 25% of the medicament (for example, powder containing bacteria and/or agents of bacterial origin (for example, mEV)); about 19.5% of mannitol (for example, mannitol SD200); about 32 % L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone (such as PVPP); about 1.5% magnesium stearate; and about 1% colloidal silica (such as Aerosil 200).

在某些實施方式中，本文描述的藥劑的固體劑型包括片劑和微型片劑。在一些實施方式中，固體劑型被腸溶包衣（例如，包括腸溶衣；例如，被腸溶衣包衣）。用一層腸溶衣或兩層腸溶衣（例如，內部腸溶衣和外部腸溶衣）包衣片劑或微型片劑。可以將腸溶包衣的微型片劑（具有一層腸溶衣或具有兩層腸溶衣（例如，內部腸溶衣和外部腸溶衣））裝入膠囊中；例如，膠囊不被腸溶包衣。In certain embodiments, the solid dosage forms of the agents described herein include tablets and microtablets. In some embodiments, the solid dosage form is enteric coated (eg, includes an enteric coating; for example, is coated with an enteric coating). Coat the tablets or mini-tablets with one enteric coating or two enteric coatings (for example, an inner enteric coating and an outer enteric coating). Enteric-coated mini-tablets (with one enteric coating or with two enteric coatings (for example, an inner enteric coating and an outer enteric coating)) can be filled into capsules; for example, the capsules are not enteric-coated Clothes.

在一些實施方式中，固體劑型包含片劑。在一些實施方式中，片劑（例如，腸溶包衣片劑）係5 mm、5.5 mm、6 mm、6.5 mm、7 mm、7.5 mm、8 mm、8.5 mm、9 mm、9.5 mm、10 mm、11 mm、12 mm、13 mm、14 mm、15 mm、16 mm、17 mm、或18 mm片劑。In some embodiments, the solid dosage form comprises a tablet. In some embodiments, the tablets (eg, enteric coated tablets) are 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablets.

在一些實施方式中，固體劑型包括微型片劑。在一些實施方式中，微型片劑（例如，腸溶包衣微型片劑）係1 mm微型片劑、1.5 mm微型片劑、2 mm微型片劑、3 mm微型片劑或4 mm微型片劑。在一些實施方式中，在膠囊中包含多個腸溶包衣微型片劑（例如0號膠囊可以包含約31至約35（例如33）個微型片劑，其中微型片劑的尺寸為3 mm）。在一些實施方式中，膠囊係00號、0號、1號、2號、3號、4號或5號膠囊。在一些實施方式中，膠囊包含HPMC（羥丙基甲基纖維素）或明膠。In some embodiments, the solid dosage form includes microtablets. In some embodiments, the microtablets (eg, enteric coated microtablets) are 1 mm microtablets, 1.5 mm microtablets, 2 mm microtablets, 3 mm microtablets, or 4 mm microtablets . In some embodiments, a plurality of enteric-coated micro-tablets are included in the capsule (for example, a size 0 capsule may contain about 31 to about 35 (for example, 33) micro-tablets, where the size of the micro-tablets is 3 mm) . In some embodiments, the capsules are No. 00, No. 0, No. 1, No. 2, No. 3, No. 4, or No. 5 capsules. In some embodiments, the capsule contains HPMC (hydroxypropyl methylcellulose) or gelatin.

在一些實施方式中，腸溶衣包含一層腸溶衣。In some embodiments, the enteric coating comprises an enteric coating.

在一些實施方式中，腸溶衣包括內部腸溶衣和外部腸溶衣。在一些實施方式中，腸溶衣包含內部腸溶衣和外部腸溶衣，並且其中內部和外部腸溶衣不相同（例如，內部和外部腸溶衣不包含相同量的相同組分）。In some embodiments, the enteric coating includes an inner enteric coating and an outer enteric coating. In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not the same (eg, the inner and outer enteric coatings do not contain the same components in the same amount).

在一些實施方式中，腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包含基於聚甲基丙烯酸酯的共聚物。In some embodiments, the enteric coating (eg, a layer of enteric coating or inner enteric coating and/or outer enteric coating) comprises a polymethacrylate-based copolymer.

在一些實施方式中，腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包含甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1 : 1）。In some embodiments, the enteric coating (eg, a layer of enteric coating or inner enteric coating and/or outer enteric coating) comprises ethyl methacrylate acrylate (MAE) copolymer (1:1).

在一些實施方式中，層腸溶衣包含甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1 : 1）（例如Kollicoat MAE 100P）。In some embodiments, the layer enteric coating comprises ethyl methacrylate acrylate (MAE) copolymer (1:1) (eg Kollicoat MAE 100P).

在一些實施方式中，層腸溶衣包含尤特奇（Eudragit）共聚物，例如尤特奇L（例如尤特奇L 100-55；尤特奇L 30 D-55）、尤特奇S、尤特奇RL、尤特奇RS、尤特奇E、或尤特奇FS（例如尤特奇FS 30 D）。In some embodiments, the layer enteric coating comprises Eudragit copolymers, such as Eudragit L (eg Eudragit L 100-55; Eudragit L 30 D-55), Eudragit S, Youtech RL, Youtech RS, Youtech E, or Youtech FS (for example, Youtech FS 30 D).

在一些實施方式中，腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包括鄰苯二甲酸乙酸纖維素（CAP）、偏苯三酸乙酸纖維素（CAT）、聚醋酸乙烯鄰苯二甲酸酯（PVAP）、羥丙基甲基纖維素鄰苯二甲酸酯（HPMCP）、脂肪酸、蠟、蟲膠（紫膠桐酸的酯）、塑膠、植物纖維、玉米醇溶蛋白、Aqua-Zein（不含醇的水性玉米醇溶蛋白配製物）、直鏈澱粉、澱粉衍生物、糊精、丙烯酸甲酯-甲基丙烯酸共聚物、醋酸琥珀酸纖維素、羥丙基甲基醋酸琥珀酸纖維素（醋酸羥丙甲纖維素琥珀酸酯）、甲基丙烯酸甲酯-甲基丙烯酸共聚物、或海藻酸鈉。In some embodiments, the enteric coating (eg, a layer of enteric coating or inner enteric coating and/or outer enteric coating) includes cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT ), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (ester of lactoic acid), plastics, plants Fiber, Zein, Aqua-Zein (aqueous zein formulation without alcohol), amylose, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate , Hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

在一些實施方式中，腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包含陰離子聚合物材料。In some embodiments, the enteric coating (eg, a layer of enteric coating or an inner enteric coating and/or an outer enteric coating) comprises an anionic polymer material.

在一些實施方式中，固體劑型例如除了腸溶衣之外還包含底衣，例如，底衣在腸溶衣下面（例如，在固體劑型和腸溶衣之間）。在一些實施方式中，底衣包含歐巴代QX，例如歐巴代QX藍。In some embodiments, the solid dosage form, for example, includes a subcoating in addition to the enteric coating, for example, the subcoating is under the enteric coating (eg, between the solid dosage form and the enteric coating). In some embodiments, the undercoat comprises Opadry QX, such as Opadry QX Blue.

藥劑可以是細菌來源的（例如，所選菌株或其試劑（組分）的混合物，例如所選菌株的混合物的微生物胞外囊泡（mEV））。藥劑可以是細菌來源的（例如，單個所選菌株和/或其試劑（組分），例如該單個所選菌株的微生物胞外囊泡（mEV））。藥劑可以是粉末，粉末包含細菌和/或其組分，並且可以包含另外藥劑，例如冷凍保護劑。例如，在一些實施方式中，藥劑係細菌和/或其組分（例如，mEV）的凍乾粉末，凍乾粉末視需要還包含另外的藥劑，例如冷凍保護劑。The agent may be of bacterial origin (for example, a mixture of selected strains or agents (components) thereof, such as microbial extracellular vesicles (mEV) of a mixture of selected strains). The agent may be of bacterial origin (eg, a single selected strain and/or reagents (components) thereof, such as microbial extracellular vesicles (mEV) of the single selected strain). The medicament may be a powder, which contains bacteria and/or components thereof, and may contain another medicament, such as a cryoprotectant. For example, in some embodiments, the medicament is a lyophilized powder of bacteria and/or its components (for example, mEV), and the lyophilized powder may further contain another medicament, such as a cryoprotectant, if necessary.

在一些實施方式中，藥劑包含細菌。In some embodiments, the medicament comprises bacteria.

在一些實施方式中，藥劑包含微生物胞外囊泡（mEV）。In some embodiments, the agent comprises microbial extracellular vesicles (mEV).

在一些實施方式中，藥劑包含細菌和微生物胞外囊泡（mEV）。In some embodiments, the agent comprises bacteria and microbial extracellular vesicles (mEV).

在一些實施方式中，例如當口服投與固體劑型時，藥劑在胃腸道外具有一種或多種有益的免疫作用。In some embodiments, such as when a solid dosage form is administered orally, the agent has one or more beneficial immune effects outside the gastrointestinal tract.

在一些實施方式中，例如當口服投與固體劑型時，藥劑調節受試者的胃腸道外的免疫作用。In some embodiments, such as when a solid dosage form is administered orally, the agent modulates the subject's immune function outside the gastrointestinal tract.

在一些實施方式中，例如當口服投與固體劑型時，藥劑引起系統性作用（例如，胃腸道外的作用）。In some embodiments, such as when a solid dosage form is administered orally, the agent causes a systemic effect (e.g., an effect outside the gastrointestinal tract).

在一些實施方式中，例如當口服投與固體劑型時，藥劑對小腸中的免疫細胞和/或上皮細胞起作用（例如引起系統性作用（例如，胃腸道外的作用））。In some embodiments, such as when a solid dosage form is administered orally, the agent acts on immune cells and/or epithelial cells in the small intestine (eg, causes a systemic effect (eg, an effect outside the gastrointestinal tract)).

在一些實施方式中，藥劑包含分離的細菌（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量））。例如，其中藥劑的至少50%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%的含量係分離的細菌（例如目的細菌）。In some embodiments, the medicament comprises isolated bacteria (eg, from one or more bacterial strains (eg, bacteria of interest) (eg, a therapeutically effective amount thereof)). For example, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the agent is isolated bacteria (for example, bacteria of interest).

在一些實施方式中，藥劑包含細菌，並且該等細菌已經經γ照射、UV照射、熱滅活、酸處理或氧噴射。In some embodiments, the medicament contains bacteria, and the bacteria have been gamma-irradiated, UV-irradiated, heat-inactivated, acid-treated, or oxygen sprayed.

在一些實施方式中，藥劑包含活細菌。In some embodiments, the medicament comprises live bacteria.

在一些實施方式中，藥劑包含死細菌。In some embodiments, the medicament contains dead bacteria.

在一些實施方式中，藥劑包含非複製型細菌。In some embodiments, the agent comprises non-replicating bacteria.

在一些實施方式中，藥劑包含來自一種細菌菌株的細菌。In some embodiments, the medicament comprises bacteria from a bacterial strain.

在一些實施方式中，細菌被凍乾（例如，凍乾的產物還包含藥學上可接受的賦形劑）（例如，粉末形式）。In some embodiments, the bacteria are lyophilized (eg, the lyophilized product also contains pharmaceutically acceptable excipients) (eg, in powder form).

在一些實施方式中，細菌經γ照射。In some embodiments, the bacteria are gamma-irradiated.

在一些實施方式中，細菌經UV照射。In some embodiments, the bacteria are irradiated with UV.

在一些實施方式中，細菌經熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。In some embodiments, the bacteria are heat-inactivated (eg, two hours at 50°C or two hours at 90°C).

在一些實施方式中，細菌經酸處理。In some embodiments, the bacteria are acid-treated.

在一些實施方式中，細菌經氧噴射（例如，以0.1 vvm持續兩小時）。In some embodiments, the bacteria are sprayed with oxygen (for example, at 0.1 vvm for two hours).

在一些實施方式中，細菌來自革蘭氏陽性細菌。In some embodiments, the bacteria are derived from Gram-positive bacteria.

在一些實施方式中，細菌來自革蘭氏陰性細菌。In some embodiments, the bacteria are from Gram-negative bacteria.

在一些實施方式中，細菌係需氧細菌。In some embodiments, the bacteria are aerobic bacteria.

在一些實施方式中，細菌係厭氧細菌。在一些實施方式中，厭氧細菌包含專性厭氧菌。在一些實施方式中，厭氧細菌包含兼性厭氧菌。In some embodiments, the bacteria are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

在一些實施方式中，細菌係嗜酸細菌。In some embodiments, the bacteria are acidophilic bacteria.

在一些實施方式中，細菌係嗜鹼細菌。In some embodiments, the bacteria are alkaliphilic bacteria.

在一些實施方式中，細菌係嗜中性細菌。In some embodiments, the bacteria are neutrophils.

在一些實施方式中，細菌係難養細菌。In some embodiments, the bacteria are refractory bacteria.

在一些實施方式中，細菌係非難養細菌。In some embodiments, the bacteria are non-difficult bacteria.

在一些實施方式中，細菌屬於表1、表2或表3中列出的分類學組（例如，綱、目、科、屬、種或菌株）。In some embodiments, the bacteria belong to the taxonomic groups listed in Table 1, Table 2, or Table 3 (eg, class, order, family, genus, species, or strain).

在一些實施方式中，細菌係表1、表2或表3中列出的細菌菌株。In some embodiments, the bacteria are strains listed in Table 1, Table 2, or Table 3.

在一些實施方式中，細菌屬於表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）。In some embodiments, the bacteria belong to the taxonomic groups listed in Table J (eg, class, order, family, genus, species, or strain).

在一些實施方式中，細菌係表J中列出的細菌菌株。In some embodiments, the bacteria are the bacterial strains listed in Table J.

在一些實施方式中，革蘭氏陰性細菌屬於Negativicutes 綱。In some embodiments, the gram-negative bacteria belong to the class Negativicutes.

在一些實施方式中，革蘭氏陰性細菌屬於韋榮氏球菌科（Veillonellaceae ）、月形單胞菌科（Selenomonadaceae ）、胺基酸球菌科（Acidaminococcaceae ）或Sporomusaceae 科。In some embodiments, the Gram-negative bacteria belonging Veillonellaceae (Veillonellaceae), Aeromonas Tsukigata Section (Selenomonadaceae), amino acid cocci families (Acidaminococcaceae) or Sporomusaceae Section.

在一些實施方式中，細菌屬於巨型球菌屬（Megasphaera ）、 月形單胞菌科屬（Selenomonas ）、 Propionospora 屬、 或胺基酸球菌屬（Acidaminococcus ）。In some embodiments, the bacteria belong to the genus Megasphaera , Selenomonas , Propionospora , or Acidaminococcus .

在一些實施方式中，細菌係巨型球菌屬物種（Megasphaera sp. ）、菲利克斯月形單胞菌（Selenomonas felix ）、腸胺基酸球菌（Acidaminococcus intestine ）、或Propionospora 屬物種細菌。In some embodiments, the bacteria are Megasphaera sp. , Selenomonas felix , Acidaminococcus intestine , or Propionospora .

在一些實施方式中，細菌屬於乳球菌屬、普雷沃菌屬、雙歧桿菌屬、或韋榮氏球菌屬。In some embodiments, the bacteria belong to the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

在一些實施方式中，細菌係乳酸乳球菌乳脂亞種細菌。In some embodiments, the bacteria is Lactococcus lactis subsp. crema bacteria.

在一些實施方式中，細菌係棲組織普雷沃菌（Prevotella histicola ）細菌。In some embodiments, the bacteria are Prevotella histicola bacteria.

在一些實施方式中，細菌係動物雙歧桿菌細菌。In some embodiments, the bacteria are Bifidobacterium animalis bacteria.

在一些實施方式中，細菌係小韋榮氏球菌（Veillonella parvula ）細菌。In some embodiments, the bacteria are Veillonella parvula bacteria.

在一些實施方式中，細菌係乳酸乳球菌乳脂亞種細菌。在一些實施方式中，乳酸乳球菌乳脂亞種細菌係與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列具有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，乳球菌屬細菌係與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，乳球菌屬細菌係乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）。In some embodiments, the bacteria is Lactococcus lactis subsp. crema bacteria. In some embodiments, the nucleotide sequence of the Lactococcus lactis subsp. crema strain A (ATCC designation number PTA-125368) has at least 90% (or at least 97%) genome, 16S and / Or strains with CRISPR sequence identity. In some embodiments, the Lactococcus bacterial strain has at least 99% genome, 16S, and/or CRISPR sequence identity to the nucleotide sequence of Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacterium is Lactococcus lactis subsp. crema strain A (ATCC designation number PTA-125368).

在一些實施方式中，細菌係普雷沃菌屬細菌。在一些實施方式中，普雷沃菌屬細菌係包含與普雷沃菌屬菌株B 50329（NRRL登錄號B 50329）的核苷酸序列具有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，普雷沃菌屬細菌係包含與普雷沃菌屬菌株B 50329（NRRL登錄號B 50329）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，普雷沃菌屬細菌來自普雷沃菌屬菌株B 50329（NRRL登錄號B 50329）。In some embodiments, the bacteria are of the genus Prevotella. In some embodiments, the Prevotella bacterial strain contains at least 90% (or at least 97%) genome, 16S, and/or the nucleotide sequence of Prevotella strain B 50329 (NRRL accession number B 50329). Or strains with CRISPR sequence identity. In some embodiments, the Prevotella bacterial strain comprises a nucleotide sequence that has at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of Prevotella strain B 50329 (NRRL accession number B 50329) Strains. In some embodiments, the Prevotella bacteria are from Prevotella strain B 50329 (NRRL accession number B 50329).

在一些實施方式中，細菌係雙歧桿菌屬細菌。在一些實施方式中，雙歧桿菌屬細菌來自與雙歧桿菌屬細菌（保藏為ATCC指定編號PTA-125097）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，雙歧桿菌屬細菌係與以ATCC指定編號PTA-125097保藏的雙歧桿菌屬細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，雙歧桿菌屬細菌係以ATCC指定編號PTA-125097保藏的雙歧桿菌屬細菌。In some embodiments, the bacteria are bacteria of the genus Bifidobacterium. In some embodiments, the bacterium of the genus Bifidobacterium is derived from a bacterium of the genus Bifidobacterium (deposited as ATCC designated number PTA-125097) with a nucleotide sequence that has at least 90% or at least 97% genome, 16S, and/or CRISPR sequence identity Sexual strains. In some embodiments, the Bifidobacterium strain has at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacterium deposited under the ATCC designation number PTA-125097. In some embodiments, the bacteria of the genus Bifidobacterium are bacteria of the genus Bifidobacterium deposited under the ATCC designation number PTA-125097.

在一些實施方式中，細菌係韋榮氏球菌屬細菌。在一些實施方式中，韋榮氏球菌屬細菌係與以ATCC指定編號PTA-125691保藏的韋榮氏球菌屬細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，韋榮氏球菌屬細菌係與以ATCC指定編號PTA-125691保藏的韋榮氏球菌屬細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，韋榮氏球菌屬細菌係以ATCC指定編號PTA-125691保藏的韋榮氏球菌屬細菌。In some embodiments, the bacterium is a bacterium of the genus Veillonella. In some embodiments, the Veillonella bacterium strain has at least 90% (or at least 97%) genome, 16S and/or nucleotide sequence of the Veillonella bacterium deposited under the ATCC designation number PTA-125691 Strains with CRISPR sequence identity. In some embodiments, the Veillonella bacterium is a strain that has at least 99% genome, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacterium deposited under the ATCC designation number PTA-125691 . In some embodiments, the bacterium of the genus Veillonella is a bacterium of the genus Veillonella deposited under the ATCC designation number PTA-125691.

在一些實施方式中，細菌來自活潑瘤胃球菌細菌。在一些實施方式中，活潑瘤胃球菌細菌係與以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，活潑瘤胃球菌細菌係與以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，活潑瘤胃球菌細菌係以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌。In some embodiments, the bacteria are from active Rumenococcus bacteria. In some embodiments, the active Rumenococcus bacterial strain has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the active Rumenococcus bacteria deposited under ATCC designation number PTA-126695 Strains. In some embodiments, the active Rumenococcus bacteria are strains that have at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the active Rumenococcus bacteria deposited under the ATCC designation number PTA-126695. In some embodiments, the active rumen cocci bacteria are the active rumen cocci bacteria deposited under the ATCC designation number PTA-126695.

在一些實施方式中，細菌係巨型球菌屬物種細菌。在一些實施方式中，巨型球菌屬物種細菌係與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，巨型球菌屬物種細菌係與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，巨型球菌屬物種細菌係以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌。In some embodiments, the bacteria are Megacoccus species bacteria. In some embodiments, the nucleotide sequence of the Megacoccus species bacterium line and the Megacoccus species bacterium deposited under the ATCC designation number PTA-126770 has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence Strains of identity. In some embodiments, the Megacoccus bacterium is a strain that has at least 99% genome, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Megacoccus bacterium deposited under the ATCC designation number PTA-126770. In some embodiments, the Megacoccus species bacteria are deposited under the ATCC designation number PTA-126770.

在一些實施方式中，細菌係Fournierella massiliensis 細菌。在一些實施方式中，Fournierella massiliensis 細菌係與以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Fournierella massiliensis 細菌係與以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Fournierella massiliensis 細菌係以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌。In some embodiments, the bacteria are Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacterial strain has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under the ATCC designation number PTA-126696 . In some embodiments, the Fournierella massiliensis bacterial strain has at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under the ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited under the ATCC designation number PTA-126696.

在一些實施方式中，細菌係Harryflintia acetispora 細菌。在一些實施方式中，Harryflintia acetispora 細菌係與以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Harryflintia acetispora 細菌係與以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Harryflintia acetispora 細菌係以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌。In some embodiments, the bacteria are Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacterial strain has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of Harryflintia acetispora deposited under the ATCC designation number PTA-126694 . In some embodiments, the Harryflintia acetispora bacterial strain has at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited under the ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited under the ATCC designation number PTA-126694.

在一些實施方式中，細菌屬於胺基酸球菌科、產鹼桿菌科、阿克曼氏菌科、擬桿菌科、雙歧桿菌科、伯克霍爾德菌科、Catabacteriaceae 科、梭菌科、紅蝽菌科、腸桿菌科、腸球菌科、梭桿菌科、毛螺菌科、李斯特菌科、分枝桿菌科、奈瑟菌科、臭桿菌科、顫螺旋菌科、消化球菌科、消化鏈球菌科、卟啉單胞菌科、普雷沃菌科、丙酸桿菌科、理研菌科、瘤胃球菌科、月形單胞菌科、Sporomusaceae 科、鏈球菌科、鏈黴菌科、薩特氏菌科、互養菌科、或韋榮氏球菌科。In some embodiments, the bacteria belong to the Acidococcus family, Alcaligenes family, Akkermaniaceae, Bacteroidesceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae family, Clostridiaceae, Rhodobacteraceae, Enterobacteriaceae, Enterococcus, Fusobacteria, Lacetospiraceae, Listeriaceae, Mycobacteriaceae, Neisseriaceae, Binobacteriaceae, Oscillatoriaceae, Peptococcus, Peptostreptococcaceae, Porphyromonasaceae, Prevotaceae , Propionibacteriaceae, Rikenbacteriaceae, Rumenococcus, Lunamonasaceae, Sporomusaceae, Streptococcus, Streptomyces, Saccharomyces Tertiellaceae, Syntrophicaceae, or Veillonellaceae.

在一些實施方式中，細菌屬於阿克曼氏菌屬、克裡斯滕森菌屬、布勞特氏菌屬、腸球菌屬、真桿菌屬、羅斯氏菌屬、擬桿菌屬、副擬桿菌屬、或丹毒絲梭菌屬。In some embodiments, the bacteria belong to the genus Akkermansia, Christensenella, Blauterella, Enterococcus, Eubacterium, Rothella, Bacteroides, Parabacteroides , Or Clostridium erysipelas.

在一些實施方式中，細菌係產氫營養型布勞特氏菌、排泄物布勞特氏菌、韋氏布勞特氏菌、糞真桿菌、扭曲真桿菌、直腸真桿菌、糞腸球菌、耐久腸球菌、絨毛腸球菌、鶉雞腸球菌；乳酸雙歧桿菌、兩歧雙歧桿菌、長雙歧桿菌、動物雙歧桿菌或短雙歧桿菌細菌。In some embodiments, the bacteria are hydrogen-producing trophic Blautella, Blautella feces, Blautella weinii, Eubacterium faecalis, Eubacterium twister, Eubacterium rectum, Enterococcus faecalis, Enterococcus durable, Enterococcus villus, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium animalis or Bifidobacterium breve bacteria.

在一些實施方式中，細菌係BCG（卡介苗）、副擬桿菌屬、布勞特氏菌屬、韋榮氏球菌屬、唾液乳桿菌、阿加薩桿菌屬（Agathobaculum ）、活潑瘤胃球菌、解苯副梭菌、Turicibacter sanguinus 、伯克霍爾德菌屬、類肺炎克雷伯氏菌擬肺炎亞種、催產克雷伯氏菌、納西利斯泰澤菌（Tyzerella nexilis ）或奈瑟菌屬細菌。In some embodiments, the bacteria are BCG (Bacille Calmette-Guerin), Parabacteroides, Blauterella, Veillonella, Lactobacillus salivarius, Agathobaculum, Active Rumenococcus, Benzene Paraclostridium, Turicibacter sanguinus , Burkholderia, Klebsiella pneumoniae subsp. pneumoniae, Klebsiella oxytoca, Tyzerella nexilis , or Neisseria bacteria .

在一些實施方式中，細菌係產氫營養型布勞特氏菌細菌。In some embodiments, the bacteria are hydrogen-producing trophic Blautella bacteria.

在一些實施方式中，細菌係排泄物布勞特氏菌細菌。In some embodiments, the bacteria are fecal Blautella bacteria.

在一些實施方式中，細菌係韋氏布勞特氏菌細菌。In some embodiments, the bacteria is Blautella weinii bacteria.

在一些實施方式中，細菌係鶉雞腸球菌細菌。In some embodiments, the bacteria is Enterococcus gallinarum bacteria.

在一些實施方式中，細菌係屎腸球菌細菌。In some embodiments, the bacteria are Enterococcus faecium bacteria.

在一些實施方式中，細菌係兩歧雙歧桿菌細菌。In some embodiments, the bacteria are Bifidobacterium bifidum bacteria.

在一些實施方式中，細菌係短雙歧桿菌細菌。In some embodiments, the bacteria are Bifidobacterium breve bacteria.

在一些實施方式中，細菌係長雙歧桿菌細菌。In some embodiments, the bacteria are Bifidobacterium longum bacteria.

在一些實施方式中，細菌係人羅斯氏菌細菌。In some embodiments, the bacteria are Rossella humana bacteria.

在一些實施方式中，細菌係多形擬桿菌（Bacteroides thetaiotaomicron ）細菌。In some embodiments, the bacteria are Bacteroides thetaiotaomicron bacteria.

在一些實施方式中，細菌係糞居擬桿菌細菌。In some embodiments, the bacteria are Bacteroides faecalis bacteria.

在一些實施方式中，細菌係Erysipelatoclostridium ramosum 細菌。In some embodiments, the bacteria are Erysipelatoclostridium ramosum bacteria.

在一些實施方式中，細菌係馬賽巨型球菌細菌。In some embodiments, the bacteria are Megacoccus marseilles bacteria.

在一些實施方式中，細菌係真桿菌屬細菌。In some embodiments, the bacteria are Eubacterium bacteria.

在一些實施方式中，細菌係狄氏副擬桿菌（Parabacteroides distasonis ）細菌。In some embodiments, the bacteria are Parabacteroides distasonis bacteria.

在一些實施方式中，細菌係植物乳桿菌細菌。In some embodiments, the bacteria are Lactobacillus plantarum bacteria.

在一些實施方式中，細菌屬於Negativicutes 綱。In some embodiments, the bacteria belong to the class Negativicutes.

在一些實施方式中，細菌屬於韋榮氏球菌科。In some embodiments, the bacterium belongs to the Veronococcus family.

在一些實施方式中，細菌屬於月形單胞菌科。In some embodiments, the bacteria belong to the family Selenomonas.

在一些實施方式中，細菌屬於胺基酸球菌科。In some embodiments, the bacteria belong to the Acidococcus family.

在一些實施方式中，細菌屬於Sporomusaceae 科。In some embodiments, the bacteria belong to the Sporomusaceae family.

在一些實施方式中，細菌屬於巨型球菌屬。In some embodiments, the bacteria belong to the genus Megacoccus.

在一些實施方式中，細菌屬於月形單胞菌屬。In some embodiments, the bacterium belongs to the genus Selenomonas.

在一些實施方式中，細菌屬於Propionospora 屬。In some embodiments, the bacteria belong to the genus Propionospora.

在一些實施方式中，細菌屬於胺基酸球菌屬。In some embodiments, the bacteria belong to the genus Acidococcus.

在一些實施方式中，細菌係巨型球菌屬物種細菌。In some embodiments, the bacteria are Megacoccus species bacteria.

在一些實施方式中，細菌來自菲利克斯月形單胞菌細菌。In some embodiments, the bacteria are derived from Selenomonas felixii bacteria.

在一些實施方式中，細菌係腸胺基酸球菌。In some embodiments, the bacterium is Acidococcus Enterobacter.

在一些實施方式中，細菌係Propionospora 屬物種細菌。In some embodiments, the bacteria are bacteria of the genus Propionospora.

在一些實施方式中，細菌屬於梭菌綱。In some embodiments, the bacteria belong to the class Clostridium.

在一些實施方式中，細菌屬於顫螺旋菌科。In some embodiments, the bacteria belong to the Oscillator family.

在一些實施方式中，細菌屬於糞桿菌屬（Faecalibacterium ）。In some embodiments, the bacteria belong to the genus Faecalibacterium (Faecalibacterium).

在一些實施方式中，細菌屬於Fournierella 屬。In some embodiments, the bacteria belong to the genus Fournierella.

在一些實施方式中，細菌屬於Harryflintia 屬。In some embodiments, the bacteria belong to the genus Harryflintia.

在一些實施方式中，細菌屬於阿加薩桿菌屬。In some embodiments, the bacteria belong to the genus Argasa.

在一些實施方式中，細菌係普氏棲糞桿菌（例如，普氏棲糞桿菌菌株A）細菌。In some embodiments, the bacteria are Faeculus prasutii (eg, Faeculus prasutii strain A) bacteria.

在一些實施方式中，細菌係Fournierella massiliensis （例如，Fournierella massiliensis 菌株A）細菌。In some embodiments, the bacteria are Fournierella massiliensis (eg, Fournierella massiliensis strain A) bacteria.

在一些實施方式中，細菌係Harryflintia acetispora （例如，Harryflintia acetispora 菌株A）細菌。In some embodiments, the bacteria are Harryflintia acetispora (eg, Harryflintia acetispora strain A) bacteria.

在一些實施方式中，細菌係阿加薩桿菌屬物種（例如，阿加薩桿菌屬物種菌株A）細菌。In some embodiments, the bacteria are bacteria of the genus Agatha (eg, strain A of the genus A) bacteria.

在一些實施方式中，細菌係阿加薩桿菌屬物種的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係與阿加薩桿菌屬物種菌株A（ATCC保藏號PTA-125892）的核苷酸序列（例如，基因組序列、16S序列、CRISPR序列）具有至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係阿加薩桿菌屬物種菌株A（ATCC保藏號PTA-125892）細菌。In some embodiments, the bacteria are strains of the genus Argasa species. In some embodiments, the Agatha species strain and the Agatha species strain A (ATCC deposit number PTA-125892) have nucleotide sequences (eg, genome sequence, 16S sequence, CRISPR sequence) at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity With at least 99.9% sequence identity). In some embodiments, the Agatha species strain is the Agatha species strain A (ATCC deposit number PTA-125892) bacteria.

在一些實施方式中，細菌屬於擬桿菌綱[擬桿菌門]。在一些實施方式中，細菌屬於擬桿菌目。在一些實施方式中，細菌屬於紫單胞菌科。在一些實施方式中，細菌屬於普雷沃菌科。在一些實施方式中，細菌屬於擬桿菌綱，其中細菌的細胞被膜結構係雙層的（diderm）。在一些實施方式中，細菌屬於擬桿菌綱、革蘭氏陰性染色。在一些實施方式中，細菌屬於擬桿菌綱，其中細菌係雙層的並且細菌係革蘭氏陰性染色。In some embodiments, the bacteria belong to the class Bacteroides [Bacteroides]. In some embodiments, the bacteria belong to the order Bacteroides. In some embodiments, the bacteria belong to the Porphyridaceae family. In some embodiments, the bacteria belong to the Prevotaceae family. In some embodiments, the bacteria belong to the class of Bacteroides, in which the cell membrane structure of the bacteria is diderm. In some embodiments, the bacteria belong to the class of Bacteroides, with Gram-negative staining. In some embodiments, the bacteria belong to the class of Bacteroides, in which the bacterial lines are bilayered and the bacterial lines are Gram-negative.

在一些實施方式中，細菌屬於梭菌綱[厚壁菌門]。在一些實施方式中，細菌屬於真細菌目（Eubacteriales ）。在一些實施方式中，細菌屬於顫螺旋菌科。在一些實施方式中，細菌屬於毛螺菌科。在一些實施方式中，細菌屬於消化鏈球菌科。在一些實施方式中，細菌屬於梭菌目XIII科/ 地位未定41。在一些實施方式中，細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的（monoderm）。在一些實施方式中，細菌屬於梭菌綱、革蘭氏陰性染色。在一些實施方式中，細菌屬於梭菌綱、革蘭氏陽性染色。在一些實施方式中，細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的並且細菌係革蘭氏陰性染色。在一些實施方式中，細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的並且細菌係革蘭氏陽性染色。In some embodiments, the bacteria belong to the class of Clostridium [Firmicutes]. In some embodiments, the bacteria belong to the order Eubacteriales (Eubacteriales). In some embodiments, the bacteria belong to the Oscillator family. In some embodiments, the bacteria belong to the Lacetospirillum family. In some embodiments, the bacteria belong to the Peptostreptococcaceae family. In some embodiments, the bacteria belong to the Clostridia order XIII family / status undetermined 41. In some embodiments, the bacteria belong to the class Clostridium, in which the cell envelope structure of the bacteria is monoderm. In some embodiments, the bacteria belong to the class of Clostridium and Gram-negative staining. In some embodiments, the bacteria belong to the class of Clostridium and Gram-positive staining. In some embodiments, the bacteria belong to the class of Clostridium, in which the cell membrane structure of the bacteria is monolayer and the bacteria are Gram-negative. In some embodiments, the bacteria belong to the class of Clostridium, in which the cell membrane structure of the bacteria is monolayer and the bacteria are Gram-positively stained.

在一些實施方式中，細菌屬於Negativicutes 綱[厚壁菌門]。在一些實施方式中，細菌屬於韋榮氏球菌目。在一些實施方式中，細菌屬於韋榮氏球菌科。在一些實施方式中，細菌屬於Selenomonadales 目。在一些實施方式中，細菌屬於月形單胞菌科。在一些實施方式中，細菌屬於Sporomusaceae 科。在一些實施方式中，細菌屬於Negativicutes 綱，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，細菌屬於Negativicutes 綱、革蘭氏陰性染色。在一些實施方式中，細菌屬於Negativicutes 綱，其中細菌的細胞被膜結構係雙層的並且細菌係革蘭氏陰性染色。In some embodiments, the bacteria belong to the class Negativicutes [Clairesteca]. In some embodiments, the bacteria belong to the order Veillonellales. In some embodiments, the bacterium belongs to the Veronococcus family. In some embodiments, the bacteria belong to the order Selenomonadales . In some embodiments, the bacteria belong to the family Selenomonas. In some embodiments, the bacteria belong to the Sporomusaceae family. In some embodiments, the bacteria belong to the class Negativicutes , in which the cell membrane structure of the bacteria is double-layered. In some embodiments, the bacteria belong to the class Negativicutes and have a Gram-negative stain. In some embodiments, the bacteria belong to the class Negativicutes , in which the cell membrane structure of the bacteria is double-layered and the bacteria are Gram-negative staining.

在一些實施方式中，細菌屬於互養菌綱[互養菌門]。在一些實施方式中，細菌屬於互養菌目。在一些實施方式中，細菌屬於互養菌科。在一些實施方式中，細菌屬於互養菌綱，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，細菌屬於互養菌綱、革蘭氏陰性染色。在一些實施方式中，細菌屬於互養菌綱，其中細菌的細胞被膜結構係雙層的並且細菌係革蘭氏陰性染色。In some embodiments, the bacteria belong to the class of Syntrophic Bacteria [Cotrophic Bacteria]. In some embodiments, the bacteria belong to the order Syntrophic bacteria. In some embodiments, the bacteria belong to the family Syntrophicaceae. In some embodiments, the bacteria belong to the class of the syntrophic bacteria, in which the cell membrane structure of the bacteria is double-layered. In some embodiments, the bacteria belong to the class of Syntrophic Bacteria, with Gram-negative staining. In some embodiments, the bacteria belong to the class of the syntrophic bacteria, in which the cell membrane structure of the bacteria is double-layered and the bacteria are Gram-negative staining.

在一些實施方式中，細菌係產生代謝產物的細菌，例如，細菌產生丁酸、肌苷、丙酸、或色胺酸代謝產物。In some embodiments, the bacteria are bacteria that produce metabolites, for example, the bacteria produce butyric acid, inosine, propionic acid, or tryptophan metabolites.

在一些實施方式中，細菌產生丁酸。在一些實施方式中，細菌來自布勞特氏菌屬；克裡斯滕森菌屬；糞球菌屬；真桿菌屬；毛螺菌科；巨型球菌屬；或羅斯氏菌屬。In some embodiments, the bacteria produce butyric acid. In some embodiments, the bacterium is from the genus Blautella; Kristensia; Coccus; Eubacterium; Lacetospiraceae; Megacoccus; or Rossella.

在一些實施方式中，細菌產生肌苷。在一些實施方式中，細菌來自雙歧桿菌屬；乳桿菌屬；或歐陸森氏菌屬。In some embodiments, the bacteria produce inosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Eurosonia.

在一些實施方式中，細菌產生丙酸。在一些實施方式中，細菌來自阿克曼氏菌屬；擬桿菌屬；戴阿利斯特菌屬（Dialister ）；真桿菌屬；巨型球菌屬；副擬桿菌屬；普雷沃菌屬；瘤胃球菌屬；或韋榮氏球菌屬。In some embodiments, the bacteria produce propionic acid. In some embodiments, bacteria from the genus Ackerman; Bacteroides;戴阿利斯特genus (Dialister); Eubacterium; Megasphaera genus; sub Bacteroides; Prevotella spp; Ruminococcus Genus; or Veillonella.

在一些實施方式中，細菌產生色胺酸代謝產物。在一些實施方式中，細菌來自乳桿菌屬或消化鏈球菌屬。In some embodiments, the bacteria produce tryptophan metabolites. In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

在一些實施方式中，細菌係產生組蛋白脫乙醯基酶3（HDAC3）的抑制劑的細菌。在一些實施方式中，細菌來自物種Bariatricus massiliensis 、普氏棲糞桿菌、馬賽巨型球菌或腸羅斯氏菌。In some embodiments, the bacteria are bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis , Faeculus procuratus, Megacoccus marseilles, or Rossella enterica.

在一些實施方式中，藥劑包含分離的mEV（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量）。例如，其中藥劑的至少50%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%的含量係細菌（例如，目的細菌）的分離的mEV。In some embodiments, the medicament comprises an isolated mEV (eg, from one or more bacterial strains (eg, bacteria of interest) (eg, a therapeutically effective amount thereof). For example, at least 50%, at least 75%, at least 80% of the medicament %, at least 85%, at least 90%, at least 95%, or at least 99% are isolated mEVs of bacteria (for example, bacteria of interest).

在一些實施方式中，藥劑包含mEV，並且mEV包含分泌型mEV（smEV）。In some embodiments, the medicament comprises mEV, and the mEV comprises secreted mEV (smEV).

在一些實施方式中，藥劑包含mEV，並且mEV包含經處理的mEV（pmEV）。In some embodiments, the medicament comprises mEV, and the mEV comprises treated mEV (pmEV).

在一些實施方式中，藥劑包含pmEV，並且pmEV由已經經γ照射、UV照射、熱滅活、酸處理或氧噴射的細菌產生。In some embodiments, the medicament contains pmEV, and pmEV is produced by bacteria that have been gamma-irradiated, UV-irradiated, heat-inactivated, acid-treated, or oxygen-sprayed.

在一些實施方式中，藥劑包含pmEV，並且pmEV由活細菌產生。In some embodiments, the medicament comprises pmEV, and pmEV is produced by live bacteria.

在一些實施方式中，藥劑包含pmEV，並且pmEV產生自死細菌。In some embodiments, the medicament comprises pmEV, and pmEV is produced from dead bacteria.

在一些實施方式中，藥劑包含pmEV，並且pmEV產生自非複製型細菌。In some embodiments, the agent comprises pmEV, and pmEV is produced from non-replicating bacteria.

在一些實施方式中，藥劑包含mEV，並且mEV來自一種細菌菌株。In some embodiments, the agent comprises mEV, and the mEV is derived from a bacterial strain.

在一些實施方式中，mEV被凍乾（例如，凍乾的產物還包含藥學上可接受的賦形劑）。In some embodiments, the mEV is lyophilized (eg, the lyophilized product also contains pharmaceutically acceptable excipients).

在一些實施方式中，mEV被γ照射。In some embodiments, mEV is gamma irradiated.

在一些實施方式中，mEV被UV照射。In some embodiments, the mEV is irradiated with UV.

在一些實施方式中，mEV被熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。In some embodiments, the mEV is heat-inactivated (eg, two hours at 50°C or two hours at 90°C).

在一些實施方式中，mEV被酸處理。In some embodiments, mEV is acid-treated.

在一些實施方式中，mEV被噴氧（例如，以0.1 vvm持續兩小時）。In some embodiments, the mEV is sprayed with oxygen (for example, at 0.1 vvm for two hours).

在一些實施方式中，mEV來自革蘭氏陽性細菌。In some embodiments, the mEV is derived from Gram-positive bacteria.

在一些實施方式中，mEV來自革蘭氏陰性細菌。In some embodiments, the mEV is derived from Gram-negative bacteria.

在一些實施方式中，mEV來自需氧細菌。In some embodiments, mEV is derived from aerobic bacteria.

在一些實施方式中，mEV來自厭氧細菌。在一些實施方式中，厭氧細菌包含專性厭氧菌。在一些實施方式中，厭氧細菌包含兼性厭氧菌。In some embodiments, mEV is derived from anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

在一些實施方式中，mEV來自嗜酸細菌。In some embodiments, the mEV is derived from acidophilic bacteria.

在一些實施方式中，mEV來自嗜鹼細菌。In some embodiments, the mEV is derived from alkalophilic bacteria.

在一些實施方式中，mEV來自嗜中性細菌。In some embodiments, the mEV is derived from neutrophilic bacteria.

在一些實施方式中，mEV來自難養細菌。In some embodiments, mEV is derived from refractory bacteria.

在一些實施方式中，mEV來自非難養細菌。In some embodiments, mEV is derived from non-difficult bacteria.

在一些實施方式中，mEV來自表1、表2或表3中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。In some embodiments, the mEV is from a bacteria of the taxonomic group (eg, class, order, family, genus, species, or strain) listed in Table 1, Table 2, or Table 3.

在一些實施方式中，mEV來自表1、表2或表3中列出的細菌菌株。In some embodiments, the mEV is from a bacterial strain listed in Table 1, Table 2, or Table 3.

在一些實施方式中，mEV來自表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。In some embodiments, the mEV is from a taxonomic group (eg, class, order, family, genus, species, or strain) of bacteria listed in Table J.

在一些實施方式中，mEV來自表J中列出的細菌菌株。In some embodiments, the mEV is from the bacterial strains listed in Table J.

在一些實施方式中，革蘭氏陰性細菌屬於Negativicutes 綱。In some embodiments, the gram-negative bacteria belong to the class Negativicutes.

在一些實施方式中，革蘭氏陰性細菌屬於韋榮氏球菌科（Veillonellaceae ）、月形單胞菌科（Selenomonadaceae ）、胺基酸球菌科（Acidaminococcaceae ）或Sporomusaceae 科。In some embodiments, the Gram-negative bacteria belonging Veillonellaceae (Veillonellaceae), Aeromonas Tsukigata Section (Selenomonadaceae), amino acid cocci families (Acidaminococcaceae) or Sporomusaceae Section.

在一些實施方式中，mEV來自以下屬的細菌：巨型球菌屬（ Megasphaera ）、 月形單胞菌屬（ Selenomonas ）、 Propionospora 、 或胺基酸球菌屬（Acidaminococcus ）。In some embodiments, mEV bacteria from the following genera: Lactococcus giant (Megasphaera), Selenomonas Xanthomonas (Selenomonas), Propionospora, Lactococcus or amino acids (Acidaminococcus).

在一些實施方式中，mEV係巨型球菌屬物種、菲利克斯月形單胞菌、腸胺基酸球菌、或Propionospora 屬物種細菌。In some embodiments, the mEV is a species of Megacoccus, Selenomonas felix, Acidococcus enterococcus, or Propionospora species.

在一些實施方式中，mEV來自乳球菌屬、普雷沃菌屬、雙歧桿菌屬、或韋榮氏球菌屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

在一些實施方式中，mEV來自乳酸乳球菌乳脂亞種細菌。In some embodiments, the mEV is derived from Lactococcus lactis subsp. crema bacteria.

在一些實施方式中，mEV來自棲組織普雷沃菌（Prevotella histicola ）細菌。In some embodiments, the mEV is derived from Prevotella histicola bacterium.

在一些實施方式中，mEV來自動物雙歧桿菌細菌。In some embodiments, the mEV is derived from the Bifidobacterium animalis bacterium.

在一些實施方式中，mEV來自小韋榮氏球菌細菌。In some embodiments, the mEV is derived from Veillonella parvum bacteria.

在一些實施方式中，mEV來自乳酸乳球菌乳脂亞種細菌。在一些實施方式中，該乳酸乳球菌乳脂亞種細菌來自與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該乳球菌屬細菌來自與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該乳球菌屬細菌來自乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）。In some embodiments, the mEV is derived from Lactococcus lactis subsp. crema bacteria. In some embodiments, the Lactococcus lactis subsp. crema bacteria is derived from the Lactococcus lactis subsp. crema strain A (ATCC designation number PTA-125368) with a nucleotide sequence of at least 90% or at least 97% genome, 16S and/ Or strains with CRISPR sequence identity. In some embodiments, the Lactococcus bacterium is derived from a strain having at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368) . In some embodiments, the Lactococcus bacteria are derived from Lactococcus lactis subsp. crema strain A (ATCC designation number PTA-125368).

在一些實施方式中，mEV來自普雷沃菌屬細菌。在一些實施方式中，該普雷沃菌屬細菌來自包含與普雷沃菌菌株B 50329（NRRL登錄號B 50329）的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該普雷沃菌屬細菌來自包含與普雷沃菌菌株B 50329（NRRL登錄號B 50329）的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該普雷沃菌屬細菌來自普雷沃菌菌株B 50329（NRRL登錄號B 50329）。In some embodiments, the mEV is derived from a bacterium of the genus Prevotella. In some embodiments, the Prevotella bacterium is derived from a genome that contains at least 90% (or at least 97%) of the genome, 16S, and/or the nucleotide sequence of Prevotella strain B 50329 (NRRL accession number B 50329). Or strains with CRISPR sequence identity. In some embodiments, the Prevotella bacterium is derived from a strain containing at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of Prevotella strain B 50329 (NRRL accession number B 50329) Strains. In some embodiments, the Prevotella bacterium is from Prevotella strain B 50329 (NRRL accession number B 50329).

在一些實施方式中，mEV來自雙歧桿菌屬細菌。在一些實施方式中，該雙歧桿菌屬細菌來自與雙歧桿菌屬細菌（保藏為ATCC指定編號PTA-125097）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該雙歧桿菌屬細菌來自與雙歧桿菌屬細菌（保藏為ATCC指定編號PTA-125097）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該雙歧桿菌屬細菌來自雙歧桿菌屬細菌（保藏為ATCC指定編號PTA-125097）。In some embodiments, the mEV is derived from a bacterium of the genus Bifidobacterium. In some embodiments, the bacterium of the genus Bifidobacterium is derived from a bacterium of the genus Bifidobacterium (deposited as ATCC designated number PTA-125097) with a nucleotide sequence of at least 90% or at least 97% genome, 16S and/or CRISPR sequence Strains of identity. In some embodiments, the Bifidobacterium bacterium is derived from a strain that has at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacterium (deposited as ATCC designation number PTA-125097) . In some embodiments, the bacteria of the genus Bifidobacterium are derived from bacteria of the genus Bifidobacterium (deposited under the ATCC designation number PTA-125097).

在一些實施方式中，mEV來自韋榮氏球菌屬細菌。在一些實施方式中，該韋榮氏球菌屬細菌來自與韋榮氏球菌屬細菌（保藏為ATCC指定編號PTA-125691）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該韋榮氏球菌屬細菌來自與韋榮氏球菌屬細菌（保藏為ATCC指定編號PTA-125691）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該韋榮氏球菌屬細菌來自韋榮氏球菌屬細菌（保藏為ATCC指定編號PTA-125691）。In some embodiments, the mEV is from a bacterium of the genus Veillonella. In some embodiments, the bacterium of the genus Veillonella is derived from a bacterium of the genus Veillonella (deposited as ATCC designated number PTA-125691) with a nucleotide sequence of at least 90% or at least 97% genome, 16S and/or Strains with CRISPR sequence identity. In some embodiments, the bacterium of the genus Veillonella is derived from a nucleotide sequence of a bacterium of the genus Veillonella (deposited under ATCC designation number PTA-125691) that has at least 99% genome, 16S and/or CRISPR sequence identity Strains. In some embodiments, the bacterium of the genus Veillonella is derived from a bacterium of the genus Veillonella (deposited under the ATCC designation number PTA-125691).

在一些實施方式中，mEV來自活潑瘤胃球菌細菌。在一些實施方式中，該活潑瘤胃球菌細菌來自與活潑瘤胃球菌細菌（保藏為ATCC指定編號PTA-126695）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該活潑瘤胃球菌細菌來自與活潑瘤胃球菌細菌（保藏為ATCC指定編號PTA-126695）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該活潑瘤胃球菌細菌來自活潑瘤胃球菌細菌（保藏為ATCC指定編號PTA-126695）。In some embodiments, the mEV is derived from active Rumenococcus bacteria. In some embodiments, the active Rumenococcus bacterium is derived from a nucleotide sequence that has at least 90% or at least 97% genomic, 16S, and/or CRISPR sequence identity with the nucleotide sequence of the Rumenococcus active bacterium (deposited under the ATCC designation number PTA-126695) Strains. In some embodiments, the active Rumenococcus bacterium is derived from a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Active Rumenococcus bacterium (deposited under the ATCC designation number PTA-126695). In some embodiments, the active rumen cocci bacteria are derived from active rumen cocci bacteria (deposited under ATCC designation number PTA-126695).

在一些實施方式中，mEV來自巨型球菌屬物種細菌。在一些實施方式中，該巨型球菌屬物種細菌來自與巨型球菌屬物種細菌（保藏為ATCC指定編號PTA-126770）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該巨型球菌屬物種細菌來自與巨型球菌屬物種細菌（保藏為ATCC指定編號PTA-126770）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該巨型球菌屬物種細菌來自巨型球菌屬物種細菌（保藏為ATCC指定編號PTA-126770）。In some embodiments, the mEV is from a bacterium of the Megacoccus species. In some embodiments, the bacterium of the genus Megacoccus is derived from a bacterium of the genus Megacoccus (deposited as ATCC designated number PTA-126770) with a nucleotide sequence of at least 90% or at least 97% of the genome, 16S and/or CRISPR sequence Strains of identity. In some embodiments, the Megacoccus species bacterium is derived from a strain that has at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Megacoccus species bacterium (deposited under the ATCC designation number PTA-126770) . In some embodiments, the Megacoccus species bacteria are derived from Megacoccus species bacteria (deposited under ATCC designation number PTA-126770).

在一些實施方式中，mEV來自Fournierella massiliensis 細菌。在一些實施方式中，Fournierella massiliensis 細菌來自與以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Fournierella massiliensis 細菌來自與以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Fournierella massiliensis 細菌來自以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌。In some embodiments, the mEV is derived from Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacterium is derived from a strain that has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under the ATCC designation number PTA-126696 . In some embodiments, the Fournierella massiliensis bacterium is derived from a strain that has at least 99% genome, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under the ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacterium is derived from the Fournierella massiliensis bacterium deposited under the ATCC designation number PTA-126696.

在一些實施方式中，mEV來自Harryflintia acetispora 細菌。在一些實施方式中，Harryflintia acetispora 細菌來自與以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Harryflintia acetispora 細菌來自與以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Harryflintia acetispora 細菌來自以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌。In some embodiments, the mEV is derived from Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacterium is derived from a strain that has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under the ATCC designation number PTA-126694 . In some embodiments, the Harryflintia acetispora bacterium is derived from a strain that has at least 99% genome, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under the ATCC designation number PTA-126694. In some embodiments, Harryflintia acetispora to bacteria from the ATCC designation number PTA-126694 deposited Harryflintia acetispora bacteria.

在一些實施方式中，mEV來自胺基酸球菌科、產鹼桿菌科、阿克曼氏菌科、擬桿菌科、雙歧桿菌科、伯克霍爾德菌科、Catabacteriaceae 科、梭菌科、紅蝽菌科、腸桿菌科、腸球菌科、梭桿菌科、毛螺菌科、李斯特菌科、分枝桿菌科、奈瑟菌科、臭桿菌科、顫螺旋菌科、消化球菌科、消化鏈球菌科、卟啉單胞菌科、普雷沃菌科、丙酸桿菌科、理研菌科、瘤胃球菌科、月形單胞菌科、Sporomusaceae 科、鏈球菌科、鏈黴菌科、薩特氏菌科、互養菌科、或韋榮氏球菌科。In some embodiments, the mEV is from the Acidococcus family, Alcaligenes family, Akkermaniaceae, Bacteroides family, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae family, Clostridiaceae, Rhodobacteraceae, Enterobacteriaceae, Enterococcus, Fusobacteria, Lacetospiraceae, Listeriaceae, Mycobacteriaceae, Neisseriaceae, Binobacteriaceae, Oscillatoriaceae, Peptococcus, Peptostreptococcaceae, Porphyromonasaceae, Prevotaceae , Propionibacteriaceae, Rikenbacteriaceae, Rumenococcus, Lunamonasaceae, Sporomusaceae, Streptococcus, Streptomyces, Saccharomyces Tertiellaceae, Syntrophicaceae, or Veillonellaceae.

在一些實施方式中，mEV來自阿克曼氏菌屬、克裡斯滕森菌屬、布勞特氏菌屬、腸球菌屬、真桿菌屬、羅斯氏菌屬、擬桿菌屬、副擬桿菌屬、或丹毒絲梭菌屬的細菌。In some embodiments, the mEV is from Akkermansia, Christensenella, Blautella, Enterococcus, Eubacterium, Rosella, Bacteroides, Parabacteroides , Or bacteria of the genus Clostridium erysipelas.

在一些實施方式中，mEV來自產氫營養型布勞特氏菌、排泄物布勞特氏菌、韋氏布勞特氏菌、糞真桿菌、扭曲真桿菌、直腸真桿菌、糞腸球菌、耐久腸球菌、絨毛腸球菌、鶉雞腸球菌；乳酸雙歧桿菌、兩歧雙歧桿菌、長雙歧桿菌、動物雙歧桿菌或短雙歧桿菌細菌。In some embodiments, the mEV is derived from hydrogen-producing trophic Blautella, fecal Blautella, Blautella weinii, Eubacterium faecalis, Eubacterium contortus, Eubacterium rectum, Enterococcus faecalis, Enterococcus durable, Enterococcus villus, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium animalis or Bifidobacterium breve bacteria.

在一些實施方式中，mEV來自BCG（卡介苗）、副擬桿菌屬、布勞特氏菌屬、韋榮氏球菌屬、唾液乳桿菌、阿加薩桿菌屬、活潑瘤胃球菌、解苯副梭菌、Turicibacter sanguinus 、伯克霍爾德菌屬、類肺炎克雷伯氏菌擬肺炎亞種、催產克雷伯氏菌、納西利斯泰澤菌或奈瑟菌屬細菌。In some embodiments, the mEV is derived from BCG (Bacille Calmette-Guerin), Parabacteroides, Blauterella, Veyronella, Lactobacillus salivarius, Agasabacterium, Active Rumenococcus, Clostridium parabens , Turicibacter sanguinus , Burkholderia, Klebsiella pneumoniae subsp. pneumoniae, Klebsiella oxytoca, Tizania narcissi, or Neisseria bacteria.

在一些實施方式中，mEV來自產氫營養型布勞特氏菌（Blautia hydrogenotrophica ） 細菌。In some embodiments, the mEV is derived from Blautia hydrogenotrophica (Blautia hydrogenotrophica) bacteria.

在一些實施方式中，mEV來自排泄物布勞特氏菌（Blautia stercoris ）細菌。In some embodiments, the mEV is derived from Blautia stercoris bacteria.

在一些實施方式中，mEV來自韋氏布勞特氏菌（Blautia wexlerae ）細菌。In some embodiments, the mEV is derived from Blautia wexlerae bacteria.

在一些實施方式中，mEV來自鶉雞腸球菌（Enterococcus gallinarum ）細菌。In some embodiments, the mEV is derived from Enterococcus gallinarum (Enterococcus gallinarum) bacteria.

在一些實施方式中，mEV來自屎腸球菌（Enterococcus faecium ）細菌。In some embodiments, the mEV is derived from Enterococcus faecium ( Enterococcus faecium ) bacteria.

在一些實施方式中，mEV來自兩歧雙歧桿菌（ Bifidobacterium bifidium ） 細菌。In some embodiments, the mEV is derived from Bifidobacterium bifidium ( Bifidobacterium bifidium) bacteria.

在一些實施方式中，mEV來自短雙歧桿菌（Bifidobacterium breve ）細菌。In some embodiments, the mEV is derived from Bifidobacterium breve (Bifidobacterium breve) bacteria.

在一些實施方式中，mEV來自長雙歧桿菌（Bifidobacterium longum ）細菌。In some embodiments, the mEV is derived from Bifidobacterium longum (Bifidobacterium longum) bacteria.

在一些實施方式中，mEV來自人羅斯拜瑞氏菌（Roseburia hominis ）細菌。In some embodiments, the mEV is derived from the bacterium Roseburia hominis .

在一些實施方式中，mEV來自多形擬桿菌（Bacteroides thetaiotaomicron ）細菌。In some embodiments, the mEV is derived from Bacteroides thetaiotaomicron (Bacteroides thetaiotaomicron) bacteria.

在一些實施方式中，mEV來自糞居擬桿菌（Bacteroides coprocola ）細菌。In some embodiments, the mEV is derived from Bacteroides coprocola bacteria.

在一些實施方式中，mEV來自Erysipelatoclostridium ramosum 細菌。In some embodiments, the mEV is from Erysipelatoclostridium ramosum bacteria.

在一些實施方式中，mEV來自馬賽巨型球菌（Megasphera massiliensis ）細菌。In some embodiments, the mEV is derived from Megasphera massiliensis bacteria.

在一些實施方式中，mEV來自真桿菌屬（Eubacterium ）細菌。In some embodiments, the mEV is from Eubacterium bacteria.

在一些實施方式中，mEV來自狄氏副擬桿菌（Parabacteroides distasonis ）細菌。In some embodiments, the mEV is derived from the Parabacteroides distasonis bacterium.

在一些實施方式中，mEV來自植物乳桿菌細菌。In some embodiments, the mEV is derived from Lactobacillus plantarum bacteria.

在一些實施方式中，mEV來自Negativicutes 綱的細菌。In some embodiments, the mEV is derived from bacteria of the class Negativicutes.

在一些實施方式中，mEV來自韋榮氏球菌科的細菌。In some embodiments, the mEV is derived from a bacterium of the Veronococcus family.

在一些實施方式中，mEV來自月形單胞菌科的細菌。In some embodiments, the mEV is derived from a bacterium of the family Selenomonas.

在一些實施方式中，mEV來自胺基酸球菌科的細菌。In some embodiments, the mEV is derived from bacteria of the Acidococcus family.

在一些實施方式中，mEV來自Sporomusaceae 科的細菌。In some embodiments, the mEV is derived from bacteria in the Sporomosaceae family.

在一些實施方式中，mEV來自巨型球菌屬的細菌。In some embodiments, the mEV is derived from a bacterium of the genus Megacoccus.

在一些實施方式中，mEV來自月形單胞菌屬的細菌。In some embodiments, the mEV is derived from a bacterium of the genus Selenomonas.

在一些實施方式中，mEV來自Propionospora 屬的細菌。In some embodiments, the mEV is derived from bacteria of the genus Propionospora.

在一些實施方式中，mEV來自胺基酸球菌屬的細菌。In some embodiments, the mEV is derived from a bacterium of the genus Acidococcus.

在一些實施方式中，mEV來自巨型球菌屬物種細菌。In some embodiments, the mEV is from a bacterium of the Megacoccus species.

在一些實施方式中，mEV來自菲利克斯月形單胞菌細菌。In some embodiments, the mEV is derived from the bacterium Selenomonas felix.

在一些實施方式中，mEV來自腸胺基酸球菌細菌。In some embodiments, the mEV is derived from Acidococcus enterica bacteria.

在一些實施方式中，mEV來自Propionospora 屬物種細菌。In some embodiments, the mEV is derived from bacteria of the genus Propionospora.

在一些實施方式中，mEV來自梭菌綱的細菌。In some embodiments, the mEV is derived from bacteria of the class Clostridia.

在一些實施方式中，mEV來自顫螺旋菌科的細菌。In some embodiments, the mEV is from a bacterium of the Oscillospiraceae family.

在一些實施方式中，mEV來自糞桿菌屬的細菌。In some embodiments, the mEV is derived from bacteria of the genus Faecalis.

在一些實施方式中，mEV來自Fournierella 屬的細菌。In some embodiments, the mEV is derived from a bacterium of the genus Fournierella.

在一些實施方式中，mEV來自Harryflintia 屬的細菌。In some embodiments, the mEV is derived from a bacterium of the genus Harryflintia.

在一些實施方式中，mEV來自阿加薩桿菌屬的細菌。In some embodiments, the mEV is derived from a bacterium of the genus Agasabacterium.

在一些實施方式中，mEV來自普氏棲糞桿菌（例如，普氏棲糞桿菌菌株A）細菌。In some embodiments, the mEV is derived from the bacterium Faecalis prasutii (eg, Faecalis prasutii strain A) bacteria.

在一些實施方式中，mEV來自Fournierella massiliensis （例如，Fournierella massiliensis 菌株A）細菌。In some embodiments, the mEV is derived from Fournierella massiliensis (eg, Fournierella massiliensis strain A) bacteria.

在一些實施方式中，mEV來自Harryflintia acetispora （例如，Harryflintia acetispora 菌株A）細菌。In some embodiments, the mEV is derived from the Harryflintia acetispora (eg, Harryflintia acetispora strain A) bacteria.

在一些實施方式中，mEV來自阿加薩桿菌屬物種（例如，阿加薩桿菌屬物種菌株A）細菌。In some embodiments, the mEV is from a bacterium of the genus Argasa (eg, strain A of the genus Agatha).

在一些實施方式中，mEV來自阿加薩桿菌屬物種的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係與阿加薩桿菌屬物種菌株A（ATCC保藏號PTA-125892）的核苷酸序列（例如，基因組序列、16S序列、CRISPR序列）具有至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係阿加薩桿菌屬物種菌株A（ATCC保藏號PTA- 125892）細菌。In some embodiments, the mEV is derived from a strain of the genus Argasa species. In some embodiments, the Agatha species strain and the Agatha species strain A (ATCC deposit number PTA-125892) have nucleotide sequences (eg, genome sequence, 16S sequence, CRISPR sequence) at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity Sex, at least 99.9% sequence identity). In some embodiments, the Agasabacterium species strain is Agasabacterium species strain A (ATCC deposit number PTA-125892) bacteria.

在一些實施方式中，mEV來自擬桿菌綱[擬桿菌門]的細菌。在一些實施方式中，mEV來自擬桿菌目的細菌。在一些實施方式中，mEV來自紫單胞菌科的細菌。在一些實施方式中，mEV來自普雷沃菌科的細菌。在一些實施方式中，mEV來自擬桿菌綱的細菌，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，mEV來自擬桿菌綱、革蘭氏陰性染色的細菌。在一些實施方式中，mEV來自擬桿菌綱的細菌，其中細菌係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the mEV is derived from bacteria of the class Bacteroides [Bacteroides]. In some embodiments, the mEV is derived from bacteria of the order Bacteroides. In some embodiments, the mEV is derived from a bacterium of the Porphyridaceae family. In some embodiments, the mEV is derived from bacteria of the Prevotaceae family. In some embodiments, the mEV is derived from bacteria of the class Bacteroides, in which the cell membrane structure of the bacteria is double-layered. In some embodiments, the mEV is from Bacteroides, Gram-negative staining bacteria. In some embodiments, the mEV is derived from bacteria of the class Bacteroides, wherein the bacterial line is bilayered and the bacterial line is Gram-negatively stained.

在一些實施方式中，mEV來自梭菌綱[厚壁菌門]的細菌。在一些實施方式中，mEV來自真細菌目的細菌。在一些實施方式中，mEV來自顫螺旋菌科的細菌。在一些實施方式中，mEV來自毛螺菌科的細菌。在一些實施方式中，mEV來自消化鏈球菌科的細菌。在一些實施方式中，mEV來自梭菌目XIII科/地位未定41的細菌。在一些實施方式中，mEV來自梭菌綱的細菌，其中細菌的細胞被膜結構係單層的。在一些實施方式中，mEV來自梭菌綱、革蘭氏陰性染色的細菌。在一些實施方式中，mEV來自梭菌綱、革蘭氏陽性染色的細菌。在一些實施方式中，mEV來自梭菌綱的細菌，其中細菌的細胞被膜結構係單層的並且該細菌係革蘭氏陰性染色。在一些實施方式中，mEV來自梭菌綱的細菌，其中細菌的細胞被膜結構係單層的並且該細菌係革蘭氏陽性染色。In some embodiments, the mEV is derived from bacteria of the Clostridium class [Clairechophylum]. In some embodiments, the mEV is derived from bacteria of the order Eubacteria. In some embodiments, the mEV is from a bacterium of the Oscillospiraceae family. In some embodiments, the mEV is derived from a bacterium of the Laospirillaceae family. In some embodiments, the mEV is derived from bacteria of the family Peptostreptococcaceae. In some embodiments, the mEV is from a bacterium of the Clostridia order XIII family/status undetermined 41. In some embodiments, the mEV is derived from bacteria belonging to the class Clostridium, in which the cell envelope structure of the bacteria is monolayered. In some embodiments, the mEV is from Clostridium, Gram-negative staining bacteria. In some embodiments, the mEV is from Clostridium, Gram-positive staining bacteria. In some embodiments, the mEV is derived from bacteria of the Clostridium class, in which the cell membrane structure of the bacteria is monolayer and the bacteria are Gram-negative staining. In some embodiments, the mEV is derived from bacteria belonging to the class Clostridium, in which the cell membrane structure of the bacteria is monolayered and the bacterial strain is Gram-positively stained.

在一些實施方式中，mEV來自Negativicutes 綱[厚壁菌門]的細菌。在一些實施方式中，mEV來自韋榮氏球菌目的細菌。在一些實施方式中，mEV來自韋榮氏球菌科的細菌。在一些實施方式中，mEV來自Selenomonadales 目的細菌。在一些實施方式中，mEV來自月形單胞菌科的細菌。在一些實施方式中，mEV來自Sporomusaceae 科的細菌。在一些實施方式中，mEV來自Negativicutes 綱的細菌，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，mEV來自Negativicutes 綱、革蘭氏陰性染色的細菌。在一些實施方式中，mEV來自Negativicutes 綱的細菌，其中細菌的細胞被膜結構係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the mEV is from a bacterium of the class Negativicutes [Clairechophyta]. In some embodiments, the mEV is derived from a bacterium of the order Veillonella. In some embodiments, the mEV is derived from a bacterium of the Veronococcus family. In some embodiments, the mEV is derived from bacteria of the order Selenomonadales. In some embodiments, the mEV is derived from a bacterium of the family Selenomonas. In some embodiments, the mEV is derived from bacteria in the Sporomosaceae family. In some embodiments, the mEV is derived from bacteria of the class Negativicutes, in which the cell membrane structure of the bacteria is double-layered. In some embodiments, the mEV is from the class Negativicutes , Gram-negative staining bacteria. In some embodiments, the mEV is derived from bacteria of the class Negativicutes, in which the cell membrane structure of the bacteria is double-layered and the bacteria are Gram-negative staining.

在一些實施方式中，mEV來自互養菌綱[互養菌門]的細菌。在一些實施方式中，mEV來自互養菌目的細菌。在一些實施方式中，mEV來自互養菌科的細菌。在一些實施方式中，mEV來自互養菌綱的細菌，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，mEV來自互養菌綱、革蘭氏陰性染色的細菌。在一些實施方式中，mEV來自互養菌綱的細菌，其中細菌的細胞被膜結構係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the mEV is derived from bacteria of the class of Syntrophic Bacteria [Cotrophic Bacteria]. In some embodiments, the mEV is derived from bacteria of the order Syntrophic bacteria. In some embodiments, the mEV is derived from bacteria of the family Syntrophicaceae. In some embodiments, the mEV is derived from bacteria in the class of Syntrophic bacteria, in which the cell membrane structure of the bacteria is double-layered. In some embodiments, the mEV is from the class of Syntrophic bacteria, Gram-negative staining bacteria. In some embodiments, the mEV is derived from bacteria of the class of Syntrophic bacteria, in which the cell membrane structure of the bacteria is double-layered and the bacteria are Gram-negative staining.

在一些實施方式中，mEV來自產生代謝產物的細菌，例如，細菌產生丁酸、肌苷、丙酸、或色胺酸代謝產物。In some embodiments, the mEV is derived from bacteria that produce metabolites, for example, the bacteria produce butyric acid, inosine, propionic acid, or tryptophan metabolites.

在一些實施方式中，細菌產生丁酸。在一些實施方式中，細菌來自布勞特氏菌屬；克裡斯滕森菌屬；糞球菌屬；真桿菌屬；毛螺菌科；巨型球菌屬；或羅斯氏菌屬。In some embodiments, the bacteria produce butyric acid. In some embodiments, the bacterium is from the genus Blautella; Kristensia; Coccus; Eubacterium; Lacetospiraceae; Megacoccus; or Rossella.

在一些實施方式中，細菌產生肌苷。在一些實施方式中，細菌來自雙歧桿菌屬；乳桿菌屬；或歐陸森氏菌屬。In some embodiments, the bacteria produce inosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Eurosonia.

在一些實施方式中，細菌產生丙酸。在一些實施方式中，細菌來自阿克曼氏菌屬；擬桿菌屬；戴阿利斯特菌屬（Dialister ）；真桿菌屬；巨型球菌屬；副擬桿菌屬；普雷沃菌屬；瘤胃球菌屬；或韋榮氏球菌屬。In some embodiments, the bacteria produce propionic acid. In some embodiments, bacteria from the genus Ackerman; Bacteroides;戴阿利斯特genus (Dialister); Eubacterium; Megasphaera genus; sub Bacteroides; Prevotella spp; Ruminococcus Genus; or Veillonella.

在一些實施方式中，細菌產生色胺酸代謝產物。在一些實施方式中，細菌來自乳桿菌屬或消化鏈球菌屬。In some embodiments, the bacteria produce tryptophan metabolites. In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

在一些實施方式中，mEV來自產生組蛋白脫乙醯基酶3（HDAC3）的抑制劑的細菌。在一些實施方式中，細菌來自物種Bariatricus massiliensis 、普氏棲糞桿菌、馬賽巨型球菌或腸羅斯氏菌。In some embodiments, the mEV is derived from bacteria that produce inhibitors of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from the species Bariatricus massiliensis , Faeculus procuratus, Megacoccus marseilles, or Rossella enterica.

在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 107 至約2 x 1012 （例如，約3 x 1010 或約1.5 x 1011 或約1.5 x 1012 ）細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 1010 至約2 x 1012 （例如，約1.6 x 1011 或約8 x 1011 或約9.6 x 1011 約12.8 x 1011 或約1.6 x 1012 ）細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the agent contains bacteria and the dose of bacteria is about 1 x 10 7 to about 2 x 10 12 (e.g., about 3 x 10 10 or about 1.5 x 10 11 or about 1.5 x 10 12 ) cells (e.g., The cell number is determined by the total cell count determined by the Coulter counter), where the dose is the dose per capsule or tablet or the dose of all mini-tablets in the capsule. In some embodiments, the medicament contains bacteria and the dose of the bacteria is from about 1 x 10 10 to about 2 x 10 12 (eg, about 1.6 x 10 11 or about 8 x 10 11 or about 9.6 x 10 11 about 12.8 x 10 11 Or about 1.6 x 10 12 ) cells (for example, the number of cells is determined by the total cell count determined by a Coulter counter), where the dose is the dose per capsule or tablet or the dose of all mini-tablets in the capsule.

在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 109 、約3 x 109 、約5 x 109 、約1.5 x 1010 、約3 x 1010 、約5 x 1010 、約1.5 x 1011 、約1.5 x 1012 或約2 x 1012 細胞，其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the agent contains bacteria and the dose of the bacteria is about 1 x 10 9 , about 3 x 10 9 , about 5 x 10 9 , about 1.5 x 10 10 , about 3 x 10 10 , about 5 x 10 10 , About 1.5 x 10 11 , about 1.5 x 10 12 or about 2 x 10 12 cells, wherein the dose is the dose per capsule or tablet or the dose of all mini-tablets in the capsule.

在一些實施方式中，藥劑包含mEV並且mEV的劑量為約1 x 105 至約7 x 1013 個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。在一些實施方式中，藥劑包含mEV並且mEV的劑量為約1 x 1010 至約7 x 1013 個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament comprises mEV and the dose of mEV is about 1 x 10 5 to about 7 x 10 13 particles (for example, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), where the dose is per The dosage of the capsule or tablet is the dosage of all the mini-tablets in the capsule. In some embodiments, the medicament comprises mEV and the dose of mEV is about 1 x 10 10 to about 7 x 10 13 particles (for example, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), where the dose is per The dosage of the capsule or tablet is the dosage of all the mini-tablets in the capsule.

在一些實施方式中，藥劑包含粉末，該粉末包含細菌和/或mEV，並且藥劑（例如包含細菌和/或mEV的粉末）的劑量為約10 mg至約3500 mg，其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament comprises a powder containing bacteria and/or mEV, and the dosage of the medicament (eg, a powder containing bacteria and/or mEV) is about 10 mg to about 3500 mg, wherein the dosage is per capsule or tablet The dose of the drug is the dose of all the mini-tablets in the capsule.

在一些實施方式中，藥劑包含粉末，該粉末包含細菌和/或mEV，並且藥劑（例如包含細菌和/或mEV的粉末）的劑量為約10 mg至約1500 mg，其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament comprises a powder containing bacteria and/or mEV, and the dosage of the medicament (eg, a powder containing bacteria and/or mEV) is about 10 mg to about 1500 mg, wherein the dosage is per capsule or tablet The dose of the drug is the dose of all the mini-tablets in the capsule.

在一些實施方式中，藥劑包含粉末，該粉末包含細菌和/或mEV，並且藥劑（例如包含細菌和/或mEV的粉末）的劑量為約30 mg至約1300 mg（按細菌和/或mEV粉末的重量計）（約25、約30、約35、約50、約75、約100、約120、約150、約250、約300、約350、約400、約500、約600、約700、約750、約800、約900、約1000、約1100、約1200、約1250、約1300、約2000、約2500、約3000、或約3500 mg，其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament contains a powder that contains bacteria and/or mEV, and the dose of the medicament (for example, a powder containing bacteria and/or mEV) is about 30 mg to about 1300 mg (according to bacteria and/or mEV powder). Weight basis) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, About 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg, wherein the dose is the dose or series per capsule or tablet The dose of all mini-tablets in the capsule.

在一些實施方式中，藥劑包含細菌和/或mEV，並且藥劑（例如細菌和/或mEV）的劑量為約2 x 106 至約2 x 1016 個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the agent contains bacteria and/or mEV, and the dose of the agent (eg bacteria and/or mEV) is about 2 x 10 6 to about 2 x 10 16 particles (for example, where NTA (nano Particle tracking analysis) to determine the particle count), where the dose is the dose of each capsule or tablet or the dose of all mini-tablets in the capsule.

在一些實施方式中，藥劑包含細菌和/或mEV，並且藥劑（例如細菌和/或mEV）的劑量為約5 mg至約900 mg總蛋白（例如，其中總蛋白藉由布拉德福德（Bradford）測定或BCA確定），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the agent comprises bacteria and/or mEV, and the dose of the agent (eg bacteria and/or mEV) is about 5 mg to about 900 mg total protein (for example, where the total protein is obtained by Bradford (Bradford) ) Determination or BCA determination), where the dose is the dose of each capsule or tablet or the dose of all mini-tablets in the capsule.

在一些實施方式中，固體劑型還包含一種或多種另外的治療劑。In some embodiments, the solid dosage form also contains one or more additional therapeutic agents.

在一些方面，本揭露提供了治療受試者（例如人）（例如需要治療的受試者）之方法，該方法包括向受試者投與本文提供的固體劑型。在一些方面，本揭露提供了本文提供的固體劑型，其用於治療受試者（例如人）（例如需要治療的受試者）。在一些方面，本揭露提供了本文提供的固體劑型在製備用於治療受試者（例如人）（例如需要治療的受試者）的藥物中的用途。In some aspects, the present disclosure provides a method of treating a subject (eg, a human) (eg, a subject in need of treatment), the method comprising administering to the subject a solid dosage form provided herein. In some aspects, the present disclosure provides a solid dosage form provided herein for use in treating a subject (such as a human) (such as a subject in need of treatment). In some aspects, the present disclosure provides the use of the solid dosage form provided herein in the preparation of a medicament for treating a subject (such as a human) (such as a subject in need of treatment).

在一些實施方式中，固體劑型經口服投與（例如用於口服投與）。In some embodiments, the solid dosage form is administered orally (eg, for oral administration).

在一些實施方式中，將固體劑型投與給處於進食或禁食狀態的受試者。在一些實施方式中，將固體劑型投與給空腹（例如，進食前一小時或進食後兩小時）受試者。在一些實施方式中，固體劑型在進食前一小時投與給受試者。在一些實施方式中，固體劑型在進食後兩小時投與給受試者。In some embodiments, the solid dosage form is administered to a subject in a fed or fasted state. In some embodiments, the solid dosage form is administered to a subject on an empty stomach (eg, one hour before eating or two hours after eating). In some embodiments, the solid dosage form is administered to the subject one hour before eating. In some embodiments, the solid dosage form is administered to the subject two hours after eating.

在一些實施方式中，固體劑型（例如，片劑或多個微型片劑（例如，包含在膠囊中））被投與（例如，用於投與）每天1、2、3或4次。在一些實施方式中，固體劑型包含片劑或多個微型片劑（例如，包含在膠囊中）並且每天1、2、3或4次投與（例如，用於投與）1、2、3或4個固體劑型（例如，片劑或多個微型片劑（例如，包含在膠囊中）。In some embodiments, a solid dosage form (eg, a tablet or multiple mini-tablets (eg, contained in a capsule)) is administered (eg, for administration) 1, 2, 3, or 4 times a day. In some embodiments, the solid dosage form comprises a tablet or a plurality of mini-tablets (for example, contained in a capsule) and is administered 1, 2, 3, or 4 times a day (for example, for administration) 1, 2, 3 Or 4 solid dosage forms (for example, a tablet or multiple mini-tablets (for example, contained in a capsule).

在一些實施方式中，固體劑型提供了藥劑在小腸中例如包含在固體劑型中的藥劑在小腸上部中的釋放。In some embodiments, the solid dosage form provides for the release of the agent in the small intestine, for example, the agent contained in the solid dosage form in the upper small intestine.

在一些實施方式中，固體劑型將藥劑遞送至小腸，其中藥劑可作用於小腸中（例如在小腸上部）的免疫細胞和/或上皮細胞，以在整個身體引起作用（例如系統性作用）。In some embodiments, a solid dosage form delivers the agent to the small intestine, where the agent can act on immune cells and/or epithelial cells in the small intestine (eg, in the upper small intestine) to cause an effect (eg, a systemic effect) throughout the body.

在一些實施方式中，例如當口服投與時，藥劑在胃腸道外提供一種或多種有益的免疫作用。In some embodiments, such as when administered orally, the agent provides one or more beneficial immune effects outside the gastrointestinal tract.

在一些實施方式中，例如當口服投與時，藥劑調節受試者的胃腸道外的免疫作用。In some embodiments, such as when administered orally, the agent modulates the subject's immune function outside the gastrointestinal tract.

在一些實施方式中，例如當口服投與時，藥劑引起系統性作用（例如，胃腸道外的作用）。In some embodiments, such as when administered orally, the agent causes a systemic effect (eg, a parenteral effect).

在一些實施方式中，例如當口服投與時，藥劑對小腸中（例如在小腸上部）的免疫細胞和/或上皮細胞起作用，例如引起系統性作用（例如，胃腸道外的作用）。In some embodiments, such as when administered orally, the agent acts on immune cells and/or epithelial cells in the small intestine (eg, in the upper small intestine), such as causing systemic effects (eg, parenteral effects).

在一些實施方式中，固體劑型經口服投與並且在胃腸道外具有一種或多種有益的免疫作用（例如，藥劑與小腸中的細胞之間的相互作用調節系統性免疫應答）。In some embodiments, the solid dosage form is administered orally and has one or more beneficial immune effects outside the gastrointestinal tract (for example, the interaction between the agent and cells in the small intestine modulates the systemic immune response).

在一些實施方式中，固體劑型經口服投與並且在胃腸道外調節免疫作用（例如，藥劑與小腸中（例如在小腸上部）的細胞之間的相互作用調節系統性免疫應答）。In some embodiments, the solid dosage form is administered orally and modulates immune effects outside the gastrointestinal tract (eg, the interaction between the agent and cells in the small intestine (eg, in the upper small intestine) modulates the systemic immune response).

在一些實施方式中，固體劑型經口服投與並激活先天抗原呈遞細胞（例如在小腸中，例如在小腸上部）。In some embodiments, the solid dosage form is administered orally and activates innate antigen presenting cells (e.g., in the small intestine, e.g., in the upper small intestine).

在一些實施方式中，受試者需要治療（和/或預防）癌症。In some embodiments, the subject is in need of treatment (and/or prevention) of cancer.

在一些實施方式中，受試者需要治療（和/或預防）自體免疫性疾病。In some embodiments, the subject is in need of treatment (and/or prevention) of an autoimmune disease.

在一些實施方式中，受試者需要治療（和/或預防）炎性疾病。In some embodiments, the subject is in need of treatment (and/or prevention) of inflammatory disease.

在一些實施方式中，受試者需要治療（和/或預防）代謝性疾病。In some embodiments, the subject is in need of treatment (and/or prevention) of a metabolic disease.

在一些實施方式中，受試者需要治療（和/或預防）菌群失調（dysbiosis）。In some embodiments, the subject requires treatment (and/or prevention) of dysbiosis.

在一些實施方式中，固體劑型與治療劑（例如，另外的治療劑）組合投與。In some embodiments, the solid dosage form is administered in combination with a therapeutic agent (eg, an additional therapeutic agent).

在某些方面，本文提供了製備藥物組成物的固體劑型之方法，該方法包括將藥劑（例如，本文揭露的細菌和/或細菌來源的試劑，例如本文揭露的mEV）和一種或多種（例如一種、兩種或三種）崩散劑組合成藥物組成物。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%或25%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的45%、40%、35%、30%或25%。在一些實施方式中，一種或多種崩散劑的總質量係藥物組成物總質量的至少30%、至少35%、至少40%、至少45%或至少50%。在一些實施方式中，一種或多種崩散劑的總質量不超過藥物組成物總質量的70%、65%、60%或55%。In certain aspects, this document provides a method for preparing a solid dosage form of a pharmaceutical composition, the method comprising combining an agent (for example, the bacteria and/or bacteria-derived agents disclosed herein, such as the mEV disclosed herein) and one or more (for example, the mEV disclosed herein) One, two or three) disintegrating powders are combined into a pharmaceutical composition. In some embodiments, the total mass of the drug is at least 5%, 10%, 15%, 20%, or 25% of the total mass of the drug composition. In some embodiments, the total mass of the medicament does not exceed 45%, 40%, 35%, 30%, or 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrants is at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrating powders does not exceed 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition.

在一些實施方式中，一種或多種崩散劑包括低取代的羥丙基纖維素（L-HPC）、交聯羧甲基纖維素鈉（Ac-Di-Sol）、和/或交聚維酮（PVPP）。在某些實施方式中，本文提供的固體劑型包含L-HPC。在一些實施方式中，L-HPC係LH-B1級。在某些實施方式中，L-HPC總質量係藥物組成物總質量的至少22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量不超過藥物組成物總質量的22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量係藥物組成物總質量的約22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，本文提供的固體劑型包含交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）。在一些實施方式中，Ac-Di-Sol係SD-711級。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量不超過藥物組成物總質量的1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的約1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，本文提供的固體劑型包含交聚維酮。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。In some embodiments, one or more disintegrants include low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (Ac-Di-Sol), and/or crospovidone ( PVPP). In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is LH-B1 grade. In some embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, Ac-Di-Sol). In some embodiments, Ac-Di-Sol is grade SD-711. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4% of the total mass of the pharmaceutical composition. %, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the solid dosage forms provided herein comprise crospovidone. In some embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%.

在一些實施方式中，固體劑型包含一定量（例如，劑量）的活性成分（例如，細菌和細菌來源的試劑（例如，組分）（例如，微生物胞外囊泡或mEV））。在一些實施方式中，可以根據在藥劑的給定製劑（例如批次）中包含的活性成分的量來調節摻入固體劑型中的藥劑（包含活性成分）的量。在一些實施方式中，然後相應地調節稀釋劑（例如甘露醇）的量。在一些實施方式中，當藥劑的量增加時，稀釋劑的量減少；並且反之亦然。在一些實施方式中，可以對藥劑和稀釋劑的量進行調整，但是一種或多種崩散劑（例如，一種、兩種或三種崩散劑）的量保持恒定，例如，對於給定的固體劑型配方的批次之間。在一些實施方式中，硬脂酸鎂和膠體二氧化矽的量也可以保持恒定，例如，對於給定的固體劑型配方的批次之間。In some embodiments, the solid dosage form contains a certain amount (eg, dose) of active ingredients (eg, bacteria and bacteria-derived agents (eg, components) (eg, microbial extracellular vesicles or mEV)). In some embodiments, the amount of the medicament (containing the active ingredient) incorporated into the solid dosage form can be adjusted according to the amount of the active ingredient contained in the prescribed formulation (for example, batch) of the medicament. In some embodiments, the amount of diluent (eg, mannitol) is then adjusted accordingly. In some embodiments, when the amount of medicament increases, the amount of diluent decreases; and vice versa. In some embodiments, the amount of medicament and diluent can be adjusted, but the amount of one or more disintegrants (for example, one, two or three disintegrants) remains constant, for example, for a given solid dosage form formulation Between batches. In some embodiments, the amounts of magnesium stearate and colloidal silica can also be kept constant, for example, between batches of a given solid dosage form formulation.

在一些實施方式中，使用含有小韋榮氏球菌粉末的藥劑來製備兩種片劑固體劑型。在一些實施方式中，三種崩散劑總計為片劑的53% w/w，具體地：32%低取代羥丙基纖維素；15%交聚維酮；和6%交聯羧甲基纖維素鈉。在一些實施方式中，片劑包含1.5% w/w硬脂酸鎂和1% w/w膠體二氧化矽。在一些實施方式中，藥劑係在8% w/w。在另一個實施方式中，藥劑係在25% w/w。在一些實施方式中，當使用8%藥劑時，甘露醇的量係36.5%甘露醇；並且當使用25%藥劑時，甘露醇的量係19.5%甘露醇。In some embodiments, two solid dosage forms of tablets are prepared using a medicament containing Verionella parvum powder. In some embodiments, the three disintegrating agents total 53% w/w of the tablet, specifically: 32% low-substituted hydroxypropyl cellulose; 15% crospovidone; and 6% croscarmellose sodium. In some embodiments, the tablet contains 1.5% w/w magnesium stearate and 1% w/w colloidal silica. In some embodiments, the medicament is at 8% w/w. In another embodiment, the medicament is at 25% w/w. In some embodiments, when 8% medicament is used, the amount of mannitol is 36.5% mannitol; and when 25% medicament is used, the amount of mannitol is 19.5% mannitol.

在一些實施方式中，使用包含棲組織普雷沃菌粉末的藥劑來製備兩種片劑固體劑型。在一些實施方式中，片劑包含三種崩散劑，總計為片劑的53% w : w，具體地：32% w/w低取代羥丙基纖維素；15% w/w交聚維酮；和6% w/w交聯羧甲基纖維素鈉。在一些實施方式中，片劑包含1.5% w/w硬脂酸鎂和1% w/w膠體二氧化矽。在一些實施方式中，以25% w/w使用藥劑。在另一個實施方式中，以23% w/w使用藥劑。在一些實施方式中，當使用25% w/w藥劑時，片劑包含的甘露醇的量係19.5% w/w甘露醇；並且當使用23% w/w藥劑時，片劑包含的甘露醇的量係21.5% w/w甘露醇。In some embodiments, two tablet solid dosage forms are prepared using a medicament containing Prevotella histosi powder. In some embodiments, the tablet contains three disintegrating agents, totaling 53% w: w of the tablet, specifically: 32% w/w low-substituted hydroxypropyl cellulose; 15% w/w crospovidone; And 6% w/w croscarmellose sodium. In some embodiments, the tablet contains 1.5% w/w magnesium stearate and 1% w/w colloidal silica. In some embodiments, the medicament is used at 25% w/w. In another embodiment, the medicament is used at 23% w/w. In some embodiments, when 25% w/w medicament is used, the amount of mannitol contained in the tablet is 19.5% w/w mannitol; and when 23% w/w medicament is used, the amount of mannitol contained in the tablet is The amount is 21.5% w/w mannitol.

在某些實施方式中，該方法還包括壓縮藥物組成物，從而形成片劑或微型片劑。在一些實施方式中，該方法還包括對片劑或微型片劑進行腸溶包衣，從而製備經腸溶包衣的片劑。在某些實施方式中，該方法還包括將微型片劑裝載到膠囊中。In certain embodiments, the method further includes compressing the pharmaceutical composition to form a tablet or mini-tablet. In some embodiments, the method further includes enteric coating the tablets or mini-tablets to prepare enteric-coated tablets. In certain embodiments, the method further includes loading the microtablets into the capsule.

本揭露部分地基於以下發現：一定量的一種或多種崩散劑（例如一種、兩種或三種崩散劑）可以改善包含細菌和細菌來源的試劑（例如組分）（例如，微生物胞外囊泡或mEV）的固體劑型的崩散時間。例如，對於包含給定量（例如劑量）的活性成分（例如細菌和細菌來源的試劑（例如組分）（例如，微生物胞外囊泡或mEV））的固體劑型，可以根據藥劑的給定製劑（例如，批次）中包含的活性成分的量來調節摻入固體劑型中的藥劑（其包含活性成分）的量。然後相應地調節稀釋劑（例如甘露醇）的量。例如，如果增加藥劑的量，則減少稀釋劑的量；並且反之亦然。如本文所述，可以對藥劑和稀釋劑的量進行調整，但是一種或多種崩散劑（例如，一種、兩種或三種崩散劑）的量保持恒定，例如，對於給定的固體劑型配方的批次之間。類似地，硬脂酸鎂和膠體二氧化矽的量也可以保持恒定，例如，對於給定的固體劑型配方的批次之間。The present disclosure is based in part on the discovery that a certain amount of one or more disintegrating agents (for example, one, two or three disintegrating agents) can improve agents (for example, components) containing bacteria and bacterial origin (for example, microbial extracellular vesicles or mEV) the disintegration time of the solid dosage form. For example, for a solid dosage form containing a given amount (such as a dose) of active ingredients (such as bacteria and bacteria-derived reagents (such as components) (such as microbial extracellular vesicles or mEV)), the dosage form can be tailored according to the dosage ( For example, the amount of active ingredient contained in the batch) adjusts the amount of medicament (which contains the active ingredient) incorporated into the solid dosage form. Then adjust the amount of diluent (e.g. mannitol) accordingly. For example, if the amount of medicament is increased, the amount of diluent is decreased; and vice versa. As described herein, the amount of medicament and diluent can be adjusted, but the amount of one or more disintegrants (for example, one, two, or three disintegrants) remains constant, for example, for a given batch of solid dosage formulations Between times. Similarly, the amount of magnesium stearate and colloidal silica can also be kept constant, for example, between batches of a given solid dosage formulation.

例如，在本文提供的工作實例中，使用含有小韋榮氏球菌粉末的藥劑來製備兩種片劑固體劑型。在這兩種製劑中，三種崩散劑總計為片劑的53%（w : w），具體地：32%低取代羥丙基纖維素；15%交聚維酮；和6%交聯羧甲基纖維素鈉。另外，兩種製劑中的硬脂酸鎂和膠體二氧化矽各自分別為1.5%和1%。然而在一種製劑中，使用了8%藥劑。在另一種製劑中，使用了25%藥劑。為了針對不同的藥劑量進行調節，甘露醇的量也不同：當使用8%藥劑時，36.5%甘露醇；當使用25%藥劑時，19.5%甘露醇。For example, in the working example provided herein, two solid dosage forms of tablets are prepared using a medicament containing Verionella minor powder. In these two formulations, the three disintegrating agents totaled 53% (w: w) of the tablet, specifically: 32% low-substituted hydroxypropyl cellulose; 15% crospovidone; and 6% croscarmellose Base cellulose sodium. In addition, the magnesium stearate and colloidal silica in the two preparations were 1.5% and 1%, respectively. However, in one formulation, 8% of the agent was used. In another formulation, 25% of the medicament was used. In order to adjust for different dosages, the amount of mannitol is also different: when using 8% medicament, 36.5% mannitol; when using 25% medicament, 19.5% mannitol.

作為另一個實例，在本文提供的工作實例中，使用含有棲組織普雷沃菌粉末的藥劑來製備兩種片劑固體劑型。在這兩種製劑中，三種崩散劑總計為片劑的53%（w : w），具體地：32%低取代羥丙基纖維素；15%交聚維酮；和6%交聯羧甲基纖維素鈉。另外，兩種製劑中的硬脂酸鎂和膠體二氧化矽各自分別為1.5%和1%。然而在一種製劑中，使用了25%藥劑。在另一種製劑中，使用了23%藥劑。為了針對不同的藥劑量進行調節，甘露醇的量也不同：當使用25%藥劑時，19.5%甘露醇；當使用23%藥劑時，21.5%甘露醇。 定義As another example, in the working example provided herein, a medicament containing Prevotella histosi powder is used to prepare two solid dosage forms of tablets. In these two formulations, the three disintegrating agents totaled 53% (w: w) of the tablet, specifically: 32% low-substituted hydroxypropyl cellulose; 15% crospovidone; and 6% croscarmellose Base cellulose sodium. In addition, the magnesium stearate and colloidal silica in the two preparations were 1.5% and 1%, respectively. However, in one formulation, 25% of the agent was used. In another formulation, 23% of the drug was used. In order to adjust for different dosages, the amount of mannitol is also different: when using 25% of the drug, 19.5% mannitol; when using 23% of the drug, 21.5% of mannitol. definition

「佐劑」或「輔助療法」在廣義上係指影響受試者（例如人類）中的免疫學或生理學應答的藥劑。例如，佐劑可增加抗原隨時間或在目的區域（如腫瘤）中的存在，幫助吸收抗原呈遞細胞抗原，活化巨噬細胞及淋巴細胞並且支持細胞介素的產生。藉由改變免疫應答，佐劑可允許使用較小劑量的免疫相互作用劑以增加特定劑量的免疫相互作用劑的有效性或安全性。例如，佐劑可預防T細胞耗竭且由此增加特定免疫相互作用劑的有效性或安全性。"Adjuvant" or "adjuvant therapy" in a broad sense refers to an agent that affects an immunological or physiological response in a subject (such as a human). For example, adjuvants can increase the presence of antigens over time or in target areas (such as tumors), help absorb antigen presenting cells, activate macrophages and lymphocytes, and support the production of cytokines. By altering the immune response, adjuvants can allow the use of smaller doses of immune interacting agents to increase the effectiveness or safety of specific doses of immune interacting agents. For example, adjuvants can prevent T cell exhaustion and thereby increase the effectiveness or safety of specific immune interacting agents.

「投與」廣義上係指將組成物（例如，藥物組成物，例如本文描述的藥劑的固體劑型）投與給受試者的途徑。投與途徑的實例包含口服投與、直腸投與、局部投與、吸入（經鼻）或注射。注射投與包含靜脈內（IV）、肌內（IM）、腫瘤內（IT）及皮下（SC）投與。本文描述的藥物組成物可以任何形式藉由任何有效途徑投與，包括（但不限於）瘤內、經口、非經腸、腸內、靜脈內、腹膜內、局部、經皮（例如，使用任何標準貼劑）、皮內、經眼、經鼻（鼻內）、局部、非經口（諸如噴霧）、吸入、皮下、肌內、頰、舌下、（經）直腸、陰道、動脈內及鞘內、經黏膜（例如，舌下、經舌、（經）頰、（經）尿道、陰道（例如，經陰道及陰道周圍）、植入、膀胱內、肺內、十二指腸內、胃內及支氣管內。在較佳的實施方式中，藉由以下形式投與本文描述的藥物組成物：經口、經直腸、經腫瘤內、經局部、經膀胱內、藉由注射至引流淋巴結中或毗鄰引流淋巴結處、經靜脈內、藉由吸入或氣溶膠或經皮下。在另一個較佳的實施方式中，本文描述的藥物組成物口服、瘤內或靜脈內投與。在另一個實施方式中，本文描述的藥物組成物經口服投與。"Administration" broadly refers to the route of administering a composition (eg, a pharmaceutical composition, such as a solid dosage form of an agent described herein) to a subject. Examples of administration routes include oral administration, rectal administration, topical administration, inhalation (nasal) or injection. Injection administration includes intravenous (IV), intramuscular (IM), intratumor (IT) and subcutaneous (SC) administration. The pharmaceutical compositions described herein can be administered in any form by any effective route, including (but not limited to) intratumoral, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (eg, use Any standard patch), intradermal, intraocular, nasal (intranasal), topical, parenteral (such as spray), inhalation, subcutaneous, intramuscular, cheek, sublingual, (trans) rectum, vagina, intraarterial And intrathecal, transmucosal (e.g., sublingual, translingual, (trans)buccal, (trans)urethra, vagina (e.g., transvaginal and around vagina), implantation, bladder, lung, duodenum, stomach And intrabronchial. In a preferred embodiment, the pharmaceutical composition described herein is administered in the following forms: oral, rectal, intratumor, local, intravesical, by injection into draining lymph nodes, or Adjacent to the draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously. In another preferred embodiment, the pharmaceutical composition described herein is administered orally, intratumorally or intravenously. In another embodiment Among them, the pharmaceutical composition described herein is administered orally.

如本文所用，術語「抗體」可指完整抗體及其抗原結合片段二者。完整抗體係包含由二硫鍵相互連接的至少兩條重（H）鏈及兩條輕（L）鏈的糖蛋白。每條重鏈包含重鏈可變區（在本文中縮寫為VH ）及重鏈恒定區。每條輕鏈包含輕鏈可變區（在本文中縮寫為VL ）及輕鏈恒定區。VH 及VL 區可進一步細分成超變區（稱為互補決定區（CDR））及更保守區（稱為框架區（FR）），二者散佈排列。每個VH 及VL 由三個CDR及四個FR構成，其自胺基-末端至羧基-末端按下列順序排列：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重鏈及輕鏈的可變區含有與抗原相互作用的結合結構域。術語「抗體」包含例如單株抗體、多株抗體、嵌合抗體、人類源化抗體、人類抗體、多特異性抗體（例如雙特異性抗體）、單鏈抗體及抗原結合抗體片段。As used herein, the term "antibody" can refer to both intact antibodies and antigen-binding fragments thereof. The complete antibody system comprises a glycoprotein of at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain includes a heavy chain variable region (abbreviated as V H herein) and a heavy chain constant region. Each light chain comprises a light chain variable region (abbreviated herein as V L) and a light chain constant region. V H and V L regions can be further subdivided into regions of hypervariability (termed complementarity determining regions (CDRs of)), and more conserved regions (termed framework regions (FR)), both dispersed arrangement. Each V H and V L four FR and three CDR configuration, the self-amino - terminus to the carboxy - terminus arranged in the following order: FR1, CDR1, FR2, CDR2 , FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The term "antibody" includes, for example, monoclonal antibodies, multiple antibodies, chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies (such as bispecific antibodies), single chain antibodies, and antigen-binding antibody fragments.

如本文所用，術語抗體的「抗原結合片段」及「抗原結合部分」係指抗體中保留結合抗原的能力的一個或多個片段。術語抗體的「抗原結合片段」內所涵蓋結合片段的實例包含Fab、Fab'、F(ab')2 、Fv、scFv、二硫化物連接的Fv、Fd、雙抗體、單鏈抗體、NANOBODIES®、經分離CDRH3及其他保留完整抗體的至少一部分可變區的抗體片段。該等抗體片段可使用常規重組和/或酶促技術來獲得且可以與完整抗體相同的方式針對抗原結合進行篩選。As used herein, the terms "antigen-binding fragment" and "antigen-binding portion" of an antibody refer to one or more fragments of the antibody that retain the ability to bind antigen. Examples of binding fragments covered by the term “antigen-binding fragment” of the antibody include Fab, Fab', F(ab') 2 , Fv, scFv, disulfide-linked Fv, Fd, diabodies, single-chain antibodies, NANOBODIES® , Isolated CDRH3 and other antibody fragments that retain at least a part of the variable region of the intact antibody. These antibody fragments can be obtained using conventional recombinant and/or enzymatic techniques and can be screened for antigen binding in the same way as intact antibodies.

「癌症」在廣義上係指宿主自有細胞的不受控、異常生長，其會侵襲宿主中的環繞組織及潛在地遠離異常細胞生長初始位點的組織。主要種類包含係上皮組織（例如皮膚、鱗狀細胞）癌症的癌瘤；係結締組織（例如骨、軟骨、脂肪、肌肉、血管等）癌症的肉瘤；係血液形成組織（例如骨髓組織）癌症的白血病；係免疫細胞癌症的淋巴瘤及骨髓瘤；及包含腦及脊柱組織癌症的中樞神經系統癌症。「一種或多種癌症」和「一種或多種贅瘤」在本文中可互換使用。如本文中所使用，「癌症」係指所有類型的新或復發癌症或贅瘤或惡性腫瘤，包含白血病、上皮癌及肉瘤。癌症的具體實例係：上皮癌、肉瘤、骨髓瘤、白血病、淋巴瘤及混合型腫瘤。癌症的非限制性實例係以下新或復發癌症：腦癌、黑色素瘤、膀胱癌、乳癌、子宮頸癌、大腸癌、頭頸癌、腎癌、肺癌、非小細胞肺癌、間皮瘤、卵巢癌、前列腺癌、肉瘤、胃癌、子宮癌及髓母細胞瘤。在一些實施方式中，癌症包括實性瘤。在一些實施方式中，癌症包括轉移。"Cancer" in a broad sense refers to the uncontrolled and abnormal growth of the host's own cells, which can invade surrounding tissues in the host and potentially far away from the initial site of abnormal cell growth. The main types include carcinomas of epithelial tissue (such as skin, squamous cell) cancer; sarcomas of connective tissue (such as bone, cartilage, fat, muscle, blood vessel, etc.) cancer; cancer of blood-forming tissues (such as bone marrow tissue) Leukemia; lymphoma and myeloma, which are cancers of immune cells; and central nervous system cancers, including cancers of brain and spine tissues. "One or more cancers" and "one or more neoplasms" are used interchangeably in this article. As used herein, "cancer" refers to all types of new or recurring cancers or neoplasms or malignant tumors, including leukemia, epithelial cancer, and sarcoma. Specific examples of cancer are epithelial cancer, sarcoma, myeloma, leukemia, lymphoma and mixed tumors. Non-limiting examples of cancers are the following new or recurrent cancers: brain cancer, melanoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, head and neck cancer, kidney cancer, lung cancer, non-small cell lung cancer, mesothelioma, ovarian cancer , Prostate cancer, sarcoma, gastric cancer, uterine cancer and medulloblastoma. In some embodiments, the cancer includes solid tumors. In some embodiments, the cancer includes metastasis.

「碳水化合物」係指糖或糖聚合物。術語「糖」、「多糖」、「碳水化合物」及「寡糖」可互換使用。大部分碳水化合物係具有許多羥基的醛或酮，通常在分子的每一碳原子上具有一個羥基。碳水化合物通常具有分子式Cn H2n On 。碳水化合物可為單糖、二糖、三糖、寡糖或多糖。最基本的碳水化合物係單糖，例如葡萄糖、蔗糖、半乳糖、甘露糖、核糖、阿拉伯糖、木糖及果糖。二糖係兩個接合的單糖。示例性二糖包含蔗糖、麥芽糖、纖維二糖及乳糖。通常，寡糖包含3至6個單糖單元（例如棉子糖、水蘇糖），且多糖包含6個或更多個單糖單元。示例性多糖包含澱粉、糖原及纖維素。碳水化合物可含有經修飾糖單元，例如2’-去氧核糖，其中去除羥基，2’-氟核糖，其中羥基經氟代替；或N-乙醯基葡萄糖胺，其為葡萄糖的含氮形式（例如2’-氟核糖、去氧核糖及己糖）。碳水化合物可以許多不同形式存在，例如構象異構物、環狀形式、非環狀形式、立體異構物、互變異構物、端基差向異構物及異構物。"Carbohydrates" refer to sugars or sugar polymers. The terms "sugar", "polysaccharide", "carbohydrate" and "oligosaccharide" are used interchangeably. Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually with one hydroxyl group on each carbon atom of the molecule. Carbohydrates generally have the molecular formula C n H 2n O n . Carbohydrates can be monosaccharides, disaccharides, trisaccharides, oligosaccharides or polysaccharides. The most basic carbohydrates are monosaccharides, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose and fructose. Disaccharides are two joined monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose. Generally, oligosaccharides contain 3 to 6 monosaccharide units (for example, raffinose, stachyose), and polysaccharides contain 6 or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified sugar units, such as 2'-deoxyribose, where the hydroxyl group is removed, 2'-fluororibose, where the hydroxyl group is replaced by fluorine; or N-acetylglucosamine, which is the nitrogen-containing form of glucose ( Such as 2'-fluororibose, deoxyribose and hexose). Carbohydrates can exist in many different forms, such as conformational isomers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomeric epimers, and isomers.

「細胞增強」廣泛地指細胞的流入或細胞在環境中的擴增，該等細胞在投與組成物之前大體上不存在於該環境中且不存在於該組成物本身中。增強環境的細胞包括免疫細胞、基質細胞、細菌及真菌細胞。特別受關注的環境係其中癌細胞駐留或定位的微環境。在一些實例中，該微環境係腫瘤微環境或腫瘤引流淋巴結。在其他實例中，該微環境係癌前組織位點或組成物的局部投與位點或其中該組成物在遠端投與後將積聚的位點。"Cell enhancement" broadly refers to the influx of cells or the expansion of cells in an environment where the cells are substantially not present in the environment and not in the composition itself before administration of the composition. Cells that enhance the environment include immune cells, stromal cells, bacteria and fungal cells. The environment of particular concern is the microenvironment in which cancer cells reside or locate. In some examples, the microenvironment is a tumor microenvironment or tumor draining lymph nodes. In other examples, the microenvironment is a precancerous tissue site or a local administration site of a composition or a site where the composition will accumulate after remote administration.

「進化枝」指系統發育樹的OTU或成員，它們係系統發育樹中的統計有效節點的下游。進化枝包含系統發育樹中的一組末端葉，其係不同的單系進化單元且在某種程度上共用序列相似性。"Clades" refer to the OTUs or members of the phylogenetic tree, which are downstream of the statistically valid nodes in the phylogenetic tree. A clade contains a group of terminal leaves in a phylogenetic tree, which are different monophyletic evolutionary units and share sequence similarity to some extent.

來自兩種或更多種菌株的細菌的「組合」包括細菌的物理共存（在相同材料或產品中或在物理連接的產品中），及來自兩種或更多種菌株的細菌的時間共投與或共定位。The "combination" of bacteria from two or more strains includes the physical coexistence of bacteria (in the same material or product or in physically connected products), and the time co-administration of bacteria from two or more strains Co-locate with or.

來自兩個或更多個微生物（例如細菌）菌株的mEV（例如smEV和/或pmEV）的「組合」包括從其獲得mEV（例如smEV和/或pmEV）的微生物在同一材料或產品中或在物理相連的產品中物理共存，以及來自兩個或更多個菌株的mEV（例如smEV和/或pmEV）在時間上共同投與或共同定位。The "combination" of mEV (such as smEV and/or pmEV) from two or more strains of microorganisms (such as bacteria) includes the microorganisms from which the mEV (such as smEV and/or pmEV) is obtained in the same material or product or in The physical coexistence of physically connected products, and the co-administration or co-location of mEVs from two or more strains (such as smEV and/or pmEV) in time.

術語「降低」或「消耗」意指變化，從而取決於治療後狀態與治療前狀態相比的差異為至少10%、20%、30%、40%、50%、60%、70%、80%、90%、1/100、1/1000、1/10,000、1/100,000、1/1,000,000或不可檢測。可降低的性質包含免疫細胞、細菌細胞、基質細胞、髓源性抑制細胞、成纖維細胞、代謝物的數量；細胞介素的水平；或另一物理參數（如耳厚度（例如，在DTH動物模型中）或腫瘤的大小）。The term "decrease" or "consumption" means a change, which depends on the difference between the state after treatment and the state before treatment of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80 %, 90%, 1/100, 1/1000, 1/10,000, 1/100,000, 1/1,000,000 or undetectable. The properties that can be reduced include the number of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; the level of cytokines; or another physical parameter (such as ear thickness (for example, in DTH animals) In the model) or the size of the tumor).

「菌群失調」係指腸道或其它身體區域的微生物群或微生物組的狀態，包括，例如，黏膜或皮膚表面（或任何其它微生物組生態位），在該狀態下宿主腸道微生物組生態網路「微生物組」的正常的多樣性和/或功能被破壞。菌群失調可能導致疾病狀態，或者僅在某些條件下或僅長期存在時可能是不健康的。菌群失調可能是由於多種因素引起的，包括環境因素、傳染原、宿主基因型、宿主飲食和/或壓力。菌群失調可能導致：一個或多個細菌類型（例如，厭氧菌）、物種和/或菌株的普遍度發生變化（例如，增加或減少），宿主微生物組群體組成的多樣性發生變化（例如，增加或減少）；導致一個或多個有益效應減少或喪失的一個或多個共生生物群體的變化（例如，增加或減少）；一個或多個病原體（例如，病原細菌）群體的過度生長；和/或僅在某些情況下引起疾病的共生生物的存在、和/或過度生長。"Bacterial dysbiosis" refers to the state of the microbiota or microbiome in the intestines or other body areas, including, for example, mucous membranes or skin surfaces (or any other microbiome niche), in which the host gut microbiome ecology The normal diversity and/or function of the Internet "microbiome" is disrupted. Bacterial dysbiosis may lead to disease states, or may be unhealthy only under certain conditions or only long-term. Bacterial imbalance may be caused by a variety of factors, including environmental factors, infectious agents, host genotype, host diet, and/or stress. Bacterial dysbiosis may result in: changes in the prevalence of one or more bacterial types (for example, anaerobic bacteria), species and/or strains (for example, increase or decrease), and changes in the diversity of the host microbiome population composition (for example , Increase or decrease); change (for example, increase or decrease) of one or more symbiotic organism groups that lead to a decrease or loss of one or more beneficial effects; overgrowth of one or more pathogen (for example, pathogenic bacteria) groups; And/or the presence of symbiotic organisms that cause disease only under certain circumstances, and/or overgrowth.

術語「生態聚生體（ecological consortium）」係交換代謝物且彼此正性共調控的一組細菌，這與經由激活互補宿主通路來誘導宿主協同作用以改進功效的兩種細菌形成對比。The term "ecological consortium" refers to a group of bacteria that exchange metabolites and positively co-regulate each other. This is in contrast to two bacteria that induce host synergy by activating complementary host pathways to improve efficacy.

術語「有效劑量」或「有效量」係對於特定的藥用劑、組成物和投與方式有效地在受試者中實現期望的治療應答的藥劑的量。The term "effective dose" or "effective amount" refers to the amount of an agent that is effective to achieve a desired therapeutic response in a subject for a particular pharmaceutical agent, composition, and mode of administration.

如本文所用，「工程改造的細菌」係藉由人類活動已在遺傳上自天然狀態改變的任何細菌及任何這類細菌的子代。工程改造的細菌包括例如靶向遺傳修飾的產物、隨機誘變篩選的產物及定向演化的產物。As used herein, "engineered bacteria" are any bacteria that have been genetically altered from their natural state through human activities and the progeny of any such bacteria. Engineered bacteria include, for example, targeted genetic modification products, random mutagenesis screening products, and directed evolution products.

術語「表位」意指可特異性結合至抗體或T細胞受體的蛋白質決定子。表位通常由如胺基酸或糖側鏈等分子的化學活性表面分組組成。某些表位可藉由抗體能夠結合的胺基酸的特定序列來定義。The term "epitope" means a protein determinant that can specifically bind to an antibody or T cell receptor. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains. Certain epitopes can be defined by the specific sequence of amino acids that the antibody can bind to.

術語「基因」在廣義上用於指與生物功能有關的任一核酸。術語「基因」適用於特定基因組序列以及由基因組序列編碼的cDNA或mRNA。The term "gene" is used in a broad sense to refer to any nucleic acid related to a biological function. The term "gene" applies to a specific genomic sequence and the cDNA or mRNA encoded by the genomic sequence.

兩種核酸分子的核酸序列間「同一性」可使用已知電腦演算法（諸如「FASTA」程式）使用（例如）如Pearson等人 (1988) Proc. Natl. Acad. Sci. USA [美國國家科學院院刊] 85: 2444中的預設參數測定為同一性百分比（其他套裝程式含GCG套裝程式（Devereux, J. 等人, Nucleic Acids Research [核酸研究] 12 (I): 387 (1984)）、BLASTP、BLASTN、FASTA Atschul, S. F. 等人, J Molec Biol [分子生物學雜誌] 215: 403 (1990)；Guide to Huge Computers [巨型電腦指南], Mrtin J. Bishop編輯, Academic Press [學術出版社], San Diego [聖地牙哥], 1994及Carillo等人 (1988) SIAM J Applied Math [工業和應用數學學會應用數學雜誌] 48: 1073）。例如，可使用國家生物技術資訊中心資料庫（National Center for Biotechnology Information database）的BLAST功能來測定同一性。其他可商業或揭露獲得的套裝程式含DNAStar 「MegAlign」程式（威斯康辛州麥迪森市（Madison, Wis.））及威斯康辛大學遺傳學電腦集團（University of Wisconsin Genetics Computer Group）（UWG）「Gap」程式（威斯康辛州麥迪森市（Madison, Wis.））。The "identity" between the nucleic acid sequences of two nucleic acid molecules can be used using known computer algorithms (such as the "FASTA" program) (for example) such as Pearson et al. (1988) Proc. Natl. Acad. Sci. USA [National Academy of Sciences Journal] 85: 2444 The default parameter is determined as the identity percentage (other packages include the GCG package (Devereux, J. et al., Nucleic Acids Research 12 (I): 387 (1984)), BLASTP, BLASTN, FASTA Atschul, SF, etc., J Molec Biol [Journal of Molecular Biology] 215: 403 (1990); Guide to Huge Computers [Guide to Huge Computers], edited by Mrtin J. Bishop, Academic Press [Academic Press] , San Diego [San Diego], 1994 and Carillo et al. (1988) SIAM J Applied Math [Society of Industrial and Applied Mathematics Journal of Applied Mathematics] 48: 1073). For example, the BLAST function of the National Center for Biotechnology Information database can be used to determine identity. Other commercially available or publicly available packages include the DNAStar "MegAlign" program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG) "Gap" program (Madison, Wis.).

如本文中所使用，術語「免疫障礙」係指由免疫系統的活動引起的任何疾病、障礙或疾病症狀，包括自體免疫性疾病、炎性疾病及過敏。免疫障礙包括（但不限於）自體免疫性疾病（例如，牛皮癬、特應性皮炎、狼瘡、硬皮病、溶血性貧血、血管炎、一型糖尿病、格雷夫病（Grave’s disease）、類風濕性關節炎、多發性硬化、古德帕斯雷綜合症（Goodpasture’s syndrome）、惡性貧血和/或肌病）、炎性疾病（例如，尋常型痤瘡、氣喘、乳糜瀉、慢性前列腺炎、腎小球性腎炎、炎性腸病、盆腔炎、再灌注損傷、類風濕性關節炎、肉狀瘤病、移植排斥、血管炎和/或間質性膀胱炎），和/或過敏（例如，食物過敏、藥物過敏和/或環境過敏）。As used herein, the term "immune disorder" refers to any disease, disorder, or disease symptoms caused by the activity of the immune system, including autoimmune diseases, inflammatory diseases, and allergies. Immune disorders include (but are not limited to) autoimmune diseases (for example, psoriasis, atopic dermatitis, lupus, scleroderma, hemolytic anemia, vasculitis, type 1 diabetes, Grave's disease, rheumatoid Arthritis, multiple sclerosis, Goodpasture’s syndrome, pernicious anemia and/or myopathy), inflammatory diseases (e.g., acne vulgaris, asthma, celiac disease, chronic prostatitis, renal small Globular nephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis and/or interstitial cystitis), and/or allergies (for example, food Allergies, drug allergies and/or environmental allergies).

「免疫療法」係使用受試者的免疫系統以治療疾病（例如，免疫疾病、炎性疾病、代謝性疾病、癌症）的治療且包括（例如）檢查點抑制劑、癌症疫苗、細胞介素、細胞療法、CAR-T細胞及樹突細胞療法。"Immunotherapy" is a treatment that uses the subject's immune system to treat diseases (for example, immune diseases, inflammatory diseases, metabolic diseases, cancer) and includes (for example) checkpoint inhibitors, cancer vaccines, cytokines, Cell therapy, CAR-T cell and dendritic cell therapy.

術語「增加」意指變化，從而取決於治療後狀態大於治療前狀態至少10%、20%、30%、40%、50%、60%、70%、80%、90%、2倍、4倍、10倍、100倍、10^3倍、10^4倍、10^5倍、10^6倍和/或10^7倍的差別。可增加的性質包含免疫細胞、細菌細胞、基質細胞、髓源性抑制細胞、成纖維細胞、代謝物的數量；細胞介素的水平；或另一物理參數（如耳厚度（例如，在DTH動物模型中）或腫瘤的大小）。The term "increase" means a change, which depends on the state after treatment being greater than the state before treatment by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2 times, 4 Times, 10 times, 100 times, 10^3 times, 10^4 times, 10^5 times, 10^6 times, and/or 10^7 times. The properties that can be increased include the number of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; the level of cytokines; or another physical parameter (such as ear thickness (for example, in DTH animals) In the model) or the size of the tumor).

「先天免疫促效劑」或「免疫佐劑」係特異性靶向先天免疫受體（包括Toll樣受體（TLR）、NOD受體、RLR、C型凝集素受體、STING-cGAS通路組分、發炎體複合物）的小分子、蛋白質或其他藥劑。例如，LPS係細菌源的或合成的TLR-4促效劑且可使用鋁作為免疫刺激佐劑。免疫佐劑係特定種類的較寬泛佐劑或輔助療法。STING促效劑的實例包括（但不限於）2'3'-cGAMP、3'3'-cGAMP、c-di-AMP、c-di-GMP、2'2'-cGAMP及2'3'-cGAM(PS)2（Rp/Sp）（2'3'-cGAMP的雙硫代磷酸酯類似物的Rp、Sp異構物）。TLR促效劑的實例包括（但不限於）TLRl、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLRlO及TLRI l。NOD促效劑的實例包括（但不限於）：N-乙醯基胞壁醯基-L-丙胺醯基-D-異麩醯胺酸（胞壁醯二肽（MDP））、γ-D-麩氨醯基-內消旋-二胺基庚二酸（iE-DAP）及去胞壁醯肽（desmuramylpeptide（DMP））。"Innate immunity agonist" or "immune adjuvant" specifically targets innate immune receptors (including Toll-like receptors (TLR), NOD receptors, RLR, C-type lectin receptors, STING-cGAS pathway group Inflammation body complex) of small molecules, proteins or other drugs. For example, LPS is a bacterial or synthetic TLR-4 agonist and aluminum can be used as an immunostimulatory adjuvant. Immune adjuvants are specific types of broad adjuvants or adjuvant therapies. Examples of STING agonists include (but are not limited to) 2'3'-cGAMP, 3'3'-cGAMP, c-di-AMP, c-di-GMP, 2'2'-cGAMP and 2'3'- cGAM(PS)2(Rp/Sp) (Rp and Sp isomers of the phosphorodithioate analog of 2'3'-cGAMP). Examples of TLR agonists include (but are not limited to) TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, and TLRI1. Examples of NOD agonists include (but are not limited to): N-Acetyl Murayl-L-Alanine-D-Isoglutamic Acid (MDP (MDP)), γ-D -Glutaminyl-meso-diaminopimelic acid (iE-DAP) and desmuramylpeptide (DMP).

「內轉錄間隔區」或「ITS」係位於通常用於識別真核物種（特別地，真菌）的共同先質轉錄本上的結構核糖體RNA（rRNA）之間的一段非功能性RNA。形成核糖體的核的真菌的rRNA經轉錄為信號基因且由8S、5.8S及28S區域及分別在8S與5.8S之間及5.8S與28S區域之間的ITS4及5組成。如先前描述，在18S與5.8S之間及5.8S與28S區域之間的這類兩個雙譯基因嵌段（intercistronic segment）藉由剪接移除且出於條碼的目的在物種之間含有顯著變化（Schoch等人, Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi. [核糖體內轉錄間隔區（ITS）係真菌的通用DNA條碼標記] PNAS [美國國家科學院院刊] 109: 6241-6246.2012）。18S rDNA傳統上用於系統發育重建，然而ITS可發揮此功能，因為其通常是高度保守的，但含有高變區，該等高變區具有足夠的核苷酸多樣性來區分大多數真菌的屬及物種。"Internal transcribed spacer" or "ITS" is a segment of non-functional RNA located between structural ribosomal RNA (rRNA) usually used to identify common precursor transcripts of eukaryotic species (especially fungi). The rRNA of the fungus that forms the nucleus of the ribosome is transcribed into a signal gene and consists of 8S, 5.8S and 28S regions and ITS4 and 5 between 8S and 5.8S and between 5.8S and 28S respectively. As previously described, these two intercistronic segments between 18S and 5.8S and between 5.8S and 28S are removed by splicing and contain significant differences between species for barcode purposes. Change (Schoch et al., Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi. [Ribosomal internal transcribed spacer (ITS) is a universal DNA barcode marker for fungi] PNAS [Proceedings of the National Academy of Sciences] 109 : 6241-6246.2012). 18S rDNA is traditionally used for phylogenetic reconstruction, but ITS can perform this function because it is usually highly conserved, but contains hypervariable regions that have sufficient nucleotide diversity to distinguish most fungi. Genus and species.

術語「分離的」或「富集的」涵蓋具有以下特徵的微生物（例如細菌）、mEV（例如smEV和/或pmEV）或其他實體或物質：(1) 與在最初產生（不論在自然界中或在實驗環境中）時與其締合的至少一些組分分離，和/或 (2) 人工產生、製備、純化和/或製造。分離的微生物或mEV可與至少約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%或更多的其最初關聯的其他組分分離。在一些實施方式中，分離的微生物或mEV係大於約80%、約85%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%或大於約99%純的。如本文所用，物質基本上不含其他組分時係「純的」。術語「純化（purify）」、「進行純化（purifying）」及「純化的（purified）」係指已與在最初產生或生成（例如不論在自然界中或在實驗環境中）時或在其初始產生之後的任一時間期間與其締合的至少一些組分分離的微生物或mEV或其他材料。如果在產生時或在產生之後諸如自含有微生物或微生物群體的材料或環境分離，則該微生物或微生物群體或mEV可視為純化的，且純化的微生物或微生物群體或mEV可含有高達約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%或高於約90%的其他材料且仍視為「分離的」。在一些實施方式中，純化的微生物或微生物群體或mEV係大於約80%、約85%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%或大於約99%純的。在本文所提供微生物組成物的情況下，存在於該組成物中的一種或多種微生物類型可與獨立於一種或多種產生和/或存在於含有該微生物類型的材料或環境中的其他微生物來純化。微生物組成物及其微生物組分（例如mEV）通常純化自殘餘生境產物。The term "isolated" or "enriched" covers microorganisms (such as bacteria), mEV (such as smEV and/or pmEV) or other entities or substances that have In the experimental environment) at least some of the components associated with it are separated, and/or (2) artificially produced, prepared, purified and/or manufactured. The isolated microorganism or mEV can be associated with at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or more of its initial association The other components are separated. In some embodiments, the isolated microorganism or mEV is greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. As used herein, a substance is "pure" when it is substantially free of other components. The terms "purify", "purifying" and "purified" refer to the fact that it has been produced or produced (for example, in nature or in an experimental environment) or at the time of its initial production Microorganisms or mEVs or other materials separated from at least some of the components with which they are associated during any time thereafter. If it is isolated from a material or environment containing microorganisms or microbial populations at the time of production or after production, the microorganisms or microbial populations or mEVs can be regarded as purified, and the purified microorganisms or microbial populations or mEVs may contain up to about 10%, About 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more than about 90% of other materials are still considered "isolated." In some embodiments, the purified microorganism or microbial population or mEV line is greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%. %, about 97%, about 98%, about 99%, or greater than about 99% pure. In the case of the microbial composition provided herein, one or more types of microorganisms present in the composition can be purified from one or more other microorganisms that are produced and/or present in the material or environment containing the type of microorganisms. . Microbial composition and its microbial components (such as mEV) are usually purified from residual habitat products.

如本文所用，「脂質」包括脂肪、油、三酸甘油酯、膽固醇、磷脂質、和任何形式的脂肪酸（包括游離脂肪酸）。脂肪、油及脂肪酸可為飽和、不飽和（順式或反式）或部分不飽和（順式或反式）。As used herein, "lipids" include fats, oils, triglycerides, cholesterol, phospholipids, and any form of fatty acids (including free fatty acids). Fats, oils and fatty acids can be saturated, unsaturated (cis or trans) or partially unsaturated (cis or trans).

術語「LPS突變體或脂多糖突變體」廣泛地是指包括LPS損失的所選細菌。LPS喪失可能是由於與脂質A生物合成相關的基因如lpxA 、lpxC 和lpxD 的突變或破壞所致。包含LPS突變體的細菌可對胺基糖苷類和多黏菌素（多黏菌素B和黏菌素）係抗性的。The term "LPS mutant or lipopolysaccharide mutant" broadly refers to selected bacteria that include loss of LPS. The loss of LPS may be due to mutation or destruction of genes related to lipid A biosynthesis, such as lpxA , lpxC, and lpxD. Bacteria containing LPS mutants can be resistant to aminoglycosides and polymyxins (polymyxin B and colistin).

如本文所用的「代謝物」係指在任何細胞或微生物代謝反應中用作底物或作為產物化合物、組成物、分子、離子、輔助因子、催化劑或營養素產生自任何細胞或微生物代謝反應的任何及所有分子化合物、組成物、分子、離子、輔助因子、催化劑或營養素。As used herein, "metabolite" refers to any compound, composition, molecule, ion, cofactor, catalyst, or nutrient produced as a substrate or as a product in any metabolic reaction of cells or microorganisms. And all molecular compounds, components, molecules, ions, cofactors, catalysts or nutrients.

「微生物」係指表徵為古生菌、寄生蟲、細菌、真菌、微觀藻類、原生動物及與該生物體相關的發育階段或生命週期階段（例如，植物、孢子（包括孢子形成、休眠及萌發）、潛伏、生物膜）的任何天然或工程改造的生物體。腸道微生物的實例包括：葛氏放線菌（Actinomyces graevenitzii ）、齲齒放線菌（Actinomyces odontolyticus ）、嗜黏蛋白阿克曼氏菌（Akkermansia muciniphila ）、糞擬桿菌（Bacteroides caccae ） 、脆弱擬桿菌（Bacteroides fragilis ）、腐敗擬桿菌（Bacteroides putredinis ）、多形擬桿菌（Bacteroides thetaiotaomicron ）、普通擬桿菌（Bacteroides vultagus ）、青春雙歧桿菌（Bifidobacterium adolescentis ）、兩歧雙歧桿菌（Bifidobacterium bifidum ）、對沃氏嗜膽菌（Bilophila wadsworthia ）、布勞特氏菌屬（Blautia ）、丁酸弧菌屬（Butyrivibrio ）、纖細彎曲桿菌（Campylobacter gracilis ）、梭菌群III （Clostridia cluster III ）、梭菌群IV（Clostridia cluster IV ）、梭菌群IX （Clostridia cluster IX ）（胺基酸球菌科群（Acidaminococcaceae group ））、梭菌群XI （Clostridia cluster XI ）、梭菌群XIII （Clostridia cluster XIII ）（消化鏈球菌群（Peptostreptococcus group ））、梭菌群XIV （Clostridia cluster XIV ）、梭菌群XV （Clostridia cluster XV ）、產氣柯林斯菌（Collinsella aerofaciens ）、糞球菌屬（Coprococcus ）、桑氏棒狀桿菌（Corynebacterium sunsvallense ）、豬脫硫單胞菌（Desulfomonas pigra ）、產甲酸多爾氏菌（Dorea formicigenerans ）、長鏈多爾氏菌（Dorea longicatena ）、大腸桿菌（Escherichia coli ）、龐大真桿菌（Eubacterium hadrum ）、直腸真桿菌（Eubacterium rectale ）、普拉梭菌（Faecalibacteria prausnitzii ）、孿生球菌屬（Gemella ）、乳球菌屬（Lactococcus ）、蘭氏螺菌屬（Lanchnospira ）、柔膜細菌群XVI （Mollicutes cluster XVI ）、柔膜細菌群XVIII （Mollicutes cluster XVIII ）、普雷沃菌屬（Prevotella ）、黏滑羅氏菌（Rothia mucilaginosa ）、伶俐瘤胃球菌（Ruminococcus callidus ）、活潑瘤胃球菌（Ruminococcus gnavus ）、扭鏈瘤胃球菌（Ruminococcus torques ）及鏈球菌屬（Streptococcus ）。"Microorganism" refers to the developmental stage or life cycle stage characterized by archaea, parasites, bacteria, fungi, microalgae, protozoa, and related organisms (e.g., plants, spores (including sporulation, dormancy, and germination) ), latent, biofilm) any natural or engineered organism. Examples of intestinal microflora comprising: Gurley actinomycetes (Actinomyces graevenitzii), caries actinomycetes (Actinomyces odontolyticus), Listeria addicted mucin Ackerman (Akkermansia muciniphila), fecal Bacteroides (Bacteroides caccae), Bacteroides fragilis (Bacteroides fragilis , Bacteroides putredinis , Bacteroides thetaiotaomicron , Bacteroides vultagus , Bifidobacterium adolescentis , Bifidobacterium bifidum , Bifidobacterium bifidum, bile addicted bacteria (Bilophila wadsworthia), Escherichia Bulao Te (Blautia), Butyrivibrio (Butyrivibrio), slender Campylobacter (Campylobacter gracilis), Clostridium group III (Clostridia cluster III), Clostridium group IV ( Clostridia cluster IV), Clostridium group IX (Clostridia cluster IX) (amino acid cocci family group (Acidaminococcaceae group)), Clostridium group XI (Clostridia cluster XI), Clostridium group XIII (Clostridia cluster XIII) (peptostreptococcus group (Peptostreptococcus group)), Clostridium group XIV (Clostridia cluster XIV), Clostridium group XV (Clostridia cluster XV), Collinsella aerofaciens (Collinsella aerofaciens), the genus dung (Coprococcus), Sang's Corynebacterium (Corynebacterium sunsvallense , Desulfomonas pigra , Dorea formicigenerans , Dorea longicatena , Escherichia coli , Eubacterium hadrum , Eubacterium rectum ( Eubacterium rectale), C. Michel (Faecalibacteria prausnitzii), Lactococcus twins (Gemella), Lactococcus (Lactococcus), the genus gram spiro (Lanchnospira), mollicutes group XVI (Mollicutes cluster XVI), mollicutes group XVIII (Mollicutes cluster XVIII), Prevotella spp. (Prevotella), slimy Roche bacteria (Rothia mucilaginosa), smart Ruminococcus (Ruminococcus callidus), active Ruminococcus (Ruminococcus gnavus), twisted strand Ruminococcus (Ruminococcus torques) And Streptococcus ( Streptococcus ).

「微生物胞外囊泡」（mEV）可從微生物如細菌、古生菌、真菌、微藻、原生動物和寄生蟲獲得。在一些實施方式中，mEV從細菌獲得。mEV包括分泌型微生物胞外囊泡（smEV）和經加工的微生物胞外囊泡（pmEV）。「分泌型微生物胞外囊泡」（smEV）係來源於微生物的自然產生的囊泡。smEV由微生物脂質和/或微生物蛋白質和/或微生物核酸和/或微生物碳水化合物部分構成，並從培養上清液中分離。該等囊泡的自然產生可以藉由操縱細菌細胞正在培養的環境（例如，藉由培養基或溫度改變）來人為地增強（例如，增加）或減少。此外，smEV組成物可以被修飾以減少，增加，添加或去除微生物成分或外來物質，以改變功效、免疫刺激、穩定性、免疫刺激能力、穩定性、器官靶向性（例如，淋巴結）、吸收（例如，胃腸道）和/或產率（例如，由此改變功效）。如本文所用，術語「純化的smEV組成物」或「smEV組成物」係指smEV的製劑，其已經從源材料中發現的至少一種相關聯物質（例如，從至少一種其他微生物組分分離）或用於製備該製劑的任何方法中與smEV相關聯的任何材料分離。也可指針對特定組分已顯著富集的組成物。「經加工的微生物胞外囊泡」（pmEV）係從人工裂解的微生物（例如，細菌）純化的微生物膜組分（例如，已與其他胞內微生物細胞組分分離的微生物膜組分）的非天然存在的集合，並且其可包含根據純化方法而具有變化的或選定的尺寸範圍的顆粒。藉由化學破壞（例如，藉由溶菌酶和/或溶葡萄球菌素）和/或物理破壞（例如，藉由機械力）微生物細胞並藉由離心和/或超速離心或其他方法將微生物膜組分與胞內組分分離來獲得pmEV池。所得pmEV混合物含有富集的微生物膜及其組分（例如，外周締合的或完整的膜蛋白、脂質、聚糖、多糖、碳水化合物、其他聚合物），使得相對於完整微生物，微生物膜組分的濃度增加，並且胞內內容物的濃度降低（例如，稀釋）。對於革蘭氏陽性細菌，pmEV可以包括細胞膜或細胞質膜。對於革蘭氏陰性細菌，pmEV可以包括內膜和外膜。pmEV可以被修飾以增加純度，調節組成物中顆粒的尺寸，和/或被修飾以減少、增加、添加或去除微生物組分或外來物質，以改變功效、免疫刺激、穩定性、免疫刺激能力、穩定性、器官靶向性（例如淋巴結）、吸收（例如胃腸道）和/或產率（例如由此改變功效）。pmEV可以藉由添加、去除、富集或稀釋特定組分（包括來自相同或其他微生物的細胞內組分）被修飾。如本文所用，術語「純化的pmEV組成物」或「pmEV組成物」係指pmEV的製劑，其已經從源材料中發現的至少一種相關聯物質（例如，從至少一種其他微生物組分分離）或用於製備該製劑的任何方法中與pmEV相關聯的任何材料分離。也可指針對特定組分已顯著富集的組成物。"Microbial extracellular vesicles" (mEV) can be obtained from microorganisms such as bacteria, archaea, fungi, microalgae, protozoa and parasites. In some embodiments, mEV is obtained from bacteria. mEV includes secretory microbial extracellular vesicles (smEV) and processed microbial extracellular vesicles (pmEV). "Secretory microbial extracellular vesicles" (smEV) are naturally produced vesicles derived from microorganisms. smEV is composed of microbial lipids and/or microbial proteins and/or microbial nucleic acids and/or microbial carbohydrate fractions, and is separated from the culture supernatant. The natural production of these vesicles can be artificially enhanced (for example, increased) or reduced by manipulating the environment in which the bacterial cells are being cultured (for example, by medium or temperature changes). In addition, smEV composition can be modified to reduce, increase, add or remove microbial components or foreign substances to change efficacy, immune stimulation, stability, immune stimulation ability, stability, organ targeting (for example, lymph nodes), absorption (For example, gastrointestinal tract) and/or yield (for example, thereby altering efficacy). As used herein, the term "purified smEV composition" or "smEV composition" refers to a preparation of smEV that has at least one related substance found in the source material (for example, separated from at least one other microbial component) or Any material associated with smEV in any method used to prepare the formulation is separated. It can also refer to a composition that has been significantly enriched for a specific component. "Processed microbial extracellular vesicles" (pmEV) are microbial membrane components (eg, microbial membrane components that have been separated from other intracellular microbial cell components) purified from artificially lysed microorganisms (eg bacteria) A collection that is not naturally occurring, and it may contain particles of varying or selected size ranges depending on the purification method. By chemical destruction (for example, by lysozyme and/or lysostaphin) and/or physical destruction (for example, by mechanical force) microbial cells and by centrifugation and/or ultracentrifugation or other methods to set microbial membranes Separate from intracellular components to obtain pmEV pool. The resulting pmEV mixture contains enriched microbial membranes and their components (for example, peripherally associated or intact membrane proteins, lipids, glycans, polysaccharides, carbohydrates, and other polymers), so that compared to intact microorganisms, the microbial membrane composition The concentration of fraction increases, and the concentration of intracellular contents decreases (for example, dilution). For gram-positive bacteria, pmEV can include cell membranes or cytoplasmic membranes. For gram-negative bacteria, pmEV can include inner and outer membranes. pmEV can be modified to increase purity, adjust the size of particles in the composition, and/or be modified to reduce, increase, add, or remove microbial components or foreign substances to change efficacy, immune stimulation, stability, immune stimulation, Stability, organ targeting (e.g. lymph nodes), absorption (e.g. gastrointestinal tract) and/or yield (e.g. thereby altering efficacy). pmEV can be modified by adding, removing, enriching or diluting specific components (including intracellular components from the same or other microorganisms). As used herein, the term "purified pmEV composition" or "pmEV composition" refers to a preparation of pmEV that has at least one related substance (eg, separated from at least one other microbial component) that has been found in the source material or Any material associated with pmEV in any method used to prepare the formulation is separated. It can also refer to a composition that has been significantly enriched for a specific component.

「微生物組」廣泛地指棲居於受試者或患者的身體部位上或中的微生物。微生物組中的微生物可包括細菌、病毒、真核微生物和/或病毒。微生物組中的個別微生物可以是代謝活性、休眠、潛伏或作為孢子存在，可以浮游形式存在或存在於生物膜中，或可以可持續或短暫的方式存在於該微生物組中。該微生物組可以是共生或健康狀態微生物組或疾病狀態微生物組。該微生物組對受試者或患者而言可以是天然的，或該微生物組的組分可因健康狀態（例如，癌前狀態或癌狀態）或處理條件（例如，抗生素治療、暴露於不同微生物）的變化而經調整、引入或消耗。在一些方面中，該微生物組出現於黏膜表面。在一些方面中，該微生物組係腸道微生物組。在一些方面中，該微生物組係腫瘤微生物組。"Microbiome" broadly refers to microorganisms that inhabit the body parts of a subject or patient. The microorganisms in the microbiome may include bacteria, viruses, eukaryotic microorganisms, and/or viruses. Individual microorganisms in the microbiome can be metabolically active, dormant, latent, or exist as spores, can exist in a planktonic form or in a biofilm, or can exist in the microbiome in a sustainable or transient manner. The microbiome can be a symbiotic or healthy state microbiome or a disease state microbiome. The microbiome may be natural to the subject or patient, or the components of the microbiome may be dependent on health conditions (for example, precancerous or cancerous conditions) or treatment conditions (for example, antibiotic treatment, exposure to different microorganisms). ) Is adjusted, introduced or consumed. In some aspects, the microbiome appears on the mucosal surface. In some aspects, the microbiome is the gut microbiome. In some aspects, the microbiome is a tumor microbiome.

組織或樣本的「微生物組譜（microbiome profile）」或「微生物組特徵（microbiome signature）」係指微生物組的細菌組成的至少部分表徵。在一些實施方式中，微生物組譜指示是否至少2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100或更多個細菌菌株存在於微生物組中或不存在於微生物組中。在一些實施方式中，微生物組譜指示是否至少2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100或更多個癌症相關細菌菌株存在於樣本中。在一些實施方式中，微生物組譜指示樣本中檢測的各細菌菌株的相對量或絕對量。在一些實施方式中，微生物組譜係癌症相關微生物組譜。癌症相關微生物組譜係以比一般群體更大的頻率出現於患有癌症的受試者中的微生物組譜。在一些實施方式中，相較於正常存在於取自未患癌症的個體的在其他方面當量的組織或樣本的微生物組中的細菌，該癌症相關微生物組譜包含更大數量或量的癌症相關細菌。The "microbiome profile" or "microbiome signature" of a tissue or sample refers to at least a partial characterization of the bacterial composition of the microbiome. In some embodiments, the microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more bacterial strains are present in the microbiome or not in the microbiome. In some embodiments, the microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more cancer-related bacterial strains are present in the sample. In some embodiments, the microbiome profile indicates the relative or absolute amount of each bacterial strain detected in the sample. In some embodiments, the microbiome lineage is a cancer-related microbiome profile. The cancer-related microbiome spectrum appears in the microbiome spectrum of subjects with cancer at a greater frequency than the general population. In some embodiments, the cancer-associated microbiome profile includes a larger number or amount of cancer-associated bacteria than the bacteria normally present in the microbiome of a tissue or sample taken from an otherwise equivalent tissue or sample from an individual without cancer. germ.

關於細菌的「經修飾的」廣泛地指自野生型形式已經變化的細菌。細菌修飾可以產生自工程菌。細菌修飾的實例包括遺傳修飾、基因表現修飾、表型修飾、配製修飾、化學修飾及劑量或濃度。經改善的性質的實例描述於整個說明書中且包括（例如）減毒、營養缺陷、歸巢或抗原性。表型修飾可包括（以實例說明的）細菌於修飾細菌的表型的培養基中生長使得其增加或降低毒力。"Modified" with regard to bacteria broadly refers to bacteria that have changed from the wild-type form. Bacterial modifications can be produced from engineered bacteria. Examples of bacterial modifications include genetic modification, gene expression modification, phenotypic modification, formulation modification, chemical modification, and dosage or concentration. Examples of improved properties are described throughout the specification and include, for example, attenuation, auxotrophy, homing, or antigenicity. Phenotypic modification may include (illustrated by way of example) the growth of bacteria in a medium that modifies the phenotype of the bacteria so that they increase or decrease virulence.

如本文中所使用的「腫瘤生物群系（oncobiome）」包含致瘤和/或癌症相關微生物區，其中該微生物區包含病毒、細菌、真菌、原生生物、寄生蟲或其他微生物中的一種或多種。"Oncobiome" as used herein includes tumorigenic and/or cancer-related microbiota, wherein the microbiota contains one or more of viruses, bacteria, fungi, protists, parasites, or other microorganisms .

「腫瘤營養性（Oncotrophic）」或「嗜腫瘤（oncophilic）」微生物及細菌係與癌症微環境高度相關聯的微生物或存在於癌症微環境中的微生物。它們可被優先選擇用於所述環境中，優先在癌症微環境中生長或適應所述環境。"Oncotrophic" or "oncophilic" microorganisms and bacteria are microorganisms that are highly related to the cancer microenvironment or microorganisms that exist in the cancer microenvironment. They can be preferentially selected for use in the environment, preferentially grow in the cancer microenvironment or adapt to the environment.

「運算分類單元」及「OTU」係指系統發生樹中的末端葉且藉由核酸序列（例如整個基因組或特定基因序列及所有與此核酸序列在物種層面共用序列同一性的序列）來定義。在一些實施方式中，特定基因序列可為16S序列或16S序列的一部分。在其他實施方式中，對兩種實體的整個基因組進行定序並進行比較。在另一個實施方式中，可以基因方式比較所選區域（例如多基因座序列標籤（MLST）、特定基因或基因集）。對於16S而言，整個16S或一些16S可變區中共有 ≥ 97%平均核苷酸同一性的OTU可視為相同OTU。參見，例如Claesson MJ, Wang Q, O’Sullivan O, Greene-Diniz R, Cole JR, Ross RP, 和O’Toole PW. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions [使用串聯可變16S rRNA基因區解析高度複雜的微生物群組成的兩種下一代定序技術的比較]. Nucleic Acids Res [核酸研究] 38: e200. Konstantinidis KT, Ramette A及Tiedje JM. 2006. The bacterial species definition in the genomic era [基因組時代的細菌物種類定義]. Philos Trans R Soc Lond B Biol Sci [倫敦皇家學會B輯：生物科學哲學學報] 361: 1929-1940。對於完整基因組、MLST、特定基因（除16S外）或基因集而言，共有 ≥ 95%平均核苷酸同一性的OTU可視為相同OTU。例如參見Achtman M及Wagner M. 2008. Microbial diversity and the genetic nature of microbial species [微生物多樣性和微生物物種的遺傳性質]. Nat. Rev. Microbiol. [微生物自然評論] 6: 431-440. Konstantinidis KT, Ramette A及Tiedje JM. 2006. The bacterial species definition in the genomic era [基因組時代的細菌物種類定義]. Philos Trans R Soc Lond B Biol Sci [倫敦皇家學會B輯：生物科學哲學學報] 361: 1929-1940。通常藉由比較生物體之間的序列來定義OTU。通常，具有不超過95%序列同一性的序列並不視為形成相同OTU的一部分。還可藉由核苷酸標誌或基因、尤其高度保守基因（例如「管家」基因）或其組合的任一組合來表徵OTU。本文提供可分配（例如）屬、物種及系統發育進化枝的運算分類單元（OTU）。"Operational taxon" and "OTU" refer to the terminal leaves in the phylogenetic tree and are defined by nucleic acid sequences (for example, the entire genome or a specific gene sequence and all sequences that share sequence identity with this nucleic acid sequence at the species level). In some embodiments, the specific gene sequence may be a 16S sequence or a part of a 16S sequence. In other embodiments, the entire genomes of the two entities are sequenced and compared. In another embodiment, selected regions can be compared genetically (eg, multilocus sequence tags (MLST), specific genes or gene sets). For 16S, OTUs that share ≥ 97% average nucleotide identity in the entire 16S or some 16S variable regions can be regarded as the same OTU. See, for example, Claesson MJ, Wang Q, O'Sullivan O, Greene-Diniz R, Cole JR, Ross RP, and O'Toole PW. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions [Comparison of two next-generation sequencing technologies using tandem variable 16S rRNA gene regions to analyze highly complex microbial composition]. Nucleic Acids Res [Nucleic Acids Research] 38: e200. Konstantinidis KT, Ramette A and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci [The Royal Society of London Series B: Journal of the Philosophy of Biological Sciences] 361: 1929-1940. For complete genomes, MLST, specific genes (except 16S), or gene sets, OTUs that share ≥ 95% average nucleotide identity can be considered the same OTU. See, for example, Achtman M and Wagner M. 2008. Microbial diversity and the genetic nature of microbial species [Microbial diversity and the genetic nature of microbial species]. Nat. Rev. Microbiol. [Microbial Nature Review] 6: 431-440. Konstantinidis KT , Ramette A and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci [The Royal Society of London Series B: Journal of the Philosophy of Biological Sciences] 361: 1929 -1940. OTU is usually defined by comparing sequences between organisms. Generally, sequences with no more than 95% sequence identity are not considered to form part of the same OTU. OTU can also be characterized by any combination of nucleotide markers or genes, particularly highly conserved genes (such as "housekeeping" genes), or combinations thereof. This article provides operational taxa (OTU) that can be assigned (for example) genera, species, and phylogenetic clades.

如本文所用，如果基因在至少一些條件下在工程改造的細菌中的表現水平高於相同物種的野生型細菌在相同條件下的表現水平，則所述基因在細菌中「過度表現」。類似地，如果基因在至少一些條件下在工程改造的細菌中的表現水平低於相同物種的野生型細菌在相同條件下的表現水平，則該基因在細菌中「表現不足」。As used herein, if the expression level of a gene in the engineered bacteria under at least some conditions is higher than the expression level of the wild-type bacteria of the same species under the same conditions, the gene is "overexpressed" in the bacteria. Similarly, if the expression level of a gene in the engineered bacteria under at least some conditions is lower than the expression level of the wild-type bacteria of the same species under the same conditions, the gene is "underexpressed" in the bacteria.

術語「多核苷酸」及「核酸」可互換使用。它們係指任何長度的核苷酸的聚合形式（去氧核糖核苷酸或核糖核苷酸）或其類似物。多核苷酸可具有任何三維結構，且可實施任何功能。多核苷酸的非限制性實例如下：基因或基因片段的編碼或非編碼區域、定義自連鎖分析的多個基因座（loci）（基因座（locus））、外顯子、內含子、信使RNA（mRNA）、微小RNA（miRNA）、緘默RNA（siRNA）、轉移RNA、核糖體RNA、核糖酶、cDNA、重組多核苷酸、分支多核苷酸、質體、載體、任何序列的經分離的DNA、任何序列的經分離的RNA、核酸探針及引子。多核苷酸可包括經修飾核苷酸，例如甲基化核苷酸及核苷酸類似物。如果存在，則可在組裝聚合物之前或之後賦予對核苷酸結構的修飾。多核苷酸可藉由如與標記組分軛合而經進一步修飾。在本文提供的所有核酸序列中，U核苷酸可與T核苷酸互換。The terms "polynucleotide" and "nucleic acid" are used interchangeably. They refer to polymerized forms (deoxyribonucleotides or ribonucleotides) or their analogs of nucleotides of any length. A polynucleotide can have any three-dimensional structure and can perform any function. Non-limiting examples of polynucleotides are as follows: coding or non-coding regions of genes or gene fragments, multiple loci (locus) defined from linkage analysis, exons, introns, messengers RNA (mRNA), microRNA (miRNA), silent RNA (siRNA), transfer RNA, ribosomal RNA, ribozyme, cDNA, recombinant polynucleotide, branched polynucleotide, plastid, vector, isolated of any sequence DNA, isolated RNA of any sequence, nucleic acid probes and primers. Polynucleotides may include modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. Polynucleotides can be further modified by, for example, conjugation with labeling components. In all nucleic acid sequences provided herein, U nucleotides can be interchanged with T nucleotides.

如本文所用，術語「預防」受試者中的疾病或病症係指對受試者投與藥劑治療，例如，投與一種或多種藥劑（例如，藥劑），使得疾病或病症的至少一個症狀的發作被延遲或預防。As used herein, the term "preventing" a disease or disorder in a subject refers to administering a drug treatment to the subject, for example, administering one or more medicaments (e.g., medicament), so that at least one symptom of the disease or disorder Onset is delayed or prevented.

如本文所用，物質基本上不含其他組分時係「純的」。術語「純化（purify）」或「進行純化（purifying）」及「純化的（purified）」係指mEV（例如smEV和/或pmEV）製劑或其他材料已與最初產生或形成（例如，無論在自然中或在實驗環境中）時或在初始產生後的任何時間期間與的相關聯的至少一些組分分離。若如果mEV（例如smEV和/或pmEV）製劑或組成物在產生時或產生後與（諸如）一種或多種其他細菌組分分離，則該mEV（例如smEV）製劑或組成物可被視為純化的，並且純化的微生物或微生物群體可含有其他材料多達約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%或超過約90%且仍被視為「純化的」。在一些實施方式中，純化的mEV（例如smEV和/或pmEV）超過約80%、約85%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%或超過約99%純。mEV（例如smEV和/或pmEV）組成物（或製劑）例如從殘餘生境產物純化。As used herein, a substance is "pure" when it is substantially free of other components. The terms "purify" or "purifying" and "purified" refer to mEV (such as smEV and/or pmEV) preparations or other materials that have been originally produced or formed (for example, whether in nature At least some of the components associated with it are separated from each other while in the experimental environment or during any time after the initial generation. If a mEV (eg smEV and/or pmEV) preparation or composition is separated from, for example, one or more other bacterial components during or after production, the mEV (eg smEV) preparation or composition can be considered purified , And the purified microorganisms or microbial populations may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% Or more than about 90% and still considered "purified". In some embodiments, the purified mEV (eg smEV and/or pmEV) exceeds about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, About 96%, about 97%, about 98%, about 99%, or more than about 99% pure. The mEV (eg smEV and/or pmEV) composition (or preparation) is, for example, purified from residual habitat products.

如本文中所使用，術語「純化的mEV組成物」或「mEV組成物」係指如下的製劑：其包括已與源材料或在用以產生該製劑的任何方法中與mEV（例如smEV和/或pmEV）相關聯的任何材料中發現的至少一種相關聯物質分離（例如，與至少一種其他細菌組分分離）的mEV（例如smEV和/或pmEV）。它還指已經顯著富集或濃縮的組成物。在一些實施方式中，mEV（例如smEV和/或pmEV）被濃縮2倍、3倍、4倍、5倍、10倍、100倍、1000倍、10,000倍或超過10,000倍。As used herein, the term "purified mEV composition" or "mEV composition" refers to a preparation that has been combined with a source material or in any method used to produce the preparation with mEV (such as smEV and/ Or pmEV) mEVs (eg smEV and/or pmEV) that are separated (eg, separated from at least one other bacterial component) of at least one related substance found in any of the related materials. It also refers to a composition that has been significantly enriched or concentrated. In some embodiments, mEV (eg, smEV and/or pmEV) is concentrated by 2 times, 3 times, 4 times, 5 times, 10 times, 100 times, 1000 times, 10,000 times, or more than 10,000 times.

「殘餘生境產物」係指自受試者內或受試者上的微生物群生境衍生的材料。例如，微生物的發酵培養物可以含有污染物，例如其他微生物菌株或形式（例如細菌、病毒、支原體和/或真菌）。例如，微生物生存於胃腸道的糞便中、皮膚本身上、唾液中、呼吸道的黏液中或泌尿生殖道的分泌物中（即，與微生物群落相關聯的生物物質）。基本上不含殘餘生境產物意指該微生物組成物不再含有與人類或動物受試者上或培養物中或人類或動物受試者中的微生物環境相關聯的生物物質且是100%不含、99%不含、98%不含、97%不含、96%不含或95%不含與該微生物群落相關聯的任何污染生物物質。殘餘生境產物可包括非生物材料（包括未經消化的食物）或其可包括非所需的微生物。基本上不含殘餘生境產物亦可意指該微生物組成物不含有來自培養物污染物或人類或動物的可檢測細胞且意指僅微生物細胞係可檢測的。在一項實施方式中，大體上不含殘餘生境產物亦可意指該微生物組成物不含有可檢測的病毒（包括細菌、病毒（例如，噬菌體））、真菌、支原體污染物。在另一個實施方式中，這意味著與微生物細胞相比，微生物組成物中少於1 x 10-2 %、1 x 10-3 %、1 x 10-4 %、1 x 10-5 %、1 x 10-6 %、1 x 10-7 %、1 x 10-8 %的活細胞係人或動物。達到此純度之方法有很多，該等方法中無任何一者係限制性的。因此，污染物可經由藉由在固體培養基上對單菌落進行多個畫線步驟，直至來自系列性單菌落的複製（例如但不限於兩個）畫線已顯示僅單一菌落形態來分離所需成分而減少。可替代地，污染物的減少可藉由多輪連續稀釋至單一所需細胞（例如，10-8 或10-9 的稀釋），諸如藉由多個10倍連續稀釋完成。此可藉由顯示多個經分離的菌落具有相似細胞形狀及革蘭氏染色行為進一步證實。用於證實足夠的純度的其他方法包括遺傳分析（例如，PCR、DNA定序）、血清學及抗原分析、酶及代謝分析及使用儀器之方法，諸如使用自污染物區分所需成分的試劑的流動式細胞測量術。"Residual habitat product" refers to materials derived from the habitat of the microbiota in or on the subject. For example, the fermentation culture of microorganisms may contain contaminants, such as other strains or forms of microorganisms (eg, bacteria, viruses, mycoplasma, and/or fungi). For example, microorganisms live in the feces of the gastrointestinal tract, on the skin itself, in saliva, mucus in the respiratory tract, or secretions in the genitourinary tract (ie, biological substances associated with the microbial community). Substantially free of residual habitat products means that the microbial composition no longer contains biological substances associated with the microbial environment on or in human or animal subjects or in the microbial environment in human or animal subjects and is 100% free , 99% free, 98% free, 97% free, 96% free or 95% free of any contaminating biological substances associated with the microbial community. Residual habitat products may include non-biological materials (including undigested food) or they may include undesired microorganisms. Substantially free of residual habitat products can also mean that the microbial composition does not contain detectable cells from culture contaminants or humans or animals and means that only microbial cell lines are detectable. In one embodiment, substantially free of residual habitat products may also mean that the microbial composition does not contain detectable viruses (including bacteria, viruses (for example, bacteriophages)), fungi, and mycoplasma contaminants. In another embodiment, this means that compared with microbial cells, there is less than 1 x 10 -2 %, 1 x 10 -3 %, 1 x 10 -4 %, 1 x 10 -5 %, 1 x 10 -6 %, 1 x 10 -7 %, 1 x 10 -8 % of living cell lines human or animal. There are many ways to achieve this purity, and none of them is restrictive. Therefore, the contaminants can be separated by performing multiple line drawing steps on a single colony on a solid medium until the duplicates (such as but not limited to two) from a series of single colonies have shown that only a single colony shape is drawn. The ingredients are reduced. Alternatively, the reduction of contaminants can be accomplished by multiple rounds of serial dilution to a single desired cell (for example, a 10 -8 or 10 -9 dilution), such as by multiple 10-fold serial dilutions. This can be further confirmed by showing that multiple isolated colonies have similar cell shapes and Gram staining behavior. Other methods used to verify sufficient purity include genetic analysis (eg, PCR, DNA sequencing), serological and antigen analysis, enzyme and metabolic analysis, and instrumental methods, such as the use of reagents that distinguish required components from contaminants Flow cytometry.

如本文所用，「特異性結合」係指抗體能夠結合至預定抗原或多肽能夠結合至其預定結合配偶體。通常，抗體或多肽以對應於約10-7 M或更小KD 的親和力特異性結合至其預定抗原或結合配偶體，且以相對於結合至非特異性及不相關抗原/結合配偶體（例如BSA、酪蛋白）小至少10倍、小至少100倍或不超過至少1000倍的其親和力的親和力（如藉由KD 所表示）結合至預定抗原/結合配偶體。可替代地，特異性結合更廣泛地適用於二組分系統，其中一種組分係蛋白質、脂質或碳水化合物或其組合且與係蛋白質、脂質、碳水化合物或其組合的第二組分以特定方式接合。As used herein, "specific binding" refers to an antibody capable of binding to a predetermined antigen or a polypeptide capable of binding to its predetermined binding partner. Generally, an antibody or polypeptide specifically binds to its predetermined antigen or binding partner with an affinity corresponding to a K D of about 10 -7 M or less, and binds to a non-specific and irrelevant antigen/binding partner ( For example, BSA, casein) binds to a predetermined antigen/binding partner with an affinity (as represented by K D ) that is at least 10 times smaller, at least 100 times smaller, or not more than at least 1000 times smaller. Alternatively, specific binding is more widely applicable to two-component systems, where one component is protein, lipid, or carbohydrate or a combination thereof, and the second component of the protein, lipid, carbohydrate, or combination thereof is specifically Way to join.

「菌株」係指具有基因簽名的細菌物種的成員，從而其可與相同細菌物種的密切相關成員區分開來。基因特徵可為不存在至少一種基因的全部或一部分、不存在至少一個調控區（例如啟動子、終止子、核糖開關、核糖體結合位點）的全部或一部分、不存在（「消除」）至少一種天然質體、存在至少一種重組基因、存在至少一種突變基因、存在至少一種外來基因（衍生自另一物種的基因）、存在至少一種突變調控區（例如啟動子、終止子、核糖開關、核糖體結合位點）、存在至少一種非天然質體、存在至少一種抗生素抗性盒或其組合。可藉由PCR擴增且視需要隨後進行一個或多個目的基因組區域或全基因組的DNA定序來鑒別不同菌株之間的基因簽名。如果一種菌株（與相同物種的另一種菌株相比）已獲得或失去抗生素抗性或獲得或失去生物合成能力（例如營養缺陷型菌株），則可藉由選擇或反選擇分別使用抗生素或營養物/代謝物來區分菌株。"Strain" refers to a member of a bacterial species that has a genetic signature so that it can be distinguished from closely related members of the same bacterial species. Gene characteristics can be the absence of all or part of at least one gene, the absence of all or part of at least one regulatory region (such as promoter, terminator, riboswitch, ribosome binding site), the absence ("elimination") of at least A natural plastid, the presence of at least one recombinant gene, the presence of at least one mutant gene, the presence of at least one foreign gene (a gene derived from another species), the presence of at least one mutation regulatory region (such as promoter, terminator, riboswitch, ribose Body binding site), the presence of at least one non-natural plastid, the presence of at least one antibiotic resistance cassette, or a combination thereof. The gene signatures between different strains can be identified by PCR amplification and subsequent DNA sequencing of one or more target genomic regions or the whole genome as needed. If a strain (compared to another strain of the same species) has acquired or lost antibiotic resistance or gained or lost biosynthetic capacity (such as auxotrophic strains), antibiotics or nutrients can be used by selection or counter-selection, respectively / Metabolites to distinguish strains.

術語「受試者」或「患者」係指任何哺乳動物。描述為「有需要」的受試者或患者係指需要治療（或預防）疾病的人。哺乳動物（即哺乳類動物）包括人、實驗室動物（例如靈長類動物、大鼠、小鼠）、家畜（例如牛、綿羊、山羊、豬）及家庭寵物（例如狗、貓、齧齒類動物）。受試者可以是人。受試者可為非人哺乳動物，包括但不限於：狗、貓、牛、馬、豬、驢、山羊、駱駝、小鼠、大鼠、天竺鼠、綿羊、駱馬、猴、大猩猩或黑猩猩。受試者可為健康的，或可患有任一發展階段的癌症，其中任一階段由癌症相關或致病病原體引起或伺機性地支持該病原體，或受試者可處於發生癌症或向其他受試者傳播癌症相關或癌症致病病原體的風險中。在一些實施方式中，受試者患有肺癌、膀胱癌、前列腺癌、漿細胞瘤、結直腸癌、直腸癌、默克爾細胞癌、唾液腺癌、卵巢癌和/或黑色素瘤。受試者可以具有腫瘤。受試者可以具有展示增強的大型胞飲作用的腫瘤，其中此過程的潛在基因組學包含Ras活化。在其他實施方式中，受試者患有另一種癌症。在一些實施方式中，受試者已經接受癌症療法。The term "subject" or "patient" refers to any mammal. A subject or patient described as "in need" refers to a person in need of treatment (or prevention) of the disease. Mammals (ie mammals) include humans, laboratory animals (such as primates, rats, mice), domestic animals (such as cows, sheep, goats, pigs) and household pets (such as dogs, cats, rodents) ). The subject can be a human. The subject can be a non-human mammal, including but not limited to: dog, cat, cow, horse, pig, donkey, goat, camel, mouse, rat, guinea pig, sheep, llama, monkey, gorilla or chimpanzee . The subject may be healthy, or may have cancer at any stage of development, where any stage is caused by a cancer-related or pathogenic pathogen or opportunistically supports the pathogen, or the subject may be in the development of cancer or other The subject is at risk of spreading cancer-related or cancer-causing pathogens. In some embodiments, the subject has lung cancer, bladder cancer, prostate cancer, plasmacytoma, colorectal cancer, rectal cancer, Merkel cell carcinoma, salivary gland cancer, ovarian cancer, and/or melanoma. The subject may have a tumor. The subject may have tumors that exhibit enhanced large pinocytosis, where the underlying genomics of this process involves Ras activation. In other embodiments, the subject has another cancer. In some embodiments, the subject has received cancer therapy.

如本文所用，在用包含本發明之細菌或mEV的藥劑（例如，包含細菌或mEV的藥劑）治療的受試者中的「系統性作用」係指在胃腸道外的一個或多個部位發生的生理作用。一種或多種系統性作用可以由免疫調節（例如，藉由增加和/或減少一種或多種免疫細胞類型或亞型（例如，CD8+ T細胞）和/或一種或多種細胞介素）產生。此類一種或多種系統性作用可能是由本發明之細菌或mEV對胃腸道中的免疫細胞或其它細胞（例如上皮細胞）調節的結果，然後這直接地或間接地導致胃腸道外的一個或多個生物化學途徑的活性改變（活化和/或失活）。系統性作用可包括治療或預防受試者的疾病或病症。As used herein, a "systemic effect" in a subject treated with an agent containing the bacteria or mEV of the present invention (for example, an agent containing bacteria or mEV) refers to the occurrence of one or more sites outside the gastrointestinal tract Physiological effects. One or more systemic effects can be produced by immunomodulation (eg, by increasing and/or decreasing one or more immune cell types or subtypes (eg, CD8+ T cells) and/or one or more cytokines). Such one or more systemic effects may be the result of the regulation of immune cells or other cells (such as epithelial cells) in the gastrointestinal tract by the bacteria or mEV of the present invention, and then this directly or indirectly leads to one or more organisms outside the gastrointestinal tract. Changes in the activity of chemical pathways (activation and/or inactivation). Systemic effects can include treating or preventing a disease or condition in the subject.

如本文中所使用，術語「治療」受試者疾病或「治療」患有或懷疑患有疾病的受試者係指對受試者投與醫藥治療（例如投與一種或多種藥劑），從而降低至少一種疾病症狀或預防其惡化。因此，在一個實施方式中，「治療」尤其是指延遲進展、促進緩解、誘導緩解、增大緩解、加速恢復、增加功效或降低替代治療的抗性，或其組合。As used herein, the term "treating" a subject's disease or "treating" a subject suffering or suspected of having a disease refers to the administration of a medical treatment (for example, administration of one or more agents) to the subject, thereby Reduce at least one disease symptom or prevent its deterioration. Therefore, in one embodiment, "treatment" especially refers to delaying progression, promoting remission, inducing remission, increasing remission, accelerating recovery, increasing efficacy or reducing resistance to alternative treatments, or a combination thereof.

如本文所使用的，如果一個值高出任何數量，則該值「大於」另一個值（例如，100、50、20、12、11、10.6、10.1、10.01和10.001中的每一個係至少10）。類似地，如本文所使用的，如果一個值低出任何數量，則該值「小於」另一個值（例如，1、2、4、6、8、9、9.2、9.4、9.6、9.8、9.9、9.99、9.999中的每一個係不超過10）。相反，如本文所使用的，當測試值四捨五入到錨定值時，測試值「係」錨定值（例如，如果「成分質量係總質量的10%」（在這種情況下，錨定值係10%），則測試值9.5、9.6、9.7、9.8、9.9、10、10.1、10.2、10.3和10.4也將滿足「成分質量係總質量的10%」特徵。 細菌As used herein, if one value is higher by any amount, the value is "greater than" the other value (for example, each of 100, 50, 20, 12, 11, 10.6, 10.1, 10.01, and 10.001 is at least 10 ). Similarly, as used herein, if one value is lower by any amount, then that value is "less than" another value (e.g., 1, 2, 4, 6, 8, 9, 9.2, 9.4, 9.6, 9.8, 9.9 Each of, 9.99 and 9.999 is no more than 10). Conversely, as used herein, when the test value is rounded to the anchor value, the test value "is" the anchor value (for example, if "the quality of the ingredient is 10% of the total mass" (in this case, the anchor value 10%), the test values 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, and 10.4 will also meet the characteristic of "10% of the total mass of the component mass". germ

本文揭露的藥物組成物的藥劑可以包含細菌和/或微生物胞外囊泡（mEV）（例如smEV和/或pmEV）。例如，本文揭露的藥物組成物的藥劑可以包含粉末，該粉末包含細菌和/或微生物胞外囊泡（mEV）（例如smEV和/或pmEV）。在包含細菌和mEV的藥劑中，mEV可以與藥劑的細菌來自相同的細菌起源（例如，相同的菌株）。藥劑可以包含來自一個或多個菌株的細菌和/或mEV。The medicament of the pharmaceutical composition disclosed herein may include bacteria and/or microbial extracellular vesicles (mEV) (for example, smEV and/or pmEV). For example, the medicament of the pharmaceutical composition disclosed herein may include a powder containing bacteria and/or microbial extracellular vesicles (mEV) (for example, smEV and/or pmEV). In the agent containing bacteria and mEV, the mEV may be from the same bacterial origin (eg, the same strain) as the bacteria of the agent. The medicament may comprise bacteria and/or mEV from one or more strains.

在一些實施方式中，對藥劑的細菌或藥劑的mEV自其獲得的細菌進行修飾以降低毒性或其他不利影響；提高遞送（例如口服遞送）（例如，藉由改良耐酸性、黏液黏著性和/或滲透性和/或對膽汁酸的抗性、消化酶、對抗微生物肽的抗性和/或抗體中和）；靶向所需細胞類型（例如，M細胞、杯狀細胞、腸上皮細胞、樹突細胞、巨噬細胞）；增強細菌和/或mEV的免疫調節和/或治療效果（例如單獨或與另一治療劑組合）；和/或藉由細菌和/或mEV（如smEV和/或pmEV）（例如藉由修飾地產生多糖、纖毛、傘毛、黏附素）增強免疫活化或抑制。在一些實施方式中，本文描述的工程改造的細菌被修飾以改善細菌和/或mEV（例如smEV和/或pmEV）製造（例如，更高的耐氧性、穩定性、改善的凍融耐受性、較短的產生時間）。例如，在一些實施方式中，本文描述的工程改造的細菌包括具有一種或多種遺傳改變的細菌，此改變包含於細菌染色體或內源性質體和/或一或多個外源性質體上的一或多個核苷酸的插入、刪除、易位或取代，或其任何組合，其中該遺傳改變可導致一或多個基因的過表現和/或低表現。工程改造的細菌可使用本領域中已知的任何技術產生，包括（但不限於）定點誘變、轉座子誘變、敲除、敲入、聚合酶鏈反應誘變、化學誘變、紫外線誘變、轉形（化學或藉由電穿孔）、噬菌體轉導、定向演化或其任何組合。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are modified to reduce toxicity or other adverse effects; improve delivery (e.g., oral delivery) (e.g., by improving acid resistance, mucus adhesion and/ Or permeability and/or resistance to bile acids, digestive enzymes, resistance to antimicrobial peptides, and/or neutralization of antibodies); targeting the desired cell types (e.g., M cells, goblet cells, intestinal epithelial cells, Dendritic cells, macrophages); enhance the immunomodulatory and/or therapeutic effects of bacteria and/or mEV (for example, alone or in combination with another therapeutic agent); and/or by bacteria and/or mEV (such as smEV and/or Or pmEV) (for example, by modifying the production of polysaccharides, cilia, fimbriae, adhesin) to enhance immune activation or suppression. In some embodiments, the engineered bacteria described herein are modified to improve the production of bacteria and/or mEVs (e.g., smEV and/or pmEV) (e.g., higher oxygen tolerance, stability, improved freeze-thaw tolerance Sex, short generation time). For example, in some embodiments, the engineered bacteria described herein include bacteria with one or more genetic alterations that are contained in one of the bacterial chromosomes or endogenous plastids and/or one or more exogenous plastids. Or insertions, deletions, translocations, or substitutions of multiple nucleotides, or any combination thereof, wherein the genetic alteration can lead to overexpression and/or underexpression of one or more genes. The engineered bacteria can be produced using any technique known in the art, including (but not limited to) site-directed mutagenesis, transposon mutagenesis, knockout, knock-in, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light Mutagenesis, transformation (chemically or by electroporation), phage transduction, directed evolution, or any combination thereof.

可用作本文描述的藥劑的細菌和/或mEV（例如smEV和/或pmEV）來源的細菌的分類學組（例如，綱、目、科、屬、種或菌株）的實例係本文提供的術語（例如，表1、表2和/或表3和/或說明書中其他地方（例如，表J）列舉的）。在一些實施方式中，細菌菌株係具有與本文列舉的菌株有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%序列同一性的基因組的細菌菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係腫瘤營養性細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係免疫調節細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係免疫刺激細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係免疫抑制細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係免疫調節細菌。在某些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係從本文提供的細菌菌株的組合產生的。在一些實施方式中，該組合係至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、20、25、30、35、40、45或50個細菌菌株的組合。在一些實施方式中，組合包括藥劑的細菌或藥劑的mEV自其獲得的細菌，該細菌來自本文列舉的細菌菌株和/或具有與本文列舉的（例如，表1、表2和/或表3中列舉的和/或說明書中其他地方（例如，表J）列舉的）菌株有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%序列同一性的基因組的細菌菌株。在某些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係從本文提供的細菌菌株產生的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌來自本文列舉的（例如，表1、表2和/或表3中列舉的和/或說明書中其他地方（例如，表J）列舉的）細菌菌株和/或具有與本文列舉的（例如，表1、表2和/或表3中列舉的和/或說明書中其他地方（例如，表J）列舉的）菌株有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%序列同一性的基因組的細菌菌株。Examples of the taxonomic group (eg, class, order, family, genus, species, or strain) of bacteria and/or mEV (eg smEV and/or pmEV)-derived bacteria that can be used as agents described herein are the terms provided herein (For example, as listed in Table 1, Table 2, and/or Table 3 and/or elsewhere in the specification (for example, Table J)). In some embodiments, the bacterial strain has a strain that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, Bacterial strains with genomes of 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are tumor vegetative bacteria. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are immunomodulatory bacteria. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are immunostimulatory bacteria. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are immunosuppressive bacteria. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are immunomodulatory bacteria. In certain embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are produced from a combination of bacterial strains provided herein. In some embodiments, the combination is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45 or A combination of 50 bacterial strains. In some embodiments, the combination includes the bacteria of the agent or the bacteria from which the mEV of the agent is obtained, the bacteria are derived from the bacterial strains listed herein and/or have the same as those listed herein (for example, Table 1, Table 2, and/or Table 3). At least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity of bacterial strains of the genome. In certain embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are produced from the bacterial strains provided herein. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are from those listed herein (e.g., listed in Table 1, Table 2 and/or Table 3 and/or elsewhere in the specification (e.g., Table J ) Listed) bacterial strains and/or strains that are at least 80 %, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, Bacterial strains with genomes of 99.6%, 99.7%, 99.8% or 99.9% sequence identity.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係革蘭氏陰性細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are Gram-negative bacteria.

在一些實施方式中，革蘭氏陰性細菌屬於Negativicutes 綱。Negativicutes 代表微生物的一個獨特綱，因為它們係厚壁菌門中唯一的雙層成員。該等厭氧生物可以在環境中發現，並且是人口腔和胃腸（GI）道的正常共生體。由於該等生物體具有外膜，因此對該綱的EV產率進行了研究。發現在以每個細胞為基礎，該等細菌產生大量的囊泡（10-150 EV/細胞）。來自該等生物的EV在體外測定中具有廣泛的刺激性和高效力。對其在幾種腫瘤學和炎症體內模型中治療性應用的研究顯示了其治療性潛力。Negativicutes 綱包括以下科：韋榮氏球菌科、月形單胞菌科、胺基酸球菌科和Sporomusaceae 科。Negativicutes 綱包括巨型球菌屬、月形單胞菌科屬、 Propionospora 屬和胺基酸球菌屬。示例性Negativicutes物種包括但不限於巨型球菌屬物種、菲利克斯月形單胞菌、腸胺基酸球菌、和Propionospora 屬物種。In some embodiments, the gram-negative bacteria belong to the class Negativicutes. Negativicutes represent a unique class of microorganisms because they are the only two-layer members of Firmicutes. These anaerobic organisms can be found in the environment and are normal symbiosis of the human oral cavity and gastrointestinal (GI) tract. Since these organisms have an outer membrane, the yield of EVs in this class was studied. It was found that on a per cell basis, these bacteria produced a large number of vesicles (10-150 EV/cell). EVs from these organisms have a wide range of irritation and high potency in in vitro assays. Research on its therapeutic application in several in vivo models of oncology and inflammation has shown its therapeutic potential. The class Negativicutes includes the following families: Veronococcus, Lunamonomonas, Aminoacidococcus and Sporomosaceae. The class of Negativicutes includes Megacoccus, Lunamonas , Propionospora, and Aminoacidococcus. Exemplary Negativicutes species include, but are not limited to, Megacoccus species, Selenomonas felix , Acidococcus enterica, and Propionospora species.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係革蘭氏陽性細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are Gram-positive bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係需氧細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are aerobic bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係厭氧細菌。在一些實施方式中，厭氧細菌包含專性厭氧菌。在一些實施方式中，厭氧細菌包含兼性厭氧菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係嗜酸細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are acidophilic bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係嗜鹼細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are alkaliphilic bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係嗜中性細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are neutrophils.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係難養細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is a dystrophic bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係非難養細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are non-difficult bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經凍乾的。In some embodiments, the bacteria of the agent or the mEV of the agent is obtained from the bacteria or the mEV itself is lyophilized.

在一些實施方式中，將藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身經γ照射（例如，以17.5或25 kGy）。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained or the mEV itself is γ-irradiated (for example, at 17.5 or 25 kGy).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經UV照射的。In some embodiments, the bacteria of the agent or the mEV of the agent is obtained from the bacteria or the mEV itself is UV-irradiated.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經熱滅活的（例如，在50°C下持續兩小時或在90°C下持續兩小時）。In some embodiments, the bacteria of the agent or the mEV of the agent are obtained from the bacteria or the mEV itself is heat-inactivated (eg, for two hours at 50°C or for two hours at 90°C).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經酸處理的。In some embodiments, the bacteria of the agent or the mEV of the agent is obtained from the bacteria or the mEV itself is acid-treated.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經氧噴射的（例如，以0.1 vvm進行兩小時）。In some embodiments, the bacteria of the agent or the mEV of the agent are obtained from the bacteria or the mEV itself is oxygen sprayed (for example, at 0.1 vvm for two hours).

生長階段會影響細菌和/或細菌產生的mEV的數量或性質。例如，在本文提供的mEV製備方法中，可以例如在對數生長期開始時、在對數生長期的中間時、和/或一旦達到穩定生長期時從培養物中分離mEV。The growth stage affects the amount or nature of the bacteria and/or mEV produced by the bacteria. For example, in the mEV preparation methods provided herein, the mEV can be isolated from the culture, for example, at the beginning of the logarithmic growth phase, in the middle of the logarithmic growth phase, and/or once the stable growth phase is reached.

在某些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌獲得自專性厭氧細菌。專性厭氧細菌的實例包括革蘭氏陰性桿菌（包括擬桿菌、普雷沃菌、卟啉單胞菌、梭桿菌、嗜膽菌及薩特氏菌屬物種的屬）、革蘭氏陽性球菌（主要為消化鏈球菌屬）、革蘭氏陽性孢子形成菌（梭菌屬）、非孢子形成桿菌（放線菌、丙酸桿菌、真桿菌、乳桿菌及雙歧桿菌屬）及革蘭氏陰性球菌（主要為韋榮氏球菌屬）。在一些實施方式中，專性厭氧細菌係選自由以下組成之群組的屬的細菌：阿加薩桿菌屬、奇異菌屬（Atopobium ）、布勞特氏菌屬（Blautia ）、伯克霍爾德菌屬（Burkholderia ）、迪爾莫菌屬（Dielma ）、長鏈菌屬（Longicatena ）、副梭菌屬（Paraclostridium ）、蘇黎世桿菌屬（Turicibacter ）及泰澤菌屬（Tyzzerella ）。In certain embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are obtained from obligate anaerobic bacteria. Examples of obligate anaerobic bacteria include Gram-negative bacilli (including genera of Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Gallophilus, and Sartreella species), Gram-positive Cocci (mainly Peptostreptococcus), Gram-positive spore-forming bacteria (Clostridium), non-spore-forming bacilli (actinomycetes, Propionibacterium, Eubacterium, Lactobacillus and Bifidobacterium) and Gram Negative cocci (mainly of the genus Veillonella). In some embodiments, the obligate anaerobic bacteria are bacteria of the genera selected from the group consisting of: Agathaea, Atopobium , Blautia , Burkho de genus (Burkholderia), the genus Dier Mo (Dielma), long-chain species (Longicatena), sub Clostridium (Paraclostridium), Zurich genus (Turicibacter) and taize genus (Tyzzerella).

Negativicutes 綱包括以下科：韋榮氏球菌科、月形單胞菌科、胺基酸球菌科和Sporomusaceae 科。Negativicutes 綱包括巨型球菌屬、月形單胞菌科屬、 Propionospora 屬和胺基酸球菌屬。示例性Negativicutes 物種包括但不限於巨型球菌屬物種、菲利克斯月形單胞菌、腸胺基酸球菌、和Propionospora 屬物種。 The class Negativicutes includes the following families: Veronococcus, Lunamonomonas, Aminoacidococcus and Sporomosaceae. The class of Negativicutes includes Megacoccus, Lunamonas , Propionospora, and Aminoacidococcus. Exemplary Negativicutes species include, but are not limited to, Megacoccus species, Selenomonas felix , Acidococcus enterica, and Propionospora species.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Negativicutes 綱。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class Negativicutes.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於韋榮氏球菌科。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Veillonella family.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌科。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the family Selenomonas.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於胺基酸球菌科。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained belongs to the Acidococcus family.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Sporomusaceae 科。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Sporomusaceae family.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於巨球形菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Macrosphaera.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained belongs to the genus Selenomonas.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Propionospora 屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Propionospora.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於胺基酸球菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belongs to the genus Acidococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係巨型球菌屬物種細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Megacoccus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係菲利克斯月形單胞菌細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Selenomonas felixus bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係腸胺基酸球菌細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Acidococcus enterica bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係Propionospora 屬物種細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Propionospora.

微生物梭菌綱中的顫螺旋菌科係脊椎動物的常見共生生物。A common symbiosis of vertebrates in the Oscillator family of the class of microorganisms Clostridium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Clostridia.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於顫螺旋菌科。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Oscillator family.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於糞桿菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Faecalis.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Fournierella 屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Fournierella.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Harryflintia 屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Harryflintia.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於阿加薩桿菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Argasa.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普氏棲糞桿菌（普氏棲糞桿菌菌株A）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Faeculus prasutii (Feccus prasutii strain A) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係Fournierella massiliensis （例如，Fournierella massiliensis 菌株A）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Fournierella massiliensis (for example, Fournierella massiliensis strain A) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係Harryflintia acetispora （例如，Harryflintia acetispora 菌株A）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Harryflintia acetispora (for example, Harryflintia acetispora strain A) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係阿加薩桿菌屬物種（例如，阿加薩桿菌屬物種菌株A）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Agathaea (for example, the genus Agathaea) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係選自由以下組成之群組的屬的細菌：大腸桿菌屬、克雷伯氏菌屬、乳桿菌屬、志賀氏菌屬和葡萄球菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genera selected from the group consisting of: Escherichia coli, Klebsiella, Lactobacillus, Shigella And Staphylococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係選自由以下組成之群組的物種：馬賽布勞特氏菌（Blautia massiliensis ）、解苯副梭菌（Paraclostridium benzoelyticum ）、Dielma fastidiosa 、Longicatena caecimuris 、乳酸乳球菌乳脂亞種、納西利斯泰澤菌（Tyzzerella nexilis ）、Hungatella effluvia 、類肺炎克雷伯氏菌擬肺炎亞種（Klebsiella quasipneumoniae subsp. Similipneumoniae ）、產酸克雷伯菌（Klebsiella oxytoca ）、和當別町韋榮氏球菌（Veillonella tobetsuensis ）。In some embodiments, the bacteria of the drug or the bacteria from which the mEV of the drug is obtained are species selected from the group consisting of: Blautia massiliensis , Paraclostridium benzoelyticum , Dielma fastidiosa, Longicatena caecimuris, Lactococcus lactis subspecies,纳西利斯泰Ze bacteria (Tyzzerella nexilis), Hungatella effluvia, like Klebsiella pneumoniae subspecies proposed (Klebsiella quasipneumoniae subsp. Similipneumoniae), acid Cray Klebsiella oxytoca , and Veillonella tobetsuensis .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，該普雷沃菌屬細菌選自由以下組成之群組：阿爾伯普雷沃菌、羊水普雷沃菌、貝根普雷沃菌、二路普雷沃菌、短普雷沃菌、布氏普雷沃菌、頰普雷沃菌、口頰普雷沃菌、糞便普雷沃菌、牙普雷沃菌、棲牙普雷沃菌、解糖腖普雷沃菌、棲組織普雷沃菌、中間普雷沃菌、小斑點普雷沃菌、馬斯普雷沃菌、產黑普雷沃菌、彩虹普雷沃菌、多形普雷沃菌、變黑普雷沃菌、口腔普雷沃菌、口普雷沃菌、齦炎普雷沃菌、蒼白普雷沃菌、唾液普雷沃菌、斯特塞拉普雷沃菌、坦納普雷沃菌、蒂莫普雷沃菌、空腸普雷沃菌、橙色普雷沃菌、保氏普雷沃菌、著色普雷沃菌、人體普雷沃菌、丹塔普雷沃菌、棲居普雷沃菌、斐氏普雷沃菌、深黑色普雷沃菌、解肝素普雷沃菌、洛氏普雷沃菌、嗜糖普雷沃菌、南錫普雷沃菌、稻普雷沃菌、沼澤普雷沃菌、胸膜炎普雷沃菌、棲瘤胃普雷沃菌、解糖普雷沃菌、靶心普雷沃菌、賽赫普雷沃菌、動膠普雷沃菌和真空腔普雷沃菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Prevotella, and the bacteria of the genus Prevotella are selected from the group consisting of: Prevotella alberis, Amniotic fluid Pravo bacillus, Prevotella bergeni, Prevotella breve, Prevotella breve, Prevotella brucei, Prevotella buccoli, Prevotella buccal, Prevotella feces, Prevotella dentata, Prevotella dentata, Prevotella saccharolyticum, Prevotella tissue, Prevotella intermedius, Prevotella microspot, Prevotella masprevot, black producing Prevotella, Rainbow Prevotella, Prevotella polymorpha, Prevotella blackened, Prevotella oral, Prevotella oralis, Prevotella gingivitis, Prevotella pallidum, Prevotella salivarius, Prevotella stasella, Prevotella tannera, Prevotella Timo, Prevotella jejuni, Prevotella orange, Prevotella paulownia, Prevotella spp Ralvobacterium, Prevotella human, Prevotella danta, Prevotella inhabiting, Prevotella fischeri, Prevotella nigra, Prevotella heparin, Prevotella loch Bacteria, Prevotella saccharophila, Prevotella nanxiensis, Prevotella oryzae, Prevotella marshes, Prevotella pleuriticus, Prevotella saccharolyticus, Prevotella saccharolyticus, Bullseye Revotella, Sahe Prevotella, Prevotella gelatinosa and Prevotella vaccum cavity.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係如下細菌菌株，該細菌菌株包含如下基因組序列，該基因組序列與表3中提供的以ATCC保藏號保藏的細菌菌株的基因組序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係如下細菌菌株，該細菌菌株包含如下16S序列，該16S序列與表3中提供的以ATCC保藏號保藏的細菌菌株的16S序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is the following bacterial strain, the bacterial strain includes the following genome sequence, and the genome sequence is the same as the genome of the bacterial strain deposited under the ATCC deposit number provided in Table 3. The sequence has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence Identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is the following bacterial strain, and the bacterial strain comprises the following 16S sequence, which is the same as the 16S of the bacterial strain deposited under the ATCC deposit number provided in Table 3. The sequence has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence Identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity).

Negativicutes 綱包括以下科：韋榮氏球菌科、月形單胞菌科、胺基酸球菌科和Sporomusaceae 科。Negativicutes 綱包括巨型球菌屬、月形單胞菌科屬、 Propionospora 屬和胺基酸球菌屬。示例性Negativicutes 物種包括但不限於巨型球菌屬物種、菲利克斯月形單胞菌、腸胺基酸球菌、和Propionospora 屬物種。 The class Negativicutes includes the following families: Veronococcus, Lunamonomonas, Aminoacidococcus and Sporomosaceae. The class of Negativicutes includes Megacoccus, Lunamonas , Propionospora, and Aminoacidococcus. Exemplary Negativicutes species include, but are not limited to, Megacoccus species, Selenomonas felix , Acidococcus enterica, and Propionospora species.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Negativicutes 綱。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class Negativicutes.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於韋榮氏球菌科。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Veillonella family.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌科。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the family Selenomonas.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於胺基酸球菌科。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained belongs to the Acidococcus family.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Sporomusaceae 科。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Sporomusaceae family.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於巨球形菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Macrosphaera.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained belongs to the genus Selenomonas.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Propionospora 屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Propionospora.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於胺基酸球菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belongs to the genus Acidococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係巨型球菌屬物種細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Megacoccus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係菲利克斯月形單胞菌細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Selenomonas felixus bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係腸胺基酸球菌細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Acidococcus enterica bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係Propionospora 屬物種細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Propionospora.

微生物梭菌綱中的顫螺旋菌科係脊椎動物的常見共生生物。A common symbiosis of vertebrates in the Oscillator family of the class of microorganisms Clostridium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Clostridia.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於顫螺旋菌科。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Oscillator family.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於糞桿菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Faecalis.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Fournierella 屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Fournierella.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Harryflintia 屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Harryflintia.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於阿加薩桿菌屬。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the genus Argasa.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普氏棲糞桿菌（普氏棲糞桿菌菌株A）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Faeculus prasutii (Feccus prasutii strain A) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係Fournierella massiliensis （例如，Fournierella massiliensis 菌株A）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Fournierella massiliensis (for example, Fournierella massiliensis strain A) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係Harryflintia acetispora （例如，Harryflintia acetispora 菌株A）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Harryflintia acetispora (for example, Harryflintia acetispora strain A) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係阿加薩桿菌屬物種（例如，阿加薩桿菌屬物種菌株A）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Agathaea (for example, the genus Agathaea) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係阿加薩桿菌屬物種的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係與阿加薩桿菌屬物種菌株A（ATCC保藏號PTA-125892）的核苷酸序列（例如，基因組序列、16S序列、CRISPR序列）具有至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係阿加薩桿菌屬物種菌株A（ATCC保藏號PTA-125892）細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is a strain of the genus Argasa. In some embodiments, the Agatha species strain and the Agatha species strain A (ATCC deposit number PTA-125892) have nucleotide sequences (eg, genome sequence, 16S sequence, CRISPR sequence) at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity With at least 99.9% sequence identity). In some embodiments, the Agatha species strain is the Agatha species strain A (ATCC deposit number PTA-125892) bacteria.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於擬桿菌綱[擬桿菌門]。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係擬桿菌目的細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於紫單胞菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於普雷沃菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係擬桿菌綱的細菌，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係擬桿菌綱、革蘭氏陰性染色的細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係擬桿菌綱的細菌，其中細菌係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Bacteroides [Bacteroides]. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the order Bacteroides. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Porphyridaceae family. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Prevotaceae. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the class Bacteroides, wherein the cell membrane structure of the bacteria is double-layered. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are Bacteroides, Gram-negative staining bacteria. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the class Bacteroides, wherein the bacteria are bilayered and the bacteria are Gram-negative staining.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係梭菌綱[厚壁菌門]的細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於真細菌目。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於顫螺旋菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於毛螺菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於消化鏈球菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌目XIII科/地位未定41。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱、革蘭氏陰性染色。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱、革蘭氏陽性染色。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的並且該細菌係革蘭氏陰性染色。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的並且該細菌係革蘭氏陽性染色。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the class Clostridium [Firmicutes]. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the order Eubacteria. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Oscillator family. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Lacetospiraceae. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Peptostreptococcaceae family. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Clostridium family XIII family/status undetermined 41. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Clostridia, in which the cell membrane structure of the bacteria is monolayer. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Clostridia, with Gram-negative staining. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Clostridia, with Gram-positive staining. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Clostridia, wherein the cell membrane structure of the bacteria is monolayer and the bacteria are Gram-negative staining. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Clostridia, in which the cell membrane structure of the bacteria is monolayer and the bacteria are Gram-positively stained.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Negativicutes 綱[厚壁菌門]。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於韋榮氏球菌目。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於韋榮氏球菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Selenomonadales 目。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係月形單胞菌科的細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Sporomusaceae 科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於Negativicutes 綱，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於藥劑的細菌或藥劑的mEV自其獲得的細菌係來自Negativicutes 綱的細菌的EV，其中細菌的細胞被膜結構係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained belongs to the class Negativicutes [Firmicutes]. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained belongs to the order Veillonella. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Veillonella family. In some embodiments, the bacteria of the medicament or the bacteria from which the mEV of the medicament is obtained belong to the order Selenononadales . In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained is a bacterium of the family Selenomonas. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the Sporomusaceae family. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class Negativicutes , in which the cell membrane structure of the bacteria is double-layered. In some embodiments, the bacteria of the drug or the mEV of the drug are derived from the bacteria belonging to the bacteria of the drug or the mEV of the drug is derived from the bacteria derived from the EV of the bacteria of the class Negativicutes , in which the cell membrane structure of the bacteria is double-layered And the bacteria are Gram-negative staining.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌綱[互養菌門]。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌目。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌綱，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌綱、革蘭氏陰性染色。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌綱，其中細菌的細胞被膜結構係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Syntrophic Bacteria [Cotrophic Bacteria]. In some embodiments, the bacteria of the medicament or the bacteria from which the mEV of the medicament is obtained belong to the order Syntrophic bacteria. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the family of the family of syntrophic bacteria. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of the syntrophic bacteria, in which the cell membrane structure of the bacteria is double-layered. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Syntrophic Bacteria with Gram-negative staining. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained belong to the class of Syntrophic bacteria, in which the cell membrane structure of the bacteria is double-layered and the bacteria are Gram-negative staining.

在某些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌來自一種細菌菌株，例如本文提供的一種菌株。In certain embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained is from a bacterial strain, such as a strain provided herein.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌來自一種細菌菌株（例如本文提供的一種菌株）或來自本文提供的一種以上的菌株。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are from one bacterial strain (eg, one strain provided herein) or from more than one strain provided herein.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係乳酸乳球菌乳脂亞種細菌，例如與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係乳球菌屬細菌，例如乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Lactococcus lactis subsp. crema bacteria, such as the nucleotide sequence of Lactococcus lactis subsp. crema strain A (ATCC designation number PTA-125368) Strains with at least 90% or at least 99% genome, 16S, and/or CRISPR sequence identity. In some embodiments, the bacteria of the agent or the bacteria of the agent's mEV are Lactococcus bacteria, such as Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如包含與普雷沃菌屬菌株B 50329（NRRL登錄號B 50329）的核苷酸序列具有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如普雷沃菌屬菌株B 50329（NRRL登錄號B 50329）。In some embodiments, the bacteria of the medicament or the bacterium from which the mEV of the medicament is obtained is a bacterium of the genus Prevotella. Strains with at least 90% or at least 99% genome, 16S, and/or CRISPR sequence identity. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Prevotella, such as Prevotella strain B 50329 (NRRL accession number B 50329).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係雙歧桿菌屬細菌，例如與以ATCC指定編號PTA-125097保藏的雙歧桿菌屬細菌的核苷酸序列有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係雙歧桿菌屬細菌，例如以ATCC指定編號PTA-125097保藏的雙歧桿菌屬細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is of the genus Bifidobacterium, for example, the nucleotide sequence of the bacterium of the genus Bifidobacterium deposited under the ATCC designation number PTA-125097 has at least 90% Or a strain with at least 99% genome, 16S and/or CRISPR sequence identity. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Bifidobacterium, for example, bacteria of the genus Bifidobacterium deposited under the ATCC designation number PTA-125097.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係韋榮球氏菌屬細菌，例如與以ATCC指定編號PTA-125691保藏的韋榮球氏菌屬細菌的核苷酸序列有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係韋榮球氏菌屬細菌，例如以ATCC指定編號PTA-125691保藏的韋榮球氏菌屬細菌。In some embodiments, the bacteria of the medicament or the bacterium from which the mEV of the medicament is obtained is a bacterium of the genus Veillonella, for example, has at least 90% of the nucleotide sequence of the bacterium of the genus Veillonella deposited under the ATCC designation number PTA-125691 Or a strain with at least 99% genome, 16S and/or CRISPR sequence identity. In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is a bacteria of the genus Veillonella, such as the bacterium of the genus Veillonella deposited under the ATCC designation number PTA-125691.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係活潑瘤胃球菌。在一些實施方式中，活潑瘤胃球菌細菌係與以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，活潑瘤胃球菌細菌係與以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，活潑瘤胃球菌細菌係以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Rumenococcus viridans. In some embodiments, the active Rumenococcus bacterial strain has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the active Rumenococcus bacteria deposited under ATCC designation number PTA-126695 Strains. In some embodiments, the active Rumenococcus bacteria are strains that have at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the active Rumenococcus bacteria deposited under the ATCC designation number PTA-126695. In some embodiments, the active rumen cocci bacteria are the active rumen cocci bacteria deposited under the ATCC designation number PTA-126695.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係巨型球菌屬物種細菌。在一些實施方式中，巨型球菌屬物種細菌係與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，巨型球菌屬物種細菌係與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，巨型球菌屬物種細菌係以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria of the genus Megacoccus. In some embodiments, the nucleotide sequence of the Megacoccus species bacterium line and the Megacoccus species bacterium deposited under the ATCC designation number PTA-126770 has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence Strains of identity. In some embodiments, the Megacoccus bacterium is a strain that has at least 99% genome, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Megacoccus bacterium deposited under the ATCC designation number PTA-126770. In some embodiments, the Megacoccus species bacteria are deposited under the ATCC designation number PTA-126770.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係Fournierella massiliensis 細菌。在一些實施方式中，Fournierella massiliensis 細菌係與以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Fournierella massiliensis 細菌係與以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Fournierella massiliensis 細菌係以ATCC指定編號PTA-126696保藏的Fournierella massiliensis 細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacterial strain has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under the ATCC designation number PTA-126696 . In some embodiments, the Fournierella massiliensis bacterial strain has at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under the ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacteria are Fournierella massiliensis bacteria deposited under the ATCC designation number PTA-126696.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係Harryflintia acetispora 細菌。在一些實施方式中，Harryflintia acetispora 細菌係與以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Harryflintia acetispora 細菌係與以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，Harryflintia acetispora 細菌係以ATCC指定編號PTA-126694保藏的Harryflintia acetispora 細菌。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained is Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacterial strain has at least 90% (or at least 97%) genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of Harryflintia acetispora deposited under the ATCC designation number PTA-126694 . In some embodiments, the Harryflintia acetispora bacterial strain has at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited under the ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacteria are Harryflintia acetispora bacteria deposited under the ATCC designation number PTA-126694.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係產生代謝產物的細菌，例如，細菌產生丁酸、肌苷、丙酸、或色胺酸代謝產物。In some embodiments, the bacteria of the agent or the bacteria from which the mEV of the agent is obtained are bacteria that produce metabolites, for example, the bacteria produce metabolites of butyric acid, inosine, propionic acid, or tryptophan.

在一些實施方式中，細菌產生丁酸。在一些實施方式中，細菌來自布勞特氏菌屬；克裡斯滕森菌屬；糞球菌屬；真桿菌屬；毛螺菌科；巨型球菌屬；或羅斯氏菌屬。In some embodiments, the bacteria produce butyric acid. In some embodiments, the bacterium is from the genus Blautella; Kristensia; Coccus; Eubacterium; Lacetospiraceae; Megacoccus; or Rossella.

在一些實施方式中，細菌產生肌苷。在一些實施方式中，細菌來自雙歧桿菌屬；乳桿菌屬；或歐陸森氏菌屬。In some embodiments, the bacteria produce inosine. In some embodiments, the bacteria are from the genus Bifidobacterium; Lactobacillus; or Eurosonia.

在一些實施方式中，細菌產生丙酸。在一些實施方式中，細菌來自阿克曼氏菌屬；擬桿菌屬；戴阿利斯特菌屬（Dialister ）；真桿菌屬；巨型球菌屬；副擬桿菌屬；普雷沃菌屬；瘤胃球菌屬；或韋榮氏球菌屬。In some embodiments, the bacteria produce propionic acid. In some embodiments, bacteria from the genus Ackerman; Bacteroides;戴阿利斯特genus (Dialister); Eubacterium; Megasphaera genus; sub Bacteroides; Prevotella spp; Ruminococcus Genus; or Veillonella.

在一些實施方式中，細菌產生色胺酸代謝產物。在一些實施方式中，細菌來自乳桿菌屬或消化鏈球菌屬。In some embodiments, the bacteria produce tryptophan metabolites. In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係產生組蛋白脫乙醯基酶3（HDAC3）的抑制劑的細菌。在一些實施方式中，細菌來自物種Bariatricus massiliensis 、普氏棲糞桿菌、馬賽巨型球菌或腸羅斯氏菌。 [表 1 ]： 細菌，按綱分 綱 目 科 屬 物種 放線菌綱 放線菌屬 分枝桿菌科 分枝桿菌屬          鏈黴菌科 鏈黴菌屬 變鉛青鏈黴菌、天藍色鏈黴菌、蘇丹鏈黴菌（Streptomyces sudanesis ）、索馬里鏈黴菌    雙歧桿菌目 雙歧桿菌科 雙歧桿菌屬 青春雙歧桿菌、動物雙歧桿菌、兩歧雙歧桿菌、短雙歧桿菌、乳酸雙歧桿菌、長雙歧桿菌、假雙歧桿菌    紅蝽桿菌目 紅蝽菌科 柯林斯氏菌屬 產氣柯林斯菌          歐陸森氏菌屬 糞歐陸森氏菌    丙酸桿菌目 丙酸桿菌科 丙酸桿菌                   芽孢桿菌綱（Bacilli ） 芽孢桿菌目 芽孢桿菌目地位未定XI 科 孿生球菌屬 溶血孿生球菌、麻疹孿生球菌       李斯特菌科 李斯特氏菌 單核細胞增多性李斯特氏菌、威氏李斯特氏菌    乳桿菌目 腸球菌科 腸球菌屬 耐久腸球菌、糞腸球菌、糞腸球菌、鶉雞腸球菌、絨毛腸球菌          乳桿菌屬 乾酪乳桿菌、發酵乳桿菌、乳酸乳球菌乳脂亞種、黏膜乳桿菌、植物乳桿菌、羅伊氏乳桿菌、鼠李糖乳桿菌、唾液乳桿菌       鏈球菌科 乳球菌屬             葡萄球菌 金黃色葡萄球菌          鏈球菌 無乳鏈球菌，金黃色鏈球菌，澳式鏈球菌，變形鏈球菌，副血鏈球菌，肺炎鏈球菌，化膿性鏈球菌，唾液鏈球菌                擬桿菌屬 擬桿菌目 擬桿菌科 擬桿菌屬 糞便擬桿菌、纖維素分解擬桿菌、糞居擬桿菌、多裡氏擬桿菌、脆弱擬桿菌、卵形擬桿菌、腐敗擬桿菌、薩氏擬桿菌、多形擬桿菌、普通擬桿菌       臭桿菌科 臭桿菌屬 內臟臭桿菌       卟啉單胞菌科 副擬桿菌屬 狄氏副擬桿菌、古氏副擬桿菌、屎副擬桿菌          卟啉單胞菌屬 牙齦卟啉單胞菌       普雷沃菌科    普雷沃菌屬 阿爾伯斯普雷沃菌、羊水普雷沃菌、橙色普雷沃菌、保氏普雷沃菌、貝根普雷沃菌、二路普雷沃菌、短普雷沃菌、布氏普雷沃菌、頰普雷沃菌、口頰普雷沃菌、著色普雷沃菌、人體普雷沃菌、糞便普雷沃菌、牙普雷沃菌、丹塔普雷沃菌、棲牙普雷沃菌、解糖腖普雷沃菌、棲居普雷沃菌、斐氏普雷沃菌、深黑色普雷沃菌、解肝素普雷沃菌、棲組織普雷沃菌、中間普雷沃菌、空腸普雷沃菌、洛氏普雷沃菌、小斑點普雷沃菌、馬斯普雷沃菌、產黑普雷沃菌、彩虹普雷沃菌、多形普雷沃菌、嗜糖普雷沃菌、南錫普雷沃菌、變黑普雷沃菌、口腔普雷沃菌、口普雷沃菌、稻普雷沃菌、齦炎普雷沃菌、蒼白普雷沃菌、沼澤普雷沃菌、胸膜炎普雷沃菌、棲瘤胃普雷沃菌、解糖普雷沃菌、唾液普雷沃菌、靶心普雷沃菌、賽赫普雷沃菌、 斯特塞拉普雷沃菌、坦納普雷沃菌、蒂莫普雷沃菌、 真空腔普雷沃菌、動膠普雷沃菌       理研菌科 另枝菌屬（Alstipes ） 普通另枝菌、殊異另枝菌、芬戈爾德氏另枝菌、不明顯另枝菌、Alistipes ihumii 、Alistipes inops 、馬賽另枝菌、Alistipes megaguti 、Alistipes obesi 、奧登多克氏另枝菌、Alistipes provencensis 、腐敗另枝菌、塞內加爾另枝菌（Alistipes senegalensis ）、賽赫另枝菌、蒂莫另枝菌                β 變形桿菌綱（Betaproteobacteria ）    霍爾德菌目 產鹼桿菌科 產鹼菌屬（Paenalcaligenes ） 人類產鹼菌          鮑特氏菌屬（Bordella ） 百日咳桿菌       伯克霍爾德菌科 伯克霍爾德菌屬 鼻疽伯克霍爾德菌、假伯克霍爾德菌          羅爾斯通菌屬（Ralstonia ） 青枯羅爾斯通菌（Ralstonia solanacearum ）       奈瑟菌科 奈瑟菌屬 腦膜炎奈瑟菌       薩特氏菌科 薩特氏菌屬 Sutterella parvirubra 、Sutterella stercoricanis 、Sutterella wadsworthensis             梭菌綱 梭菌目 Catabacteriaceae 海鷗菌屬（Catabacter ） 香港海鷗菌       梭菌科 Aminiphila Anaerosphaera aminiphila          克裡斯滕森菌科（Christensenellaceae ） 馬氏克裡斯滕森菌、蒂莫克裡斯滕森菌          Hungatella Hungatella effluvia       真桿菌科 真桿菌屬 扭曲真桿菌、耐久腸球菌、挑剔真桿菌、糞真桿菌、糞腸球菌、鶉雞腸球菌、龐大真桿菌、霍氏真桿菌、黏液真桿菌、細枝真桿菌、直腸真桿菌、絨毛腸球菌       毛螺菌科 厭氧棒狀菌屬（Anaerostipes ） 糞厭氧棒狀菌、哈氏厭氧棒狀菌（Anaerostipes hadrus ）          布勞特氏菌屬 產氫營養型布勞特氏菌、馬賽布勞特氏菌、排泄物布勞特氏菌、韋氏布勞特氏菌          卡托氏菌屬 痰卡托氏菌          糞球菌屬 靈巧糞球菌、陪伴糞球菌、一致糞球菌          戴阿利斯特菌屬 渾濁戴阿利斯特菌（Dialister invisus ）、微好氣戴阿利斯特菌（Dialister micraeophilus ）、嗜琥珀酸戴阿利斯特菌（Dialister succinatiphilus ）          多爾氏菌屬 產甲酸多爾氏菌、長鏈多爾氏菌、          Johnsonella 懶惰約翰森菌（Johnsonella ignava ）          口腔桿菌屬 微小口腔桿菌（Oribacterium parvum ）、竇菌口腔桿菌（Oribacterium sinus ）          毛形桿菌屬（Lachnobacterium ）             Lachnoclostridium             Lacrimispora Lacrimispora sacchaarolytica          羅斯氏菌屬 人羅斯氏菌、腸羅斯氏菌          泰澤菌屬 納西利斯泰澤菌       顫螺旋菌科 顫桿菌屬 產戊酸顫桿菌          Harryflintia 屬 Harryflinta acetispora       消化球菌科             消化鏈球菌科    副梭菌屬 解苯副梭菌          消化鏈球菌屬 羅氏消化鏈球菌       瘤胃球菌科    阿加薩桿菌屬物種          Fournierella 屬 Fournierella masssiliensis          瘤胃球菌屬 白色瘤胃球菌、布氏瘤胃球菌、伶俐瘤胃球菌、活潑瘤胃球菌、食菊糖瘤胃球菌（Ruminococcus inulinivorans ）、卵瘤胃球菌、扭鏈瘤胃球菌             糞桿菌屬 普氏棲糞桿菌       梭菌目XIII 科/地位未定    Intestimonas butyriciproducens                梭桿菌門 梭桿菌目 梭桿菌科 梭桿菌屬 核粒梭桿菌、舟形梭桿菌       纖毛菌科（Leptotrichiaceae ） 纖發菌屬             纖毛菌屬                   丙型變形菌綱 腸桿菌目（Enterobacterales ） 腸桿菌科 克雷伯氏菌屬 產酸克雷伯菌、肺炎克雷伯菌、類肺炎克雷伯氏菌擬肺炎亞種、          大腸桿菌屬 大腸桿菌菌株Nissle 1917 （EcN ） 大腸桿菌菌株ECOR12 大腸桿菌菌株ECOR63          志賀氏菌屬                   Negativicutes    胺基酸球菌科（Acidaminococcaceae ） 胺基酸球菌屬 發酵胺基酸球菌、腸胺基酸球菌          考拉桿菌屬（Phascolarctobacterium ） 糞考拉桿菌、琥珀考拉桿菌       月形單孢菌科 月形單胞菌屬 菲利克斯月形單胞菌、地位未定月形單胞菌、生痰月形單胞菌       Sporomusaceae Selenomonadales 目          韋榮氏球菌科 阿裡松氏菌屬（Allisonella ）             厭氧球形菌屬 Anaeroglobus germinatus          Caecibacter             Colibacter             韋榮氏球菌屬 小韋榮氏球菌          巨型球菌屬 埃氏巨型球菌（Megasphera elsedenii ）、馬賽巨型球菌、微核巨型球菌（Megasphera micronuciformis ） 巨型球菌屬物種          擬芽孢桿菌屬（Massilibacillus ） 馬賽擬芽孢桿菌（ Massilibacillus massiliensis ）          丙酸螺菌屬（Propionispira ）             Negativicoccus Negativicoccus succinicivornas          韋榮氏球菌屬 殊異韋榮氏球菌、小韋榮氏球菌、鼠韋榮氏球菌（Veillonella ratti ）、當別町韋榮氏球菌    互養菌目 互養菌科 胺基桿菌屬 移動胺基桿菌          氯酸桿菌屬（Cloacibacillus ） 埃夫裡桿菌          Rarimicrobium Rarimicrobium hominis                疣微菌綱 疣微菌目 阿克曼氏菌科 阿克曼氏菌屬 嗜黏蛋白阿克曼氏菌 [表 2 ]： 示例性細菌菌株 OTU 揭露 DB 登錄號 伴放線放線桿菌 AY362885 小放線桿菌 ACFT01000025 胸膜肺炎放線桿菌 NR_074857 產琥珀酸放線桿菌 CP000746 脲放線桿菌 AEVG01000167 馬西裡氏放線棒菌 AF487679 夏氏放線棒菌 AY957507 放線棒菌屬BM#101342 AY282578 放線棒菌屬P2P_19 P1 AY207066 嗜黏蛋白阿克曼氏菌 CP001071 芬戈爾德氏另枝菌 NR_043064 不明顯另枝菌 AB490804 奧登多克氏另枝菌 NR_043318 腐敗另枝菌 ABFK02000017 沙氏另枝菌 FP929032 另枝菌屬HGB5 AENZ01000082 另枝菌屬物種JC50 JF824804 另枝菌屬RMA 9912 GQ140629 糞厭氧棒狀菌 ABAX03000023 厭氧棒狀菌屬3_2_56FAA ACWB01000002 風化芽孢桿菌 NR_025557 嗜氣芽孢桿菌 NR_042339 艾氏芽孢桿菌 GQ980243 嗜鹼芽孢桿菌 X76436 解澱粉芽孢桿菌 NR_075005 炭疽芽孢桿菌 AAEN01000020 萎縮芽孢桿菌 NR_075016 栗褐芽孢桿菌 NR_036893 蠟樣芽孢桿菌 ABDJ01000015 環狀芽孢桿菌 AB271747 克勞氏芽孢桿菌 FN397477 凝結芽孢桿菌 DQ297928 堅韌芽孢桿菌 NR_025842 彎曲芽孢桿菌 NR_024691 福氏芽孢桿菌 NR_025786 明膠芽孢桿菌 NR_025595 鹽沼芽孢桿菌 NR_026144 耐鹽芽孢桿菌 AY144582 黑佈施泰因芽孢桿菌 NR_042286 霍爾氏芽孢桿菌 NR_036860 病研所芽孢桿菌 NR_043268 遲緩芽孢桿菌 NR_040792 地衣芽孢桿菌 NC_006270 巨大芽孢桿菌 GU252124 尼氏芽孢桿菌 NR_044546 農研所芽孢桿菌 NR_043334 菸酸芽孢桿菌 NR_024695 抱川芽孢桿菌 NR_041377 短小芽孢桿菌 NR_074977 沙福芽孢桿菌 JQ624766 單純芽孢桿菌 NR_042136 索諾氏芽孢桿菌 NR_025130 芽孢桿菌屬10403023 MM10403188 CAET01000089 芽孢桿菌屬2_A_57_CT2 ACWD01000095 芽孢桿菌屬2008724126 GU252108 芽孢桿菌屬物種2008724139 GU252111 芽孢桿菌屬物種7_16AIA FN397518 芽孢桿菌屬物種9_3AIA FN397519 芽孢桿菌屬物種AP8 JX101689 芽孢桿菌屬B27 （ 2008 ） EU362173 芽孢桿菌屬物種BT1B_CT2 ACWC01000034 芽孢桿菌屬物種GB1.1 FJ897765 芽孢桿菌屬物種GB9 FJ897766 芽孢桿菌屬物種HU19.1 FJ897769 芽孢桿菌屬物種HU29 FJ897771 芽孢桿菌屬物種HU33.1 FJ897772 芽孢桿菌屬物種JC6 JF824800 芽孢桿菌屬口腔分類群F26 HM099642 芽孢桿菌屬口腔分類群F28 HM099650 芽孢桿菌屬口腔分類群F79 HM099654 芽孢桿菌屬物種SRC_DSF1 GU797283 芽孢桿菌屬物種SRC_DSF10 GU797292 芽孢桿菌屬物種SRC_DSF2 GU797284 芽孢桿菌屬物種SRC_DSF6 GU797288 芽孢桿菌屬物種tc09 HQ844242 芽孢桿菌屬物種zh168 FJ851424 球形芽孢桿菌 DQ286318 產孢芽孢桿菌 NR_026010 枯草芽孢桿菌 EU627588 嗜熱澱粉芽孢桿菌 NR_029151 魏氏芽孢桿菌 NR_074926 擬桿菌目細菌ph8 JN837494 擬桿菌屬複合群P1 AY341819 擬桿菌屬複合群P2 口腔殖株MB1_G13 DQ003613 擬桿菌屬複合群P3 口腔殖株MB1_G34 DQ003615 擬桿菌屬複合群P4 口腔殖株MB2_G17 DQ003617 擬桿菌屬複合群P5 口腔殖株MB2_P04 DQ003619 擬桿菌屬複合群P6 口腔殖株MB3_C19 DQ003634 擬桿菌屬複合群P7 口腔殖株MB3_P19 DQ003623 擬桿菌屬複合群P8 口腔殖株MB4_G15 DQ003626 生酸擬桿菌 NR_028607 巴氏桿菌擬桿菌 NR_041446 人糞擬桿菌 EU136686 解纖維素擬桿菌 ACCH01000108 克拉氏擬桿菌 AFBM01000011 凝固擬桿菌 AB547639 糞居擬桿菌 ABIY02000050 嗜糞擬桿菌 ACBW01000012 多裡氏擬桿菌 ABWZ01000093 埃氏擬桿菌 ACWG01000065 糞便擬桿菌 GQ496624 芬戈爾德氏擬桿菌 AB222699 麯黴擬桿菌 AFBN01000029 脆弱擬桿菌 AP006841 半乳糖醛酸擬桿菌 DQ497994 潰瘍擬桿菌 CP002352 解肝素擬桿菌 JN867284 腸擬桿菌 ABJL02000006 馬賽擬桿菌 AB200226 諾德擬桿菌 NR_043017 擬南芥擬桿菌（Bacteroides oleiciplenus ） AB547644 卵形擬桿菌 ACWH01000036 果膠擬桿菌 ABVQ01000036 平常擬桿菌 AB200218 化膿性擬桿菌 NR_041280 Bacteroides salanitronis CP002530 薩利爾斯氏擬桿菌（Bacteroides salyersiae ） EU136690 擬桿菌屬1_1_14 ACRP01000155 擬桿菌屬1_1_30 ADCL01000128 擬桿菌屬1_1_6 ACIC01000215 擬桿菌屬2_1_22 ACPQ01000117 擬桿菌屬2_1_56FAA ACWI01000065 擬桿菌屬2_2_4 ABZZ01000168 擬桿菌屬20_3 ACRQ01000064 擬桿菌屬3_1_19 ADCJ01000062 擬桿菌屬3_1_23 ACRS01000081 擬桿菌屬物種3_1_33FAA ACPS01000085 擬桿菌屬物種3_1_40A ACRT01000136 擬桿菌屬3_2_5 ACIB01000079 擬桿菌屬315_5 FJ848547 擬桿菌屬物種31SF15 AJ583248 擬桿菌屬物種31SF18 AJ583249 擬桿菌屬物種35AE31 AJ583244 擬桿菌屬物種35AE37 AJ583245 擬桿菌屬物種35BE34 AJ583246 擬桿菌屬物種35BE35 AJ583247 擬桿菌屬4_1_36 ACTC01000133 擬桿菌屬物種4_3_47FAA ACDR02000029 擬桿菌屬物種9_1_42FAA ACAA01000096 擬桿菌屬物種AR20 AF139524 擬桿菌屬物種AR29 AF139525 擬桿菌屬物種B2 EU722733 擬桿菌屬物種D1 ACAB02000030 擬桿菌屬物種D2 ACGA01000077 擬桿菌屬物種D20 ACPT01000052 擬桿菌屬物種D22 ADCK01000151 擬桿菌屬物種F_4 AB470322 擬桿菌屬物種NB_8 AB117565 擬桿菌屬物種WH2 AY895180 擬桿菌屬物種XB12B AM230648 擬桿菌屬物種XB44A AM230649 排泄物擬桿菌 ABFZ02000022 多形擬桿菌 NR_074277 單形擬桿菌 AB050110 解尿素擬桿菌 GQ167666 普通擬桿菌 CP000139 木聚糖酶擬桿菌 ADKP01000087 擬桿菌門細菌口腔分類群D27 HM099638 擬桿菌門細菌口腔分類群F31 HM099643 擬桿菌門細菌口腔分類群F44 HM099649 腸道巴氏桿菌 AB370251 雙歧桿菌屬複合群C1 AY278612 青春雙歧桿菌 AAXD02000018 角雙歧桿菌 ABYS02000004 動物雙歧桿菌 CP001606 兩歧雙歧桿菌 ABQP01000027 短雙歧桿菌 CP002743 鏈狀雙歧桿菌 ABXY01000019 牙雙歧桿菌 CP001750 沒食子雙歧桿菌 ABXB03000004 嬰兒雙歧桿菌 AY151398 卡氏雙歧桿菌 AB491757 長雙歧桿菌 ABQQ01000041 假鏈狀雙歧桿菌 ABXX02000002 偽長雙歧桿菌 NR_043442 斯氏雙歧桿菌 AJ307005 雙歧桿菌屬HM2 AB425276 雙歧桿菌屬物種HMLN12 JF519685 雙歧桿菌屬物種M45 HM626176 雙歧桿菌屬物種MSX5B HQ616382 雙歧桿菌屬物種TM_7 AB218972 嗜熱雙歧桿菌 DQ340557 尿雙歧桿菌 AJ278695 球形布勞特氏菌 AB571656 格魯氏布勞特氏菌（Blautia glucerasea ） AB588023 格魯斯布勞特氏菌（Blautia glucerasei ） AB439724 漢森布勞特氏菌 ABYU02000037 產氫營養型布勞特氏菌 ACBZ01000217 盧氏布勞特氏菌 AB691576 生產性布勞特氏菌 AB600998 申克布勞特氏菌 NR_026312 布勞特氏菌屬M25 HM626178 排泄物布勞特氏菌 HM626177 韋氏布勞特氏菌 EF036467 支氣管炎鮑特氏菌 NR_025949 霍爾氏鮑特氏菌 AB683187 副百日咳鮑特氏菌 NR_025950 百日咳鮑特氏菌 BX640418 阿氏螺旋體 ABCU01000001 伯氏螺旋體 ABGI01000001 麝鼠勺螺旋體 DQ057990 達頓螺旋體 NC_011229 伽氏螺旋體 ABJV01000001 赫氏螺旋體 AY597657 西班牙螺旋體 DQ057988 伊朗包柔氏螺旋體 HM161645 回歸熱包柔氏螺旋體 AF107367 螺旋體屬NE49 AJ224142 斯皮爾曼螺旋體 ABKB01000002 墨西哥包柔氏螺旋體 NC_008710 法雷斯螺旋體 ABCY01000002 綿羊布氏桿菌 NC_009504 布氏桿菌屬83_13 ACBQ01000040 布氏桿菌屬BO1 EU053207 豬布氏桿菌 ACBK01000034 須芒草伯克霍爾德菌 AAUZ01000009 新洋蔥伯克霍爾德菌 AAHI01000060 洋蔥伯克霍爾德菌 NR_041719 鼻疽伯克霍爾德菌 CP000547 多食伯克霍爾德菌 NC_010086 俄克拉何馬伯克霍爾德菌 DQ108388 類鼻疽伯克霍爾德菌 CP001408 產根黴素伯克霍爾德菌 HQ005410 伯克霍爾德菌屬383 CP000151 食異生素伯克霍爾德菌 U86373 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食神鞘胺醇桿菌 ACHA02000013 刺狀鞘胺醇單胞菌 NR_024700 鞘胺醇單胞菌屬口腔殖株FI012 AY349411 鞘胺醇單胞菌屬物種口腔殖株FZ016 AY349412 鞘胺醇單胞菌屬口腔分類群A09 HM099639 鞘胺醇單胞菌屬物種口腔分類群F71 HM099645 葡萄球菌科細菌NML 92_0017 AY841362 金黃色葡萄球菌 CP002643 耳葡萄球菌 JQ624774 頭狀葡萄球菌 ACFR01000029 山羊葡萄球菌 ACRH01000033 肉葡萄球菌 NR_075003 科氏葡萄球菌 JN175375 香料葡萄球菌 NR_029345 表皮葡萄球菌 ACHE01000056 馬胃葡萄球菌 NR_027520 弗氏葡萄球菌 NR_041326 溶血性葡萄球菌 NC_007168 人葡萄球菌 AM157418 路鄧葡萄球菌 AEQA01000024 巴氏葡萄球菌 FJ189773 假中間葡萄球菌 CP002439 解糖葡萄球菌 NR_029158 腐生性葡萄球菌 NC_007350 松鼠葡萄球菌 NR_025520 葡萄球菌屬殖株bottae7 AF467424 葡萄球菌屬H292 AB177642 葡萄球菌屬物種H780 AB177644 琥珀酸葡萄球菌 NR_028667 小牛葡萄球菌 NR_024670 瓦氏葡萄球菌 ACPZ01000009 木糖葡萄球菌 AY395016 念珠狀鏈桿菌 NR_027615 無乳鏈球菌 AAJO01000130 非解乳鏈球菌 NR_041781 咽峽炎鏈球菌 AECT01000011 澳大利亞鏈球菌 AEQR01000024 牛鏈球菌 AEEL01000030 犬鏈球菌 AJ413203 星座鏈球菌 AY277942 脊鏈球菌 AEVC01000028 道恩鏈球菌 AEKN01000002 停乳鏈球菌 AP010935 馬鏈球菌 CP001129 馬腸鏈球菌 AEVB01000043 解沒食子酸鏈球菌 FR824043 鏈球菌屬複合群C1 AY278629 鏈球菌屬複合群C2 AY278630 鏈球菌屬複合群C3 AY278631 鏈球菌屬複合群C4 AY278632 鏈球菌屬複合群C5 AY278633 鏈球菌屬複合群C6 AY278634 鏈球菌屬複合群C7 AY278635 鏈球菌屬複合群C8 AY278609 戈登氏鏈球菌 NC_009785 小兒鏈球菌 ABJK02000017 嬰兒鏈球菌 AFNN01000024 中間鏈球菌 NR_028736 巴黎鏈球菌 NR_037096 馬賽鏈球菌 AY769997 米勒鏈球菌 X81023 緩症鏈球菌 AM157420 突變鏈球菌 AP010655 寡發酵鏈球菌 AY099095 口腔鏈球菌 ADMV01000001 副血鏈球菌 AEKM01000012 巴氏鏈球菌 AP012054 泛口腔鏈球菌 AEVF01000016 肺炎鏈球菌 AE008537 豕鏈球菌 EF121439 假性肺炎鏈球菌 FJ827123 假豕鏈球菌 AENS01000003 釀膿鏈球菌 AE006496 鼠鏈球菌 X58304 唾液鏈球菌 AGBV01000001 血鏈球菌 NR_074974 中華鏈球菌 AF432857 鏈球菌屬16362 JN590019 鏈球菌屬2_1_36FAA ACOI01000028 鏈球菌屬2285_97 AJ131965 鏈球菌屬物種69130 X78825 鏈球菌屬物種AC15 HQ616356 鏈球菌屬物種ACS2 HQ616360 鏈球菌屬物種AS20 HQ616366 鏈球菌屬物種BS35a HQ616369 鏈球菌屬物種C150 ACRI01000045 鏈球菌屬物種CM6 HQ616372 鏈球菌屬物種CM7 HQ616373 鏈球菌屬物種ICM10 HQ616389 鏈球菌屬物種ICM12 HQ616390 鏈球菌屬物種ICM2 HQ616386 鏈球菌屬物種ICM4 HQ616387 鏈球菌屬物種ICM45 HQ616394 鏈球菌屬物種M143 ACRK01000025 鏈球菌屬物種M334 ACRL01000052 鏈球菌屬物種OBRC6 HQ616352 鏈球菌屬物種口腔殖株ASB02 AY923121 鏈球菌屬物種口腔殖株ASCA03 DQ272504 鏈球菌屬物種口腔殖株ASCA04 AY923116 鏈球菌屬物種口腔殖株ASCA09 AY923119 鏈球菌屬物種口腔殖株ASCB04 AY923123 鏈球菌屬物種口腔殖株ASCB06 AY923124 鏈球菌屬物種口腔殖株ASCC04 AY923127 鏈球菌屬物種口腔殖株ASCC05 AY923128 鏈球菌屬物種口腔殖株ASCC12 DQ272507 鏈球菌屬物種口腔殖株ASCD01 AY923129 鏈球菌屬物種口腔殖株ASCD09 AY923130 鏈球菌屬物種口腔殖株ASCD10 DQ272509 鏈球菌屬物種口腔殖株ASCE03 AY923134 鏈球菌屬物種口腔殖株ASCE04 AY953253 鏈球菌屬物種口腔殖株ASCE05 DQ272510 鏈球菌屬物種口腔殖株ASCE06 AY923135 鏈球菌屬物種口腔殖株ASCE09 AY923136 鏈球菌屬物種口腔殖株ASCE10 AY923137 鏈球菌屬物種口腔殖株ASCE12 AY923138 鏈球菌屬物種口腔殖株ASCF05 AY923140 鏈球菌屬物種口腔殖株ASCF07 AY953255 鏈球菌屬物種口腔殖株ASCF09 AY923142 鏈球菌屬物種口腔殖株ASCG04 AY923145 鏈球菌屬物種口腔殖株BW009 AY005042 鏈球菌屬物種口腔殖株CH016 AY005044 鏈球菌屬物種口腔殖株GK051 AY349413 鏈球菌屬物種口腔殖株GM006 AY349414 鏈球菌屬口腔殖株P2PA_41 P2 AY207051 鏈球菌屬物種口腔殖株P4PA_30 P4 AY207064 鏈球菌屬口腔分類群071 AEEP01000019 鏈球菌屬口腔分類群G59 GU432132 鏈球菌屬物種口腔分類群G62 GU432146 鏈球菌屬物種口腔分類群G63 GU432150 鏈球菌屬物種SHV515 Y07601 豬鏈球菌 FM252032 嗜熱鏈球菌 CP000419 乳房鏈球菌 HQ391900 尿鏈球菌 DQ303194 前庭鏈球菌 AEKO01000008 綠色鏈球菌 AF076036 莫比利尼薩特菌 AJ832129 帕維魯布拉柴維爾特菌 AB300989 血根薩特菌 AJ748647 薩特菌屬YIT 12072 AB491210 犬糞薩特菌 NR_025600 華德薩特菌 ADMF01000048 互養菌屬複合群C1 AY278615 互養菌屬RMA 14551 DQ412722 互養菌門細菌ADV897 GQ258968 互養菌門細菌LBVCM1157 GQ258969 互養菌門細菌口腔分類群362 GU410752 互養菌門細菌口腔分類群D48 GU430992 Turicibacter sanguinis AF349724 非典型韋榮氏球菌 AEDS01000059 殊異韋榮氏球菌 ACIK02000021 韋榮氏球菌屬複合群P1 口腔殖株MB5_P17 DQ003631 蒙皮立韋榮氏球菌 AF473836 小韋榮氏球菌 ADFU01000009 韋榮氏球菌屬3_1_44 ADCV01000019 韋榮氏球菌屬6_1_27 ADCW01000016 韋榮氏球菌屬ACP1 HQ616359 韋榮氏球菌屬物種AS16 HQ616365 韋榮氏球菌屬物種BS32b HQ616368 韋榮氏球菌屬物種ICM51a HQ616396 韋榮氏球菌屬物種MSA12 HQ616381 韋榮氏球菌屬NVG 100cf EF108443 韋榮氏球菌屬物種OK11 JN695650 韋榮氏球菌屬口腔殖株ASCA08 AY923118 韋榮氏球菌屬物種口腔殖株ASCB03 AY923122 韋榮氏球菌屬物種口腔殖株ASCG01 AY923144 韋榮氏球菌屬物種口腔殖株ASCG02 AY953257 韋榮氏球菌屬物種口腔殖株OH1A AY947495 韋榮氏球菌屬口腔分類群158 AENU01000007 韋榮氏球菌科細菌口腔分類群131 GU402916 韋榮氏球菌科細菌口腔分類群155 GU470897 霍亂弧菌 AAUR01000095 河流弧菌 X76335 弗氏弧菌 CP002377 擬態弧菌 ADAF01000001 副溶血性弧菌 AAWQ01000116 弧菌屬RC341 ACZT01000024 創傷弧菌 AE016796 阿氏耶爾森氏菌 AJ871363 阿裡克謝耶爾森氏菌 AJ627597 貝氏耶爾森氏菌 AF366377 小腸結腸炎耶爾森菌 FR729477 弗氏耶爾森氏菌 AF366379 中間耶爾森氏菌 AF366380 克裡斯滕耶爾森氏菌 ACCA01000078 莫氏耶爾森氏菌 NR_027546 鼠疫耶爾森氏菌 AE013632 假結核耶爾森氏菌 NC_009708 羅氏耶爾森氏菌 ACCD01000071 [表 3 ]：示例性細菌菌株 菌株 保藏號 古氏副擬桿菌 PTA-126574 動物雙歧桿菌乳酸亞種菌株A PTA-125097 馬賽布勞特氏菌菌株A PTA-125134 普雷沃菌屬菌株B NRRL登錄號B 50329 棲組織普雷沃菌 PTA-126140 布勞特氏菌菌株A PTA-125346 乳酸乳球菌乳脂亞種菌株A PTA-125368 唾液乳桿菌 PTA-125893 活潑瘤胃球菌菌株 PTA-125706 納西利斯泰澤菌菌株 PTA-125707 解苯副梭菌 PTA-125894 活潑瘤胃球菌（又稱Mediterraneibacter gnavus ） PTA-126695 小韋榮氏球菌 PTA-125710 非典型韋榮氏球菌菌株A PTA-125709 非典型韋榮氏球菌菌株B PTA-125711 小韋榮氏球菌菌株A PTA-125691 小韋榮氏球菌菌株B PTA-125711 當別町韋榮氏球菌菌株A PTA-125708 阿加薩桿菌屬物種 PTA-125892 Turicibacter sanguinis PTA-125889 類肺炎克雷白氏菌擬肺炎亞種 PTA-125891 催產克雷白氏菌 PTA-125890 巨型球菌屬物種菌株A PTA-126770 巨型球菌屬物種 PTA-126837 Harryflintia acetispora PTA-126694 Fournierella massiliensis PTA-126696 經修飾的細菌和mEVIn some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained is a bacterium that produces an inhibitor of histone deacetylase 3 (HDAC3). In some embodiments, the bacteria are from speciesBariatricus massiliensis , Faeculus prasutii, Megacoccus marseille or Rossella enterica. [surface 1 ]: Bacteria, classified by class Class Item division Belong to Species Actinomycetes Actinomyces Mycobacteriaceae Mycobacterium Streptomyces Streptomyces Streptomyces lividans, Streptomyces coelicolor, Streptomyces sudanesis , Streptomyces somalicum Bifidobacteriales Bifidobacteriaceae Bifidobacterium Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium pseudobacillus Rhodobacter Rhododactylaceae Collinsella Collins aerogenes Eurosinia Eurosonia faecalis Propionibacteriales Propionibacteriaceae Propionibacterium Bacilli Bacillus Bacillus order undetermined status XI family Geminicoccus Geminicoccus haemolyticus, Geminicoccus measles Listeriaceae Listeria Listeria monocytogenes, Listeria weisneri Lactobacillus Enterococcus Enterococcus Enterococcus durable, Enterococcus faecalis, Enterococcus faecalis, Enterococcus gallinarum, Enterococcus villus Lactobacillus Lactobacillus casei, Lactobacillus fermentum, Lactococcus lactis subsp. lactis, Lactobacillus mucosa, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius Streptococcus Lactococcus staphylococcus Staphylococcus aureus Streptococcus Streptococcus agalactiae, Streptococcus aureus, Streptococcus aureus, Streptococcus mutans, Streptococcus parasanis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus salivarius Bacteroides Bacteroides Bacteroides Bacteroides Bacteroides faecalis, Bacteroides cellulolyticum, Bacteroides faecalis, Bacteroides dorisi, Bacteroides fragilis, Bacteroides ovatus, Bacteroides putrefaciens, Bacteroides sachsii, Bacteroides polymorpha, Bacteroides vulgaris Strobacteraceae Otterobacter Odorbacterium viscera Porphyromonaceae Parabacteroides Parabacteroides dienii, Parabacteroides greekii, Parabacteroides faecium Porphyromonas Porphyromonas gingivalis Prevotaceae Prevotella Albers Prevotella, Amniotic Fluid Prevotella, Orange Prevotella, Prevotella paulownia, Prevotella bergeni, Prevotella two-way, Prevotella breve, Brucella Revobacterium, Prevotella buccal, Prevotella buccal, Prevotella pigmentosa, Prevotella human, Prevotella feces, Prevotella dental, Prevotella danta, Tooth Prevotella, Prevotella saccharolyticus, Prevotella inhabiting, Prevotella fischerii, Prevotella aeruginosa, Prevotella heparinii, Prevotella hepatolytica, Prevotella intermedius Pravo bacillus, Prevotella jejuni, Prevotella roche, Prevotella small spotted, Prevotella masprevo, Prevotella niger, Prevotella rainbow, Prevotella polymorpha , Prevotella saccharophila, Prevotella nanxiensis, Prevotella black, Prevotella oral, Prevotella mouth, Prevotella oryzae, Prevotella gingivitis, Prevotella palliata Vortex, Prevotella marshes, Prevotella pleuriticus, Prevotella rumen, Prevotella saccharolyticus, Prevotella salivary, Prevotella salivarius, Prevotella sachs, Stellite Serra Prevo, Tanner Prevo, Timo Prevo, Vacuum Cavity Prevo, and Movable Prevot Riken Fungi Alstipes Common Alternate Mycobacterium, Extra Alternate Alternate, Fingold’s Alternate, Unobvious Alternate, Alistipes ihumii , Alistipes inops , Marseille Alternate, Alistipes Megaguti , Alistipes obesi , Odendok’s Alternate Bacteria, Alistipes provencensis , Corruption, Alistipes senegalensis , Saihe, Timo β Proteobacteria (Betaproteobacteria) Holderomycetes Alcaligenesceae Alcaligenes (Paenalcaligenes) Alcaligenes human Bordella Bacillus pertussis Burkholderiaceae Burkholderia Burkholderia pseudomallei, Burkholderia pseudomalle Ralstonia Ralstonia solanacearum (Ralstonia solanacearum) Neisseriaceae Neisseria Neisseria meningitidis Sartorellaceae Sartreella Sutterella parvirubra , Sutterella stercoricanis , Sutterella wadsworthensis Clostridium Clostridiales Catabacteriaceae Catabacter Hongkong Seagull Clostridaceae Aminiphila Anaerosphaera aminiphila Christensen bacteria Branch (Christensenellaceae) Kristensenia martensii, Kristensia Timo Hungatella Hungatella effluvia Eubacteriaceae Eubacterium Eubacterium contortus, Enterococcus durable, Eubacterium fusiformis, Eubacterium faecalis, Enterococcus faecalis, Enterococcus gallinarum, Eubacterium variabilis, Eubacterium hosei, Eubacterium mucous, Eubacterium mycobacterium, Eubacterium rectum, Enterococcus villus Laospirillaceae Anaerobic coryneform bacteria ( Anaerostipes ) Fecal anaerobic coryneform bacteria, Anaerostipes hadrus (Anaerostipes hadrus) Broutella Hydrotrophic Blautella, Blautella marseille, Blautella fecal, Blautella weinii Cattorella Cattorella sputum Faecoccus Faecoccus dexterous, Faecoccus companion, Faecoccus uniform Dialistria 戴阿利斯特turbid bacteria (Dialister invisus), micro-aerobic bacteria戴阿利斯特(Dialister micraeophilus), succinic戴阿利斯特addicted bacteria (Dialister succinatiphilus) Dallella Dallella formate, Dallella long-chain, Johnsonella Lazy Johnson ( Johnsonella ignava ) Oral bacillus Oribacterium parvum , Oribacterium sinus Lachnobacterium Lachnoclostridium Lacrimispora Lacrimispora sacchaarolytica Rossella Rossella human, Rossella enterica Tyzzeria Tyzer narcissi Oscillospiraceae Oscillatoria Vibrio valerobacter Harryflintia Harryflinta acetispora Peptococcus Peptostreptococcaceae Paraclostridium Clostridium parabenbens Peptostreptococcus Peptostreptococcus Roche Rumencoccaceae Agatha species Fournierella Fournierella masssiliensis Rumenococcus Rumencoccus albicans , Rumencoccus brucella, Rumencoccus lucidum, Rumencoccus active, Ruminococcus inulinivorans (Ruminococcus inulinivorans), Ruminococcus ovale, Rumenococcus twisted Faebacterium Faecalis prasutii Clostridial XIII family/status undetermined Intestimonas butyriciproducens Fusobacteria Fusobacteriales Fusobacteriaceae Fusobacterium Fusobacterium nucleoside, Fusobacterium navicularis Leptotrichiaceae (Leptotrichiaceae) Fibromyces Ciliates Proteobacteria Enterobacter mesh (Enterobacterales) Enterobacteriaceae Klebsiella Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella pneumoniae subsp. pneumoniae, Escherichia E. coli strain Nissle 1917 ( EcN ) E. coli strain ECOR12 E. coli strain ECOR63 Shigella Negativicutes Acidaminococcaceae (Acidaminococcaceae) Acidococcus Acidococcus fermentans, Acidococcus enterococcus Phascolarctobacterium (Phascolarctobacterium) Kolamella faecalis, Kolamella succinate Lunamonaceae Lunamonas Lunamonas felix, Lunamonas undetermined, Lunamonas sputum Sporomusaceae Selenomonadales Veillonellaceae Allisonella ( Allisonella ) Anaerobic Coccus Anaeroglobus germinatus Caecibacter Colibacter Veillonella Veillonella parvum Megacoccus Megasphera elsedenii (Megasphera elsedenii), Megacoccus marseilles, Megasphera micronuciformis (Megasphera micronuciformis) Megasphera species Massilibacillus Quasi Bacillus Marseille (Massilibacillus massiliensis) Propionispira ( Propionispira ) Negativicoccus Negativicoccus succinicivornas Veillonella Veillonella specific, Veillonella minor, Veillonella ratti , Veillonella ratti Syntrophicles Syntrophicaceae Amidobacterium Amidobacterium mobile Cloacibacillus (Cloacibacillus) Evribacterium Rarimicrobium Rarimicrobium hominis Verrucobacterium Verrucomicroles Akkermaniaceae Akkermansia Akkermansia muciniphila [surface 2 ]: Exemplary bacterial strains OTU Expose the DB access number Actinobacillus with actinomycetes AY362885 Actinobacillus parvum ACFT01000025 Actinobacillus pleuropneumoniae NR_074857 Actinobacillus succinogenes CP000746 Actinobacillus urea AEVG01000167 Actinomycetes marcili AF487679 Actinomycetes char AY957507 Actinomycetes BM#101342 AY282578 Actinomycetes P2P_19 P1 AY207066 Akkermansia muciniphila CP001071 Alternative Mycobacterium fingoldi NR_043064 Unobvious alternative mycobacterium AB490804 Alternative Mycobacterium odendrobii NR_043318 Alternative Mycobacterium putrefaction ABFK02000017 Alternaria serratia FP929032 Alternative Mycobacterium HGB5 AENZ01000082 Alternative Mycobacterium Species JC50 JF824804 Alternative Mycobacterium RMA 9912 GQ140629 Anaerobic coryneform feces ABAX03000023 Anaerobic Corynebacterium 3_2_56FAA ACWB01000002 Bacillus weathering NR_025557 Bacillus aerophilus NR_042339 Bacillus escherichia GQ980243 Alkalophilic Bacillus X76436 Bacillus amyloliquefaciens NR_075005 Bacillus anthracis AAEN01000020 Bacillus atrophicus NR_075016 Bacillus chestnut NR_036893 Bacillus cereus ABDJ01000015 Bacillus circulans AB271747 Bacillus clausii FN397477 Bacillus coagulans DQ297928 Bacillus tenacious NR_025842 Bacillus flexus NR_024691 Bacillus flexneri NR_025786 Bacillus gelatinus NR_025595 Bacillus salina NR_026144 Halotolerant Bacillus AY144582 Bacillus hebstein NR_042286 Bacillus Halli NR_036860 Bacillus Bacillus NR_043268 Bacillus lentus NR_040792 Bacillus licheniformis NC_006270 Bacillus megaterium GU252124 Bacillus niseri NR_044546 Bacillus of Agricultural Research Institute NR_043334 Bacillus nicotinicum NR_024695 Pocheon Bacillus NR_041377 Bacillus pumilus NR_074977 Bacillus sarfas JQ624766 Bacillus simplex NR_042136 Bacillus sonosii NR_025130 Bacillus 10403023 MM10403188 CAET01000089 Bacillus 2_A_57_CT2 ACWD01000095 Bacillus 2008724126 GU252108 Bacillus species 2008724139 GU252111 Bacillus species 7_16AIA FN397518 Bacillus species 9_3AIA FN397519 Bacillus species AP8 JX101689 Bacillus B27 ( 2008 ) EU362173 Bacillus species BT1B_CT2 ACWC01000034 Bacillus species GB1.1 FJ897765 Bacillus species GB9 FJ897766 Bacillus species HU19.1 FJ897769 Bacillus species HU29 FJ897771 Bacillus species HU33.1 FJ897772 Bacillus species JC6 JF824800 Bacillus oral taxa F26 HM099642 Bacillus oral taxa F28 HM099650 Bacillus oral taxa F79 HM099654 Bacillus species SRC_DSF1 GU797283 Bacillus species SRC_DSF10 GU797292 Bacillus species SRC_DSF2 GU797284 Bacillus species SRC_DSF6 GU797288 Bacillus species tc09 HQ844242 Bacillus species zh168 FJ851424 Bacillus sphaericus DQ286318 Bacillus sporogenes NR_026010 Bacillus subtilis EU627588 Bacillus thermophilus NR_029151 Bacillus wischii NR_074926 Bacteroides ph8 JN837494 Bacteroides complex P1 AY341819 Bacteroides complex P2 oral clone MB1_G13 DQ003613 Bacteroides complex P3 oral clone MB1_G34 DQ003615 Bacteroides complex P4 oral clone MB2_G17 DQ003617 Bacteroides complex P5 oral clone MB2_P04 DQ003619 Bacteroides complex P6 oral clone MB3_C19 DQ003634 Bacteroides complex P7 oral clone MB3_P19 DQ003623 Bacteroides complex P8 oral clone MB4_G15 DQ003626 Bacteroides acidophilus NR_028607 Pasteurella Bacteroides NR_041446 Bacteroides faecalis EU136686 Bacteroides cellulolyticum ACCH01000108 Bacteroides clarinii AFBM01000011 Bacteroides coagulans AB547639 Bacteroides faecalis ABIY02000050 Bacteroides faecalis ACBW01000012 Bacteroides dorisei ABWZ01000093 Bacteroides escherichia ACWG01000065 Bacteroides faecalis GQ496624 Bacteroides fingoldi AB222699 Aspergillus Bacteroides AFBN01000029 Bacteroides fragilis AP006841 Bacteroides galacturonan DQ497994 Bacteroides ulcerans CP002352 Bacteroides heparinolyticus JN867284 Enterobacter ABJL02000006 Bacteroides marseille AB200226 Bacteroides Nord NR_043017 Bacteroides oleiciplenus AB547644 Bacteroides ovatus ACWH01000036 Bacteroides pectinosa ABVQ01000036 Bacteroides vulgaris AB200218 Bacteroides pyogenes NR_041280 Bacteroides salanitronis CP002530 Bacteroides salyersiae EU136690 Bacteroides 1_1_14 ACRP01000155 Bacteroides 1_1_30 ADCL01000128 Bacteroides 1_1_6 ACIC01000215 Bacteroides 2_1_22 ACPQ01000117 Bacteroides 2_1_56FAA ACWI01000065 Bacteroides 2_2_4 ABZZ01000168 Bacteroides 20_3 ACRQ01000064 Bacteroides 3_1_19 ADCJ01000062 Bacteroides 3_1_23 ACRS01000081 Bacteroides species 3_1_33FAA ACPS01000085 Bacteroides species 3_1_40A ACRT01000136 Bacteroides 3_2_5 ACIB01000079 Bacteroides 315_5 FJ848547 Bacteroides species 31SF15 AJ583248 Bacteroides species 31SF18 AJ583249 Bacteroides species 35AE31 AJ583244 Bacteroides species 35AE37 AJ583245 Bacteroides species 35BE34 AJ583246 Bacteroides species 35BE35 AJ583247 Bacteroides 4_1_36 ACTC01000133 Bacteroides species 4_3_47FAA ACDR02000029 Bacteroides species 9_1_42FAA ACAA01000096 Bacteroides species AR20 AF139524 Bacteroides species AR29 AF139525 Bacteroides species B2 EU722733 Bacteroides species D1 ACAB02000030 Bacteroides species D2 ACGA01000077 Bacteroides species D20 ACPT01000052 Bacteroides species D22 ADCK01000151 Bacteroides species F_4 AB470322 Bacteroides species NB_8 AB117565 Bacteroides species WH2 AY895180 Bacteroides species XB12B AM230648 Bacteroides species XB44A AM230649 Bacteroides feces ABFZ02000022 Bacteroides polymorpha NR_074277 Bacteroides monomorphs AB050110 Bacteroides urealyticum GQ167666 Bacteroides vulgaris CP000139 Bacteroides xylanase ADKP01000087 Bacteroides phylum Bacterial Oral Taxonomy D27 HM099638 Bacteroides phylum Bacterial Oral Taxonomy F31 HM099643 Bacteroides phylum Bacterial Oral Taxonomy F44 HM099649 Pasteurella enterica AB370251 Bifidobacterium complex C1 AY278612 Bifidobacterium adolescentis AAXD02000018 Bifidobacterium hornis ABYS02000004 Bifidobacterium animalis CP001606 Bifidobacterium bifidum ABQP01000027 Bifidobacterium breve CP002743 Bifidobacterium chain ABXY01000019 Bifidobacterium dental CP001750 Bifidobacterium gallbae ABXB03000004 Bifidobacterium infantis AY151398 Bifidobacterium carinii AB491757 Bifidobacterium longum ABQQ01000041 Bifidobacterium pseudochain ABXX02000002 Bifidobacterium pseudolongum NR_043442 Bifidobacterium sternii AJ307005 Bifidobacterium HM2 AB425276 Bifidobacterium species HMLN12 JF519685 Bifidobacterium species M45 HM626176 Bifidobacterium species MSX5B HQ616382 Bifidobacterium species TM_7 AB218972 Bifidobacterium thermophilus DQ340557 Bifidobacterium urinaria AJ278695 Broutella sphaeroides AB571656 Blautia glucerasea AB588023 Blautia glucerasei AB439724 Brautella hansenii ABYU02000037 Hydrotrophic Brautella ACBZ01000217 Blautella rugosa AB691576 Productive Broutella AB600998 Schenkerbrutella NR_026312 Broutella M25 HM626178 Broutella feces HM626177 Broutella weinii EF036467 Bordetella bronchitis NR_025949 Bordetella holsii AB683187 Bordetella parapertussis NR_025950 Bordetella pertussis BX640418 Astrii spirochetes ABCU01000001 Burgdorferi ABGI01000001 Muskrat Spirochetes DQ057990 Darton spirochetes NC_011229 Garneria spirochetes ABJV01000001 Treponema Hermannii AY597657 Spanish spirochetes DQ057988 Treponema pallidum HM161645 Recursively hot-packed burgundy spirochetes AF107367 Spirochetes NE49 AJ224142 Spearman spirochetes ABKB01000002 Treponema pallidum NC_008710 Fares spirochetes ABCY01000002 Brucella ovis NC_009504 Brucella 83_13 ACBQ01000040 Brucella BO1 EU053207 Brucella suis ACBK01000034 Burkholderia sibiricum AAUZ01000009 Burkholderia cepacia AAHI01000060 Burkholderia cepacia NR_041719 Burkholderia pseudomallei CP000547 Burkholderia polyphagous NC_010086 Burkholderia Oklahoma DQ108388 Burkholderia pseudomallei CP001408 Burkholderia rhizo-producing HQ005410 Burkholderia 383 CP000151 Burkholderia xenobiotics U86373 Burkholderia bacterium 1_1_47 ADCQ01000066 Vibrio spicate ABWN01000012 Vibrio cellulolyticus U41172 Chlamydia Murine AE002160 Chlamydia psittaci NR_036864 Chlamydia trachomatis U68443 Chlamydia NS11 JN606074 Citrobacter malonate FR870441 Citrobacter brucei NR_028687 Citrobacter method AF025371 Citrobacter freundii NR_028894 Citrobacter gilly AF025367 Citrobacter Klebsiella NC_009792 Citrobacter moline AF025369 Citrobacter murine NR_074903 Citrobacter sei AF025364 Citrobacter 30_2 ACDJ01000053 Citrobacter KMSI_3 GQ468398 Citrobacter Walkermann AF025373 Citrobacter youngii ABWL02000011 Evribacterium GQ258966 Clostridial bacteria END_2 EF451053 Clostridiaceae JC13 JF824807 Clostridium bacteria 1_7_47FAA ABQR01000074 Clostridium bacteria 9400853 HM587320 Clostridium bacteria 9403326 HM587324 Clostridium bacteria oral colony P4PA_66 P1 AY207065 Clostridium bacteria oral taxa 093 GQ422712 Clostridium bacterial oral taxa F32 HM099644 Clostridium ph2 JN837487 Clostridium bacteria SY8519 AB477431 Clostridium complex BVAB3 CP001850 Clostridium SM4_1 FP929060 Clostridium species SS3_4 AY305316 Clostridium species SSC_2 FP929061 Acetobutylic acid NR_074511 Oxygen-resistant fusidic acid X76163 Clostridium ardennes NR_043680 Clostridium Aldrich NR_026099 Clostridium algae NR_041746 Clostridium xylanum NR_028726 Clostridium valeric acid NR_029245 Clostridium amygdalus AY353957 Clostridium argentina NR_029232 Clostridium asparagus ACCJ01000522 Clostridium pastoris NR_029229 Clostridium Bartelli ABEZ02000012 Clostridium beijerinckii NR_074434 Clostridium bienzyme X73437 Clostridium baumannii ABCC02000039 Clostridium botulinum NC_010723 Clostridium butyricum ABDT01000017 Clostridium cadavericum AB542932 Clostridium carbooxidans FR733710 Clostridium carnosus NR_044716 Clostridium hiding X77844 Fast-growing Clostridium JQ246092 Clostridium Cellulose NR_044624 Clostridium choworthia EU106372 Clostridium citronella ADLJ01000059 Clostridium clarified NR_041235 Clostridium clostridium M59089 Clostridium fusiformis NR_044715 Clostridium sphaericus EF025906 Clostridium scapularis NR_044717 Clostridium cochlea NR_026495 Clostridium canis FJ957863 Clostridium partridge NR_026151 Clostridium difficile NC_013315 Clostridium bisporus NR_026491 Clostridium Esterification NR_042153 Clostridium flexneri NR_044714 Clostridium favososporum X76749 Clostridium fesinia AF270502 Clostridium cold NR_024919 Clostridium aerogenes NR_024945 Clostridium gordonii AB542933 Clostridium ethylene glycol FJ384385 Clostridium faecalis AB233029 Clostridium haemolyticus NR_024749 Clostridium harveyi AY552788 Clostridium Hirano AB023970 Clostridium histolyticum HF558362 Clostridium hayesii AB023973 Clostridium indole AF028351 Innocuous clostridium M23732 Clostridium irregular NR_029249 Clostridium isatidis NR_026347 Clostridium Klebsiella NR_074165 Clostridium fermentum NR_025651 Clostridium Lavalise EF564277 Clostridium tenella AJ305238 Clostridium sludge FR870444 Clostridium major X77835 Clostridium notorious FR749893 Clostridium mayobe FR733682 Clostridium pentoses methyl ACEC01000059 Clostridium knotweed X73443 Clostridium novei NR_074343 Clostridium butyricum Y18187 Clostridium orotate FR749922 Clostridium paraspoilage AB536771 Clostridium perfringens ABDW01000023 Clostridium fermentum NR_074652 Clostridium pilaris D14639 Clostridium putrefaction NR_024995 Clostridium quinescens NR_026149 Clostridium polybrinum M23731 Clostridium rectum NR_029271 Clostridium saccharophaga DQ100445 Clostridium saccharobacillus CP002109 Clostridium Sardinia NR_041006 Clostridium paniculata NR_026490 Clostridium lysate AF262238 Clostridium septicum NR_026020 Clostridium sorghum AB448946 Clostridium 7_2_43FAA ACDK01000101 Clostridium species D5 ADBG01000142 Clostridium species HGF2 AENW01000022 Clostridium species HPB_46 AY862516 Clostridium species JC122 CAEV01000127 Clostridium species L2_50 AAYW02000018 Clostridium LMG 16094 X95274 Clostridium species M62_1 ACFX02000046 Clostridium species MLG055 AF304435 Clostridium MT4 E FJ159523 Clostridium species NMBHI_1 JN093130 Clostridium NML 04A032 EU815224 Clostridium species SS2_1 ABGC03000041 Clostridium species SY8519 AP012212 Clostridium species TM_40 AB249652 Clostridium species YIT 12069 AB491207 Clostridium species YIT 12070 AB491208 Clostridium cuneiformis X73449 Clostridium spiralis X73441 Clostridium sporogenes ABKW02000003 Clostridium sporosphaeroides NR_044835 Clostridium faecalis NR_025100 Clostridium sticklandii L04167 Clostridium Stravins NR_024829 Clostridium proximal NR_041795 Clostridium thioproducing NR_044161 Symbiotic Clostridium ADLQ01000114 Clostridium tertiary Y18174 Clostridium tetani NC_004557 Clostridium thermocellum NR_074629 Clostridium Tyrobutyricum NR_044718 Clostridium viridans NR_026204 Clostridium xylanisolvens NR_037068 Collins aerogenes AAVN02000007 Collins enterica ABXH02000037 Collins bacteria ABXJ01000150 Collins tanaka AB490807 Faecium streptococcus AB030218 Faecalis 29_1 ADKX01000057 Faecalis D7 ACDT01000199 Faecococcus dexteris EU266552 Accompanying Coccus ABVR01000038 Faecococcus uniform EF031543 Faecococcus ART55_1 AY350746 Allisteria turbid ACIM02000001 Alisteria spp AFBB01000028 Alisteria microaerophila AENT01000008 Alisteria invading lung HM596297 Allisteria propionate NR_043231 Oral taxa 502 of the genus Alisteria GQ422739 Allisteria succinate AB370249 D. formate AAXA02000006 Dallella long-chain AJ132842 Saccharomyces ACYI01000081 Enterobacter aerogenes AJ251468 Enterobacter abbeyi NR_024640 Carcinogenic Enterobacter Z96078 Enterobacter cloacae FP929040 Enterobacter coriolis NR_025566 Enterobacter hosei AFHR01000079 Enterobacter 247BMC HQ122932 Enterobacter 638 NR_074777 Enterobacter species JC163 JN657217 Enterobacter SCSS HM007811 Enterobacter species TSE38 HM156134 Enterobacteriaceae 9_2_54FAA ADCU01000033 Enterobacteriaceae CF01Ent_1 AJ489826 Enterobacteriaceae Smarlab 3302238 AY538694 Enterococcus avium AF133535 Enterococcus faecalis AY943820 Enterococcus casei AEWT01000047 Enterococcus durable AJ276354 Enterococcus faecalis AE016830 Enterococcus faecium AM157434 Enterococcus gallinarum AB269767 Enterococcus griseophylla AY033814 Enterococcus hawaii AY321377 Enterococcus hirschii AF061011 Enterococcus italy AEPV01000109 Enterococcus monseri NR_024906 Enterococcus raffinose FN600541 Enterococcus BV2CASA2 JN809766 Enterococcus species CCRI_16620 GU457263 Enterococcus species F95 FJ463817 Enterococcus species RfL6 AJ133478 Enterococcus Thailand AY321376 Erysipelas bacteria 3_1_53 ACTJ01000113 Erysipelas bacteria 5_2_54FAA ACZW01000054 E. coli ABKX01000012 Escherichia coli NC_008563 Ferguson Escherichia coli CU928158 Hermann's Escherichia coli HQ407266 Escherichia 1_1_43 ACID01000033 Escherichia 4_1_40B ACDM02000056 Escherichia species B4 EU722735 Escherichia Wound NR_041927 Eubacteriaceae P4P_50 P4 AY207060 Eubacteria Bakkeri NR_044661 Eubacterium biformis ABYT01000002 Eubacterium brevis U13038 Eubacterium brucella NR_024682 Eubacterium carinii NR_026330 Eubacterium cellulolyticus AY178842 Eubacterium contortus FR749946 Eubacterium fecalsterolum HM037995 Eubacterium cylindrica FP929041 Eubacterium streptobacter NR_044644 Eubacterium longum L34682 Fussy Eubacterium CP001104 Eubacterium FR749935 Eubacterium magnum FR749933 Eubacterium hosei L34621 Eubacterium fragrans U13039 Eubacterium silt CP002273 Eubacter pneumoniae HF558373 Eubacterium polymorpha NR_024683 Eubacterium nitrite NR_024684 Eubacterium entangled U13041 Mycobacterium mycobacterium AJ011522 Eubacterium rectum FP929042 Eubacterium ruminant NR_024661 Eubacterium halitosis AB525414 Cryptomycobacterium NR_026031 Eubacterium inert ABCA03000054 Eubacterium 3_1_31 ACTL01000045 Eubacterium AS15b HQ616364 Eubacterium species OBRC9 HQ616354 Eubacterium oral colony GI038 AY349374 Eubacterium sp. Oral clone IR009 AY349376 Eubacterium sp. Oral clone JH012 AY349373 Eubacteria species oral colony JI012 AY349379 Eubacteria species oral colony JN088 AY349377 Eubacteria species oral colony JS001 AY349378 Eubacteria species oral colony OH3A AY947497 Eubacterium WAL 14571 FJ687606 Eubacterium gracilis M59118 Bacillus polytrimonium NR_044648 Eubacterium bulgingis L34421 Eubacterium xylanophilus L34628 Eubacterium eubacterium AEES01000073 Fusobacterium canis AY162222 Fusobacterium complex C1 AY278616 Fusobacterium complex C2 AY278617 Fusobacterium microbiota ACET01000043 Fusobacterium mortal ACDB02000034 Fusobacterium navicularis HQ223106 Fusobacterium gangrene X55408 Fusobacterium necrosis AM905356 Fusobacterium nucleoside ADVK01000034 Fusobacterium periodontalum ACJY01000002 Fusobacterium ragsii NR_044687 Fusobacterium 1_1_41FAA ADGG01000053 Fusobacterium 11_3_2 ACUO01000052 Fusobacterium species 12_1B AGWJ01000070 Fusobacterium 2_1_31 ACDC02000018 Fusobacterium 3_1_27 ADGF01000045 Fusobacterium 3_1_33 ACQE01000178 Fusobacterium species 3_1_36A2 ACPU01000044 Fusobacterium species 3_1_5R ACDD01000078 Fusobacterium species AC18 HQ616357 Fusobacterium species ACB2 HQ616358 Fusobacterium species AS2 HQ616361 Fusobacterium species CM1 HQ616371 Fusobacterium species CM21 HQ616375 Fusobacterium species CM22 HQ616376 Fusobacterium species D12 ACDG02000036 Fusobacterium oral colony ASCF06 AY923141 Fusobacterium species oral colony ASCF11 AY953256 Fusobacterium ulcerans ACDH01000090 Fusobacterium Proteus ACIE01000009 Geminicoccus haemolyticus ACDZ02000012 Geminicoccus measles NR_025904 Geminicoccus measles ACRX01000010 Geminicoccus sanguineus ACRY01000057 Oral colony of Geminicoccus ASCE02 AY923133 Oral colony of Geminicoccus ASCF04 AY923139 Oral clone of Geminicoccus ASCF12 AY923143 Geminicoccus WAL 1945J EU427463 Klebsiella oxytoca AY292871 Klebsiella pneumoniae CP000647 Klebsiella AS10 HQ616362 Klebsiella species Co9935 DQ068764 Klebsiella enriched culture strain SRC_DSD25 HM195210 Klebsiella species OBRC7 HQ616353 Klebsiella SP_BA FJ999767 Klebsiella species SRC_DSD1 GU797254 Klebsiella species SRC_DSD11 GU797263 Klebsiella species SRC_DSD12 GU797264 Klebsiella species SRC_DSD15 GU797267 Klebsiella species SRC_DSD2 GU797253 Klebsiella species SRC_DSD6 GU797258 Klebsiella mutans CP001891 Pseudomonas bovis GU324407 Lacetospirillum prolificum FR733699 Chaetospirillum pectinosa L14675 Laospirillaceae bacteria 1_1_57FAA ACTM01000065 Laospirillaceae bacteria 1_4_56FAA ACTN01000028 Laospirillaceae bacteria 2_1_46FAA ADLB01000035 Laospirillaceae bacteria 2_1_58FAA ACTO01000052 Trichospiraceae bacteria 3_1_57FAA_CT1 ACTP01000124 Laospirillaceae bacteria 4_1_37FAA ADCR01000030 Laospirillaceae bacteria 5_1_57FAA ACTR01000020 Laospirillaceae bacteria 5_1_63FAA ACTS01000081 Laospirillaceae bacteria 6_1_63FAA ACTV01000014 Laospirillaceae bacteria 8_1_57FAA ACWQ01000079 Laospirillaceae Bacteria 9_1_43BFAA ACTX01000023 Labeospiraceae Bacteria A4 DQ789118 Laospirillaceae bacteria DJF VP30 EU728771 Labeospiraceae Bacteria ICM62 HQ616401 Lacetospirillum MSX33 HQ616384 Oral taxa of Lacetospirillaceae bacteria 107 ADDS01000069 Labeospirillaceae bacterial oral taxa F15 HM099641 Laospirillaceae Complex C1 AY278618 Lactobacillus acidis NR_024718 Lactobacillus acidophilus CP000033 Food Lactobacillus NR_044701 Lactobacillus amyloliquefaciens ADNY01000006 Lactobacillus amylovora CP002338 Lactobacillus antrum ACLL01000037 Lactobacillus brevis EU194349 Lactobacillus buchneri ACGH01000101 Lactobacillus casei CP000423 Lactobacillus chain M23729 Lactobacillus human vagina ACOH01000030 Lactobacillus coryneformis NR_044705 Lactobacillus crispatus ACOG01000151 Lactobacillus flexus NR_042437 Lactobacillus deerbrückii CP002341 Lactobacillus dextrin NR_036861 Lactobacillus sausage NR_044707 Lactobacillus fermentum CP002033 Lactobacillus gasseri ACOZ01000018 Gastric Lactobacillus AICN01000060 Lactobacillus complex C1 AY278619 Lactobacillus complex C2 AY278620 Lactobacillus helveticus ACLM01000202 Lactobacillus hilsii ACGP01000200 Lactobacillus human FR681902 Lactobacillus inert AEKJ01000002 Lactobacillus jannaschii ACQD01000066 Lactobacillus johnsonii AE017198 Lactobacillus cari NR_029083 Lactobacillus equine NR_042440 Lactobacillus caucasus NR_042230 Lactobacillus Kimchi NR_025045 Lactobacillus Leichmannii JX986966 Lactobacillus mucosa FR693800 Lactobacillus murine NR_042231 Lactobacillus nordensisi NR_041629 Lactobacillus alcohol NR_043095 Lactobacillus oris AEKL01000077 Lactobacillus brevis NR_042456 Lactobacillus brucei NR_041294 Lactobacillus paracasei ABQV01000067 Lactobacillus caucasus NR_029039 Lactobacillus pentosus JN813103 Lactobacillus odorifera NR_029360 Lactobacillus plantarum ACGZ02000033 Lactobacillus pontine HM218420 Lactobacillus reuteri ACGW02000012 Lactobacillus rhamnosus ABWJ01000068 Lactobacillus rosenbergii GU269544 Lactobacillus rumen ACGS02000043 Lactobacillus sake DQ989236 Lactobacillus salivarius AEBA01000145 Lactobacillus saniviri AB602569 Lactobacillus senile AB602570 Lactobacillus 66c FR681900 Lactobacillus species BT6 HQ616370 Lactobacillus KLDS 1.0701 EU600905 Lactobacillus species KLDS 1.0702 EU600906 Lactobacillus species KLDS 1.0703 EU600907 Lactobacillus species KLDS 1.0704 EU600908 Lactobacillus species KLDS 1.0705 EU600909 Lactobacillus species KLDS 1.0707 EU600911 Lactobacillus species KLDS 1.0709 EU600913 Lactobacillus species KLDS 1.0711 EU600915 Lactobacillus species KLDS 1.0712 EU600916 Lactobacillus species KLDS 1.0713 EU600917 Lactobacillus species KLDS 1.0716 EU600921 Lactobacillus species KLDS 1.0718 EU600922 Lactobacillus species KLDS 1.0719 EU600923 Lactobacillus oral colony HT002 AY349382 Lactobacillus species oral colony HT070 AY349383 Lactobacillus oral taxa 052 GQ422710 Lactobacillus saturnus NR_042194 Lactobacillus ulanensis ACGU01000081 Lactobacillus vaginalis ACGV01000168 Lactobacillus wine NR_042196 Lactobacillus calf NR_041305 Lactobacillus maize NR_037122 Lactococcus gasseri AF061005 Lactococcus lactis CP002365 Lactococcus raffinose NR_044359 Listeria greischii ACCR02000003 Non-toxic Listeria JF967625 Listeria escherichia X56151 Listeria monocytogenes CP002003 Listeria weseri AM263198 Megacoccus escherichia AY038996 Megacoccus complex C1 AY278622 Megacoccus complex group type_1 ADGP01000010 Megacoccus micronucleus AECS01000020 Megacoccus BLPYG_07 HM990964 Megacoccus UPII 199_6 AFIJ01000040 Microbacterium archatum NR_025098 Microbacterium lactis EU714351 Mitsuoka jasminum NR_028840 Mitooka polyacidae ABWK02000005 Oral taxa of genus Mitsuoka 521 GU413658 Oral taxa G68 GU432166 Mycobacterium abscessus AGQU01000002 Mycobacterium africanum AF480605 Mycobacterium alsiensis AJ938169 Mycobacterium avium CP000479 Mycobacterium chelonae AB548610 Mycobacterium columbia AM062764 Mycobacterium elephantiasis AF385898 Mycobacterium gordonii GU142930 Mycobacterium intracellulare GQ153276 Mycobacterium Kansas AF480601 Mycobacterium Lacus NR_025175 Mycobacterium leprosy FM211192 Mycobacterium leprae EU203590 Mycobacterium mckii FR798914 Mycobacterium mansoni FJ042897 Mycobacterium marinum NC_010612 Mycobacterium voles NR_025234 Mycobacterium neogureus AF268445 Mycobacterium parascrotum ADNV01000350 Mycobacterium paraterrane EU919229 Mycobacterium phlei GU142920 Mycobacterium smegmatis DQ536403 Mycobacterium smegmatis CP000480 Mycobacterium 1761 EU703150 Mycobacterium species 1776 EU703152 Mycobacterium species 1781 EU703147 Mycobacterium species 1791 EU703148 Mycobacterium species 1797 EU703149 Mycobacterium AQ1GA4 HM210417 Mycobacterium species B10_07.09.0206 HQ174245 Mycobacterium species GN_10546 FJ497243 Mycobacterium species GN_10827 FJ497247 Mycobacterium species GN_11124 FJ652846 Mycobacterium species GN_9188 FJ497240 Mycobacterium species GR_2007_210 FJ555538 Mycobacterium species HE5 AJ012738 Mycobacterium species NLA001000736 HM627011 Mycobacterium W DQ437715 Mycobacterium tuberculosis CP001658 Mycobacterium ulcerans AB548725 Mycobacterium fragilis EU834055 Mycoplasma agalactiae AF010477 Mycoplasma biformis AY531656 Mycoplasma arthritis NC_011025 Mycoplasma bovis NR_025987 Mycoplasma Pharyngeal NR_024983 Mycoplasma fermentum CP002458 Mycoplasma flocculus X62699 Mycoplasma Genitalium L43967 Mycoplasma hominis AF443616 Oral Mycoplasma AY796060 Mycoplasma ovipneumoniae NR_025989 Mycoplasma penetrating NC_004432 Mycoplasma pneumoniae NC_000912 Mycoplasma Corrupt U26055 Mycoplasma salivarius M24661 Mycoplasma complex P1 oral clone MB1_G23 DQ003614 Neisseria rod AFAY01000058 Neisseria griseus ACDY01000037 Neisseria longum ADBF01000003 Neisseria lutea ACQV01000025 Neisseria complex P2 oral colony MB5_P15 DQ003630 Neisseria gonorrhoeae CP002440 Neisseria lactose ACEQ01000095 Neisseria macaque AFQE01000146 Neisseria meningitidis NC_003112 Neisseria mucosa ACDX01000110 Neisseria pharyngeal AJ239281 Neisseria polysaccharides ADBE01000137 Neisseria dry ACKO02000016 Neisseria KEM232 GQ203291 Neisseria oral clone AP132 AY005027 Neisseria species oral colony JC012 AY349388 Neisseria oral strain B33KA AY005028 Neisseria Oral Taxonomy 014 ADEA01000039 Neisseria species SMC_A9199 FJ763637 Neisseria species TM10_1 DQ279352 Neisseria lutea ACEO01000067 Pseudomonas AB490805 Odorbacterium viscera CP002544 Oscillatoria G2 HM626173 Vibrio valerobacter NR_074793 Oscillatoria crux AB040495 Bacillus barcelona NR_042272 Bacillus barenguez NR_042756 Bacillus chinensis NR_040885 Bacillus kucherii NR_025372 Bacillus tenacious NR_037017 Bacillus gluconolyticus D78470 Bacillus lactis NR_025739 Paenibacillus splendidus NR_040882 Bacillus fodder NR_040853 Bacillus polymyxa NR_037006 Bacillus chaferi NR_040888 Paenibacillus CIP 101062 HM212646 Parabacteroides diundii CP000140 Parabacteroides gurnii AY974070 Parabacteroides gordonii AB470344 Parabacter johnsonii ABYH01000014 Parabacteroides faecium EU136685 Parabacteroides D13 ACPW01000017 Parabacteroides species NS31_3 JN029805 Peptococcus niger NR_029221 Peptococcus oral clone JM048 AY349389 Peptococcus oral taxa 167 GQ422727 Saccharotrophic Bacteria D14145 Durdaniels EU526290 Hygrophila NR_026358 Indoleophilus AY153431 Iverophilus Y07840 Lacrimal Glandophilus ADDO01000050 Brinophilus gpac007 AM176517 Brinophilus species gpac018A AM176519 Brinophilus species gpac077 AM176527 Bacillus sp. gpac148 AM176535 Hygrophila species JC140 JF824803 Oral taxa of the genus Hygrophila 386 ADCS01000031 Oral taxa of genus Hygrophila 836 AEAA01000090 Peptostreptococcaceae bacteria ph1 JN837495 Anaerobic digestive streptococcus AY326462 Peptostreptococcus parvum AM176538 Peptostreptococcus 9succ1 X90471 Peptostreptococcus oral clone AP24 AB175072 Peptostreptococcus species oral clone FJ023 AY349390 Peptostreptococcus P4P_31 P3 AY207059 Peptostreptococcus stomatitis ADGQ01000048 Porphyromonas bacteria NML 060648 EF184292 Porphyromonas saccharolyticus AENO01000048 Porphyromonas dental pulp ACNN01000021 Porphyromonas gingivalis AE015924 Porphyromonas leishii NR_025907 Porphyromonas rhesus NR_025908 Porphyromonas sola AB547667 Porphyromonas oral clone BB134 AY005068 Oral clone of Porphyromonas species F016 AY005069 Porphyromonas oral colony P2PB_52 P1 AY207054 Oral clone of Porphyromonas species P4GB_100 P2 AY207057 Porphyromonas UQD 301 EU012301 Porphyromonas Ueno ACLR01000152 Albers Prevotella NR_025300 Prevotella annasii AB547670 Prevotella berghei ACKS01000100 Prevotella Ⅱ ADFO01000096 Revotella brevis NR_041954 Prevotella Buccalis ACRB01000001 Prevotella cheek JN867261 Prevotella faecalis ACBX02000014 Prevotella human L16465 Prevotella dentata AB547678 Prevotella dentata CP002589 Prevotella AEDO01000026 Prevotella complex C1 AY278624 Prevotella complex C2 AY278625 Prevotella complex P7 oral clone MB2_P31 DQ003620 Prevotella complex P8 oral clone MB3_P13 DQ003622 Prevotella complex P9 oral clone MB7_G16 DQ003633 Prevotella heparinii GQ422742 Prevotella histobialis JN867315 Prevotella intermedia AF414829 Prevotella roche JN867231 Prevotella melanosa AGEK01000035 Prevotella mazei AEEI01000070 Prevotella melanogenes CP002122 Prevotella rainbow AGWK01000061 Prevotella polymorpha AEWX01000054 Prevotella polysaccharides AFJE01000016 Prevotella nancy JN867228 Prevotella melanoides AFPX01000069 Oral Prevotella AEPE01000021 Prevotella ADDV01000091 Prevotella gingivitis L16472 Prevotella pallidum AFPY01000135 Prevotella rumen CP002006 Prevotella saliva AB108826 Prevotella BI_42 AJ581354 Prevotella species CM38 HQ610181 Prevotella species ICM1 HQ616385 Prevotella species ICM55 HQ616399 Prevotella JCM 6330 AB547699 Prevotella oral clone AA020 AY005057 Prevotella species oral clone ASCG10 AY923148 Prevotella species oral clone ASCG12 DQ272511 Prevotella species oral clone AU069 AY005062 Oral clone of Prevotella species CY006 AY005063 Prevotella species oral clone DA058 AY005065 Prevotella species oral clone FL019 AY349392 Oral clone of Prevotella species FU048 AY349393 Prevotella species oral clone FW035 AY349394 Oral clone of Prevotella species GI030 AY349395 Prevotella species oral clone GI032 AY349396 Prevotella species oral clone GI059 AY349397 Prevotella species oral clone GU027 AY349398 Oral clone of Prevotella species HF050 AY349399 Prevotella species oral clone ID019 AY349400 Prevotella species oral clone IDR_CEC_0055 AY550997 Prevotella species oral clone IK053 AY349401 Prevotella species oral clone IK062 AY349402 Prevotella oral clone P4PB_83 P2 AY207050 Prevotella oral taxa 292 GQ422735 Prevotella species oral taxa 299 ACWZ01000026 Prevotella species oral taxa 300 GU409549 Prevotella species oral taxa 302 ACZK01000043 Prevotella species oral taxa 310 GQ422737 Prevotella species oral taxa 317 ACQH01000158 Prevotella species oral taxa 472 ACZS01000106 Prevotella species oral taxa 781 GQ422744 Prevotella species oral taxa 782 GQ422745 Prevotella oral taxa F68 HM099652 Prevotella species oral taxa G60 GU432133 Prevotella species oral taxa G70 GU432179 Prevotella species oral taxa G71 GU432180 Prevotella species SEQ053 JN867222 Prevotella species SEQ065 JN867234 Prevotella species SEQ072 JN867238 Prevotella species SEQ116 JN867246 Prevotella species SG12 GU561343 Prevotella sp24 AB003384 Prevotella sp34 AB003385 Prevotella faecalis AB244774 Prevotella tansii ACIJ02000018 Timmons Prevotella ADEF01000012 Prevotella euphorbia ACVA01000027 Prevotaceae bacteria P4P_62 P1 AY207061 Propionibacteriaceae NML 02_0265 EF599122 Propionibacterium Propionigenes NC_019395 Propionibacterium acnes ADJM01000010 Propionibacterium Greedy AJ003055 Propionibacterium frederi NR_036972 Propionibacterium granulosum FJ785716 Propionibacterium jensenensis NR_042269 Propionibacterium Propionibacterium NR_025277 Propionibacterium 434_HC2 AFIL01000035 Propionibacterium species H456 AB177643 Propionibacterium LG AY354921 Propionibacterium oral taxa 192 GQ422728 Propionibacterium species S555a AB264622 Propionibacterium turnei NR_042270 Pseudomonas aeruginosa AABQ07000001 Pseudomonas fluorescens AY622220 Pseudomonas gaii FJ943496 Pseudomonas mendoza AAUL01000021 Pseudomonas monseri NR_024910 Pseudomonas phlei GU188951 Pseudomonas alcaligenes NR_037000 Pseudomonas putida AF094741 Pseudomonas 2_1_26 ACWU01000257 Pseudomonas G1229 DQ910482 Pseudomonas species NP522b EU723211 Pseudomonas stutzeri AM905854 Pseudomonas torah AF320988 Pseudomonas chrysogenum NR_042764 Ralstonia piercei NC_010682 Ralstonia 5_7_47FAA ACUF01000076 Rosbyia cecum GU233441 Barresia faecalis AY804149 Rossiella faecalis AY305310 Rosbyella hominis AJ270482 Rossbyrella enterica FP929050 Rothbyia inulina AJ270473 Rossbyresia 11SE37 FM954975 Rossbyresia species 11SE38 FM954976 R. sky DQ673320 Rosella caries ADDW01000024 Rosella slime ACVO01000020 Rosella Murinosus NR_025310 Rosella oral taxa 188 GU470892 Ruminant amylophilus NR_026450 Rumenococcus bacteria D16 ADDX01000083 Rumencoccus albicans AY445600 Rumenococcus brucei EU266549 Rumen Cocci NR_029160 Ruminococcus champanellensis FP929052 Rumenococcus chrysogenum NR_025931 Rumenococcus active X94967 Rumenococcus hansenii M59114 Rumenococcus lactis ABOU02000049 Gastrococcus ovalifolia AY169419 Rumenococcus 18P13 AJ515913 Rumencoccus species 5_1_39BFAA ACII01000172 Rumencoccus species 9SE51 FM954974 Rumencoccus species ID8 AY960564 Rumenococcus species K_1 AB222208 Rumenococcus twisted AAVP02000002 Salmonella bongore NR_041699 Salmonella enteritidis NC_011149 Salmonella enteritidis NC_011205 Salmonella enteritidis DQ344532 Salmonella enteritidis ABEH02000004 Salmonella enteritidis ABAK02000001 Salmonella enteritidis NC_011080 Salmonella enteritidis EU118094 Salmonella enteritidis NC_011094 Salmonella enteritidis AE014613 Salmonella enteritidis ABFH02000001 Salmonella enteritidis ABEM01000001 Salmonella enteritidis ABAM02000001 Salmonella typhimurium DQ344533 Salmonella typhimurium AF170176 Ceratomonas arachnida HM596274 Ceratomonas GQ422719 Leunomonas flexneri AF287803 Selenomonas complex C1 AY278627 Luminomonas complex C2 AY278628 Lunamonas complex P5 AY341820 Oral clone MB3_C41 of the genus Lumenomonas complex P6 DQ003636 Oral clone MB5_C08 of luteomonas complex P7 DQ003627 Oral clone MB5_P06 of the genus Lumenomonas complex P8 DQ003628 Crescentomonas lesions AF287802 Lunomonas harmful GU470909 Luminomonas ruminant NR_075026 Selenomonas FOBRC9 HQ616378 Oral clone FT050 AY349403 Oral clone GI064 AY349404 Oral clone GT010 AY349405 Oral clone HU051 AY349406 Oral clone IK004 AY349407 Oral clone IQ048 AY349408 Oral clone JI021 AY349409 Oral clone JS031 AY349410 Oral clone OH4A AY947498 Oral clone P2PA_80 P4 AY207052 Oral taxa 137 AENV01000007 Oral taxa of genus Selenomonas 149 AEEJ01000007 Leucomonas sputum ACKP02000033 Serratia vulgaris NR_025339 Serratia liquefaciens NR_042062 Serratia marcescens GU826157 Serratia odora ADBY01000001 Banserratia mutans AAUN01000015 Shigella Boydii AAKA01000007 Shigella dysenteriae NC_007606 Shigella flexneri AE005674 Shigella sonnei NC_007384 Sphingomyces faecalis NR_025537 Sphingomyces waternii JF708889 Sphingosine multivorum NR_040953 Sphingomyces sphingomyces ACHA02000013 Sphingomonas spinosa NR_024700 Sphingomonas oral clone FI012 AY349411 Sphingomonas species oral clone FZ016 AY349412 Sphingomonas oral taxa A09 HM099639 Sphingomonas species oral taxa F71 HM099645 Staphylococcus bacteria NML 92_0017 AY841362 Staphylococcus aureus CP002643 Staphylococcus auris JQ624774 Staphylococcus capitis ACFR01000029 Staphylococcus goat ACRH01000033 Staphylococcus carnosus NR_075003 Staphylococcus coriolis JN175375 Staphylococcus spice NR_029345 Staphylococcus epidermidis ACHE01000056 Staphylococcus equi NR_027520 Staphylococcus freundii NR_041326 Staphylococcus hemolyticus NC_007168 Staphylococcus hominis AM157418 Staphylococcus ludunensis AEQA01000024 Staphylococcus pastoris FJ189773 Staphylococcus pseudointermediate CP002439 Staphylococcus saccharolyticus NR_029158 Staphylococcus saprophyticus NC_007350 Staphylococcus squirrel NR_025520 Staphylococcus clone bottae7 AF467424 Staphylococcus H292 AB177642 Staphylococcus species H780 AB177644 Staphylococcus succinate NR_028667 Staphylococcus calf NR_024670 Staphylococcus ACPZ01000009 Staphylococcus xylosus AY395016 Streptobacter candidiasis NR_027615 Streptococcus agalactiae AAJO01000130 Non-lactococcus NR_041781 Streptococcus anginae AECT01000011 Australian Streptococcus AEQR01000024 Streptococcus bovis AEEL01000030 Streptococcus canis AJ413203 Streptococcus constellation AY277942 Streptococcus spinosus AEVC01000028 Streptococcus Dawn AEKN01000002 Streptococcus lactis AP010935 Streptococcus equi CP001129 Enterococcus equi AEVB01000043 Streptococcus gallicans FR824043 Streptococcus complex C1 AY278629 Streptococcus complex C2 AY278630 Streptococcus complex C3 AY278631 Streptococcus complex C4 AY278632 Streptococcus complex C5 AY278633 Streptococcus complex C6 AY278634 Streptococcus complex C7 AY278635 Streptococcus complex C8 AY278609 Streptococcus gordonii NC_009785 Streptococcus pediatrics ABJK02000017 Streptococcus infantis AFNN01000024 Streptococcus intermedius NR_028736 Streptococcus paris NR_037096 Streptococcus marseille AY769997 Streptococcus miller X81023 Streptococcus mitis AM157420 Streptococcus mutans AP010655 Streptococcus oligofermentum AY099095 Oral Streptococcus ADMV01000001 Streptococcus parasanis AEKM01000012 Streptococcus pastoris AP012054 Streptococcus panoralis AEVF01000016 Streptococcus pneumoniae AE008537 Streptococcus porica EF121439 Streptococcus pseudopneumoniae FJ827123 Streptococcus pseudoporus AENS01000003 Streptococcus pyogenes AE006496 Streptococcus murine X58304 Streptococcus salivarius AGBV01000001 Streptococcus sanguis NR_074974 Streptococcus sinensis AF432857 Streptococcus 16362 JN590019 Streptococcus 2_1_36FAA ACOI01000028 Streptococcus 2285_97 AJ131965 Streptococcus species 69130 X78825 Streptococcus species AC15 HQ616356 Streptococcus species ACS2 HQ616360 Streptococcus species AS20 HQ616366 Streptococcus species BS35a HQ616369 Streptococcus species C150 ACRI01000045 Streptococcus species CM6 HQ616372 Streptococcus species CM7 HQ616373 Streptococcus species ICM10 HQ616389 Streptococcus species ICM12 HQ616390 Streptococcus species ICM2 HQ616386 Streptococcus species ICM4 HQ616387 Streptococcus species ICM45 HQ616394 Streptococcus species M143 ACRK01000025 Streptococcus species M334 ACRL01000052 Streptococcus species OBRC6 HQ616352 Streptococcus species oral clone ASB02 AY923121 Streptococcus species oral clone ASCA03 DQ272504 Streptococcus species oral clone ASCA04 AY923116 Streptococcus species oral clone ASCA09 AY923119 Streptococcus species oral colony ASCB04 AY923123 Streptococcus species oral clone ASCB06 AY923124 Streptococcus species oral clone ASCC04 AY923127 Streptococcus species oral clone ASCC05 AY923128 Streptococcus species oral clone ASCC12 DQ272507 Streptococcus species oral clone ASCD01 AY923129 Streptococcus species oral clone ASCD09 AY923130 Streptococcus species oral clone ASCD10 DQ272509 Streptococcus species oral colony ASCE03 AY923134 Streptococcus species oral colony ASCE04 AY953253 Streptococcus species oral colony ASCE05 DQ272510 Streptococcus species oral colony ASCE06 AY923135 Streptococcus species oral colony ASCE09 AY923136 Streptococcus species oral colony ASCE10 AY923137 Streptococcus species oral colony ASCE12 AY923138 Streptococcus species oral colony ASCF05 AY923140 Streptococcus species oral colony ASCF07 AY953255 Streptococcus species oral clone ASCF09 AY923142 Streptococcus species oral colony ASCG04 AY923145 Streptococcus species oral clone BW009 AY005042 Streptococcus species oral clone CH016 AY005044 Streptococcus species oral clone GK051 AY349413 Streptococcus species oral clone GM006 AY349414 Streptococcus oral clone P2PA_41 P2 AY207051 Streptococcus species oral clone P4PA_30 P4 AY207064 Streptococcus oral taxa 071 AEEP01000019 Streptococcus oral taxa G59 GU432132 Streptococcus species oral taxa G62 GU432146 Streptococcus species oral taxa G63 GU432150 Streptococcus species SHV515 Y07601 Streptococcus suis FM252032 Streptococcus thermophilus CP000419 Streptococcus uberis HQ391900 Streptococcus urinaria DQ303194 Streptococcus vestibularis AEKO01000008 Streptococcus viridans AF076036 Mobilinisate AJ832129 Pavilella AB300989 Sartorius sanguineus AJ748647 Sartreella YIT 12072 AB491210 S. faecalis NR_025600 Wardesatella ADMF01000048 Syntrophic bacteria complex C1 AY278615 Syntrophic bacteria RMA 14551 DQ412722 Syntrophic bacteria ADV897 GQ258968 Syntrophic bacteria LBVCM1157 GQ258969 Oral taxa 362 GU410752 Oral taxa D48 of Syntrophic bacteria GU430992 Turicibacter sanguinis AF349724 Atypical Veillonella AEDS01000059 Isovirionella ACIK02000021 Veillonella complex P1 oral colony MB5_P17 DQ003631 Levironella montenegro AF473836 Veillonella parvum ADFU01000009 Veillonella 3_1_44 ADCV01000019 Veillonella 6_1_27 ADCW01000016 Veillonella ACP1 HQ616359 Veillonella species AS16 HQ616365 Veillonella species BS32b HQ616368 Veillonella species ICM51a HQ616396 Veillonella species MSA12 HQ616381 Veillonella NVG 100cf EF108443 Veillonella species OK11 JN695650 Veillonella oral colony ASCA08 AY923118 Veillonella species oral colony ASCB03 AY923122 Veillonella species oral colony ASCG01 AY923144 Veillonella species oral colony ASCG02 AY953257 Veillonella species oral clone OH1A AY947495 Veillonella oral taxa 158 AENU01000007 Oral taxa of veillonellaceae bacteria 131 GU402916 Oral taxa of Veronococcus bacteria 155 GU470897 Vibrio cholerae AAUR01000095 Vibrio fluvialis X76335 Vibrio freundii CP002377 Vibrio mimicus ADAF01000001 Vibrio parahaemolyticus AAWQ01000116 Vibrio RC341 ACZT01000024 Vibrio vulnificus AE016796 Yersinia asheri AJ871363 Yersinia alixii AJ627597 Yersinia bechii AF366377 Yersinia enterocolitica FR729477 Yersinia freundii AF366379 Yersinia intermedia AF366380 Yersinia kristenia ACCA01000078 Yersinia morii NR_027546 Yersinia pestis AE013632 Yersinia pseudotuberculosis NC_009708 Yersinia Roche ACCD01000071 [surface 3 ]: Exemplary bacterial strains Strains Deposit number Parabacteroides gurnii PTA-126574 Bifidobacterium animalis subsp. lactis strain A PTA-125097 Blautella marseille strain A PTA-125134 Prevotella strain B NRRL accession number B 50329 Prevotella histobialis PTA-126140 Broutella strain A PTA-125346 Lactococcus lactis subsp. cremoris strain A PTA-125368 Lactobacillus salivarius PTA-125893 Active Rumenococcus Strains PTA-125706 Nasiris Tyzer Strains PTA-125707 Clostridium parabenbens PTA-125894 Active rumen cocci (also known as Mediterraneibacter gnavus ) PTA-126695 Veillonella parvum PTA-125710 Atypical Veillonella Strain A PTA-125709 Atypical Veillonella Strain B PTA-125711 Veillonella parvum Strain A PTA-125691 Veillonella parvum strain B PTA-125711 Veillonella strain A PTA-125708 Agatha species PTA-125892 Turicibacter sanguinis PTA-125889 Klebsiella pneumoniae subsp. pneumoniae PTA-125891 Klebsiella oxytoca PTA-125890 Megacoccus species strain A PTA-126770 Megacoccus species PTA-126837 Harryflintia acetispora PTA-126694 Fournierella massiliensis PTA-126696 Modified bacteria and mEV

在一些方面，本文描述的細菌和/或mEV（例如smEV和/或pmEV）經修飾，使得它們包含、連接至和/或結合治療性部分。In some aspects, the bacteria and/or mEVs described herein (eg, smEV and/or pmEV) are modified such that they contain, connect to, and/or bind to therapeutic moieties.

在一些實施方式中，該治療性部分係癌症特異性部分。在一些實施方式中，該癌症特異性部分對癌細胞具有結合特異性（例如對癌症特異性抗原具有結合特異性）。在一些實施方式中，該癌症特異性部分包含抗體或其抗原結合片段。在一些實施方式中，該癌症特異性部分包含T細胞受體或嵌合抗原受體（CAR）。在一些實施方式中，該癌症特異性部分包含表現於癌細胞表面上受體的配位基或其受體結合片段。在一些實施方式中，該癌症特異性部分係二分（bipartite）融合蛋白，其具有兩個部分：結合至和/或連接至細菌的第一部分及可結合至癌細胞（例如藉由對癌症特異性抗原具有結合特異性）的第二部分。在一些實施方式中，該第一部分係全長肽聚糖識別蛋白（諸如PGRP）的片段或全長肽聚糖識別蛋白。在一些實施方式中，該第一部分對mEV具有結合特異性（例如藉由對細菌抗原具有結合特異性）。在一些實施方式中，該第一和/或第二部分包含抗體或其抗原結合片段。在一些實施方式中，該第一和/或第二部分包含T細胞受體或嵌合抗原受體（CAR）。在一些實施方式中，該第一和/或第二部分包含表現於癌細胞表面上受體的配位基或其受體結合片段。在某些實施方式中，癌症特異性部分及藥劑的共投與（組合投與或分開投與）增加藥劑靶向癌細胞。In some embodiments, the therapeutic moiety is a cancer-specific moiety. In some embodiments, the cancer-specific portion has binding specificity for cancer cells (eg, has binding specificity for cancer-specific antigens). In some embodiments, the cancer-specific portion comprises an antibody or antigen-binding fragment thereof. In some embodiments, the cancer-specific portion comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the cancer-specific portion comprises a ligand or receptor binding fragment thereof that is expressed on a receptor on the surface of cancer cells. In some embodiments, the cancer-specific part is a bipartite fusion protein, which has two parts: the first part that binds to and/or connects to the bacteria and the first part that binds to cancer cells (for example, by being specific to cancer Antigen has the second part of binding specificity). In some embodiments, the first part is a fragment of a full-length peptidoglycan recognition protein (such as PGRP) or a full-length peptidoglycan recognition protein. In some embodiments, the first part has binding specificity for mEV (eg, by having binding specificity for bacterial antigens). In some embodiments, the first and/or second part comprises an antibody or antigen-binding fragment thereof. In some embodiments, the first and/or second part comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the first and/or second part comprises a ligand or receptor binding fragment thereof that is expressed on a receptor on the surface of a cancer cell. In certain embodiments, the co-administration (combined administration or separate administration) of the cancer-specific moiety and the agent increases the targeting of the agent to cancer cells.

在一些實施方式中，本文描述的細菌和/或mEV可以是經修飾的，使得它們包含、連接至和/或結合磁性和/或順磁性部分（例如磁珠）。在一些實施方式中，該磁性和/或順磁性部分包含細菌和/或直接連接至細菌。在一些實施方式中，該磁性和/或順磁性部分連接至結合至細菌或mEV的細菌或mEV結合部分的一部分和/或為結合至細菌或mEV的細菌或mEV結合部分的一部分。在一些實施方式中，細菌或mEV結合部分係全長肽聚糖識別蛋白（諸如PGRP）的片段或全長肽聚糖識別蛋白。在一些實施方式中，細菌或mEV結合部分具有對細菌或mEV的結合特異性（例如藉由對細菌抗原具有結合特異性）。在一些實施方式中，細菌或mEV結合部分包含抗體或其抗原結合片段。在一些實施方式中，細菌或mEV結合部分包含T細胞受體或嵌合抗原受體（CAR）。在一些實施方式中，細菌或mEV結合部分包含表現於癌細胞表面上受體的配位基或其受體結合片段。在某些實施方式中，磁性和/或順磁性部分及細菌或mEV的共投與（一起投與或分開投與）可用以增加mEV靶向（例如靶向癌症細胞和/或受試者存在癌細胞的一部分）。 經加工的微生物胞外囊泡（pmEV）的產生In some embodiments, the bacteria and/or mEVs described herein may be modified such that they contain, connect to, and/or bind magnetic and/or paramagnetic moieties (eg, magnetic beads). In some embodiments, the magnetic and/or paramagnetic moiety contains bacteria and/or is directly connected to the bacteria. In some embodiments, the magnetic and/or paramagnetic moiety is attached to and/or is part of a bacteria or mEV binding moiety that binds to bacteria or mEV. In some embodiments, the bacterial or mEV binding portion is a fragment of a full-length peptidoglycan recognition protein (such as PGRP) or a full-length peptidoglycan recognition protein. In some embodiments, the bacteria or mEV binding portion has binding specificity for bacteria or mEV (eg, by having binding specificity for bacterial antigens). In some embodiments, the bacteria or mEV binding portion comprises an antibody or antigen binding fragment thereof. In some embodiments, the bacterial or mEV binding portion comprises a T cell receptor or chimeric antigen receptor (CAR). In some embodiments, the bacteria or mEV binding moiety comprises a ligand or receptor binding fragment thereof that is expressed on a receptor on the surface of a cancer cell. In certain embodiments, the co-administration of magnetic and/or paramagnetic moieties and bacteria or mEV (administered together or separately) can be used to increase mEV targeting (eg, targeting cancer cells and/or the presence of a subject) Part of cancer cells). Production of processed microbial extracellular vesicles (pmEV)

在某些方面，本文描述的pmEV可以使用本領域已知的任何方法製備。In certain aspects, the pmEV described herein can be prepared using any method known in the art.

在一些實施方式中，在沒有pmEV純化步驟的情況下製備pmEV。例如，在一些實施方式中，本文描述的pmEV自其釋放的細菌藉由使用讓細菌pmEV保持完整之方法被殺死且將所得的細菌組分（包括pmEV）用於本文描述之方法及組成物中。在一些實施方式中，該等細菌藉由使用抗生素（例如，使用本文描述的抗生素）被殺死。在一些實施方式中，該等細菌藉由使用UV輻射被殺死。In some embodiments, pmEV is prepared without a pmEV purification step. For example, in some embodiments, the bacteria released from pmEV described herein are killed by using a method that keeps the bacteria pmEV intact and the resulting bacterial components (including pmEV) are used in the methods and compositions described herein middle. In some embodiments, the bacteria are killed by using antibiotics (eg, using antibiotics described herein). In some embodiments, the bacteria are killed by using UV radiation.

在一些實施方式中，本文描述的pmEV純化自一種或多種其他細菌組分。從細菌（和視需要的其他細菌組分）純化pmEV之方法係本領域已知的。在一些實施方式中，pmEV藉由使用Thein, 等人.（J. Proteome Res. [蛋白質組學研究雜誌] 9 (12): 6135-6147 (2010)）或Sandrini, 等人.（Bio-protocol [生物方案] 4 (21): e1287 (2014)）中描述之方法從細菌培養物製備，該等文獻的各者以全文引用的方式併入本文中。在一些實施方式中，該等細菌經培養至高光密度及然後經離心以使細菌集結成粒（例如，在室溫或4°C下10,000-15,000 x g 10-15分鐘）。在一些實施方式中，丟棄上清液，並將細胞沈澱物在-80℃冷凍。在一些實施方式中，將細胞沈澱物在冰上解凍，並重懸於補充有1 mg/mL DNA酶I的100 mM Tris-HCl（pH 7.5）中。在一些實施方式中，在製造商建議的條件下使用Emulsiflex C-3（奧維斯丁公司（Avestin, Inc.））裂解細胞。在一些實施方式中，藉由在4°C下以10,000 x g離心15分鐘來沈澱碎片和未裂解的細胞。在一些實施方式中，然後將上清液在4°C下以120,000 x g離心1小時。在一些實施方式中，將沈澱物重懸於冰冷的pH 11的100 mM碳酸鈉中，在4°C下攪拌孵育1小時，然後在4°C下以120,000 x g離心1小時。在一些實施方式中，將沈澱重懸於pH 7.5的100 mM Tris-HCl中，在4°C下以120,000 x g再離心20分鐘，然後重懸於0.1 M Tris-HCl（pH 7.5）中或於PBS中。在一些實施方式中，樣本被存儲在-20°C。In some embodiments, the pmEV described herein is purified from one or more other bacterial components. Methods of purifying pmEV from bacteria (and other bacterial components as needed) are known in the art. In some embodiments, pmEV uses Thein, et al. ( J. Proteome Res. [Journal of Proteomics Research] 9 (12): 6135-6147 (2010)) or Sandrini, et al. ( Bio-protocol [Biological solution] The method described in 4 (21): e1287 (2014)) is prepared from bacterial culture, and each of these documents is incorporated herein by reference in its entirety. In some embodiments, the bacteria are cultured to a high optical density and then centrifuged to aggregate the bacteria into pellets (for example, 10,000-15,000 xg for 10-15 minutes at room temperature or 4°C). In some embodiments, the supernatant is discarded and the cell pellet is frozen at -80°C. In some embodiments, the cell pellet is thawed on ice and resuspended in 100 mM Tris-HCl (pH 7.5) supplemented with 1 mg/mL DNase I. In some embodiments, Emulsiflex C-3 (Avestin, Inc.) is used to lyse cells under the conditions recommended by the manufacturer. In some embodiments, debris and unlysed cells are pelleted by centrifugation at 10,000 xg for 15 minutes at 4°C. In some embodiments, the supernatant is then centrifuged at 120,000 xg for 1 hour at 4°C. In some embodiments, the pellet is resuspended in ice-cold 100 mM sodium carbonate at pH 11, incubated at 4°C with stirring for 1 hour, and then centrifuged at 120,000 xg for 1 hour at 4°C. In some embodiments, the pellet is resuspended in 100 mM Tris-HCl pH 7.5, centrifuged at 120,000 xg for another 20 minutes at 4°C, and then resuspended in 0.1 M Tris-HCl (pH 7.5) or in PBS. In some embodiments, the sample is stored at -20°C.

在某些方面，pmEV係藉由改編自Sandrini等人（2014年）之方法獲得的。在一些實施方式中，細菌培養物在室溫或4°C下以10,000-15,500 x g離心10-15分鐘。在一些實施方式中，將細胞沈澱物在-80°C冷凍，並丟棄上清液。在一些實施方式中，將細胞沈澱物在冰上解凍，並重懸於10 mM Tris-HCl（pH 8.0）、補充有0.1 mg/mL溶菌酶的1 mM EDTA中。在一些實施方式中，將樣本在室溫或37°C下混合孵育30分鐘。在一些實施方式中，將樣本在-80°C下重新冷凍，然後再次在冰上解凍。在一些實施方式中，添加DNA酶I至終濃度為1.6 mg/mL，並添加MgCl2至終濃度為100 mM。在一些實施方式中，使用QSonica Q500超音波儀以30秒開啟和30秒關閉的7個循環對樣本進行超音波處理。在一些實施方式中，藉由在4°C下以10,000 x g離心15分鐘來沈澱碎片和未裂解的細胞。在一些實施方式中，然後將上清液在4°C下以110,000 x g離心15分鐘。在一些實施方式中，將沈澱重懸於10 mM Tris-HCl（pH 8.0）、2%曲通X-100中，並在室溫下混合孵育30-60分鐘。在一些實施方式中，將樣本在4°C下以110,000 x g離心15分鐘。在一些實施方式中，將沈澱物重懸於PBS中並儲存在-20°C。In some respects, pmEV was obtained by adapting the method from Sandrini et al. (2014). In some embodiments, the bacterial culture is centrifuged at 10,000-15,500 x g for 10-15 minutes at room temperature or 4°C. In some embodiments, the cell pellet is frozen at -80°C, and the supernatant is discarded. In some embodiments, the cell pellet is thawed on ice and resuspended in 10 mM Tris-HCl (pH 8.0), 1 mM EDTA supplemented with 0.1 mg/mL lysozyme. In some embodiments, the sample is mixed and incubated for 30 minutes at room temperature or 37°C. In some embodiments, the sample is re-frozen at -80°C and then thawed on ice again. In some embodiments, DNase I is added to a final concentration of 1.6 mg/mL, and MgCl2 is added to a final concentration of 100 mM. In some embodiments, a QSonica Q500 ultrasonic instrument is used to ultrasonically process the samples in 7 cycles of 30 seconds on and 30 seconds off. In some embodiments, debris and unlysed cells are pelleted by centrifugation at 10,000 x g for 15 minutes at 4°C. In some embodiments, the supernatant is then centrifuged at 110,000 x g for 15 minutes at 4°C. In some embodiments, the pellet is resuspended in 10 mM Tris-HCl (pH 8.0), 2% Triton X-100, and incubated with mixing at room temperature for 30-60 minutes. In some embodiments, the sample is centrifuged at 110,000 x g for 15 minutes at 4°C. In some embodiments, the pellet is resuspended in PBS and stored at -20°C.

在某些方面，本文描述的形成（例如，製備）分離的細菌pmEV之方法包括以下步驟：(a) 離心細菌培養物，從而形成第一沈澱物和第一上清液，其中該第一沈澱物包含細胞；(b) 丟棄該第一上清液；(c) 將該第一沈澱物重懸於溶液中；(d) 裂解細胞；(e) 離心裂解的細胞，從而形成第二沈澱物和第二上清液；(f) 丟棄該第二沈澱物並離心該第二上清液，從而形成第三沈澱物和第三上清液；(g) 丟棄該第三上清液並將該第三沈澱物重懸於第二溶液中，從而形成分離的細菌pmEV。In certain aspects, the method of forming (eg, preparing) isolated bacterial pmEV described herein includes the following steps: (a) centrifuging the bacterial culture to form a first precipitate and a first supernatant, wherein the first precipitate The substance contains cells; (b) discard the first supernatant; (c) resuspend the first pellet in the solution; (d) lyse the cells; (e) centrifuge the lysed cells to form a second pellet And the second supernatant; (f) discard the second precipitate and centrifuge the second supernatant to form a third precipitate and a third supernatant; (g) discard the third supernatant and The third precipitate is resuspended in the second solution, thereby forming isolated bacterial pmEV.

在一些實施方式中，該方法還包括以下步驟：(h) 離心步驟 (g) 的溶液，從而形成第四沈澱物和第四上清液；(i) 丟棄該第四上清液，並將該第四沈澱物重懸於第三溶液中。在一些實施方式中，該方法還包括以下步驟：(j) 離心步驟 (i) 的溶液，從而形成第五沈澱物和第五上清液；和 (k) 丟棄該第五上清液，並將該第五沈澱物重懸於第四溶液中。In some embodiments, the method further includes the following steps: (h) centrifuging the solution of step (g), thereby forming a fourth precipitate and a fourth supernatant; (i) discarding the fourth supernatant, and The fourth precipitate is resuspended in the third solution. In some embodiments, the method further includes the following steps: (j) centrifuging the solution of step (i), thereby forming a fifth precipitate and a fifth supernatant; and (k) discarding the fifth supernatant, and The fifth precipitate was resuspended in the fourth solution.

在一些實施方式中，步驟 (a) 的離心係以10,000 x g進行的。在一些實施方式中，步驟 (a) 的離心進行10-15分鐘。在一些實施方式中，步驟 (a) 的離心係在4°C或室溫下進行的。在一些實施方式中，步驟 (b) 還包括將第一沈澱物在-80°C冷凍。在一些實施方式中，步驟 (c) 中的溶液係補充有1 mg/ml DNA酶I的100 mM Tris-HCl（pH 7.5）。在一些實施方式中，步驟 (c) 中的溶液係10 mM Tris-HCl（pH 8.0）、1 mM EDTA，補充有0.1 mg/ml溶菌酶。在一些實施方式中，步驟 (c) 還包括在37°C或室溫下孵育30分鐘。在一些實施方式中，步驟 (c) 還包括將第一沈澱物在-80°C冷凍。在一些實施方式中，步驟 (c) 還包括將DNA酶I添加至1.6 mg/ml的終濃度。在一些實施方式中，步驟 (c) 還包括添加MgCl2 至100 mM的終濃度。在一些實施方式中，在步驟 (d) 中藉由勻漿裂解細胞。在一些實施方式中，在步驟 (d) 中藉由emulsiflex C3裂解細胞。在一些實施方式中，在步驟 (d) 中藉由超音波裂解細胞。在一些實施方式中，將細胞超音波處理7個循環，其中每個循環包括30秒的超音波處理和30秒的不超音波處理。在一些實施方式中，步驟 (e) 的離心係以10,000 x g。在一些實施方式中，步驟 (e) 的離心進行15分鐘。在一些實施方式中，步驟 (e) 的離心係在4°C或室溫下進行的。In some embodiments, the centrifugation in step (a) is performed at 10,000 xg. In some embodiments, the centrifugation of step (a) is performed for 10-15 minutes. In some embodiments, the centrifugation in step (a) is performed at 4°C or room temperature. In some embodiments, step (b) further includes freezing the first precipitate at -80°C. In some embodiments, the solution in step (c) is 100 mM Tris-HCl (pH 7.5) supplemented with 1 mg/ml DNase I. In some embodiments, the solution in step (c) is 10 mM Tris-HCl (pH 8.0), 1 mM EDTA, and supplemented with 0.1 mg/ml lysozyme. In some embodiments, step (c) further includes incubating at 37°C or room temperature for 30 minutes. In some embodiments, step (c) further includes freezing the first precipitate at -80°C. In some embodiments, step (c) further includes adding DNase I to a final concentration of 1.6 mg/ml. In some embodiments, step (c) further includes adding MgCl 2 to a final concentration of 100 mM. In some embodiments, the cells are lysed by homogenization in step (d). In some embodiments, the cells are lysed by emulsiflex C3 in step (d). In some embodiments, the cells are lysed by ultrasound in step (d). In some embodiments, the cells are ultrasonically processed for 7 cycles, where each cycle includes 30 seconds of ultrasonic processing and 30 seconds of non-ultrasonic processing. In some embodiments, the centrifugation in step (e) is performed at 10,000 xg. In some embodiments, the centrifugation of step (e) is performed for 15 minutes. In some embodiments, the centrifugation in step (e) is performed at 4°C or room temperature.

在一些實施方式中，步驟 (f) 的離心係以120,000 x g進行的。在一些實施方式中，步驟 (f) 的離心係以110,000 x g進行的。在一些實施方式中，步驟 (f) 的離心進行1小時。在一些實施方式中，步驟 (f) 的離心進行15分鐘。在一些實施方式中，步驟 (f) 的離心係在4°C或室溫下進行的。在一些實施方式中，步驟 (g) 中的第二溶液係pH 11的100 mM碳酸鈉。在一些實施方式中，步驟 (g) 中的第二溶液係10 mM Tris-HCl pH 8.0、2%曲通X-100。在一些實施方式中，步驟 (g) 還包括將溶液在4°C下孵育1小時。在一些實施方式中，步驟 (g) 還包括將溶液在室溫下孵育30-60分鐘。在一些實施方式中，步驟 (h) 的離心係以120,000 x g。在一些實施方式中，步驟 (h) 的離心係以110,000 x g進行的。在一些實施方式中，步驟 (h) 的離心進行1小時。在一些實施方式中，步驟 (h) 的離心進行15分鐘。在一些實施方式中，步驟 (h) 的離心係在4°C或室溫下進行的。在一些實施方式中，步驟 (i) 中的第三溶液係100 mM Tris-HCl（pH 7.5）。在一些實施方式中，步驟 (i) 中的第三溶液係PBS。在一些實施方式中，步驟 (j) 的離心係以120,000 x g。在一些實施方式中，步驟 (j) 的離心進行20分鐘。在一些實施方式中，步驟 (j) 的離心係在4°C或室溫下進行的。在一些實施方式中，步驟 (k) 中的第四溶液係100 mM Tris-HCl（pH 7.5）或PBS。In some embodiments, the centrifugation of step (f) is performed at 120,000 x g. In some embodiments, the centrifugation in step (f) is performed at 110,000 x g. In some embodiments, the centrifugation of step (f) is performed for 1 hour. In some embodiments, the centrifugation of step (f) is performed for 15 minutes. In some embodiments, the centrifugation in step (f) is performed at 4°C or room temperature. In some embodiments, the second solution in step (g) is 100 mM sodium carbonate at pH 11. In some embodiments, the second solution in step (g) is 10 mM Tris-HCl pH 8.0, 2% Triton X-100. In some embodiments, step (g) further includes incubating the solution at 4°C for 1 hour. In some embodiments, step (g) further includes incubating the solution at room temperature for 30-60 minutes. In some embodiments, the centrifugation in step (h) is at 120,000 x g. In some embodiments, the centrifugation in step (h) is performed at 110,000 x g. In some embodiments, the centrifugation of step (h) is performed for 1 hour. In some embodiments, the centrifugation of step (h) is performed for 15 minutes. In some embodiments, the centrifugation in step (h) is performed at 4°C or room temperature. In some embodiments, the third solution in step (i) is 100 mM Tris-HCl (pH 7.5). In some embodiments, the third solution in step (i) is PBS. In some embodiments, the centrifugation in step (j) is at 120,000 x g. In some embodiments, the centrifugation of step (j) is performed for 20 minutes. In some embodiments, the centrifugation in step (j) is performed at 4°C or room temperature. In some embodiments, the fourth solution in step (k) is 100 mM Tris-HCl (pH 7.5) or PBS.

藉由本文提供之方法獲得的pmEV可藉由基於尺寸的柱層析法、藉由親和層析法及藉由梯度超離心，使用可包括但不限於使用蔗糖梯度或Optiprep梯度之方法加以進一步純化。簡言之，在使用蔗糖梯度方法時，如果使用硫酸銨沈澱或超離心來濃縮經過濾上清液，將沈澱物重新懸浮於60%蔗糖、30 mM pH 8.0 Tris中。如果使用過濾來濃縮經過濾上清液，則使用Amicon Ultra柱將濃縮物緩衝液交換至60%蔗糖、30 mM pH 8.0 Tris中。將樣本施加至35%-60%不連續蔗糖梯度中並在4°C下以200,000 × g離心持續3-24小時。簡言之，在使用Optiprep梯度方法時，如果使用硫酸銨沈澱或超離心來濃縮經過濾上清液，則將集結粒懸浮於PBS中的35% Optiprep中。在一些實施方式中，如果使用過濾來濃縮經過濾上清液，則使用60% Optiprep將濃縮物稀釋至最終濃度為35% Optiprep。將樣本施加至35%-60%不連續蔗糖梯度中並在4°C下以200,000 × g離心持續3-24小時。The pmEV obtained by the methods provided herein can be further purified by size-based column chromatography, by affinity chromatography, and by gradient ultracentrifugation, using methods that may include, but are not limited to, the use of sucrose gradients or Optiprep gradients . In short, when using the sucrose gradient method, if ammonium sulfate precipitation or ultracentrifugation is used to concentrate the filtered supernatant, the precipitate is resuspended in 60% sucrose, 30 mM pH 8.0 Tris. If filtration is used to concentrate the filtered supernatant, use an Amicon Ultra column to exchange the concentrate buffer into 60% sucrose, 30 mM pH 8.0 Tris. The sample is applied to a 35%-60% discontinuous sucrose gradient and centrifuged at 200,000 × g at 4°C for 3-24 hours. In short, when using the Optiprep gradient method, if ammonium sulfate precipitation or ultracentrifugation is used to concentrate the filtered supernatant, the aggregate particles are suspended in 35% Optiprep in PBS. In some embodiments, if filtration is used to concentrate the filtered supernatant, 60% Optiprep is used to dilute the concentrate to a final concentration of 35% Optiprep. The sample is applied to a 35%-60% discontinuous sucrose gradient and centrifuged at 200,000 × g at 4°C for 3-24 hours.

在一些實施方式中，為證實pmEV製劑的無菌性及分離，將pmEV連續稀釋至瓊脂培養基（其用於測試中的細菌的例行培養）上，並使用例行條件進行培養。使未經滅菌的製劑通過0.22 um過濾器以去除完整細胞。為進一步增加純度，分離的pmEV可用DNA酶或蛋白酶K處理。In some embodiments, in order to confirm the sterility and isolation of the pmEV preparation, pmEV is serially diluted on agar medium (which is used for the routine culture of the bacteria under test) and cultured using routine conditions. Pass the unsterilized formulation through a 0.22 um filter to remove intact cells. To further increase the purity, the separated pmEV can be treated with DNase or proteinase K.

在一些實施方式中，pmEV製劑的無菌性可藉由將一部分pmEV接種至瓊脂培養基（其用於用以產生pmEV的細菌的標準培養）上及使用標準條件進行培養加以證實。In some embodiments, the sterility of the pmEV preparation can be confirmed by inoculating a portion of pmEV on an agar medium (used for standard culture of bacteria used to produce pmEV) and culturing using standard conditions.

在一些實施方式中，藉由層析法及pmEV上的結合表面部分來分離所選pmEV並富集。在其他實施方式中，所選pmEV藉由螢光細胞分選藉由使用親和試劑、化學染料、重組蛋白之方法或熟悉該項技術者已知的其他方法分離和/或富集。In some embodiments, the selected pmEV is separated and enriched by chromatography and the binding surface portion on pmEV. In other embodiments, the selected pmEV is separated and/or enriched by fluorescent cell sorting by methods using affinity reagents, chemical dyes, recombinant proteins, or other methods known to those skilled in the art.

可以對pmEV進行分析，例如，如Jeppesen等人Cell [細胞] 177: 428 (2019) 所述。The pmEV can be analyzed, for example, as described in Jeppesen et al. Cell [Cell] 177: 428 (2019).

在一些實施方式中，凍乾pmEV。In some embodiments, pmEV is lyophilized.

在一些實施方式中，pmEV經γ照射（例如，以17.5或25 kGy）。In some embodiments, pmEV is gamma irradiated (eg, at 17.5 or 25 kGy).

在一些實施方式中，pmEV被UV照射。In some embodiments, pmEV is irradiated with UV.

在一些實施方式中，pmEV被熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。In some embodiments, pmEV is heat-inactivated (eg, two hours at 50°C or two hours at 90°C).

在一些實施方式中，pmEV被酸處理。In some embodiments, pmEV is acid-treated.

在一些實施方式中，pmEV經氧噴射（例如，以0.1 vvm持續兩小時）。In some embodiments, pmEV is injected with oxygen (eg, at 0.1 vvm for two hours).

生長階段會影響細菌的數量或性質。例如，在本文提供的pmEV製備方法中，可以例如在對數生長期開始時、在對數生長期的中間時、和/或一旦達到穩定生長期時從培養物中分離pmEV。 分泌型微生物胞外囊泡（smEV）的產生The growth stage affects the number or nature of bacteria. For example, in the pmEV preparation methods provided herein, pmEV can be isolated from the culture, for example, at the beginning of the logarithmic growth phase, in the middle of the logarithmic growth phase, and/or once the stable growth phase is reached. Production of secretory microbial extracellular vesicles (smEV)

在某些方面，本文描述的smEV可以使用本領域已知的任何方法製備。In certain aspects, the smEV described herein can be prepared using any method known in the art.

在一些實施方式中，在沒有smEV純化步驟的情況下製備smEV。例如，在一些實施方式中，本文描述的細菌藉由使用讓smEV保持完整之方法被殺死且將所得的細菌組分（包括smEV）用於本文描述之方法及組成物中。在一些實施方式中，該等細菌藉由使用抗生素（例如，使用本文描述的抗生素）被殺死。在一些實施方式中，該等細菌藉由使用UV輻射被殺死。在一些實施方式中，細菌被熱殺死。In some embodiments, smEV is prepared without a smEV purification step. For example, in some embodiments, the bacteria described herein are killed by using methods that keep smEV intact and the resulting bacterial components (including smEV) are used in the methods and compositions described herein. In some embodiments, the bacteria are killed by using antibiotics (eg, using antibiotics described herein). In some embodiments, the bacteria are killed by using UV radiation. In some embodiments, the bacteria are killed by heat.

在一些實施方式中，本文描述的smEV純化自一種或多種其他細菌組分。用於自細菌純化smEV之方法為本領域中已知。在一些實施方式中，smEV藉由使用S. Bin Park等人, PLoS ONE. 6 (3): e17629 (2011) 或G. Norheim等人, PLoS ONE. [公共科學圖書館·綜合] 10 (9): e0134353 (2015) 或Jeppesen等人 Cell [細胞] 177: 428 (2019) 中描述之方法製備自細菌培養物，該等文獻的各者以全文引用的方式併入本文中。在一些實施方式中，該等細菌經培養至高光密度及然後經離心以使細菌沈澱（例如，在4°C下以10,000 x g離心30 min，在4°C下以15,500 x g離心15 min）。在一些實施方式中，然後使培養上清液通過過濾器以排除完整細菌細胞（例如，0.22 µm過濾器）。在一些實施方式中，然後對上清液進行切向流過濾，在此過程中，將上清液濃縮，除去小於100 kDa的物質，並用PBS對培養基進行部分交換。在一些實施方式中，經過濾的上清液經離心以使細菌smEV沈澱（例如，在4°C下以100,000至150,000 x g離心1至3小時，在4°C下以200,000 x g離心1至3小時）。在一些實施方式中，該等smEV藉由重新懸浮所得smEV沈澱物（例如，於PBS中），並將重新懸浮的smEV施用至Optiprep（碘克沙醇）梯度或梯度（例如30%至60%不連續的梯度、0-45%不連續的梯度），接著離心（例如，在4°C下以200,000 x g離心4至20小時）加以進一步純化。可以收集smEV帶，用PBS稀釋並離心以使smEV沈澱（例如，在4°C下以150,000 x g離心3小時，在4°C下以200,000 x g離心1小時）。純化的smEV可經儲存（例如，在-80°C或-20°C下）直至使用。在一些實施方式中，該等smEV藉由用DNA酶和/或蛋白酶K處理加以進一步純化。In some embodiments, the smEV described herein is purified from one or more other bacterial components. Methods for purifying smEV from bacteria are known in the art. In some embodiments, smEV is used by S. Bin Park et al., PLoS ONE. 6 (3): e17629 (2011) or G. Norheim et al., PLoS ONE. [Public Science Library·General] 10 (9 ): e0134353 (2015) or the method described in Jeppesen et al. Cell [Cell] 177: 428 (2019) is prepared from bacterial culture, and each of these documents is incorporated herein by reference in its entirety. In some embodiments, the bacteria are cultured to a high optical density and then centrifuged to pellet the bacteria (eg, 10,000 x g for 30 min at 4°C, and 15,500 x g for 15 min at 4°C). In some embodiments, the culture supernatant is then passed through a filter to exclude intact bacterial cells (eg, 0.22 µm filter). In some embodiments, the supernatant is then subjected to tangential flow filtration. In this process, the supernatant is concentrated to remove substances less than 100 kDa, and the medium is partially exchanged with PBS. In some embodiments, the filtered supernatant is centrifuged to precipitate bacterial smEV (eg, 100,000 to 150,000 xg at 4°C for 1 to 3 hours, and 200,000 xg at 4°C for 1 to 3 Hour). In some embodiments, the smEV is obtained by resuspending the resulting smEV pellet (for example, in PBS), and applying the resuspended smEV to an Optiprep (iodixanol) gradient or gradient (for example, 30% to 60%). Discontinuous gradient, 0-45% discontinuous gradient), followed by centrifugation (for example, 200,000 xg at 4°C for 4 to 20 hours) for further purification. The smEV band can be collected, diluted with PBS and centrifuged to pellet the smEV (for example, 150,000 x g at 4°C for 3 hours, and 200,000 x g at 4°C for 1 hour). The purified smEV can be stored (for example, at -80°C or -20°C) until use. In some embodiments, the smEVs are further purified by treatment with DNase and/or proteinase K.

例如，在一些實施方式中，細菌的培養物可在4°C下以11,000 x g離心20至40分鐘以使細菌沈澱。可使培養上清液通過0.22 µm過濾器以排除完整細菌細胞。然後可使用可包括但不限於硫酸銨沈澱、超離心或過濾之方法濃縮經過濾的上清液。例如，就硫酸銨沈澱而言，可將1.5-3 M硫酸銨緩慢添加至經過濾的上清液，同時在4°C下攪拌。可在4°C下將沈澱培養8至48小時及然後在4°C下以11,000 x g離心20至40分鐘。所得沈澱物含有細菌smEV及其他碎片。可使用超離心，經過濾的上清液在4°C下以100,000至200,000 x g離心1至16小時。此離心的沈澱物含有細菌smEV和其他碎片（例如大蛋白複合物）。在一些實施方式中，使用過濾技術，如藉由使用Amicon超自旋過濾器或藉由切向流過濾，上清液可經過濾以便於保留分子量 ＞ 50或100 kDa的物質。For example, in some embodiments, a culture of bacteria can be centrifuged at 11,000 x g at 4°C for 20 to 40 minutes to pellet the bacteria. The culture supernatant can be passed through a 0.22 µm filter to exclude intact bacterial cells. The filtered supernatant can then be concentrated using methods that may include, but are not limited to, ammonium sulfate precipitation, ultracentrifugation, or filtration. For example, for ammonium sulfate precipitation, 1.5-3 M ammonium sulfate can be slowly added to the filtered supernatant while stirring at 4°C. The pellet can be incubated at 4°C for 8 to 48 hours and then centrifuged at 11,000 x g for 20 to 40 minutes at 4°C. The resulting sediment contains bacterial smEV and other debris. Ultracentrifugation can be used, and the filtered supernatant is centrifuged at 100,000 to 200,000 x g for 1 to 16 hours at 4°C. This centrifuged pellet contains bacterial smEV and other debris (such as large protein complexes). In some embodiments, using filtration techniques, such as by using Amicon super-spin filters or by tangential flow filtration, the supernatant can be filtered so as to retain substances with a molecular weight> 50 or 100 kDa.

可替代地，例如藉由將生物反應器連接至細胞培養交替切向流（ATF）系統（例如來自Repligen的XCell ATF），可在生長期間或在生長期間的選定時間點，從細菌培養物連續獲得smEV。該ATF系統保留完整細胞（＞ 0.22 um）於生物反應器中，及容許較小組分（例如，smEV、游離蛋白質）通過過濾器以供收集。例如，該系統可經結構設計使得 ＜ 0.22 um濾液然後通過100 kDa的第二過濾器，容許收集如在0.22 µm與100 kDa之間的smEV的物質，並將小於100 kDa的種類泵送回生物反應器中。可替代地，該系統可經結構設計以容許生物反應器中的培養基在培養物的生長期間得到補充和/或修飾。藉由此方法收集的smEV可藉由如上文描述用於經過濾的上清液的超離心或過濾進行進一步純化和/或濃縮。Alternatively, for example, by connecting the bioreactor to a cell culture alternating tangential flow (ATF) system (such as XCell ATF from Repligen), the bacterial culture can be continuously removed from the bacterial culture during growth or at selected time points during growth. Get smEV. The ATF system retains intact cells (> 0.22 um) in the bioreactor, and allows smaller components (for example, smEV, free protein) to pass through the filter for collection. For example, the system can be structured so that the filtrate <0.22 um is then passed through a second filter of 100 kDa, allowing the collection of substances such as smEV between 0.22 µm and 100 kDa, and the pumping of species less than 100 kDa back to the organism In the reactor. Alternatively, the system may be structurally designed to allow the medium in the bioreactor to be replenished and/or modified during the growth of the culture. The smEV collected by this method can be further purified and/or concentrated by ultracentrifugation or filtration for the filtered supernatant as described above.

藉由本文提供之方法獲得的smEV可藉由基於尺寸的柱層析法、藉由親和層析法、藉由離子交換層析法及藉由梯度超離心，使用可包括但不限於使用蔗糖梯度或Optiprep梯度之方法加以進一步純化。簡言之，在使用蔗糖梯度方法時，如果使用硫酸銨沈澱或超離心來濃縮經過濾上清液，將沈澱物重新懸浮於60%蔗糖、30 mM pH 8.0 Tris中。如果使用過濾來濃縮經過濾上清液，則使用Amicon Ultra柱將濃縮物緩衝液交換至60%蔗糖、30 mM pH 8.0 Tris中。將樣本施加至35%-60%不連續蔗糖梯度中並在4°C下以200,000 × g離心持續3-24小時。簡而言之，在使用Optiprep梯度方法時，如果使用硫酸銨沈澱或超離心來濃縮經過濾上清液，則將沈澱物懸浮於PBS中並向樣本中添加3體積的60% Optiprep。在一些實施方式中，如果使用過濾來濃縮經過濾上清液，則使用60% Optiprep將濃縮物稀釋至最終濃度為35% Optiprep。將樣本施加至0-45%不連續的Optiprep梯度，並在4°C下以200,000 x g離心3至24小時，例如，在4°C下離心4至24小時。The smEV obtained by the method provided herein can be obtained by size-based column chromatography, by affinity chromatography, by ion exchange chromatography, and by gradient ultracentrifugation. The use may include, but is not limited to, the use of a sucrose gradient Or Optiprep gradient method for further purification. In short, when using the sucrose gradient method, if ammonium sulfate precipitation or ultracentrifugation is used to concentrate the filtered supernatant, the precipitate is resuspended in 60% sucrose, 30 mM pH 8.0 Tris. If filtration is used to concentrate the filtered supernatant, use an Amicon Ultra column to exchange the concentrate buffer into 60% sucrose, 30 mM pH 8.0 Tris. The sample is applied to a 35%-60% discontinuous sucrose gradient and centrifuged at 200,000 × g at 4°C for 3-24 hours. In short, when using the Optiprep gradient method, if ammonium sulfate precipitation or ultracentrifugation is used to concentrate the filtered supernatant, the precipitate is suspended in PBS and 3 volumes of 60% Optiprep are added to the sample. In some embodiments, if filtration is used to concentrate the filtered supernatant, 60% Optiprep is used to dilute the concentrate to a final concentration of 35% Optiprep. The sample is applied to a 0-45% discontinuous Optiprep gradient and centrifuged at 200,000 x g at 4°C for 3 to 24 hours, for example, at 4°C for 4 to 24 hours.

在一些實施方式中，為證實smEV製劑的無菌性及分離，將smEV連續稀釋至瓊脂培養基（其用於測試中的細菌的例行培養）上，並使用例行條件進行培養。使未經滅菌的製劑通過0.22 um過濾器以去除完整細胞。為進一步增加純度，分離的smEV可用DNA酶或蛋白酶K處理。In some embodiments, in order to confirm the sterility and isolation of smEV preparations, smEV is serially diluted onto agar medium (which is used for routine culture of bacteria under test) and cultured using routine conditions. Pass the unsterilized formulation through a 0.22 um filter to remove intact cells. To further increase the purity, the isolated smEV can be treated with DNase or proteinase K.

在一些實施方式中，為製備用於體內注射的smEV，純化的smEV如先前描述進行處理（G. Norheim等人, PLoS ONE. [公共科學圖書館·綜合] 10 (9): e0134353 (2015)）。簡而言之，在蔗糖梯度離心後，將含有smEV的帶於含有3%蔗糖的溶液中或熟悉該項技術者已知的適用於體內注射的其他溶液中重新懸浮至50 µg/mL的終濃度。此溶液還可含有濃度為0-0.5%（w/v）的佐劑（例如氫氧化鋁）。在一些實施方式中，為了製備用於體內注射的smEV，將PBS中的smEV無菌過濾至 ＜ 0.22 um。In some embodiments, to prepare smEV for in vivo injection, purified smEV is processed as previously described (G. Norheim et al., PLoS ONE. [Public Science Library·General] 10 (9): e0134353 (2015) ). In short, after sucrose gradient centrifugation, the smEV-containing solution is resuspended in a solution containing 3% sucrose or other solutions known to those skilled in the art that are suitable for in vivo injection to a final end of 50 µg/mL. concentration. This solution can also contain an adjuvant (such as aluminum hydroxide) at a concentration of 0-0.5% (w/v). In some embodiments, in order to prepare smEV for in vivo injection, smEV in PBS is sterile filtered to <0.22 um.

在某些實施方式中，為製備與其他測試（例如用以在TEM成像或活體外分析之前去除蔗糖）相容的樣本，使用過濾（例如，Amicon Ultra柱）將樣本緩衝液交換至PBS或30 mM pH 8.0 Tris中，透析，或超離心（200,000 × g，≥ 3小時，4°C）並重懸。In some embodiments, to prepare samples that are compatible with other tests (for example, to remove sucrose prior to TEM imaging or in vitro analysis), filtration (for example, Amicon Ultra columns) is used to exchange the sample buffer to PBS or 30 Dialysis, or ultracentrifugation (200,000 × g, ≥ 3 hours, 4°C) in mM pH 8.0 Tris and resuspend.

在一些實施方式中，smEV製劑的無菌性可藉由將一部分smEV接種至瓊脂培養基（其用於用以產生smEV的細菌的標準培養）上及使用標準條件進行培養加以證實。In some embodiments, the sterility of smEV preparations can be confirmed by inoculating a portion of smEV on an agar medium (which is used for standard culture of bacteria used to produce smEV) and culturing using standard conditions.

在一些實施方式中，藉由層析法及smEV上的結合表面部分來分離所選smEV並富集。在其他實施方式中，所選smEV藉由螢光細胞分選藉由使用親和試劑、化學染料、重組蛋白之方法或熟悉該項技術者已知的其他方法分離和/或富集。In some embodiments, the selected smEV is separated and enriched by chromatography and the binding surface portion on the smEV. In other embodiments, the selected smEV is separated and/or enriched by fluorescent cell sorting by methods using affinity reagents, chemical dyes, recombinant proteins, or other methods known to those skilled in the art.

可以對smEV進行分析，例如，如Jeppesen等人Cell [細胞] 177: 428 (2019) 所述。The smEV can be analyzed, for example, as described in Jeppesen et al. Cell [Cell] 177: 428 (2019).

在一些實施方式中，凍乾smEV。In some embodiments, smEV is lyophilized.

在一些實施方式中，smEV被γ照射（例如，在17.5或25 kGy下）。In some embodiments, smEV is gamma irradiated (eg, at 17.5 or 25 kGy).

在一些實施方式中，smEV被UV照射。In some embodiments, smEV is irradiated with UV.

在一些實施方式中，smEV被熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。In some embodiments, smEV is heat inactivated (eg, two hours at 50°C or two hours at 90°C).

在一些實施方式中，smEV被酸處理。In some embodiments, smEV is acid treated.

在一些實施方式中，smEV被噴氧（例如，以0.1 vvm持續兩小時）。In some embodiments, smEV is sprayed with oxygen (for example, at 0.1 vvm for two hours).

生長階段會影響細菌和/或細菌產生的smEV的數量或性質。例如，在本文提供的smEV製備方法中，可以例如在對數生長期開始時、在對數生長期的中間時、和/或一旦達到穩定生長期時從培養物中分離smEV。The growth stage affects the amount or nature of smEV produced by bacteria and/or bacteria. For example, in the smEV preparation methods provided herein, smEV can be isolated from the culture, for example, at the beginning of the logarithmic growth phase, in the middle of the logarithmic growth phase, and/or once the stable growth phase is reached.

生長環境（如培養條件）可影響細菌產生smEV的量。例如，smEV誘導因子可以增加smEV的產率，如表4所示。 [表 4 ]：增加 smEV 產率的培養技術 smEV誘導 smEV誘導因子 作用於 溫度          加熱 應激應答    RT至37°C溫度變化 模擬感染    37°C至40°C溫度變化 熱性感染 ROS          白花丹素 氧化應激應答    氫過氧化物異丙苯 氧化應激應答    過氧化氫 氧化應激應答 抗生素          環丙沙星 細菌SOS應答    建它黴素 蛋白質合成    多黏菌素B 外膜    D-環絲胺酸 細胞壁 滲壓劑          NaCl 滲透應激 金屬離子應激          鐵螯合 鐵水平    EDTA 去除二價陽離子    低氯化血紅素 鐵水平 培養基添加劑或去除          乳酸鹽 生長    胺基酸剝奪 應激    十六烷 應激    葡萄糖 生長    碳酸氫鈉 ToxT誘導    PQS 水泡劑（vesiculator）（來自細菌）    二胺 + DFMO 膜錨定（僅negativicutes）    高營養素 增強的生長    低營養素    其他機制          氧 厭氧生物中的氧應激    無半胱胺酸 厭氧生物中的氧應激    誘導生物膜或絮凝       兩階段生長       噬菌體       尿素    The growth environment (such as culture conditions) can affect the amount of smEV produced by the bacteria. For example, smEV inducing factors can increase the yield of smEV, as shown in Table 4. [ Table 4 ] : Cultivation techniques to increase the yield of smEV smEV induction smEV inducer Acting on temperature heating Stress response RT to 37°C temperature change Mock infection 37°C to 40°C temperature change Febrile infection ROS Plumbagin Oxidative stress response Cumene Hydroperoxide Oxidative stress response hydrogen peroxide Oxidative stress response antibiotic Ciprofloxacin Bacterial SOS response Gentamycin Protein synthesis Polymyxin B Outer membrane D-cycloserine Cell wall Osmotic agent NaCl Osmotic stress Metal ion stress Iron chelation Iron level EDTA Removal of divalent cations Hypochlorinated heme Iron level Medium additives or removal Lactate Grow Amino acid deprivation Stress Hexadecane Stress glucose Grow Sodium bicarbonate ToxT induction PQS Vesiculator (from bacteria) Diamine + DFMO Membrane anchoring (negativicutes only) High nutrient Enhanced growth Low nutrients Other mechanisms oxygen Oxygen stress in anaerobic organisms Cysteine Free Oxygen stress in anaerobic organisms Inducing biofilm or flocculation Two-stage growth Bacteriophage Urea

在本文提供的製備smEV之方法中，該方法可視需要包括在從細菌培養物中分離smEV之前，將細菌培養物暴露於smEV誘導因子。細菌培養物可以在對數生長期開始時、在對數生長期的中間時、和/或一旦達到穩定生長期時暴露於smEV誘導因子。 固體劑型組成物In the method for preparing smEV provided herein, the method may optionally include exposing the bacterial culture to a smEV-inducing factor before isolating the smEV from the bacterial culture. The bacterial culture may be exposed to the smEV-inducing factor at the beginning of the logarithmic growth phase, in the middle of the logarithmic growth phase, and/or once the stable growth phase is reached. Solid dosage form composition

在某些實施方式中，本文提供了包含藥劑的固體劑型（例如，具有固體劑型的藥物產品），該藥劑含有細菌和/或mEV（例如smEV和/或pmEV）。在一些實施方式中，藥劑可以視需要包含一種或多種另外的組分，例如冷凍保護劑。可以將藥劑凍乾（例如，產生粉末）。藥劑可以與固體劑型中的一種或多種賦形劑（例如藥學上可接受的賦形劑）組合。In certain embodiments, provided herein is a solid dosage form containing a medicament (for example, a pharmaceutical product having a solid dosage form), the medicament containing bacteria and/or mEV (for example, smEV and/or pmEV). In some embodiments, the medicament may optionally contain one or more additional components, such as cryoprotectants. The medicament can be lyophilized (for example, to produce a powder). The medicament can be combined with one or more excipients (for example, pharmaceutically acceptable excipients) in the solid dosage form.

在某些方面，本文提供了藥物組成物的固體劑型。在某些實施方式中，固體劑型包含藥劑（例如細菌和/或細菌起源（例如mEV）的藥劑（例如組分），包含細菌和/或細菌起源（例如mEV）的藥劑（例如組分）的粉末）和一種或多種崩散劑。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%或25%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的45%、40%、35%、30%或25%。在一些實施方式中，一種或多種崩散劑的總質量係藥物組成物總質量的至少30%、至少35%、至少40%、至少45%或至少50%。在一些實施方式中，一種或多種崩散劑的總質量不超過藥物組成物總質量的70%、65%、60%或55%。在一些實施方式中，一種或多種崩散劑包括低取代的羥丙基纖維素（L-HPC，例如LH-B1）、交聯羧甲基纖維素鈉（例如，Ac-Di-Sol、Ac-Di-Sol SD-711）、和/或交聚維酮（PVPP，例如科利當，例如科利當CL-F）。In certain aspects, solid dosage forms of pharmaceutical compositions are provided herein. In some embodiments, the solid dosage form contains an agent (for example, an agent (for example, a component) of bacteria and/or a bacterial origin (for example, mEV), and an agent (for example, a component) that includes an agent (for example, a component) of bacteria and/or a bacterial origin (for example, mEV). Powder) and one or more disintegrating powders. In some embodiments, the total mass of the drug is at least 5%, 10%, 15%, 20%, or 25% of the total mass of the drug composition. In some embodiments, the total mass of the medicament does not exceed 45%, 40%, 35%, 30%, or 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrants is at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrating powders does not exceed 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition. In some embodiments, one or more disintegrants include low-substituted hydroxypropyl cellulose (L-HPC, for example LH-B1), croscarmellose sodium (for example, Ac-Di-Sol, Ac- Di-Sol SD-711), and/or crospovidone (PVPP, such as Colidom, such as Colidom CL-F).

在某些方面，本文提供了藥物組成物的固體劑型。在某些實施方式中，固體劑型包含藥劑（其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉末））和一種或多種崩散劑（例如一種、兩種或三種崩散劑）。在某些實施方式中，固體劑型包含藥劑（其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉末））和三種崩散劑。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少20%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的25%。在一些實施方式中，一種或多種崩散劑的總質量係藥物組成物總質量的至少30%、至少35%、至少40%、至少45%或至少50%。在一些實施方式中，一種或多種崩散劑的總質量不超過藥物組成物總質量的70%、65%、60%或55%。在一些實施方式中，一種或多種崩散劑包括低取代的羥丙基纖維素（L-HPC，例如LH-B1）、交聯羧甲基纖維素鈉（例如，Ac-Di-Sol、Ac-Di-Sol SD-711）、和/或交聚維酮（PVPP，例如科利當，例如科利當CL-F）。In certain aspects, solid dosage forms of pharmaceutical compositions are provided herein. In certain embodiments, the solid dosage form contains a pharmaceutical agent (where the pharmaceutical agent contains Prevotella histobialis bacteria (such as bacteria and/or powder containing bacteria)) and one or more disintegrating agents (such as one, two or three disintegrating agents). Powder). In certain embodiments, the solid dosage form contains a pharmaceutical agent (where the pharmaceutical agent contains Prevotella histobialis bacteria (eg bacteria and/or powder containing bacteria)) and three disintegrating agents. In some embodiments, the total mass of the drug is at least 20% of the total mass of the drug composition. In some embodiments, the total mass of the medicament does not exceed 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrants is at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrating powders does not exceed 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition. In some embodiments, one or more disintegrants include low-substituted hydroxypropyl cellulose (L-HPC, for example LH-B1), croscarmellose sodium (for example, Ac-Di-Sol, Ac- Di-Sol SD-711), and/or crospovidone (PVPP, such as Colidom, such as Colidom CL-F).

在一些實施方式中，本文提供的固體劑型包含：(i) 藥劑，其具有的藥劑總質量係藥物組成物總質量的至少20%且不超過藥物組成物總質量的25%，(ii) L-HPC（例如，LH-B1級的L-HPC），其具有的L-HPC總質量係藥物組成物總質量的至少22%（例如，至少22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、或42%）且不超過藥物組成物總質量的42%（例如，不超過22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、或42%）；(iii) 交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）（例如SD-711級的Ac-Di-Sol），其具有的交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的至少0.01%（例如，至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、或16%）且不超過藥物組成物總質量的16%（例如，不超過1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、或16%）；以及 (iv) 交聚維酮，其具有的交聚維酮總質量係藥物組成物總質量的至少5%（例如，至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）且不超過藥物組成物總質量的25%（例如，不超過5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）。在某些實施方式中，L-HPC總質量加上交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量加上交聚維酮總質量係藥物組成物總質量的至少35%、40%、45%或50%。在一些實施方式中，固體劑型包含：L-HPC總質量係藥物組成物總質量的約32%；交聯羧甲基纖維素鈉（例如Ac-Di-Sol）總質量係藥物組成物總質量的約6%；交聚維酮總質量係藥物組成物總質量的約15%。In some embodiments, the solid dosage form provided herein comprises: (i) a medicament, the total mass of which is at least 20% of the total mass of the pharmaceutical composition and no more than 25% of the total mass of the pharmaceutical composition, (ii) L -HPC (for example, L-HPC of LH-B1 level), which has a total mass of L-HPC that is at least 22% (for example, at least 22%, 23%, 24%, 25%, 26%) of the total mass of the pharmaceutical composition %, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% ) And not more than 42% of the total mass of the pharmaceutical composition (for example, not more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%); (iii) croscarmellose sodium (for example, Ac-Di- Sol) (for example, Ac-Di-Sol of SD-711 grade), the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is at least 0.01% of the total mass of the pharmaceutical composition (for example , At least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%) and not more than 16% of the total mass of the pharmaceutical composition (for example, not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%); and (iv) crospovidone, which has a total mass of crospovidone that is at least 5 percent of the total mass of the pharmaceutical composition % (For example, at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%) and not more than 25% of the total mass of the pharmaceutical composition (for example, not more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In some embodiments, the total mass of L-HPC plus the total mass of croscarmellose sodium (for example, Ac-Di-Sol) plus the total mass of crospovidone is at least 35 percent of the total mass of the pharmaceutical composition. %, 40%, 45% or 50%. In some embodiments, the solid dosage form comprises: the total mass of L-HPC is about 32% of the total mass of the pharmaceutical composition; the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is the total mass of the pharmaceutical composition The total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含L-HPC。在一些實施方式中，L-HPC係LH-B1級（或包含LH-B1級的L-HPC）。在某些實施方式中，L-HPC總質量係藥物組成物總質量的至少22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量不超過藥物組成物總質量的22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量係藥物組成物總質量的約22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量係藥物組成物總質量的約29%至約35%。在某些實施方式中，L-HPC（LH-B1）總質量係藥物組成物總質量的約32%。In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is LH-B1 grade (or L-HPC including LH-B1 grade). In some embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC is about 29% to about 35% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of L-HPC (LH-B1) is about 32% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）。在一些實施方式中，交聯羧甲基纖維素鈉係SD-711級的Ac-Di-Sol。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量不超過藥物組成物總質量的1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的約1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的約3%至約9%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）（例如，Ac-Di-Sol SD-711）總質量係藥物組成物總質量的約6%。In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, Ac-Di-Sol). In some embodiments, croscarmellose sodium is SD-711 grade Ac-Di-Sol. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4% of the total mass of the pharmaceutical composition. %, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is about 3% to about 9% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) (for example, Ac-Di-Sol SD-711) is about 6% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聚維酮（PVPP，例如，科利當，例如，科利當CL-F）。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聯維酮總質量係藥物組成物總質量的約12%至約18%。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的約15%。In certain embodiments, the solid dosage forms provided herein comprise crospovidone (PVPP, for example, Coledon, for example, Coledon CL-F). In some embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crosvidone is about 12% to about 18% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition.

在一些實施方式中，本文提供的固體劑型包含：(i) 藥劑，其具有的藥劑總質量係藥物組成物總質量的至少5%且不超過藥物組成物總質量的35%，(ii) L-HPC（例如，LH-B1級的L-HPC），其具有的L-HPC總質量係藥物組成物總質量的至少22%（例如，至少22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、或42%）且不超過藥物組成物總質量的42%（例如，不超過22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、或42%）；(iii) 交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）（例如SD-711級的Ac-Di-Sol），其具有的交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的至少0.01%（例如，至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、或16%）且不超過藥物組成物總質量的16%（例如，不超過1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、或16%）；以及 (iv) 交聚維酮，其具有的交聚維酮總質量係藥物組成物總質量的至少5%（例如，至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）且不超過藥物組成物總質量的25%（例如，不超過5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）。在某些實施方式中，L-HPC總質量加上交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量加上交聚維酮總質量係藥物組成物總質量的至少35%、40%、45%或50%。在一些實施方式中，固體劑型包含：L-HPC總質量係藥物組成物總質量的約32%；交聯羧甲基纖維素鈉（例如Ac-Di-Sol）總質量係藥物組成物總質量的約6%；交聚維酮總質量係藥物組成物總質量的約15%。In some embodiments, the solid dosage form provided herein includes: (i) a medicament, the total mass of which is at least 5% of the total mass of the pharmaceutical composition and no more than 35% of the total mass of the pharmaceutical composition, (ii) L -HPC (for example, L-HPC of LH-B1 level), which has a total mass of L-HPC that is at least 22% (for example, at least 22%, 23%, 24%, 25%, 26%) of the total mass of the pharmaceutical composition %, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% ) And not more than 42% of the total mass of the pharmaceutical composition (for example, not more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%); (iii) croscarmellose sodium (for example, Ac-Di- Sol) (for example, Ac-Di-Sol of SD-711 grade), the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is at least 0.01% of the total mass of the pharmaceutical composition (for example , At least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%) and not more than 16% of the total mass of the pharmaceutical composition (for example, not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%); and (iv) crospovidone, which has a total mass of crospovidone that is at least 5 percent of the total mass of the pharmaceutical composition % (For example, at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%) and not more than 25% of the total mass of the pharmaceutical composition (for example, not more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In some embodiments, the total mass of L-HPC plus the total mass of croscarmellose sodium (for example, Ac-Di-Sol) plus the total mass of crospovidone is at least 35 percent of the total mass of the pharmaceutical composition. %, 40%, 45% or 50%. In some embodiments, the solid dosage form comprises: the total mass of L-HPC is about 32% of the total mass of the pharmaceutical composition; the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is the total mass of the pharmaceutical composition The total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型還包含甘露醇。在某些實施方式中，甘露醇係（或包含）甘露醇SD200。在某些實施方式中，甘露醇總質量係藥物組成物總質量的至少10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，甘露醇總質量不超過藥物組成物總質量的10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%或40%。在某些實施方式中，甘露醇總質量係藥物組成物總質量的約10%、11%、12%、13%、14%、15%、15.5%、16%、16.5%、17%、17.5%、18%、18.5%、19%、19.5%、20%、20.5%、21%、21.5%、22%、22.5%、23%、23.5%、24%、24.5%、25%、25.5%、26%、26.5%、27%、27.5%、28%、28.5%、29%、29.5%、30%、30.5%、31%、31.5%、32%、32.5%、33%、33.5%、34%、34.5%、35%、35.5%、36%、36.5%、37%、37.5%、38%、38.5%、39%、39.5%或40%。在某些實施方式中，總甘露醇質量係藥物組成物總質量的至少18%。在某些實施方式中，總甘露醇質量不超過藥物組成物總質量的25%。在某些實施方式中，總甘露醇質量係藥物組成物總質量的約18%、18.5%、19%、19.5%、20%、20.5%、21%、21.5%、22%、22.5%、23%、23.5%、24%、24.5%、或25%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約18%至約25%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約22%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約21.5%。In certain embodiments, the solid dosage forms provided herein further comprise mannitol. In some embodiments, mannitol is based on (or includes) mannitol SD200. In some embodiments, the total mass of mannitol is at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% of the total mass of the pharmaceutical composition. %, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of mannitol does not exceed 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% of the total mass of the pharmaceutical composition. %, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40%. In some embodiments, the total mass of mannitol is about 10%, 11%, 12%, 13%, 14%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5 of the total mass of the pharmaceutical composition. %, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34% , 34.5%, 35%, 35.5%, 36%, 36.5%, 37%, 37.5%, 38%, 38.5%, 39%, 39.5% or 40%. In some embodiments, the total mass of mannitol is at least 18% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol does not exceed 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol is about 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23% of the total mass of the pharmaceutical composition. %, 23.5%, 24%, 24.5%, or 25%. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 18% to about 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 22% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 21.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含硬脂酸鎂。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約0.01%、0.1%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、10%或11%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1.5%。In certain embodiments, the solid dosage forms provided herein comprise magnesium stearate. In some embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition. , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In some embodiments, the total mass of magnesium stearate is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含膠體二氧化矽。在某些實施方式中，膠體二氧化矽係（或包含）Aerosil 200。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，總膠體二氧化矽質量係藥物組成物總質量的約0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，膠體二氧化矽（例如Aerosil 200）總質量係藥物組成物總質量的約1%。In certain embodiments, the solid dosage forms provided herein comprise colloidal silica. In some embodiments, the colloidal silica is based on (or includes) Aerosil 200. In some embodiments, the total mass of colloidal silica is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition. , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition. , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of colloidal silica (such as Aerosil 200) is about 1% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含約23%藥劑，其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉劑）；約22%甘露醇（例如甘露醇SD200）；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮（例如PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200）。In certain embodiments, the solid dosage form provided herein contains about 23% of the medicament, wherein the medicament contains Prevotella histobialis bacteria (such as bacteria and/or powders containing bacteria); about 22% mannitol (such as mannitol) SD200); about 32% L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone ( Such as PVPP); about 1% magnesium stearate; and about 1% colloidal silica (such as Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約23%藥劑，其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉劑）；約21.5%甘露醇；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage form provided herein contains about 23% of the medicament, wherein the medicament contains Prevotella histobialis bacteria (eg bacteria and/or powders containing bacteria); about 21.5% mannitol; about 32% L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone; about 1.5% stearic acid Magnesium; and about 1% colloidal silica (such as Aerosil 200P).

在一些實施方式中，棲組織普雷沃菌細菌來自包含與普雷沃菌屬菌株B 50329（NRRL登錄號B 50329）的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該普雷沃菌屬細菌來自包含與普雷沃菌菌株B 50329（NRRL登錄號B 50329）的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該普雷沃菌屬細菌來自普雷沃菌菌株B 50329（NRRL登錄號B 50329）。In some embodiments, the Prevotella histioides bacterium is derived from a nucleotide sequence of at least 90% (or at least 97%) of the genome of Prevotella strain B 50329 (NRRL accession number B 50329), 16S and / Or strains with CRISPR sequence identity. In some embodiments, the Prevotella bacterium is derived from a strain containing at least 99% genome, 16S and/or CRISPR sequence identity to the nucleotide sequence of Prevotella strain B 50329 (NRRL accession number B 50329) Strains. In some embodiments, the Prevotella bacterium is from Prevotella strain B 50329 (NRRL accession number B 50329).

在一些實施方式中，藥劑包含棲組織普雷沃菌細菌並且細菌的劑量為約2.4 x 1011 至約4.0 x 1011 個細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係每片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament comprises Prevotella histobialis bacterium and the dose of the bacterium is about 2.4 x 10 11 to about 4.0 x 10 11 cells (for example, where the cell number is determined by the total cell count determined by the Coulter counter ), where the dose is the dose per tablet or the dose of all mini-tablets in the capsule.

在一些實施方式中，藥劑包含棲組織普雷沃菌細菌並且細菌的劑量為約2.8 x 1011 至約3.6 x 1011 個細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係每片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament comprises Prevotella histohis bacterium and the dose of the bacterium is about 2.8 x 10 11 to about 3.6 x 10 11 cells (for example, where the cell number is determined by the total cell count determined by the Coulter counter ), where the dose is the dose per tablet or the dose of all mini-tablets in the capsule.

在一些實施方式中，藥劑包含棲組織普雷沃菌細菌並且細菌的劑量為約2.4 x 1011 、約2.8 x 1011 、約3.2 x 1011 、約3.6 x 1011 、或約4.0 x 1011 個細胞，其中劑量係每片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament comprises Prevotella histosci bacteria and the dose of the bacteria is about 2.4 x 10 11 , about 2.8 x 10 11 , about 3.2 x 10 11 , about 3.6 x 10 11 , or about 4.0 x 10 11 A cell, where the dose is the dose of each tablet or the dose of all the mini-tablets in the capsule.

在一些實施方式中，藥劑包含棲組織普雷沃菌細菌並且細菌的劑量為約3.2 x 1011 個細胞，其中劑量係每片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament contains Prevotella histosci bacteria and the dose of the bacteria is about 3.2 x 10 11 cells, wherein the dose is the dose per tablet or the dose of all mini-tablets in the capsule.

在某些方面，本文提供了製備藥物組成物的固體劑型之方法，該方法包括將藥劑（其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉末））和一種或多種（例如一種、兩種或三種）崩散劑組合成藥物組成物。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少20%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的25%。在一些實施方式中，一種或多種崩散劑的總質量係藥物組成物總質量的至少30%、至少35%、至少40%、至少45%或至少50%。在一些實施方式中，一種或多種崩散劑的總質量不超過藥物組成物總質量的70%、65%、60%或55%。In certain aspects, provided herein is a method of preparing a solid dosage form of a pharmaceutical composition, the method comprising combining a pharmaceutical agent (wherein the pharmaceutical agent contains Prevotella histobialis bacteria (such as bacteria and/or powder containing bacteria)) and one or Multiple (for example, one, two or three) disintegrating powders are combined into a pharmaceutical composition. In some embodiments, the total mass of the drug is at least 20% of the total mass of the drug composition. In some embodiments, the total mass of the medicament does not exceed 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrants is at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrating powders does not exceed 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition.

在一些實施方式中，一種或多種崩散劑包括低取代的羥丙基纖維素（L-HPC）、交聯羧甲基纖維素鈉（如，Ac-Di-Sol）、和/或交聚維酮（PVPP）。在某些實施方式中，本文提供的固體劑型包含L-HPC。在一些實施方式中，L-HPC係LH-B1級。在某些實施方式中，L-HPC總質量係藥物組成物總質量的至少22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量不超過藥物組成物總質量的22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量係藥物組成物總質量的約22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，本文提供的固體劑型包含交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）。在一些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）係SD-711級的Ac-Di-Sol。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量不超過藥物組成物總質量的1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的約1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，本文提供的固體劑型包含交聚維酮。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。In some embodiments, one or more disintegrants include low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (eg, Ac-Di-Sol), and/or croscarmellose Ketone (PVPP). In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is LH-B1 grade. In some embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, Ac-Di-Sol). In some embodiments, croscarmellose sodium (for example, Ac-Di-Sol) is SD-711 grade Ac-Di-Sol. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4% of the total mass of the pharmaceutical composition. %, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the solid dosage forms provided herein comprise crospovidone. In some embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%.

在某些實施方式中，該方法還包括組合約23%藥劑，其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉末）；約22%甘露醇（例如甘露醇SD200）；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮（例如PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200）。In certain embodiments, the method further comprises combining about 23% of the agent, wherein the agent comprises Prevotella histohis bacteria (e.g. bacteria and/or powder containing bacteria); about 22% mannitol (e.g. mannitol SD200 ); about 32% L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone (such as PVPP); about 1% magnesium stearate; and about 1% colloidal silica (such as Aerosil 200).

在某些實施方式中，該方法還包括組合約23%藥劑，其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉末）；約21.5%甘露醇；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the method further comprises combining about 23% of the agent, wherein the agent comprises Prevotella histobialis bacteria (such as bacteria and/or powder containing bacteria); about 21.5% mannitol; about 32% L -HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone; about 1.5% magnesium stearate ; And about 1% colloidal silica (such as Aerosil 200P).

因此，在某些實施方式中，本文提供了包含含有細菌的藥劑的固體劑型。細菌可以是活細菌（例如，其粉末或生物質）；非活（死）細菌（例如，其粉末或生物質）；非複製型細菌（例如，其粉末或生物質）；經γ照射的細菌（例如，其粉末或其生物質）；和/或凍乾細菌（例如，其粉末或生物質）。Therefore, in certain embodiments, provided herein is a solid dosage form comprising a medicament containing bacteria. The bacteria can be live bacteria (for example, its powder or biomass); non-live (dead) bacteria (for example, its powder or biomass); non-replicating bacteria (for example, its powder or biomass); γ-irradiated bacteria (For example, its powder or its biomass); and/or freeze-dried bacteria (for example, its powder or its biomass).

在某些實施方式中，本文提供了包含含有mEV的藥劑的固體劑型。mEV可來自培養基（例如，培養上清液）。mEV可來自活細菌（例如，其粉末或生物質）；mEV可來自非活（死）細菌（例如，其粉末或生物質）；mEV可來自非複製型細菌（例如其粉末或生物質）；mEV可來自經γ照射的細菌（例如，其粉末或生物質）；和/或mEV可來自凍乾細菌（例如，其粉末或生物質）。In certain embodiments, provided herein is a solid dosage form comprising an mEV-containing medicament. The mEV can be derived from the culture medium (eg, culture supernatant). mEV can be derived from live bacteria (for example, powder or biomass); mEV can be derived from non-live (dead) bacteria (for example, powder or biomass); mEV can be derived from non-replicating bacteria (for example, powder or biomass); The mEV can be derived from gamma-irradiated bacteria (eg, powder or biomass thereof); and/or mEV can be derived from freeze-dried bacteria (eg, powder or biomass thereof).

在一些實施方式中，藥劑包含基本上或完全不含細菌（例如，整個細菌）、細菌（例如，活細菌、死（例如，被殺死的）細菌、非複製型細菌、減毒細菌）的mEV。在一些實施方式中，藥物組成物包含mEV及細菌（例如，完整細菌）（例如，活細菌、被殺死的細菌、減毒細菌）。在一些實施方式中，藥劑包含來自本文列舉的細菌菌株或物種或分類學組中的一種或多種（例如，1、2、3、4、5、6、7、8、9、10或更多）的細菌和/或mEV。在一些實施方式中，藥劑包含來自本文列舉的細菌菌株或物種或分類學組中的一種的細菌和/或mEV。在一些實施方式中，藥劑包含來自本文描述的細菌菌株或物種中的一種的細菌和/或mEV，例如，乳球菌屬、普雷沃菌屬、雙歧桿菌屬、韋榮氏球菌屬、Fournierella 屬、 Harryflintia 屬、巨型球菌屬；例如，乳酸乳球菌乳脂亞種棲組織普雷沃菌；動物雙歧桿菌乳酸亞種；小韋榮氏球菌；Fournierella massiliensis ； Harryflintia acetispora ；或巨型球菌屬物種。In some embodiments, the medicament comprises substantially or completely free of bacteria (eg, whole bacteria), bacteria (eg, live bacteria, dead (eg, killed) bacteria, non-replicating bacteria, attenuated bacteria) mEV. In some embodiments, the pharmaceutical composition includes mEV and bacteria (eg, whole bacteria) (eg, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the agent comprises one or more from the bacterial strains or species or taxonomic groups listed herein (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ) Bacteria and/or mEV. In some embodiments, the agent comprises bacteria and/or mEV from one of the bacterial strains or species or taxonomic groups listed herein. In some embodiments, the medicament comprises bacteria and/or mEV from one of the bacterial strains or species described herein, for example, Lactococcus, Prevotella, Bifidobacterium, Veillonella, Fournierella Genus , Harryflintia , Megacoccus; for example, Lactococcus lactis subsp. Histivos Prevobacterium; Bifidobacterium animalis subsp . lactis; Veillonella minor; Fournierella massiliensis ; Harryflintia acetispora; or Megacoccus species.

在一些實施方式中，藥劑包含凍乾的棲組織普雷沃菌細菌。In some embodiments, the medicament comprises freeze-dried Prevotella histobialis bacteria.

在一些實施方式中，藥劑包含凍乾的細菌和/或mEV。在一些實施方式中，藥劑包含經γ照射的細菌和/或mEV。mEV（如smEV和/或pmEV）可以在mEV被分離（如製備）之後進行γ照射。In some embodiments, the medicament comprises lyophilized bacteria and/or mEV. In some embodiments, the agent comprises gamma-irradiated bacteria and/or mEV. The mEV (such as smEV and/or pmEV) can be gamma-irradiated after the mEV is separated (such as prepared).

在一些實施方式中，為定量樣本中存在的mEV（例如smEV和/或pmEV）和/或細菌的數量，可使用電子顯微術（例如，超薄冷凍切片的EM）以觀測mEV（例如smEV和/或pmEV）和/或細菌並計數它們的相對數量。可替代地，可使用奈米顆粒跟蹤分析（NTA）、庫爾特計數或動態光散射（DLS）或該等技術的組合。NTA及庫爾特計數器計數顆粒並顯示它們的尺寸。DLS給出顆粒的粒度分佈，而非濃度。細菌通常具有1至2 um（微米）的直徑。完整範圍係0.2至20 um。來自庫爾特計數及NTA的組合結果可揭示給定樣本中的細菌和/或mEV（如smEV和/或pmEV）數量。庫爾特計數揭示具有0.7至10 um的直徑的顆粒的數量。對於大多數細菌和/或mEV（如smEV和/或pmEV）樣本，僅庫爾特計數器就可以顯示樣本中細菌和/或mEV（如smEV和/或pmEV）的數量。pmEV的直徑係20 nm-600 nm。對於NTA，可以從瑪律文泛分析公司（Malvern Pananlytical）獲得Nanosight儀器。例如，NS300可以在10-2000 nm範圍內視覺化和測量懸浮液中的顆粒。NTA允許計數例如直徑為50-1000 nm的顆粒的數目。DLS揭示具有於1 nm至3 um的近似範圍內的不同直徑的顆粒的分佈。In some embodiments, in order to quantify the number of mEVs (such as smEV and/or pmEV) and/or bacteria present in a sample, electron microscopy (such as ultra-thin frozen section EM) can be used to observe mEV (such as smEV). And/or pmEV) and/or bacteria and count their relative numbers. Alternatively, nanoparticle tracking analysis (NTA), Coulter counting or dynamic light scattering (DLS) or a combination of these techniques can be used. NTA and Coulter counters count particles and display their size. DLS gives the particle size distribution, not the concentration. Bacteria usually have a diameter of 1 to 2 um (micrometers). The full range is 0.2 to 20 um. The combined results from the Coulter count and NTA can reveal the number of bacteria and/or mEV (such as smEV and/or pmEV) in a given sample. The Coulter count reveals the number of particles having a diameter of 0.7 to 10 um. For most bacteria and/or mEV (such as smEV and/or pmEV) samples, only the Coulter counter can display the number of bacteria and/or mEV (such as smEV and/or pmEV) in the sample. The diameter of pmEV is 20 nm-600 nm. For NTA, Nanosight instruments can be obtained from Malvern Pananlytical. For example, NS300 can visualize and measure particles in suspension in the 10-2000 nm range. NTA allows counting, for example, the number of particles with a diameter of 50-1000 nm. DLS reveals the distribution of particles with different diameters in the approximate range of 1 nm to 3 um.

mEV可以藉由本領域已知的分析方法（例如Jeppesen等人Cell [細胞] 177: 428 (2019)）來表徵。mEV can be characterized by analytical methods known in the art (for example, Jeppesen et al. Cell [Cell] 177: 428 (2019)).

在一些實施方式中，可以基於顆粒計數來量化細菌和/或mEV。例如，可以使用NTA測量細菌和/或mEV製劑的總顆粒計數。In some embodiments, bacteria and/or mEV can be quantified based on particle counts. For example, NTA can be used to measure the total particle count of bacteria and/or mEV preparations.

在一些實施方式中，可以基於蛋白質、脂質或碳水化合物的量來定量細菌和/或mEV。例如，可以使用布拉德福德測定或BCA來測量細菌和/或製劑的總蛋白含量。In some embodiments, bacteria and/or mEV can be quantified based on the amount of protein, lipid, or carbohydrate. For example, the Bradford assay or BCA can be used to measure the total protein content of bacteria and/or preparations.

在一些實施方式中，mEV與源細菌或細菌培養物的一種或多種其他細菌組分分離。在一些實施方式中，細菌與源細菌培養物的一種或多種其他細菌組分分離。在一些實施方式中，藥劑還包含其他細菌組分。In some embodiments, the mEV is separated from the source bacteria or one or more other bacterial components of the bacterial culture. In some embodiments, the bacteria are separated from one or more other bacterial components of the source bacterial culture. In some embodiments, the medicament also contains other bacterial components.

在某些實施方式中，從源細菌獲得的mEV製劑可基於亞群的物理特性（例如，大小、密度、蛋白含量、結合親和力）被分級成亞群。然後可以將mEV亞群中的一個或多個併入到本發明之藥劑中。In certain embodiments, mEV preparations obtained from source bacteria can be classified into subpopulations based on the physical characteristics of the subpopulations (eg, size, density, protein content, binding affinity). One or more of the mEV subgroups can then be incorporated into the medicament of the invention.

在某些方面，本文提供了包含藥劑（其包含細菌和/或mEV（例如smEV和/或pmEV））的固體劑型，可用於治療和/或預防疾病（例如，癌症、自體免疫性疾病、炎性疾病、代謝性疾病或菌群失調）；或治療和/或預防細菌性敗血症性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）；或降低炎性細胞介素表現（例如降低IL-8、IL-6、IL-1β和/或TNFα的表現水平），以及製造和/或鑒定此類細菌和/或mEV之方法，以及和單獨使用或與其他治療劑組合使用藥劑及其固體劑型之方法（例如，用於治療癌症、自體免疫性疾病、炎性疾病或代謝性疾病、菌群失調、細菌性敗血症性休克、細胞介素風暴和/或病毒感染，或降低炎性細胞介素表現）。在一些實施方式中，藥劑包含mEV（如smEV和/或pmEV）及細菌（例如，整個細菌）（例如，活細菌、死（例如，被殺死的）細菌、非複製型細菌、減毒細菌）。在一些實施方式中，藥劑包含在不存在mEV（例如smEV和/或pmEV）的情況下的細菌。在一些實施方式中，藥劑包含在不存在細菌的情況下的mEV（例如smEV和/或pmEV）。在一些實施方式中，藥劑包含來自表1、表2和/或表3中列舉的細菌菌株或物種中的一種或多種的mEV（例如smEV和/或pmEV）和/或細菌。在一些實施方式中，藥物組成物包含來自本文列舉的細菌菌株或物種或分類學組中的一種的mEV（例如smEV和/或pmEV）和/或細菌。在一些實施方式中，藥劑包含來自本文描述的細菌菌株或物種中的一種的細菌和/或mEV，例如，乳球菌屬、普雷沃菌屬、雙歧桿菌屬、韋榮氏球菌屬、Fournierella 屬、 Harryflintia 屬、巨型球菌屬；例如，乳酸乳球菌乳脂亞種棲組織普雷沃菌；動物雙歧桿菌乳酸亞種；小韋榮氏球菌；Fournierella massiliensis ； Harryflintia acetispora ；或巨型球菌屬物種。In certain aspects, provided herein is a solid dosage form containing a medicament (which includes bacteria and/or mEV (such as smEV and/or pmEV)) that can be used to treat and/or prevent diseases (such as cancer, autoimmune diseases, Inflammatory diseases, metabolic diseases or flora disorders); or to treat and/or prevent bacterial septic shock, cytokine storm and/or viral infections (such as coronavirus infections, influenza infections and/or respiratory syncytial virus infections) ); or reduce the expression of inflammatory cytokines (for example, reduce the expression level of IL-8, IL-6, IL-1β and/or TNFα), and methods of manufacturing and/or identifying such bacteria and/or mEV, and The method of using the medicament and its solid dosage form alone or in combination with other therapeutic agents (for example, for the treatment of cancer, autoimmune diseases, inflammatory diseases or metabolic diseases, flora disorders, bacterial septic shock, cell Interleukin storm and/or viral infection, or reduce the performance of inflammatory cytokines). In some embodiments, the agent includes mEV (such as smEV and/or pmEV) and bacteria (eg, whole bacteria) (eg, live bacteria, dead (eg, killed) bacteria, non-replicating bacteria, attenuated bacteria ). In some embodiments, the medicament contains bacteria in the absence of mEV (eg, smEV and/or pmEV). In some embodiments, the medicament comprises mEV in the absence of bacteria (eg smEV and/or pmEV). In some embodiments, the agent comprises mEV (for example, smEV and/or pmEV) and/or bacteria from one or more of the bacterial strains or species listed in Table 1, Table 2, and/or Table 3. In some embodiments, the pharmaceutical composition comprises mEV (eg smEV and/or pmEV) and/or bacteria from one of the bacterial strains or species or taxonomic groups listed herein. In some embodiments, the medicament comprises bacteria and/or mEV from one of the bacterial strains or species described herein, for example, Lactococcus, Prevotella, Bifidobacterium, Veillonella, Fournierella Genus , Harryflintia , Megacoccus; for example, Lactococcus lactis subsp. Histivos Prevobacterium; Bifidobacterium animalis subsp . lactis; Veillonella minor; Fournierella massiliensis ; Harryflintia acetispora; or Megacoccus species.

在某些方面，提供了用於向受試者（例如人受試者）投與的藥劑。在一些實施方式中，藥劑與另外的活性和/或非活性材料組合以產生最終產品，其可呈單劑量單位或呈多劑量形式。在一些實施方式中，藥劑與佐劑如免疫佐劑（例如STING促效劑、TLR促效劑或NOD促效劑）組合。In certain aspects, medicaments for administration to subjects (eg, human subjects) are provided. In some embodiments, the medicament is combined with additional active and/or inactive materials to produce a final product, which may be in a single-dose unit or in multiple-dose form. In some embodiments, the agent is combined with an adjuvant such as an immune adjuvant (eg, STING agonist, TLR agonist, or NOD agonist).

在一些實施方式中，固體劑型包含至少一種碳水化合物。In some embodiments, the solid dosage form contains at least one carbohydrate.

在一些實施方式中，固體劑型包含至少一種脂質。在一些實施方式中，脂質包含至少一種選自以下的脂肪酸：月桂酸（12 : 0）、肉豆蔻酸（14 : 0）、棕櫚酸（16 : 0）、棕櫚油酸（16 : 1）、珍珠酸（17 : 0）、十七碳烯酸（17 : 1）、硬脂酸（18 : 0）、油酸（18 : 1）、亞油酸（18 : 2）、亞麻酸（18 : 3）、十八碳四烯酸（18 : 4）、花生酸（20 : 0）、二十碳烯酸（20 : 1）、二十碳二烯酸（20 : 2）、二十碳四烯酸（20 : 4）、二十碳五烯酸（20 : 5）（EPA）、二十二烷酸（22 : 0）、二十二碳烯酸（22 : 1）、二十二碳五烯酸（22 : 5）、二十二碳六烯酸（22 : 6）（DHA）及二十四烷酸（24 : 0）。In some embodiments, the solid dosage form contains at least one lipid. In some embodiments, the lipid comprises at least one fatty acid selected from the group consisting of lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), Pearl acid (17: 0), heptadecenoic acid (17: 1), stearic acid (18: 0), oleic acid (18: 1), linoleic acid (18: 2), linolenic acid (18: 3), stearidonic acid (18: 4), arachidic acid (20: 0), eicosenoic acid (20: 1), eicosadienoic acid (20: 2), eicosatetraenoic acid (20: 2) Acrylic acid (20: 4), eicosapentaenoic acid (20: 5) (EPA), behenic acid (22:0), docosenoic acid (22:1), behenic acid Pentaenoic acid (22: 5), docosahexaenoic acid (22: 6) (DHA) and tetracosanoic acid (24:0).

在一些實施方式中，固體劑型包含至少一種礦物質或礦物質源。礦物質的實例包括但不限於：氯化物、鈉、鈣、鐵、鉻、銅、碘、鋅、鎂、錳、鉬、磷、鉀及硒。任一前述礦物質的合適形式包含可溶性礦物質鹽、微溶性礦物質鹽、不溶性礦物質鹽、螯合礦物質、礦物質複合物、非反應性礦物質（例如羰基礦物質及經還原礦物質）及其組合。In some embodiments, the solid dosage form contains at least one mineral or mineral source. Examples of minerals include, but are not limited to: chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the foregoing minerals include soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals (such as carbonyl minerals and reduced minerals). ) And combinations thereof.

在一些實施方式中，固體劑型包含至少一種維生素。至少一種維生素可為脂肪可溶性或水可溶性維生素。合適維生素包括但不限於維生素C、維生素A、維生素E、維生素B12、維生素K、核黃素、菸酸（niacin）、維生素D、維生素B6、葉酸、吡哆醇（pyridoxine）、硫胺素、泛酸及生物素。任一前述物質的合適形式係維生素鹽、維生素衍生物、與維生素具有相同或類似活性的化合物及維生素代謝物。In some embodiments, the solid dosage form contains at least one vitamin. The at least one vitamin may be a fat-soluble or water-soluble vitamin. Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, Pantothenic acid and biotin. Suitable forms of any of the foregoing substances are vitamin salts, vitamin derivatives, compounds having the same or similar activity as vitamins, and vitamin metabolites.

在一些實施方式中，固體劑型包含賦形劑。合適賦形劑的非限制性實例包括稀釋劑、緩衝劑、防腐劑、穩定劑、黏結劑和/或黏合劑、壓實劑、潤滑劑和/或助流劑、分散增強劑、崩散劑、矯味劑、甜味劑及著色劑。In some embodiments, the solid dosage form contains excipients. Non-limiting examples of suitable excipients include diluents, buffers, preservatives, stabilizers, binders and/or binders, compacting agents, lubricants and/or glidants, dispersion enhancers, disintegrating agents, Flavoring agent, sweetening agent and coloring agent.

可以包含在固體劑型中的合適賦形劑可以是本領域已知的一種或多種藥學上可接受的賦形劑。例如，參見Rowe, Sheskey, 和Quinn編輯,Handbook of Pharmaceutical Excipients [藥物賦形劑手冊], 第六版2009; Pharmaceutical Press and American Pharmacists Association [製藥出版社和美國藥劑師協會]。 固體劑型Suitable excipients that can be included in the solid dosage form can be one or more pharmaceutically acceptable excipients known in the art. For example, see Rowe, Sheskey, and Quinn editors, Handbook of Pharmaceutical Excipients , Sixth Edition 2009; Pharmaceutical Press and American Pharmacists Association. Solid dosage form

本文描述的固體劑型可以是，例如片劑或微型片劑。此外，多個微型片劑可以處於（例如，裝入）膠囊中。The solid dosage forms described herein can be, for example, tablets or microtablets. In addition, multiple microtablets may be in (eg, filled) in a capsule.

在一些實施方式中，固體劑型包含片劑（＞ 4 mm）（例如5 mm-17 mm）。例如，片劑係5 mm、5.5 mm、6 mm、6.5 mm、7 mm、7.5 mm、8 mm、8.5 mm、9 mm、9.5 mm、10 mm、11 mm、12 mm、13 mm、14 mm、15 mm、16 mm、17 mm或18 mm片劑。在一些實施方式中，片劑係13 mm、14 mm、15 mm、16 mm、17 mm或18 mm片劑。在一些實施方式中，片劑係17 mm片劑。如本領域中已知的，該尺寸係指片劑的直徑。如本文所用，該片劑的尺寸係指在應用腸溶衣之前的片劑的尺寸。In some embodiments, the solid dosage form comprises tablets (>4 mm) (eg, 5 mm-17 mm). For example, tablets are 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm or 18 mm tablets. In some embodiments, the tablet is a 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablet. In some embodiments, the tablet is a 17 mm tablet. As known in the art, the size refers to the diameter of the tablet. As used herein, the size of the tablet refers to the size of the tablet before the enteric coating is applied.

在一些實施方式中，固體劑型包括微型片劑。微型片劑的尺寸範圍可以為1 mm-4 mm。例如，微型片劑可以是1 mm微型片劑、1.5 mm微型片劑、2 mm微型片劑、3 mm微型片劑或4 mm微型片劑。如本領域中已知的，尺寸係指微型片劑的直徑。如本文所用，微型片劑的尺寸係指在應用腸溶衣之前的微型片劑的尺寸。In some embodiments, the solid dosage form includes microtablets. The size of microtablets can range from 1 mm to 4 mm. For example, a mini tablet may be a 1 mm mini tablet, a 1.5 mm mini tablet, a 2 mm mini tablet, a 3 mm mini tablet, or a 4 mm mini tablet. As known in the art, size refers to the diameter of the microtablet. As used herein, the size of the microtablet refers to the size of the microtablet before the enteric coating is applied.

微型片劑可以是在膠囊中。該膠囊可以是00號、0號、1號、2號、3號、4號或5號膠囊。包含微型片劑的膠囊可以包含HPMC（羥丙基甲基纖維素）或明膠。微型片劑可以放在膠囊內：膠囊內的微型片劑的數量將取決於膠囊的尺寸和微型片劑的尺寸。例如，0號膠囊可容納31-35（平均33）個3 mm的微型片劑。在一些實施方式中，膠囊在裝入後鑲邊。在一些實施方式中，將膠囊用基於HPMC的鑲邊溶液鑲邊。 包衣Microtablets can be in capsules. The capsule can be a No. 00, No. 0, No. 1, No. 2, No. 3, No. 4, or No. 5 capsule. Capsules containing mini-tablets may contain HPMC (hydroxypropyl methyl cellulose) or gelatin. Microtablets can be placed in capsules: the number of microtablets in the capsule will depend on the size of the capsule and the size of the microtablets. For example, No. 0 capsule can hold 31-35 (average 33) 3 mm mini-tablets. In some embodiments, the capsule is bordered after being filled. In some embodiments, the capsule is rimmed with an HPMC-based edging solution. Coating

本文描述的固體劑型（例如片劑或微型片劑）可以用例如一層腸溶衣或兩層腸溶衣（例如，內部腸溶衣和外部腸溶衣）進行腸溶包衣。內部腸溶衣和外部腸溶衣不相同（例如，內部腸溶衣和外部腸溶衣不包含相同量的相同組分）。腸溶衣允許藥劑在例如小腸中（例如上小腸上部，例如十二指腸和/或空腸）釋放。The solid dosage forms described herein (for example, tablets or minitablets) may be enteric coated with, for example, one enteric coating or two enteric coatings (for example, an inner enteric coating and an outer enteric coating). The inner and outer enteric coatings are not the same (for example, the inner and outer enteric coatings do not contain the same components in the same amount). The enteric coating allows the agent to be released in, for example, the small intestine (eg, the upper part of the upper small intestine, such as the duodenum and/or jejunum).

藥劑在小腸例中（例如小腸上部，例如十二指腸或空腸中）的釋放允許藥劑靶向並影響在該等特定的位置處定位的細胞（例如上皮細胞和/或免疫細胞），例如，這可以在小腸中引起局部作用和/或引起系統性作用（例如，胃腸道外的作用）。The release of the agent in the small intestine (such as the upper part of the small intestine, such as the duodenum or jejunum) allows the agent to target and affect cells located at these specific locations (such as epithelial cells and/or immune cells). For example, this can be Causes a local effect and/or causes a systemic effect in the small intestine (for example, an effect outside the gastrointestinal tract).

EUDRAGIT係各種基於聚甲基丙烯酸酯的共聚物的商標名稱。它包括基於甲基丙烯酸和甲基丙烯酸/丙烯酸酯或其衍生物的陰離子、陽離子和中性共聚物。EUDRAGIT is the brand name of various polymethacrylate-based copolymers. It includes anionic, cationic and neutral copolymers based on methacrylic acid and methacrylic acid/acrylate or its derivatives.

可用於腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）的其他材料的實例包括鄰苯二甲酸乙酸纖維素（CAP）、偏苯三酸乙酸纖維素（CAT）、聚醋酸乙烯鄰苯二甲酸酯（PVAP）、羥丙基甲基纖維素鄰苯二甲酸酯（HPMCP）、脂肪酸、蠟、蟲膠（紫膠桐酸的酯）、塑膠、植物纖維、玉米醇溶蛋白、AQUA-ZEIN®（不含醇的水性玉米醇溶蛋白配製物）、直鏈澱粉、澱粉衍生物、糊精、丙烯酸甲酯-甲基丙烯酸共聚物、醋酸琥珀酸纖維素、羥丙基甲基醋酸琥珀酸纖維素（醋酸羥丙甲纖維素琥珀酸酯）、甲基丙烯酸甲酯-甲基丙烯酸共聚物、和/或海藻酸鈉。Examples of other materials that can be used for enteric coating (eg, a layer of enteric coating or inner enteric coating and/or outer enteric coating) include cellulose acetate phthalate (CAP), cellulose acetate trimellitate ( CAT), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (ester of lactoic acid), plastics, Vegetable fiber, zein, AQUA-ZEIN® (aqueous zein formulation without alcohol), amylose, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, acetic acid succinic acid Cellulose, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, and/or sodium alginate.

腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）可以包含甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1 : 1）。The enteric coating (for example, a layer of enteric coating or inner enteric coating and/or outer enteric coating) may comprise ethyl methacrylate acrylate (MAE) copolymer (1:1).

該層腸溶衣可以包含甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1 : 1）（例如Kollicoat MAE 100P）。The enteric coating may contain methacrylate ethyl acrylate (MAE) copolymer (1:1) (for example, Kollicoat MAE 100P).

該層腸溶衣可包含尤特奇共聚物，例如尤特奇L（例如尤特奇L 100-55；尤特奇L 30 D-55），尤特奇S、尤特奇RL、尤特奇RS、尤特奇E、或尤特奇FS（例如尤特奇FS 30 D）。This layer of enteric coating may contain Eudragit Copolymers, such as Eudragit L (e.g. Eudragit L 100-55; Eudragit L 30 D-55), Eudragit S, Eudragit RL, and Eudragit L 30 D-55. Youtech RS, Youtech E, or Youtech FS (for example, Youtech FS 30 D).

可以在腸溶衣中使用的材料的其他實例（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包括在如下中描述的那些，例如U.S. 6312728；U.S. 6623759；U.S. 4775536；U.S. 5047258；U.S. 5292522；U.S. 6555124；U.S. 6638534；U.S. 2006/0210631；U.S. 2008/200482；U.S. 2005/0271778；U.S. 2004/0028737；WO 2005/044240。Other examples of materials that can be used in enteric coatings (for example, a layer of enteric coating or inner enteric coating and/or outer enteric coating) include those described below, such as US 6312728; US 6623759; US 4775536; US 5047258; US 5292522; US 6555124; US 6638534; US 2006/0210631; US 2008/200482; US 2005/0271778; US 2004/0028737; WO 2005/044240.

還參見，例如，U.S. 9233074，其提供了可與本文提供的固體劑型一起使用的pH依賴性腸溶聚合物，包括甲基丙烯酸共聚物、聚乙酸乙烯酯鄰苯二甲酸酯、羥丙基甲基纖維素乙酸琥珀酸酯、羥丙基甲基纖維素鄰苯二甲酸酯和乙酸鄰苯二甲酸纖維素；合適的甲基丙烯酸共聚物包括：聚(甲基丙烯酸, 甲基丙烯酸甲酯) 1 : 1固體，例如以商品名尤特奇L100出售；聚(甲基丙烯酸, 丙烯酸乙酯) 1 : 1固體，例如以商品名尤特奇L100-55出售；部分中和的聚(甲基丙烯酸, 丙烯酸乙酯) 1 : 1固體，例如以商品名Kollicoat MAE-100P出售；以及聚(甲基丙烯酸, 甲基丙烯酸甲酯) 1 : 2固體，例如以尤特奇S100商品名出售的。See also, for example, US 9233074, which provides pH-dependent enteric polymers that can be used with the solid dosage forms provided herein, including methacrylic acid copolymers, polyvinyl acetate phthalate, hydroxypropyl Methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate and cellulose acetate phthalate; suitable methacrylic acid copolymers include: poly(methacrylic acid, methyl methacrylate) Ester) 1: 1 solid, for example sold under the trade name Youdchy L100; poly(methacrylic acid, ethyl acrylate) 1: 1 solid, for example, sold under the trade name Youdchy L100-55; partially neutralized poly( Methacrylic acid, ethyl acrylate) 1: 1 solid, for example, sold under the trade name Kollicoat MAE-100P; and poly(methacrylic acid, methyl methacrylate) 1: 2 solid, for example, sold under the trade name Utraki S100 of.

在某些方面，本文描述的固體劑型（例如片劑或微型片劑）還包含底衣。在一些實施方式中，固體劑型例如除了腸溶衣之外還包含底衣，例如，底衣在腸溶衣下面（例如，在固體劑型和腸溶衣之間）。在一些實施方式中，底衣包含歐巴代QX，例如歐巴代QX藍。粉衣層可以例如用於視覺上掩蓋治療劑的外觀。 劑量In certain aspects, the solid dosage forms described herein (eg, tablets or microtablets) also include a subcoat. In some embodiments, the solid dosage form, for example, includes a subcoating in addition to the enteric coating, for example, the subcoating is under the enteric coating (eg, between the solid dosage form and the enteric coating). In some embodiments, the undercoat comprises Opadry QX, such as Opadry QX Blue. The powder coating layer can be used, for example, to visually mask the appearance of the therapeutic agent. dose

藥劑的劑量（例如，對於人類受試者）係每膠囊或片劑的劑量或係膠囊中使用的全部微型片劑的劑量。The dose of the agent (for example, for human subjects) is the dose per capsule or tablet or the dose of all mini-tablets used in the capsule.

在藉由總細胞計數（TCC）確定劑量的實施方式中，可以藉由Coulter計數器確定的總細胞計數。In the embodiment in which the dose is determined by the total cell count (TCC), the total cell count can be determined by a Coulter counter.

在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 107 至約2 x 1012 （例如，約3 x 1010 或約1.5 x 1011 或約1.5 x 1012 ）細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 1010 至約2 x 1012 （例如，約1.6 x 1011 或約8 x 1011 或約9.6 x 1011 約12.8 x 1011 或約1.6 x 1012 ）細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the agent contains bacteria and the dose of bacteria is about 1 x 10 7 to about 2 x 10 12 (e.g., about 3 x 10 10 or about 1.5 x 10 11 or about 1.5 x 10 12 ) cells (e.g., The cell number is determined by the total cell count determined by the Coulter counter), where the dose is the dose per capsule or tablet or the dose of all the mini-tablets in the capsule. In some embodiments, the medicament contains bacteria and the dose of bacteria is from about 1 x 10 10 to about 2 x 10 12 (eg, about 1.6 x 10 11 or about 8 x 10 11 or about 9.6 x 10 11 about 12.8 x 10 11 Or about 1.6 x 10 12 ) cells (for example, where the number of cells is determined by the total cell count determined by a Coulter counter), where the dose is the dose per capsule or tablet or the dose of all mini-tablets in the capsule.

在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 109 、約3 x 109 、約5 x 109 、約1.5 x 1010 、約3 x 1010 、約5 x 1010 、約1.5 x 1011 、約1.5 x 1012 或約2 x 1012 細胞，其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament contains bacteria and the dose of bacteria is about 1 x 10 9 , about 3 x 10 9 , about 5 x 10 9 , about 1.5 x 10 10 , about 3 x 10 10 , about 5 x 10 10 , About 1.5 x 10 11 , about 1.5 x 10 12 or about 2 x 10 12 cells, wherein the dose is the dose per capsule or tablet or the dose of all mini-tablets in the capsule.

在一些實施方式中，藥劑包含mEV並且mEV的劑量為約1 x 105 至約7 x 1013 個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。在一些實施方式中，藥劑包含mEV並且mEV的劑量為約1 x 1010 至約7 x 1013 個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament comprises mEV and the dose of mEV is about 1 x 10 5 to about 7 x 10 13 particles (for example, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), where the dose is The dosage of the capsule or tablet is the dosage of all the mini-tablets in the capsule. In some embodiments, the medicament comprises mEV and the dose of mEV is about 1 x 10 10 to about 7 x 10 13 particles (for example, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), where the dose is per The dosage of the capsule or tablet is the dosage of all the mini-tablets in the capsule.

在其中藥劑包含mEV的一些實施方式中，mEV的劑量為約2 x 106 至約2 x 1016 個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments where the medicament comprises mEV, the dose of mEV is about 2 x 10 6 to about 2 x 10 16 particles (for example, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), where the dose is The dose per capsule or tablet is the dose of all mini-tablets in the capsule.

在一些方面，本揭露提供了治療受試者（例如人）（例如需要治療的受試者）之方法，該方法包括向受試者投與本文提供的固體劑型。In some aspects, the present disclosure provides a method of treating a subject (eg, a human) (eg, a subject in need of treatment), the method comprising administering to the subject a solid dosage form provided herein.

在一些方面，本揭露提供了本文提供的固體劑型在製備用於治療受試者（例如人）（例如需要治療的受試者）的藥物中的用途。In some aspects, the present disclosure provides the use of the solid dosage form provided herein in the preparation of a medicament for treating a subject (such as a human) (such as a subject in need of treatment).

在一些實施方式中，固體劑型經口服投與（例如用於口服投與）。In some embodiments, the solid dosage form is administered orally (eg, for oral administration).

在一些實施方式中，固體劑型被投與（例如，用於投與）每天1、2、3或4次。在一些實施方式中，1、2、3、4或5種固體劑型（例如，片劑）被投與（例如，用於投與）每天1、2、3或4次。在一些實施方式中，2、4、6、8或10種固體劑型（例如，片劑）被投與（例如，用於投與）每天1、2、3或4次。在一些實施方式中，1種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次。在一些實施方式中，2種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次。在一些實施方式中，3種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次。在一些實施方式中，4種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次。在一些實施方式中，5種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次。In some embodiments, the solid dosage form is administered (eg, for administration) 1, 2, 3, or 4 times a day. In some embodiments, 1, 2, 3, 4, or 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1, 2, 3, or 4 times a day. In some embodiments, 2, 4, 6, 8, or 10 solid dosage forms (eg, tablets) are administered (eg, for administration) 1, 2, 3, or 4 times a day. In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) 1 or 2 times a day. In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times a day. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times a day. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times a day. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times a day.

在一些實施方式中，1種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次，其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量。在一些實施方式中，2種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次，其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量。在一些實施方式中，3種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次，其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量。在一些實施方式中，4種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次，其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量。在一些實施方式中，5種固體劑型（例如，片劑）被投與（例如，用於投與）每天1或2次，其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量。In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) 1 or 2 times a day, wherein the solid dosage form contains a bacterial dose of about 3.2×10 11 cells. In some embodiments, two solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times a day, wherein the solid dosage form contains a bacterial dose of about 3.2×10 11 cells. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times a day, wherein the solid dosage form contains a bacterial dose of about 3.2×10 11 cells. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times a day, wherein the solid dosage form contains a bacterial dose of about 3.2×10 11 cells. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times a day, wherein the solid dosage form contains a bacterial dose of about 3.2×10 11 cells.

在一些實施方式中，1種固體劑型（例如，片劑）被每天投與（例如，用於投與），其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量（例如，導致總共約3.2 x 1011 個細胞被投與）。在一些實施方式中，2種固體劑型（例如，片劑）被每天投與（例如，用於投與），其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量（例如，導致在2個片劑情況下總共約6.4 x 1011 個細胞被投與）。在一些實施方式中，3種固體劑型（例如，片劑）被每天投與（例如，用於投與），其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量（例如，導致在3個片劑情況下總共約9.6 x 1011 個細胞被投與）。在一些實施方式中，4種固體劑型（例如，片劑）被每天投與（例如，用於投與），其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量（例如，導致在4個片劑情況下總共約12.8 x 1011 個細胞被投與）。在一些實施方式中，5種固體劑型（例如，片劑）被每天投與（例如，用於投與），其中該固體劑型包含約3.2 × 1011 個細胞的細菌劑量（例如，導致在5個片劑情況下總共約16 x 1011 個細胞被投與）。In some embodiments, 1 solid dosage form (e.g., tablet) is administered daily (e.g., for administration), wherein the solid dosage form contains a bacterial dose of about 3.2 × 10 11 cells (e.g., resulting in a total of about 3.2 x 10 11 cells were administered). In some embodiments, two solid dosage forms (e.g., tablets) are administered daily (e.g., for administration), wherein the solid dosage form contains a bacterial dose of approximately 3.2 × 10 11 cells (e.g., resulting in 2 In the case of a tablet, a total of approximately 6.4 x 10 11 cells are administered). In some embodiments, 3 solid dosage forms (e.g., tablets) are administered daily (e.g., for administration), wherein the solid dosage form contains a bacterial dose of approximately 3.2 × 10 11 cells (e.g., resulting in 3 In the case of a tablet, a total of approximately 9.6 x 10 11 cells are administered). In some embodiments, 4 solid dosage forms (e.g., tablets) are administered daily (e.g., for administration), wherein the solid dosage form contains a bacterial dose of approximately 3.2 × 10 11 cells (e.g., resulting in 4 In the case of a tablet, a total of approximately 12.8 x 10 11 cells are administered). In some embodiments, 5 solid dosage forms (e.g., tablets) are administered daily (e.g., for administration), wherein the solid dosage form contains a bacterial dose of approximately 3.2 × 10 11 cells (e.g., resulting in 5 In the case of a tablet, a total of approximately 16 x 10 11 cells are administered).

在一些實施方式中，藥劑劑量可以是按藥劑（例如，包含細菌和/或細菌來源的試劑（例如mEV）的粉末）的重量確定的毫克（mg）劑量。藥劑的劑量係每膠囊或片劑的劑量或係例如膠囊中全部微型片劑的劑量。In some embodiments, the dose of the agent may be a milligram (mg) dose determined by the weight of the agent (eg, powder containing bacteria and/or agents derived from bacteria (eg, mEV)). The dose of the drug is the dose per capsule or tablet or, for example, the dose of all mini-tablets in the capsule.

例如，為了投與約400 mg的1x劑量的藥劑，每個膠囊存在約200 mg的藥劑並且投與兩個膠囊，從而產生約400 mg的劑量。這兩個膠囊可以例如每天1x或2x投與。For example, to administer a 1x dose of about 400 mg of medicament, there is about 200 mg of medicament per capsule and two capsules are administered, resulting in a dose of about 400 mg. These two capsules can be administered, for example, 1x or 2x daily.

例如，對於微型片劑：每個微型片劑可以包含約0.1至約3.5 mg（0.1、0.35、1.0、3.5 mg）的藥劑。微型片劑可以放在膠囊內：膠囊內的微型片劑的數量將取決於膠囊的尺寸和微型片劑的尺寸。例如，平均33（範圍為31-35）個3 mm微型片劑裝於0號膠囊內。作為實例，每微型片劑0.1-3.5 mg藥劑，劑量範圍為每膠囊3.3 mg-115.5 mg（0號膠囊中33個微型片劑）（3.1 mg-108.5 mg，0號膠囊中31個微型片劑）（3.5 mg- 122.5 mg，0號膠囊中35個微型片劑）。可以投與多個膠囊和/或更大的膠囊以增加投與的劑量和/或可以每天投與一次或多次以增加投與的劑量。For example, for microtablets: each microtablet may contain about 0.1 to about 3.5 mg (0.1, 0.35, 1.0, 3.5 mg) of medicament. Microtablets can be placed in capsules: the number of microtablets in the capsule will depend on the size of the capsule and the size of the microtablets. For example, an average of 33 (range 31-35) 3 mm mini-tablets are packed in size 0 capsules. As an example, 0.1-3.5 mg medicament per microtablet, with a dose range of 3.3 mg-115.5 mg per capsule (33 microtablets in No. 0 capsule) (3.1 mg-108.5 mg, 31 microtablets in No. 0 capsule) ) (3.5 mg-122.5 mg, 35 mini-tablets in No. 0 capsule). Multiple capsules and/or larger capsules can be administered to increase the dose administered and/or one or more times per day to increase the dosage administered.

在一些實施方式中，藥劑的每膠囊或片劑的劑量或例如膠囊中全部微型片劑的劑量可以是約3 mg至約125 mg。In some embodiments, the dosage per capsule or tablet of the medicament or, for example, the dosage of all mini-tablets in the capsule may be about 3 mg to about 125 mg.

在一些實施方式中，藥劑的劑量可以是約35 mg至約1200 mg（例如，約35 mg、約125 mg、約350 mg或約1200 mg）。In some embodiments, the dose of the agent may be about 35 mg to about 1200 mg (eg, about 35 mg, about 125 mg, about 350 mg, or about 1200 mg).

在一些實施方式中，藥劑包含粉末，該粉末包含細菌和/或mEV，並且藥劑（例如包含細菌和/或mEV的粉末）的劑量為約10 mg至約1500 mg，其中劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。In some embodiments, the medicament comprises a powder containing bacteria and/or mEV, and the dosage of the medicament (eg, a powder containing bacteria and/or mEV) is about 10 mg to about 1500 mg, wherein the dosage is per capsule or tablet The dose of the drug is the dose of all the mini-tablets in the capsule.

在一些實施方式中，藥劑的劑量可以是約30 mg至約3500 mg（約25、約50、約75、約100、約150、約250、約300、約350、約400、約500、約600、約750、約1000、約1250、約1300、約2000、約2500、約3000或約3500 mg）。In some embodiments, the dose of the agent can be about 30 mg to about 3500 mg (about 25, about 50, about 75, about 100, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 750, about 1000, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg).

可以基於對模型生物（例如，小鼠）投與的劑量的異速比例（allometric scaling）來適當地計算人劑量。The human dose can be appropriately calculated based on allometric scaling of the dose administered to the model organism (eg, mouse).

在一些實施方式中，一個或兩個片劑膠囊可以一天投與一次或兩次。In some embodiments, one or two tablet capsules can be administered once or twice a day.

在一些實施方式中，可以每天投與一個或兩個片劑。In some embodiments, one or two tablets may be administered daily.

在一些實施方式中，可以每天一次或兩次投與3、4或5個片劑。In some embodiments, 3, 4, or 5 tablets may be administered once or twice a day.

在一些實施方式中，可以每天投與3、4或5個片劑。In some embodiments, 3, 4, or 5 tablets may be administered daily.

在一些實施方式中，可以每天一次或兩次投與4個片劑。In some embodiments, 4 tablets may be administered once or twice a day.

在一些實施方式中，可以每天投與4個片劑。In some embodiments, 4 tablets may be administered per day.

藥劑包含細菌和/或細菌來源的試劑（例如mEV），或包含含有細菌和/或細菌來源的試劑（例如mEV）的粉末，並且還可以包含一種或多種另外組分，例如防凍劑等。The medicament includes bacteria and/or bacteria-derived agents (for example, mEV), or powders containing bacteria and/or bacteria-derived agents (for example, mEV), and may also include one or more additional components, such as antifreeze and the like.

在一些實施方式中，藥劑的mg（按重量計）劑量為例如每膠囊或每片劑或係例如膠囊中使用的全部微型片劑約1 mg至約500 mg。 使用方法In some embodiments, the mg (by weight) dose of the medicament is, for example, about 1 mg to about 500 mg per capsule or tablet or all mini-tablets used in a capsule, for example. Instructions

例如，本文描述的固體劑型允許口服投與其中包含的藥劑。For example, the solid dosage forms described herein allow oral administration of the agents contained therein.

具有揭露的崩散劑的組合和/或量的固體劑型提供了崩散時間的減少（例如2倍、4倍、6倍、8倍），這可以進一步導致與不具有所揭露的崩散劑組合的相同固體劑型相比具有增加的治療功效和/或生理效果。The solid dosage form with the combination and/or amount of the disclosed disintegrant provides a reduction in disintegration time (for example, 2 times, 4 times, 6 times, 8 times), which can further lead to a combination of disintegrant without the disclosed disintegrant. Compared with the same solid dosage form, it has increased therapeutic efficacy and/or physiological effect.

本文描述的固體劑型可用於治療和/或預防癌症、炎症、自體免疫、代謝病症或菌群失調。The solid dosage forms described herein can be used to treat and/or prevent cancer, inflammation, autoimmunity, metabolic disorders, or flora imbalance.

本文描述的固體劑型可用於治療和/或預防細菌性敗血症性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）。The solid dosage forms described herein can be used to treat and/or prevent bacterial septic shock, interleukin storm, and/or viral infections (such as coronavirus infections, influenza infections, and/or respiratory syncytial virus infections).

本文描述的固體劑型可用於降低炎性細胞介素表現（例如降低IL-8、IL-6、IL-1β和/或TNFα表現水平）。The solid dosage forms described herein can be used to reduce the expression of inflammatory cytokines (eg, reduce the expression levels of IL-8, IL-6, IL-1β, and/or TNFα).

本文描述了使用包含藥劑（例如其治療有效量）的固體劑型（例如用於口服投與）（例如用於製藥用途）之方法，其中該藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中該固體劑型還包含揭露的崩散劑。Described herein is a method of using a solid dosage form (for example for oral administration) (for example for pharmaceutical use) containing an agent (for example, a therapeutically effective amount thereof), wherein the agent contains bacteria and/or microbial extracellular vesicles (mEV) And wherein the solid dosage form also contains the disclosed disintegrating powder.

例如，本文描述之方法和投與的固體劑型允許口服投與其中包含的藥劑。固體劑型可投與給處於進食或禁食狀態的受試者。固體劑型可以例如空腹（例如，進食前一小時或進食後兩小時）投與。固體劑型可在進食前一小時投與。固體劑型可在進食後兩小時投與。For example, the methods and solid dosage forms for administration described herein allow oral administration of the agents contained therein. The solid dosage form can be administered to subjects in a fed or fasted state. The solid dosage form can be administered, for example, on an empty stomach (for example, one hour before eating or two hours after eating). The solid dosage form can be administered one hour before eating. The solid dosage form can be administered two hours after eating.

本文提供了用於治療和/或預防癌症、炎症、自體免疫、代謝病症或菌群失調的固體劑型。Provided herein are solid dosage forms for the treatment and/or prevention of cancer, inflammation, autoimmunity, metabolic disorders, or flora imbalance.

本文提供了用於治療和/或預防細菌性敗血症性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）的固體劑型。Provided herein are solid dosage forms for the treatment and/or prevention of bacterial septic shock, interleukin storm, and/or viral infections (such as coronavirus infections, influenza infections, and/or respiratory syncytial virus infections).

本文提供了用於降低炎性細胞介素表現（例如降低IL-8、IL-6、IL-1β和/或TNFα表現水平）的固體劑型。Provided herein is a solid dosage form for reducing the expression of inflammatory cytokines (eg, reducing the expression level of IL-8, IL-6, IL-1β, and/or TNFα).

本文提供了固體劑型在製備用於治療和/或預防癌症、炎症、自體免疫、代謝病症或菌群失調的藥物中的用途。Provided herein is the use of a solid dosage form in the preparation of a medicament for the treatment and/or prevention of cancer, inflammation, autoimmunity, metabolic disorders or flora imbalance.

本文提供了固體劑型在製備用於治療和/或預防細菌性敗血症性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）的藥物中的用途。This article provides solid dosage forms in the preparation of medicaments for the treatment and/or prevention of bacterial septic shock, interleukin storm and/or viral infections (such as coronavirus infections, influenza infections and/or respiratory syncytial virus infections) use.

本文提供了固體劑型在製備用於治療和/或預防細菌性敗血症性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）的藥物中的用途。 製備固體劑型之方法This article provides solid dosage forms in the preparation of medicaments for the treatment and/or prevention of bacterial septic shock, interleukin storm and/or viral infections (such as coronavirus infections, influenza infections and/or respiratory syncytial virus infections) use. Method for preparing solid dosage form

在某些方面，本文提供了製備藥物組成物的固體劑型之方法，該方法包括將藥劑（例如，本文揭露的細菌和/或試劑（例如組分）或包含本文揭露的細菌和/或細菌來源的試劑（例如組分）（例如mEV）的粉末）和一種或多種（例如一種、兩種或三種）崩散劑組合成藥物組成物。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%或25%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的45%、40%、35%、30%或25%。在一些實施方式中，一種或多種崩散劑的總質量係藥物組成物總質量的至少30%、至少35%、至少40%、至少45%或至少50%。在一些實施方式中，一種或多種崩散劑的總質量不超過藥物組成物總質量的70%、65%、60%或55%。In certain aspects, provided herein is a method for preparing a solid dosage form of a pharmaceutical composition, the method comprising combining an agent (for example, the bacteria and/or reagents (for example, components) disclosed herein or containing the bacteria and/or a source of bacteria disclosed herein The reagents (such as components) (such as mEV) powder) and one or more (such as one, two or three) disintegrating powders are combined to form a pharmaceutical composition. In some embodiments, the total mass of the drug is at least 5%, 10%, 15%, 20%, or 25% of the total mass of the drug composition. In some embodiments, the total mass of the medicament does not exceed 45%, 40%, 35%, 30%, or 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrants is at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more disintegrating powders does not exceed 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition.

在一些實施方式中，一種或多種崩散劑包括低取代的羥丙基纖維素（L-HPC）、交聯羧甲基纖維素鈉（如，Ac-Di-Sol）、和/或交聚維酮（PVPP）。在某些實施方式中，本文提供的固體劑型包含L-HPC。在一些實施方式中，L-HPC係LH-B1級。在某些實施方式中，L-HPC總質量係藥物組成物總質量的至少22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量不超過藥物組成物總質量的22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，L-HPC總質量係藥物組成物總質量的約22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%。在某些實施方式中，本文提供的固體劑型包含交聯羧甲基纖維素鈉（Ac-Do-Sol）。在一些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）係SD-711級的Ac-Di-Sol。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量不超過藥物組成物總質量的1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，交聯羧甲基纖維素鈉（例如，Ac-Di-Sol）總質量係藥物組成物總質量的約1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%或16%。在某些實施方式中，本文提供的固體劑型包含交聚維酮。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。In some embodiments, one or more disintegrants include low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (eg, Ac-Di-Sol), and/or croscarmellose Ketone (PVPP). In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is LH-B1 grade. In some embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In some embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%. In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (Ac-Do-Sol). In some embodiments, croscarmellose sodium (for example, Ac-Di-Sol) is SD-711 grade Ac-Di-Sol. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4% of the total mass of the pharmaceutical composition. %, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In some embodiments, the total mass of croscarmellose sodium (for example, Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition. %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the solid dosage forms provided herein comprise crospovidone. In some embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition. , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%.

在某些實施方式中，該方法還包括組合甘露醇。在一些實施方式中，甘露醇係甘露醇SD200。在某些實施方式中，總甘露醇質量係藥物組成物總質量的至少18%。在某些實施方式中，總甘露醇質量不超過藥物組成物總質量的25%。在某些實施方式中，總甘露醇質量係藥物組成物總質量的約18%、18.5%、19%、19.5%、20%、20.5%、21%、21.5%、22%、22.5%、23%、23.5%、24%、24.5%、或25%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約18%至約25%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約22%。在某些實施方式中，甘露醇（例如，甘露醇SD200）總質量係藥物組成物總質量的約21.5%。In certain embodiments, the method further includes combining mannitol. In some embodiments, the mannitol is mannitol SD200. In some embodiments, the total mass of mannitol is at least 18% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol does not exceed 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol is about 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23% of the total mass of the pharmaceutical composition. %, 23.5%, 24%, 24.5%, or 25%. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 18% to about 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 22% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of mannitol (eg, mannitol SD200) is about 21.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，該方法還包括組合硬脂酸鎂。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約0.01%、0.1%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、10%或11%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1.5%。In certain embodiments, the method further includes combining magnesium stearate. In some embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition. , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In some embodiments, the total mass of magnesium stearate is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，該方法還包括組合包含膠體二氧化矽。在一些實施方式中，膠體二氧化矽係Aerosil 200。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，總膠體二氧化矽質量係藥物組成物總質量的約0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，膠體二氧化矽（例如Aerosil 200）總質量係藥物組成物總質量的約1%。In some embodiments, the method further includes combining colloidal silica. In some embodiments, the colloidal silica is Aerosil 200. In some embodiments, the total mass of colloidal silica is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition. , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition. , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silica is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of colloidal silica (such as Aerosil 200) is about 1% of the total mass of the pharmaceutical composition.

在某些實施方式中，該方法還包括組合約23%藥劑，其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉末）；約22%甘露醇（例如甘露醇SD200）；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮（例如PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200）。In certain embodiments, the method further comprises combining about 23% of the agent, wherein the agent comprises Prevotella histohis bacteria (e.g. bacteria and/or powder containing bacteria); about 22% mannitol (e.g. mannitol SD200 ); about 32% L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone (such as PVPP); about 1% magnesium stearate; and about 1% colloidal silica (such as Aerosil 200).

在某些實施方式中，該方法還包括組合約23%藥劑，其中該藥劑包含棲組織普雷沃菌細菌（例如細菌和/或包含細菌的粉末）；約21.5%甘露醇；約32% L-HPC（例如L-HPC LH-B1）；約6%交聯羧甲基纖維素鈉（例如Ac-Di-Sol SD-711）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the method further comprises combining about 23% of the agent, wherein the agent comprises Prevotella histobialis bacteria (such as bacteria and/or powder containing bacteria); about 21.5% mannitol; about 32% L -HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone; about 1.5% magnesium stearate ; And about 1% colloidal silica (such as Aerosil 200P).

在某些實施方式中，該方法還包括壓縮藥物組成物，從而形成片劑或微型片劑。在一些實施方式中，該方法還包括對片劑或微型片劑進行腸溶包衣，從而製備經腸溶包衣的片劑。在某些實施方式中，該方法還包括將微型片劑裝載到膠囊中。在某些實施方式中，該方法還包括將包含微型片劑的膠囊鑲邊。 固體劑型的另外方面In certain embodiments, the method further includes compressing the pharmaceutical composition to form a tablet or mini-tablet. In some embodiments, the method further includes enteric coating the tablets or mini-tablets to prepare enteric-coated tablets. In certain embodiments, the method further includes loading the microtablets into the capsule. In certain embodiments, the method further includes rimming the capsule containing the microtablets. Other aspects of solid dosage forms

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的崩散劑）可以向受試者例如人提供治療有效量的藥劑。For example, a solid dosage form containing a pharmaceutical agent (eg, a therapeutically effective amount thereof) as described herein (where the pharmaceutical agent contains bacterial and/or microbial extracellular vesicles (mEV), and wherein the solid dosage form also contains the disintegrating powder described) can be applied to The subject, such as a human, provides a therapeutically effective amount of the agent.

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的崩散劑）可以向受試者例如人提供非天然量的治療有效組分（例如，存在於藥劑中）。For example, a solid dosage form containing a pharmaceutical agent (eg, a therapeutically effective amount thereof) as described herein (where the pharmaceutical agent contains bacterial and/or microbial extracellular vesicles (mEV), and wherein the solid dosage form also contains the disintegrating powder described) can be applied to A subject, such as a human, provides a non-natural amount of a therapeutically effective component (eg, present in a medicament).

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的崩散劑）可以向受試者例如人提供非天然數量的治療有效組分（例如，存在於藥劑中）。For example, a solid dosage form containing a pharmaceutical agent (eg, a therapeutically effective amount thereof) as described herein (where the pharmaceutical agent contains bacterial and/or microbial extracellular vesicles (mEV), and wherein the solid dosage form also contains the disintegrating powder described) can be applied to A subject, such as a human, provides an unnatural amount of a therapeutically effective component (eg, present in a medicament).

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的崩散劑）可以給受試者例如人帶來一個或多個變化，例如治療或預防疾病或健康失調。For example, a solid dosage form containing a pharmaceutical agent (eg, a therapeutically effective amount thereof) as described herein (where the pharmaceutical agent contains bacterial and/or microbial extracellular vesicles (mEV), and wherein the solid dosage form also contains the disintegrating powder described) can be administered The subject, such as a human, brings about one or more changes, such as treating or preventing diseases or health disorders.

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的崩散劑）具有潛在的重大效用，例如影響受試者（例如人），例如治療或預防疾病或健康失調。 另外的治療劑For example, a solid dosage form containing an agent (eg, a therapeutically effective amount thereof) as described herein (where the agent contains bacteria and/or microbial extracellular vesicles (mEV), and where the solid dosage form also contains the disintegrating powder described) has potential Significant utility of, such as affecting subjects (such as humans), such as treating or preventing diseases or health disorders. Additional therapeutic agent

在某些方面，本文提供之方法包括向受試者單獨地或與另外的治療劑組合地投與本文描述的固體劑型。在一些實施方式中，另外的治療劑係免疫抑制劑、抗炎劑、類固醇和/或癌症治療劑。In certain aspects, the methods provided herein include administering the solid dosage forms described herein to the subject alone or in combination with additional therapeutic agents. In some embodiments, the additional therapeutic agent is an immunosuppressant, anti-inflammatory agent, steroid, and/or cancer therapeutic agent.

在一些實施方式中，在投與另外的治療劑之前（例如之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小時或之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天）向受試者投與固體劑型。在一些實施方式中，在投與另外的治療劑之後（例如之後至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小時或之後至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天）向受試者投與固體劑型。在一些實施方式中，同時或接近同時（例如，彼此在一小時內投與）向受試者投與固體劑型及另外的治療劑。In some embodiments, prior to administration of the additional therapeutic agent (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer a solid dosage form to the subject. In some embodiments, after administration of the additional therapeutic agent (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours or later at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer a solid dosage form to the subject. In some embodiments, the solid dosage form and the additional therapeutic agent are administered to the subject at the same time or near the same time (eg, administered within one hour of each other).

在一些實施方式中，在向受試者投與固體劑型之前（例如之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小時或之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天）向受試者投與抗生素。在一些實施方式中，在向受試者投與固體劑型之後（例如之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小時或之後至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天）向受試者投與抗生素。在一些實施方式中，向受試者同時或接近同時投與（例如，彼此在一小時內投與）固體劑型及抗生素。In some embodiments, before administering the solid dosage form to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) administer antibiotics to the subject. In some embodiments, after the solid dosage form is administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours or later at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) administer antibiotics to the subject. In some embodiments, the solid dosage form and the antibiotic are administered to the subject at or near the same time (eg, within one hour of each other).

在一些實施方式中，另外的治療劑係癌症治療劑。在一些實施方式中，癌症治療劑係化學治療劑。該等化學治療劑的實例包含（但不限於）烷基化劑，例如噻替哌（thiotepa）及環磷醯胺（cyclosphosphamide）；磺酸烷基酯，例如白消安（busulfan）、英丙舒凡（improsulfan）及哌泊舒凡（piposulfan）；氮丙啶，例如苯并多巴（benzodopa）、卡波醌（carboquone）、米得哌（meturedopa）及烏得哌（uredopa）；乙撐亞胺及甲基密胺，包含六甲密胺（altretamine）、三伸乙基密胺（triethylenemelamine）、三伸乙基磷醯胺、三伸乙基硫化磷醯胺及三羥甲基密胺（trimethylolomelamine）；番荔枝內酯（acetogenin）（尤其布拉他辛（bullatacin）及布拉他辛酮（bullatacinone））；喜樹鹼（camptothecin）（包含合成類似物托泊替康（topotecan））；苔蘚蟲素（bryostatin）；卡利抑制素（callystatin）；CC-1065（包含其合成類似物阿多來新（adozelesin）、卡折來新（carzelesin）及比折來新（bizelesin））；念珠藻素（cryptophycin）（尤其念珠藻素1及念珠藻素8）；朵拉司他汀（dolastatin）；多卡米星（duocarmycin）（包含合成類似物KW-2189及CB1-TM1）；艾榴塞洛素（eleutherobin）；水鬼蕉鹼（pancratistatin）；匍枝珊瑚醇（sarcodictyin）；海綿抑制素（spongistatin）；氮芥（nitrogen mustard），例如苯丁酸氮芥（chlorambucil）、萘氮芥（chlornaphazine）、氯磷醯胺（cholophosphamide）、雌氮芥（estramustine）、異環磷醯胺（ifosfamide）、氮芥（mechlorethamine）、鹽酸甲氧氮芥、美法侖（melphalan）、新氮芥（novembichin）、苯乙酸氮芥膽甾醇酯（phenesterine）、潑尼莫司汀（prednimustine）、曲磷胺（trofosfmaide）、尿嘧啶氮芥；亞硝基脲，例如卡莫司汀（carmustine）、氯脲菌素（chlorozotocin）、福莫司汀（fotemustine）、洛莫司汀（lomustine）、尼莫司汀（nimustine）及雷莫司汀（ranimnustine）；抗生素，例如烯二炔抗生素（例如卡奇黴素（calicheamicin），尤其卡奇黴素γlI及卡奇黴素Ωl1；達內黴素（dynemicin），包含達內黴素A；雙膦酸鹽類，例如氯膦酸鹽（clodronate）；埃斯培拉黴素（esperamicin）；以及新製癌菌素發色團（neocarzinostatin chromophore）及相關色蛋白烯二炔抗生素發色團）、阿克拉黴素（aclacinomysin）、放線菌素（actinomycin）、安麯黴素（authramycin）、氮雜絲胺酸、博來黴素（bleomycin）、放線菌素C（cactinomycin）、卡拉黴素（carabicin）、洋紅黴素（caminomycin）、嗜癌素（carzinophilin）、色黴素（chromomycin）、放線菌素D（dactinomycin）、柔紅黴素（daunorubicin）、地托比星（detorubicin）、6-重氮基-5-側氧基-L-正白胺酸、多柔比星（doxorubicin）（包含𠰌啉基-多柔比星、氰𠰌啉基-多柔比星、2-吡咯啉基-多柔比星及去氧多柔比星）、表柔比星（epirubicin）、依索比星（esorubicin）、伊達比星（idarubicin）、麻西羅黴素（marcellomycin）、絲裂黴素（mitomycin）（例如絲裂黴素C）、黴酚酸（mycophenolic acid）、諾拉黴素（nogalamycin）、橄欖黴素（olivomycin）、培洛黴素（peplomycin）、泊非黴素（potfiromycin）、嘌呤黴素（puromycin）、三鐵阿黴素（quelamycin）、羅多比星（rodorubicin）、鏈黑菌素（streptonigrin）、鏈脲菌素（streptozocin）、殺結核菌素（tubercidin）、烏苯美司（ubenimex）、淨司他丁（zinostatin）、佐柔比星（zorubicin）；抗代謝物，例如胺甲蝶呤（methotrexate）及5-氟尿嘧啶（5-FU）；葉酸類似物，例如二甲葉酸（denopterin）、胺甲喋呤、蝶羅呤（pteropterin）、曲美沙特（trimetrexate）；嘌呤類似物，例如氟達拉濱（fludarabine）、6-巰基嘌呤、硫咪嘌呤（thiamiprine）、硫鳥嘌呤；嘧啶類似物，例如安西他濱（ancitabine）、阿紮胞苷（azacitidine）、6-阿紮尿苷（6-azauridine）、卡莫氟（carmofur）、阿糖胞苷（cytarabine）、二去氧尿苷、去氧氟尿苷（doxifluridine）、依諾他濱（enocitabine）、氟尿苷（floxuridine）；雄激素，例如卡普睪酮（calusterone）、丙酸屈他雄酮（dromostanolone propionate）、環硫雄醇（epitiostanol）、美雄烷（mepitiostane）、睪內酯酮（testolactone）；抗腎上腺素，例如胺魯米特（aminoglutethimide）、米托坦（mitotane）、曲洛司坦（trilostane）；葉酸補充劑，例如亞葉酸；乙醯葡醛酸內酯（aceglatone）；醛磷醯胺糖苷（aldophosphamide glycoside）；胺基乙醯丙酸（aminolevulinic acid）；恩尿嘧啶（eniluracil）；安吖啶（amsacrine）；百思布希（bestrabucil）；比生群（bisantrene）；依達曲沙（edatraxate）；地磷醯胺（defofamine）；秋水仙胺（demecolcine）；地吖醌（diaziquone）；依氟鳥胺酸（eflornithine）；依利乙銨（elliptinium acetate）；埃博黴素（epothilone）；依託格魯（etoglucid）；硝酸鎵；羥基脲；蘑菇多糖（lentinan）；氯尼達明（lonidainine）；類美坦辛（maytansinoid），例如美坦辛（maytansine）及柄型菌素（ansamitocin）；米托胍腙（mitoguazone）；米托蒽醌（mitoxantrone）；莫哌達醇（mopidanmol）；尼群克林（nitraerine）；噴托他汀（pentostatin）；蛋胺氮芥（phenamet）；吡柔比星（pirarubicin）；洛索蒽醌（losoxantrone）；鬼臼酸（podophyllinic acid）；2-乙基醯肼；丙卡巴肼（procarbazine）；PSK多糖複合物）；雷佐生（razoxane）；根黴素（rhizoxin）；西佐喃（sizofuran）；鍺螺胺（spirogermanium）；細交鏈孢菌酮酸（tenuazonic acid）；三亞胺醌（triaziquone）；2,2',2"-三氯三乙胺；單端孢黴烯（trichothecene）（尤其T-2毒素、疣皰菌素（verrucarin）A、桿孢菌素（roridin）A及蛇形菌素（anguidine））；烏拉坦（urethan）；長春地辛（vindesine）；達卡巴𠯤（dacarbazine）；甘露莫司汀（mannomustine）；二溴甘露醇（mitobronitol）；二溴衛矛醇（mitolactol）；哌泊溴烷（pipobroman）；噶薩托辛（gacytosine）；阿拉伯糖苷（arabinoside）（「Ara-C」）；環磷醯胺；噻替派；紫杉烷（taxoid），例如太平洋紫杉醇（paclitaxel）及多西紫杉醇（doxetaxel）；苯丁酸氮芥；吉西他濱（gemcitabine）；6-硫鳥嘌呤；巰基嘌呤；胺甲喋呤；鉑配位錯合物，例如順鉑（cisplatin）、奧沙利鉑（oxaliplatin）及卡鉑（carboplatin）；長春花鹼（vinblastine）；鉑；依託泊苷（etoposide）（VP-16）；異環磷醯胺；米托蒽醌（mitoxantrone）；長春新鹼（vincristine）；長春瑞濱（vinorelbine）；諾安托（novantrone）；替尼泊苷（teniposide）；依達曲沙；道諾黴素（daunomycin）；胺蝶呤（aminopterin）；希羅達（xeloda）；伊班膦酸鹽（ibandronate）；伊立替康（irinotecan）（例如CPT-11）；拓撲異構酶抑制劑RFS 2000；二氟甲基鳥胺酸（DMFO）；類視黃醇，例如視黃酸；卡培他濱（capecitabine）；以及上述任何一種的藥學上可接受的鹽、酸或衍生物。In some embodiments, the additional therapeutic agent is a cancer therapeutic agent. In some embodiments, the cancer therapeutic agent is a chemotherapeutic agent. Examples of such chemotherapeutic agents include (but are not limited to) alkylating agents, such as thiotepa and cyclosphosphamide; sulfonic acid alkyl esters, such as busulfan, propyl Improsulfan and piposulfan; aziridines, such as benzodopa, carboquone, metredopa and uredopa; ethylene Imine and methyl melamine, including altretamine, triethylenemelamine, triethylene phosphamide, triethylene sulfide phosphamide and trimethylol melamine ( trimethylolomelamine); acetogenin (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); Bryostatin; callystatin; CC-1065 (including its synthetic analogues adozelesin, carzelesin and bizelesin); Rosary Cryptophycin (especially Nostocin 1 and Nostocin 8); Dolastatin; Duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); Eleusine Eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil and chlorambucil ( chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, methoxine hydrochloride, melphalan, neomustine ( novembichin, phenesterine, prednimustine, trofosfmaide, uracil; nitrosourea, such as carmustine, chlorine Ureamycin (chlorozotocin), formustine (fotemustine), lomustine (lomustine), Nimustine and ranimnustine; antibiotics, such as enediyne antibiotics (such as calicheamicin, especially calicheamicin γlI and calicheamicin Ωl1; danamycin ( dynemicin), including danomycin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophore (neocarzinostatin chromophore) and related Chromophore (chromophore of chromophore), aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, actinomycin C (cactinomycin), carabicin (carabicin), caminomycin (caminomycin), carzinophilin (carzinophilin), chromomycin (chromomycin), actinomycin D (dactinomycin), daunorubicin (daunorubicin), Tobycin (detorubicin), 6-diazo-5-oxo-L-ortho-leucine, doxorubicin (including 𠰌line-doxorubicin, cyanoline-doxorubicin) Rubicin, 2-pyrrolinyl-doxorubicin and deoxydoxorubicin), epirubicin (epirubicin), esorubicin (esorubicin), idarubicin (idarubicin), methiromycin Marcellomycin, mitomycin (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycin, peplomycin ), pofiromycin (potfiromycin), puromycin (puromycin), triiron adriamycin (quelamycin), rhodoubicin (rodorubicin), streptomycin (streptonigrin), streptozocin (streptozocin), Tubercidin (tubercidin), Ubenimex (ubenimex), Zinostatin (zinostatin), Zorubicin (zorubicin); antimetabolites, such as methotrexate and 5-fluorouracil (5 -FU); folate analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6 Sulfhydryl Purine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur ), cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone , Dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergic, such as aminoglutethimide, mitotane (Mitotane), trilostane; folic acid supplements, such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid ); eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; colchicine (Demecolcine); diaziquone; eflornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; mushroom Polysaccharides (lentinan); lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone ); mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; ghost Podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK polysaccharide complex; razoxane; rhizoxin; sizo furan; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecene ) (Especially T-2 toxin, verrucarin A, roridin A and anguidine); urethan; vindesine; dakaba 𠯤 (dacarbazine); mannomustine (mannomustine); dibromomannitol (mitobronitol); mitolactol (mitolactol); pipobroman; gacytosine (gacytosine); arabinoside ) ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes, such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum ; Etoposide (VP-16); Ifosfamide; Mitoxantrone (mitoxantrone); Vincristine (vincristine); Vinorelbine (vinorelbine); Novantrone; Tinib Teniposide; edatrexa; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (for example CPT-11); topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids, such as retinoic acid; capecitabine; and the pharmacy of any of the above Acceptable salts, acids or derivatives.

在一些實施方式中，癌症治療劑係癌症免疫療法藥劑。免疫療法係指使用受試者的免疫系統來治療癌症的治療，例如檢查點抑制劑、癌症疫苗、細胞介素、細胞療法、CAR-T細胞及樹突細胞療法。檢查點抑制劑免疫療法的非限制性實例包含尼沃魯單抗（Nivolumab）（BMS，抗PD-1）、派姆單抗（Pembrolizumab）（Merck，抗PD-1）、伊匹單抗（Ipilimumab）（BMS，抗CTLA-4）、MEDI4736（阿斯利康公司（AstraZeneca），抗PD-L1）及MPDL3280A（羅氏公司（Roche），抗PD-L1）。其他免疫療法可為腫瘤疫苗，例如Gardail、Cervarix、BCG、西普賽爾-T（sipulencel-T）、Gp100: 209-217、AGS-003、DCVax-L、阿爾土賽爾-L（Algenpantucel-L）、特爾土賽爾-L（Tergenpantucel-L）、TG4010、ProstAtak、Prostvac-V/R-TRICOM、林多莫爾（Rindopepimul）、E75乙酸肽、IMA901、POL-103A、貝拉土賽爾-L（Belagenpumatucel-L）、GSK1572932A、MDX-1279、GV1001及替西泰德（Tecemotide）。免疫療法藥劑可經由注射（例如經靜脈內、經腫瘤內、經皮下或注射至淋巴結中）來投與，但還可經口、經局部或經由氣溶膠來投與。免疫療法可包括佐劑（例如細胞介素）。In some embodiments, the cancer therapeutic agent is a cancer immunotherapy agent. Immunotherapy refers to treatments that use the subject's immune system to treat cancer, such as checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cell and dendritic cell therapy. Non-limiting examples of checkpoint inhibitor immunotherapy include Nivolumab (BMS, anti-PD-1), Pembrolizumab (Merck, anti-PD-1), Ipilimumab ( Ipilimumab) (BMS, anti-CTLA-4), MEDI4736 (AstraZeneca, anti-PD-L1) and MPDL3280A (Roche, anti-PD-L1). Other immunotherapies can be tumor vaccines, such as Gardail, Cervarix, BCG, Sipulencel-T, Gp100: 209-217, AGS-003, DCVax-L, Algenpantucel-L (Algenpantucel-T) L), Tergenpantucel-L (Tergenpantucel-L), TG4010, ProstAtak, Prostvac-V/R-TRICOM, Lindopepimul, E75 acetate peptide, IMA901, POL-103A, Belatucel Er-L (Belagenpumatucel-L), GSK1572932A, MDX-1279, GV1001 and Tecemotide. Immunotherapy agents can be administered via injection (for example, intravenously, intratumorally, subcutaneously, or into lymph nodes), but can also be administered orally, locally, or via aerosol. Immunotherapy may include adjuvants (e.g., cytokines).

在一些實施方式中，免疫療法藥劑係免疫檢查點抑制劑。免疫檢查點抑制在廣義上係指抑制癌細胞可產生的檢查點以預防或下調免疫應答。免疫檢查點蛋白的實例包括但不限於CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG3、TIM-3或VISTA。免疫檢查點抑制劑可為結合至並抑制免疫檢查點蛋白的抗體或其抗原結合片段。免疫檢查點抑制劑的實例包括但不限於尼沃魯單抗、派姆單抗、匹利珠單抗（pidilizumab）、AMP-224、AMP-514、STI-A1110、TSR-042、RG-7446、BMS-936559、MEDI-4736、MSB-0020718C、AUR-012及STI-A1010。In some embodiments, the immunotherapy agent is an immune checkpoint inhibitor. Immune checkpoint suppression in a broad sense refers to the suppression of checkpoints that cancer cells can produce to prevent or down-regulate the immune response. Examples of immune checkpoint proteins include, but are not limited to, CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3, or VISTA. The immune checkpoint inhibitor may be an antibody or antigen-binding fragment thereof that binds to and inhibits the immune checkpoint protein. Examples of immune checkpoint inhibitors include, but are not limited to, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG-7446 , BMS-936559, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010.

在一些實施方式中，本文提供之方法包括投與本文描述的藥物組成物與一種或多種另外的治療劑的組合。在一些實施方式中，本文揭示之方法包括投與兩種免疫療法藥劑（例如，免疫檢查點抑制劑）。例如，本文提供之方法包括將本文描述的藥物組成物與PD-1抑制劑（例如派姆單抗或尼沃魯單抗或匹利珠單抗）或CLTA-4抑制劑（例如伊匹單抗）或PD-L1抑制劑組合投與。In some embodiments, the methods provided herein include administering the pharmaceutical composition described herein in combination with one or more additional therapeutic agents. In some embodiments, the methods disclosed herein include the administration of two immunotherapy agents (eg, immune checkpoint inhibitors). For example, the method provided herein includes combining the pharmaceutical composition described herein with a PD-1 inhibitor (such as pembrolizumab or nivolumab or pilizumab) or a CLTA-4 inhibitor (such as ipilimumab). Anti-) or PD-L1 inhibitor combination administration.

在一些實施方式中，免疫療法藥劑係（例如）結合至癌症相關抗原的抗體或其抗原結合片段。癌症相關抗原的實例包括但不限於親脂素（adipophilin）、AIM-2、ALDH1A1、α-輔肌動蛋白-4、α-胎蛋白（「AFP」）、ARTC1、B-RAF、BAGE-1、BCLX（L）、BCR-ABL融合蛋白b3a2、β-鏈蛋白、BING-4、CA-125、CALCA、癌胚抗原（「CEA」）、CASP-5、CASP-8、CD274、CD45、Cdc27、CDK12、CDK4、CDKN2A、CEA、CLPP、COA-1、CPSF、CSNK1A1、CTAG1、CTAG2、週期蛋白D1、週期蛋白-A1、dek-can融合蛋白、DKK1、EFTUD2、延長因子2、ENAH（hMena）、Ep-CAM、EpCAM、EphA3、上皮腫瘤抗原（「ETA」）、ETV6-AML1融合蛋白、EZH2、FGF5、FLT3-ITD、FN1、G250/MN/CAIX、GAGE-1,2,8、GAGE-3,4,5,6,7、GAS7、磷脂醯肌醇蛋白聚糖-3、GnTV、gp100/Pmel17、GPNMB、HAUS3、海普森（Hepsin）、HER-2/neu、HERV-K-MEL、HLA-A11、HLA-A2、HLA-DOB、hsp70-2、IDO1、IGF2B3、IL13Rα2、腸羧基酯酶、K-ras、激肽釋放素4、KIF20A、KK-LC-1、KKLC1、KM-HN-1、KMHN1（又稱為CCDC110）、LAGE-1、LDLR-岩藻糖基轉移酶AS融合蛋白、萊格西因（Lengsin）、M-CSF、MAGE-A1、MAGE-A10、MAGE-A12、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A9、MAGE-C1、MAGE-C2、蘋果酸酶、乳腺珠蛋白-A、MART2、MATN、MC1R、MCSP、mdm-2、ME1、Melan-A/MART-1、Meloe、中期因子、MMP-2、MMP-7、MUC1、MUC5AC、黏蛋白、MUM-1、MUM-2、MUM-3、肌凝蛋白、I類肌凝蛋白、N-raw、NA88-A、新-PAP、NFYC、NY-BR-1、NY-ESO-1/LAGE-2、OA1、OGT、OS-9、P多肽、p53、PAP、PAX5、PBF、pml-RARα融合蛋白、多態上皮黏蛋白（「PEM」）、PPP1R3B、PRAME、PRDX5、PSA、PSMA、PTPRK、RAB38/NY-MEL-1、RAGE-1、RBAF600、RGS5、RhoC、RNF43、RU2AS、SAGE、分離蛋白1、SIRT2、SNRPD1、SOX10、Sp17、SPA17、SSX-2、SSX-4、STEAP1、存活蛋白、SYT-SSX1或-SSX2融合蛋白、TAG-1、TAG-2、端粒酶、TGF-βRII、TPBG、TRAG-3、磷酸丙糖異構酶、TRP-1/gp75、TRP-2、TRP2-INT2、酪胺酸酶、酪胺酸酶（「TYR」）、VEGF、WT1、XAGE-1b/GAGED2a。在一些實施方式中，抗原係新抗原。In some embodiments, the immunotherapy agent is, for example, an antibody or antigen-binding fragment thereof that binds to a cancer-associated antigen. Examples of cancer-related antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, α-actinin-4, α-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1 , BCLX(L), BCR-ABL fusion protein b3a2, β-chain protein, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27 , CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, cyclin-A1, dek-can fusion protein, DKK1, EFTUD2, elongation factor 2, ENAH (hMena) , Ep-CAM, EpCAM, EphA3, Epithelial Tumor Antigen ("ETA"), ETV6-AML1 Fusion Protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS7, Glypican-3, GnTV, gp100/Pmel17, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL , HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Rα2, intestinal carboxyl esterase, K-ras, kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM- HN-1, KMHN1 (also known as CCDC110), LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE- A12, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, Malic enzyme, Mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm- 2. ME1, Melan-A/MART-1, Meloe, midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, myosin, class I Myosin, N-raw, NA88-A, New-PAP, NFYC, NY-BR-1, NY-ESO-1/LAGE-2, OA1, OGT, OS-9, P peptide, p53, PAP, PAX5 , PBF, pml-RARα fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTP RK, RAB38/NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, Protein Isolate 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEP1, Survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, telomerase, TGF-βRII, TPBG, TRAG-3, triose phosphate isomerase, TRP-1/gp75, TRP-2 , TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE-1b/GAGED2a. In some embodiments, the antigen is a neoantigen.

在一些實施方式中，免疫療法藥劑係癌症疫苗和/或癌症疫苗的組分（例如抗原性肽和/或蛋白質）。癌症疫苗可為蛋白質疫苗、核酸疫苗或其組合。例如，在一些實施方式中，癌症疫苗包括含有癌症相關抗原的表位的多肽。在一些實施方式中，癌症疫苗包括編碼癌症相關抗原的表位的核酸（例如DNA或RNA（例如mRNA））。癌症相關抗原的實例包括但不限於親脂素（adipophilin）、AIM-2、ALDH1A1、α-輔肌動蛋白-4、α-胎蛋白（「AFP」）、ARTC1、B-RAF、BAGE-1、BCLX（L）、BCR-ABL融合蛋白b3a2、β-鏈蛋白、BING-4、CA-125、CALCA、癌胚抗原（「CEA」）、CASP-5、CASP-8、CD274、CD45、Cdc27、CDK12、CDK4、CDKN2A、CEA、CLPP、COA-1、CPSF、CSNK1A1、CTAG1、CTAG2、週期蛋白D1、週期蛋白-A1、dek-can融合蛋白、DKK1、EFTUD2、延長因子2、ENAH（hMena）、Ep-CAM、EpCAM、EphA3、上皮腫瘤抗原（「ETA」）、ETV6-AML1融合蛋白、EZH2、FGF5、FLT3-ITD、FN1、G250/MN/CAIX、GAGE-1,2,8、GAGE-3,4,5,6,7、GAS7、磷脂醯肌醇蛋白聚糖-3、GnTV、gp100/Pmel17、GPNMB、HAUS3、海普森（Hepsin）、HER-2/neu、HERV-K-MEL、HLA-A11、HLA-A2、HLA-DOB、hsp70-2、IDO1、IGF2B3、IL13Rα2、腸羧基酯酶、K-ras、激肽釋放素4、KIF20A、KK-LC-1、KKLC1、KM-HN-1、KMHN1（又稱為CCDC110）、LAGE-1、LDLR-岩藻糖基轉移酶AS融合蛋白、萊格西因（Lengsin）、M-CSF、MAGE-A1、MAGE-A10、MAGE-A12、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A9、MAGE-C1、MAGE-C2、蘋果酸酶、乳腺珠蛋白-A、MART2、MATN、MC1R、MCSP、mdm-2、ME1、Melan-A/MART-1、Meloe、中期因子、MMP-2、MMP-7、MUC1、MUC5AC、黏蛋白、MUM-1、MUM-2、MUM-3、肌凝蛋白、I類肌凝蛋白、N-raw、NA88-A、新-PAP、NFYC、NY-BR-1、NY-ESO-1/LAGE-2、OA1、OGT、OS-9、P多肽、p53、PAP、PAX5、PBF、pml-RARα融合蛋白、多態上皮黏蛋白（「PEM」）、PPP1R3B、PRAME、PRDX5、PSA、PSMA、PTPRK、RAB38/NY-MEL-1、RAGE-1、RBAF600、RGS5、RhoC、RNF43、RU2AS、SAGE、分離蛋白1、SIRT2、SNRPD1、SOX10、Sp17、SPA17、SSX-2、SSX-4、STEAP1、存活蛋白、SYT-SSX1或-SSX2融合蛋白、TAG-1、TAG-2、端粒酶、TGF-βRII、TPBG、TRAG-3、磷酸丙糖異構酶、TRP-1/gp75、TRP-2、TRP2-INT2、酪胺酸酶、酪胺酸酶（「TYR」）、VEGF、WT1、XAGE-1b/GAGED2a。在一些實施方式中，抗原係新抗原。在一些實施方式中，將癌症疫苗與佐劑一起投與。佐劑的實例包括但不限於免疫調節蛋白、佐劑65、α-GalCer、磷酸鋁、氫氧化鋁、磷酸鈣、β-葡聚糖肽、CpG ODN DNA、GPI-0100、脂質A、脂多糖、利波夫（Lipovant）、蒙塔尼（Montanide）、N-乙醯基-胞壁醯基-L-丙胺醯基-D-異麩醯胺酸、Pam3CSK4、quil A、霍亂毒素（CT）及來自腸毒性大腸桿菌（Escherichia coli ）的不耐熱毒素（LT），包括這類的衍生物（CTB、mmCT、CTA1-DD、LTB、LTK63、LTR72、dmLT）及海藻糖二黴菌酸酯。In some embodiments, the immunotherapy agent is a cancer vaccine and/or a component of a cancer vaccine (eg, antigenic peptides and/or proteins). The cancer vaccine can be a protein vaccine, a nucleic acid vaccine, or a combination thereof. For example, in some embodiments, cancer vaccines include polypeptides containing epitopes of cancer-associated antigens. In some embodiments, cancer vaccines include nucleic acids (eg, DNA or RNA (eg, mRNA)) encoding epitopes of cancer-associated antigens. Examples of cancer-related antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, α-actinin-4, α-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1 , BCLX(L), BCR-ABL fusion protein b3a2, β-chain protein, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27 , CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, cyclin-A1, dek-can fusion protein, DKK1, EFTUD2, elongation factor 2, ENAH (hMena) , Ep-CAM, EpCAM, EphA3, Epithelial Tumor Antigen ("ETA"), ETV6-AML1 Fusion Protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS7, Glypican-3, GnTV, gp100/Pmel17, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL , HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Rα2, intestinal carboxyl esterase, K-ras, kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM- HN-1, KMHN1 (also known as CCDC110), LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE- A12, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, Malic enzyme, Mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm- 2. ME1, Melan-A/MART-1, Meloe, midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, myosin, class I Myosin, N-raw, NA88-A, New-PAP, NFYC, NY-BR-1, NY-ESO-1/LAGE-2, OA1, OGT, OS-9, P peptide, p53, PAP, PAX5 , PBF, pml-RARα fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTP RK, RAB38/NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, protein isolate 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEP1 Survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, telomerase, TGF-βRII, TPBG, TRAG-3, triose phosphate isomerase, TRP-1/gp75, TRP-2 , TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE-1b/GAGED2a. In some embodiments, the antigen is a neoantigen. In some embodiments, the cancer vaccine is administered with an adjuvant. Examples of adjuvants include, but are not limited to, immunomodulatory protein, adjuvant 65, α-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-glucan peptide, CpG ODN DNA, GPI-0100, lipid A, lipopolysaccharide , Lipovant, Montanide, N-Acetyl-Muralic-L-Alanine-D-Isoglutamic Acid, Pam3CSK4, Quill A, Cholera Toxin (CT) And heat labile toxins (LT) from Escherichia coli , including such derivatives (CTB, mmCT, CTA1-DD, LTB, LTK63, LTR72, dmLT) and trehalose bismycoate.

在一些實施方式中，免疫療法藥劑係用於受試者的免疫調節蛋白。在一些實施方式中，該免疫調節蛋白係細胞介素或趨化因子。免疫調節蛋白的實例包括但不限於B淋巴細胞趨化因子（「BLC」）、C-C模體趨化因子11（「Eotaxin-1」）、嗜酸性球性趨化蛋白2（「Eotaxin-2」）、顆粒性白血球群落刺激因子（「G-CSF」）、顆粒球巨噬細胞株刺激因子（「GM-CSF」）、1-309、細胞間黏附分子1（「ICAM-1」）、干擾素α（「IFN-α」）、干擾素β（「IFN-β」）干擾素γ（「IFN-γ」）介白素-1α（「IL-1α」）、介白素-1β（「IL-1β」）、介白素1受體拮抗劑（「IL-1 ra」）、介白素-2（「IL-2」）、介白素-4（「IL-4」）、介白素-5（「IL-5」）、介白素-6（「IL-6」）、介白素-6可溶性受體（「IL-6 sR」）、介白素-7（「IL-7」）、介白素-8（「IL-8」）、介白素10（「IL-10」）、介白素-11（「IL-11」）、介白素-12的亞基β（「IL-12 p40」或「IL-12 p70」）、介白素-13（「IL-13」）、介白素-15（「IL-15」）、介白素-16（「IL-16」）、介白素-17A-F（「IL-17A-F」）、介白素-18（「IL-18」）、介白素-21（「IL-21」）、介白素-22（「IL-22」）、介白素-23（「IL-23」）、介白素-33（「IL-33」）、趨化因子（C-C模體）配位基2（「MCP-1」）、巨噬細胞群落刺激因子（「M-CSF」）、γ干擾素誘導的單核因子（「MIG」）、趨化因子（C-C模體）配位基2（「MIP-1α」）、趨化因子（C-C模體）配位基4（「MIP-1β」）、巨噬細胞炎性蛋白-1-δ（「MIP-1δ」）、血小板衍生的生長因子亞基B（「PDGF-BB」）、趨化因子（C-C模體）配位基5（激活調節，正常T細胞表現和分泌）（「RANTES」）、TIMP金屬肽酶抑制劑1（「TIMP-1」）、TIMP金屬肽酶抑制劑2（「TIMP-2」）、腫瘤壞死因子、淋巴毒素-α（「TNFα」）、腫瘤壞死因子、淋巴毒素-β（「TNFβ」）、1型可溶性TNF受體（「sTNFRI」）、sTNFRIIAR、腦源性神經營養因子（BDNF）、鹼性成纖維細胞生長因子（「bFGF」）、骨成形性蛋白質4（「BMP-4」）、骨成形性蛋白質5（「BMP-5」）、骨成形性蛋白質7（「BMP-7」）、神經生長因子（「b-NGF」）、表皮生長因子（「EGF」）、表皮生長因子受體（「EGFR」）、內分泌腺源性血管內皮生長因子（「EG-VEGF」）、成纖維細胞生長因子4（「FGF-4」）、角質形成細胞生長因子（「FGF-7」）、生長分化因子15（「GDF-15」）、神經膠質細胞源性神經營養因子（「GDNF」）、生長激素、肝素結合性EGF樣生長因子（「HB-EGF」）、肝細胞生長因子（「HGF」）、胰島素樣生長因子結合蛋白1（「IGFBP-1」）、胰島素樣生長因子結合蛋白2（「IGFBP-2」）、胰島素樣生長因子結合蛋白3（「IGFBP-3」）、胰島素樣生長因子結合蛋白4（「IGFBP-4」）、胰島素樣生長因子結合蛋白6（「IGFBP-6」）、胰島素樣生長因子1（「IGF-1」）、胰島素、巨噬細胞群落刺激因子（「M-CSF R」）、神經生長因子受體（「NGF R」）、神經營養因子-3（「NT-3」）、神經營養因子-4（「NT-4」）、破骨細胞生成抑制因子（「骨保護素」）、血小板源性生長因子受體（「PDGF-AA」）、磷脂醯肌醇-聚糖生物合成（「PIGF」）、Skp、Cullin、含F-盒的複合物（「SCF」）、幹細胞介素受體（「SCF R」）、轉化生長因子α（「TGFα」）、轉化生長因子β-1（「TGFβ1」）、轉化生長因子β-3（「TGFβ3」）、血管內皮生長因子（「VEGF」）、血管內皮生長因子受體2（「VEGFR2」）、血管內皮生長因子受體3（「VEGFR3」）、VEGF-D 6Cine、酪胺酸蛋白激酶受體UFO（「Axl」）、乙胞素（「BTC」）、黏膜相關的上皮趨化因子（「CCL28」）、趨化因子（C-C模體）配位基27（「CTACK」）、趨化因子（C-X-C模體）配位基16（「CXCL16」）、C-X-C模體趨化因子5（「ENA-78」）、趨化因子（C-C模體）配位基26（「Eotaxin-3」）、粒細胞趨化蛋白2（「GCP-2」）、GRO、趨化因子（C-C模體）配位基14（「HCC-l」）、趨化因子（C-C模體）配位基16（「HCC-4」）、介白素-9（「IL-9」）、介白素-17 F（「IL-17F」）、介白素-18結合蛋白（「IL-18 BPa」）、介白素-28A（「IL-28A」）、介白素29（「IL-29」）、介白素31（「IL-31」）、C-X-C模體趨化因子10（「IP-10」）、趨化因子受體CXCR3（「I-TAC」）、白血病抑制因子（「LIF」）、萊特蛋白（Light）、趨化因子（C模體）配位基（「淋巴細胞趨化因子」）、單核細胞趨化蛋白2（「MCP-2」）、單核細胞趨化蛋白3（「MCP-3」）、單核細胞趨化蛋白4（「MCP-4」）、巨噬細胞源性趨化因子（「MDC」）、巨噬細胞遷移抑制因子（「MIF」）、趨化因子（C-C模體）配位基20（「MIP-3α」）、C-C模體趨化因子19（「MIP-3β」）、趨化因子（C-C模體）配位基23（「MPIF-1」）、巨噬細胞刺激蛋白α鏈（「MSPα」）、核小體裝配蛋白1-樣4（「NAP-2」）、分泌型磷蛋白1（「骨橋蛋白」）、肺和激活調節的細胞介素（「PARC」）、血小板因子4（「PF4」）、基質細胞源性因子-1α（「SDF-1α」）、趨化因子（C-C模體）配位基17（「TARC」）、胸腺表現的趨化因子（「TECK」）、胸腺基質淋巴細胞生成素（「TSLP 4-IBB」）、CD 166抗原（「ALCAM」）、分化簇80（「B7-1」）、腫瘤壞死因子受體超家族成員17（「BCMA」）、分化簇14（「CD14」）、分化簇30（「CD30」）、分化簇40（「CD40配位基」）、癌胚抗原相關細胞黏附分子1（膽汁糖蛋白）（「CEACAM-1」）、死亡受體6（「DR6」）、去氧胸苷激酶（「Dtk」）、1型膜糖蛋白（「內皮糖蛋白」）、受體酪胺酸蛋白激酶erbB-3（「ErbB3」）、內皮細胞-白血球黏附分子1（「E-選擇素」）、凋亡抗原1（「Fas」）、Fms樣酪胺酸激酶3（「Flt-3L」）、腫瘤壞死因子受體超家族成員1（「GITR」）、腫瘤壞死因子受體超家族成員14（「HVEM」）、細胞間黏附分子3（「ICAM-3」）、IL-1 R4、IL-1 RI、IL-10 Rβ、IL-17R、IL-2Rγ、IL-21R、溶酶體膜蛋白2（「LIMPII」）、中性粒細胞明膠酶相關脂蛋白（「脂質運載蛋白-2」）、CD62L（「L-選擇素」）、淋巴管內皮細胞（「LYVE-1」）、MHC I類多肽相關序列A（「MICA」）、MHC I類多肽相關序列B（「MICB」）、NRG1-βl、β型血小板源性生長因子受體（「PDGF Rβ」）、血小板內皮細胞黏附分子（「PECAM-1」）、RAGE、甲型肝炎病毒細胞受體1（「TIM-1」）、腫瘤壞死因子受體超家族成員IOC（「TRAIL R3」）、Trappin蛋白轉麩醯胺酸酶結合結構域（「Trappin-2」）、尿激酶受體（「uPAR」）、血管細胞黏附蛋白1（「VCAM-1」）、XEDAR活化素A、鼠灰色基因（Agouti）相關蛋白（「AgRP」）、核糖核酸酶5（「血管生成素」）、血管生成素1、血管抑素、Catheprin S、CD40、隱秘家族蛋白IB（「Cripto-1」）、DAN、Dickkopf相關蛋白1（「DKK-1」）、E-鈣黏素、上皮細胞黏附分子（「EpCAM」）、Fas配位基（FasL或CD95L）、Fcg RIIB/C、FoUistatin、半乳凝素-7、細胞間黏附分子2（「ICAM-2」）、IL-13 Rl、IL-13R2、IL-17B、IL-2 Ra、IL-2 Rb、IL-23、LAP、神經細胞黏附分子（「NrCAM」）、纖溶酶原激活物抑制劑-1（「PAI-1」）、血小板源性生長因子受體（「PDGF-AB」）、抵抗素、基質細胞源性因子1（「SDF-1β」）、sgpl30、分泌型捲曲相關蛋白2（「ShhN」）、結合唾液酸的免疫球蛋白型凝集素（「Siglec-5」）、ST2、轉化生長因子-β2（「TGFβ2」）、Tie-2、血小板生成素（「TPO」）、腫瘤壞死因子受體超家族成員10D（「TRAIL R4」）、在髓樣細胞1上表現的觸發受體（「TREM-1」）、血管內皮生長因子C（「VEGF-C」）、VEGFR1脂聯素、降脂蛋白（「AND」）、α-胎蛋白（「AFP」）、血管生成素樣4（「ANGPTL4」）、β-2-微球蛋白（「B2M」）、基底細胞黏附分子（「BCAM」）、碳水化合物抗原125（「CA125」）、癌症抗原15-3（「CA15-3」）、癌胚抗原（「CEA」）、cAMP受體蛋白（「CRP」）、人表皮生長因子受體2（「ErbB2」）、卵泡抑素、促卵泡激素（「FSH」）、趨化因子（C-X-C模體）配位基1（「GROα」）、人絨毛膜促性腺激素（「βHCG」）、胰島素樣生長因子1受體（「IGF-1 sR」）、IL-1 sRII、IL-3、IL-18 Rb、IL-21、瘦素、基質金屬蛋白酶-1（「MMP-1」）、基質金屬蛋白酶-2（「MMP-2」）、基質金屬蛋白酶-3（「MMP-3」）、基質金屬蛋白酶-8（「MMP-8」）、基質金屬蛋白酶-9（「MMP-9」）、基質金屬蛋白酶-10（「MMP-10」）、基質金屬蛋白酶-13（「MMP-13」）、神經細胞黏附分子（「NCAM-1」）、巢蛋白（「巢蛋白-1」）、神經元特異性烯醇化酶（「NSE」）、抑瘤素M（「OSM」）、前降鈣素、催乳素、前列腺特異性抗原（「PSA」）、結合唾液酸的Ig樣凝集素9（「Siglec-9」）、ADAM 17內肽酶（「TACE」）、甲狀腺球蛋白、金屬蛋白酶抑制劑4（「TIMP-4」）、TSH2B4、含有整合素和金屬蛋白酶結構域的蛋白9（「ADAM-9」）、血管生成素2、腫瘤壞死因子配位基超家族成員13/富含酸性白胺酸的核磷蛋白32家族成員B（「APRIL」）、骨成形性蛋白質2（「BMP-2」）、骨成形性蛋白質9（「BMP-9」）、補體組分5a（「C5a」）、組織蛋白酶L、CD200、CD97、趨化素、腫瘤壞死因子受體超家族成員6B（「DcR3」）、脂肪酸結合蛋白2（「FABP2」）、成纖維細胞激活蛋白、α（「FAP」）、成纖維細胞生長因子19（「FGF-19」）、半乳凝素-3、肝細胞生長因子受體（「HGF R」）、IFN-γ/βR2、胰島素樣生長因子2（「IGF-2」）、胰島素樣生長因子2受體（「IGF-2 R」）、介白素-1受體6（「IL-1R6」）、介白素24（「IL-24」）、介白素33（「IL-33」、激肽釋放酶14、天冬醯胺基內肽酶（「豆莢蛋白」）、氧化的低密度脂蛋白受體1（「LOX-1」）、甘露糖結合凝集素（「MBL」）、腦啡肽酶（「NEP」）、Notch同系物1、易位相關（果蠅）（「Notch-1」）、腎母細胞瘤過度表現（「NOV」）、骨激活素（Osteoactivin）、計劃性細胞死亡蛋白1（「PD-1」）、N-乙醯基胞壁醯基-L-丙胺酸醯胺酶（「PGRP-5」）、絲胺酸蛋白酶抑制劑A4、分泌型捲曲相關蛋白3（「sFRP-3」）、血栓調節素、Toll樣受體2（「TLR2」）、腫瘤壞死因子受體超家族成員10A（「TRAIL R1」）、轉鐵蛋白（「TRF」）、WIF-LACE-2、白蛋白、AMICA、血管生成素4、B細胞激活因子（「BAFF」）、碳水化合物抗原19-9（「CA19-9」）、CD 163、簇集素、CRT AM、趨化因子（C-X-C模體）配位基14（「CXCL14」）、胱抑素C、核心蛋白聚糖（「DCN」）、Dickkopf相關蛋白3（「Dkk-3」）、δ樣蛋白1（「DLL1」）、胎球蛋白A、肝素結合生長因子1（「aFGF」）、葉酸受體α（「FOLR1」）、弗林蛋白酶、GPCR相關的分選蛋白1（「GASP-1」）、GPCR相關的分選蛋白2（「GASP-2」）、顆粒性白血球群落刺激因子受體（「GCSF R」）、絲胺酸蛋白酶hepsin（「HAI-2」）、介白素-17B受體（「IL-17B R」）、介白素27（「IL-27」）、淋巴細胞啟動基因3（「LAG-3」）、載脂蛋白A-V（「LDL R」）、胃蛋白酶原I、視黃醇結合蛋白4（「RBP4」）、SOST、硫酸乙醯肝素蛋白聚糖（「多配位基蛋白聚糖-1」）、腫瘤壞死因子受體超家族成員13B（「TACI」）、組織因子途徑抑制劑（「TFPI」）、TSP-1、腫瘤壞死因子受體超家族成員10b（「TRAIL R2」）、TRANCE、肌鈣蛋白I、尿激酶纖溶酶原啟動劑（「uPA」）、鈣黏素5、2型或VE-鈣黏素（血管內皮細胞）（也稱為CD144（「VE-鈣黏素」））、WNT1誘導信號通路蛋白1（「WISP-1」）、和核因子κB受體啟動劑（「RANK」）。In some embodiments, the immunotherapy agent is an immunomodulatory protein for the subject. In some embodiments, the immunomodulatory protein is a cytokine or a chemokine. Examples of immunomodulatory proteins include, but are not limited to, B lymphocyte chemokine ("BLC"), CC motif chemokine 11 ("Eotaxin-1"), eosinophil chemotactic protein 2 ("Eotaxin-2") ), granular white blood cell community stimulating factor ("G-CSF"), granular macrophage cell line stimulating factor ("GM-CSF"), 1-309, intercellular adhesion molecule 1 ("ICAM-1"), interference Interleukin α ("IFN-α"), Interleukin β ("IFN-β"), Interleukin γ ("IFN-γ"), Interleukin-1α ("IL-1α"), Interleukin-1β (" IL-1β"), interleukin-1 receptor antagonist ("IL-1 ra"), interleukin-2 ("IL-2"), interleukin-4 ("IL-4"), interleukin-1 Interleukin-5 ("IL-5"), Interleukin-6 ("IL-6"), Interleukin-6 Soluble Receptor ("IL-6 sR"), Interleukin-7 ("IL -7”), interleukin-8 (“IL-8”), interleukin 10 (“IL-10”), interleukin-11 (“IL-11”), sub-interleukin-12 Base β ("IL-12 p40" or "IL-12 p70"), interleukin-13 ("IL-13"), interleukin-15 ("IL-15"), interleukin-16 ( "IL-16"), interleukin-17A-F ("IL-17A-F"), interleukin-18 ("IL-18"), interleukin-21 ("IL-21"), Interleukin-22 ("IL-22"), interleukin-23 ("IL-23"), interleukin-33 ("IL-33"), chemokine (CC motif) ligand 2 ("MCP-1"), macrophage community stimulating factor ("M-CSF"), interferon-gamma-induced mononuclear factor ("MIG"), chemokine (CC motif) ligand 2 ( "MIP-1α"), chemokine (CC motif) ligand 4 ("MIP-1β"), macrophage inflammatory protein-1-δ ("MIP-1δ"), platelet-derived growth factor Subunit B ("PDGF-BB"), chemokine (CC motif) ligand 5 (activation regulation, normal T cell expression and secretion) ("RANTES"), TIMP metalopeptidase inhibitor 1 ("TIMP -1"), TIMP metallopeptidase inhibitor 2 ("TIMP-2"), tumor necrosis factor, lymphotoxin-α ("TNFα"), tumor necrosis factor, lymphotoxin-β ("TNFβ"), type 1 Soluble TNF receptor ("sTNFRI"), sTNFRIIAR, brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor ("bFGF"), bone forming protein 4 ("BMP-4"), bone formation Protein 5 ("BMP-5"), Bone Morphogenetic Protein 7 ("BMP-7"), Nerve Growth Factor ("b-NGF") , Epidermal growth factor ("EGF"), epidermal growth factor receptor ("EGFR"), endocrine gland-derived vascular endothelial growth factor ("EG-VEGF"), fibroblast growth factor 4 ("FGF-4") , Keratinocyte growth factor ("FGF-7"), growth differentiation factor 15 ("GDF-15"), glial cell-derived neurotrophic factor ("GDNF"), growth hormone, heparin-binding EGF-like growth factor ("HB-EGF"), hepatocyte growth factor ("HGF"), insulin-like growth factor binding protein 1 ("IGFBP-1"), insulin-like growth factor binding protein 2 ("IGFBP-2"), insulin-like Growth factor binding protein 3 ("IGFBP-3"), insulin-like growth factor binding protein 4 ("IGFBP-4"), insulin-like growth factor binding protein 6 ("IGFBP-6"), insulin-like growth factor 1 (" IGF-1"), insulin, macrophage community stimulating factor ("M-CSF R"), nerve growth factor receptor ("NGF R"), neurotrophic factor-3 ("NT-3"), neurotrophic Factor-4 ("NT-4"), osteoclastogenesis inhibitor ("osteoprotegerin"), platelet-derived growth factor receptor ("PDGF-AA"), phosphoinositide-glycan biosynthesis ( "PIGF"), Skp, Cullin, F-box containing complex ("SCF"), stem cell interleukin receptor ("SCF R"), transforming growth factor alpha ("TGFα"), transforming growth factor beta-1 ("TGFβ1"), transforming growth factor β-3 ("TGFβ3"), vascular endothelial growth factor ("VEGF"), vascular endothelial growth factor receptor 2 ("VEGFR2"), vascular endothelial growth factor receptor 3 (" VEGFR3"), VEGF-D 6Cine, tyrosine protein kinase receptor UFO ("Axl"), betacellin ("BTC"), mucosal-associated epithelial chemokine ("CCL28"), chemokine (CC Motif) ligand 27 ("CTACK"), chemokine (CXC motif) ligand 16 ("CXCL16"), CXC motif chemokine 5 ("ENA-78"), chemokine ( CC motif) ligand 26 ("Eotaxin-3"), granulocyte chemoattractant protein 2 ("GCP-2"), GRO, chemokine (CC motif) ligand 14 ("HCC-l" ), chemokine (CC motif) ligand 16 ("HCC-4"), interleukin-9 ("IL-9"), interleukin-17 F ("IL-17F"), interleukin Interleukin-18 binding protein ("IL-18 BPa"), interleukin-28A ("IL-28A"), interleukin 29 ("IL-29"), interleukin 31 ("IL-31" ), CXC motif chemokine 10 ("IP-10 "), chemokine receptor CXCR3 ("I-TAC"), leukemia inhibitory factor ("LIF"), light protein (Light), chemokine (C motif) ligand ("lymphocyte chemokine "), monocyte chemotactic protein 2 ("MCP-2"), monocyte chemotactic protein 3 ("MCP-3"), monocyte chemotactic protein 4 ("MCP-4"), macrophage Cell-derived chemokine ("MDC"), macrophage migration inhibitory factor ("MIF"), chemokine (CC motif) ligand 20 ("MIP-3α"), CC motif chemokine 19 ("MIP-3β"), chemokine (CC motif) ligand 23 ("MPIF-1"), macrophage stimulating protein alpha chain ("MSPα"), nucleosome assembly protein 1-like 4 ("NAP-2"), secreted phosphoprotein 1 ("osteopontin"), lung and activation-regulated cytokines ("PARC"), platelet factor 4 ("PF4"), stromal cell-derived factor -1α ("SDF-1α"), chemokine (CC motif) ligand 17 ("TARC"), chemokine expressed in the thymus ("TECK"), thymic stromal lymphopoietin ("TSLP 4 -IBB”), CD 166 antigen (“ALCAM”), cluster of differentiation 80 (“B7-1”), tumor necrosis factor receptor superfamily member 17 (“BCMA”), cluster of differentiation 14 (“CD14”), differentiation Cluster 30 ("CD30"), cluster of differentiation 40 ("CD40 ligand"), carcinoembryonic antigen-related cell adhesion molecule 1 (bile glycoprotein) ("CEACAM-1"), death receptor 6 ("DR6") , Deoxythymidine kinase ("Dtk"), membrane glycoprotein type 1 ("endoglin"), receptor tyrosine protein kinase erbB-3 ("ErbB3"), endothelial cell-leukocyte adhesion molecule 1 (" E-selectin"), apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), tumor necrosis factor receptor superfamily member 1 ("GITR"), tumor necrosis factor Receptor superfamily member 14 ("HVEM"), intercellular adhesion molecule 3 ("ICAM-3"), IL-1 R4, IL-1 RI, IL-10 Rβ, IL-17R, IL-2Rγ, IL- 21R, Lysosomal membrane protein 2 ("LIMPII"), neutrophil gelatinase-associated lipoprotein ("Lipocalin-2"), CD62L ("L-selectin"), lymphatic endothelial cells ("LYVE -1"), MHC class I polypeptide related sequence A ("MICA"), MHC class I polypeptide related sequence B ("MICB"), NRG1-βl, β-type platelet-derived growth factor receptor ("PDGF Rβ") , Platelet Endothelial Cell Adhesion Molecule ("PECAM-1"), RAGE, Hepatitis A Virus Cell Receptor 1 ("TIM-1"), Tumor necrosis factor receptor superfamily member IOC ("TRAIL R3"), Traappin protein transglutaminase binding domain ("Trappin-2"), urokinase receptor ("uPAR"), vascular cell adhesion protein 1 ("VCAM-1"), XEDAR Activin A, Murine Gray Gene (Agouti) Related Protein ("AgRP"), Ribonuclease 5 ("Angiopoietin"), Angiopoietin 1, Angiostatin, Catheprin S , CD40, cryptic family protein IB ("Cripto-1"), DAN, Dickkopf-related protein 1 ("DKK-1"), E-cadherin, epithelial cell adhesion molecule ("EpCAM"), Fas ligand ( FasL or CD95L), Fcg RIIB/C, FoUistatin, Galectin-7, Intercellular Adhesion Molecule 2 ("ICAM-2"), IL-13 Rl, IL-13R2, IL-17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, nerve cell adhesion molecule ("NrCAM"), plasminogen activator inhibitor-1 ("PAI-1"), platelet-derived growth factor receptor ("PDGF- AB"), resistin, stromal cell-derived factor 1 ("SDF-1β"), sgpl30, secreted frizzled-related protein 2 ("ShhN"), sialic acid-binding immunoglobulin-type lectin ("Siglec-5 "), ST2, transforming growth factor-β2 ("TGFβ2"), Tie-2, thrombopoietin ("TPO"), tumor necrosis factor receptor superfamily member 10D ("TRAIL R4"), in myeloid cell 1 Trigger receptor ("TREM-1"), vascular endothelial growth factor C ("VEGF-C"), VEGFR1 adiponectin, lipid-lowering protein ("AND"), alpha-fetoprotein ("AFP") , Angiopoietin-like 4 ("ANGPTL4"), β-2-microglobulin ("B2M"), basal cell adhesion molecule ("BCAM"), carbohydrate antigen 125 ("CA125"), cancer antigen 15-3 ("CA15-3"), carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), human epidermal growth factor receptor 2 ("ErbB2"), follostatin, follicle stimulating hormone ("FSH "), chemokine (CXC motif) ligand 1 ("GROα"), human chorionic gonadotropin ("βHCG"), insulin-like growth factor 1 receptor ("IGF-1 sR"), IL -1 sRII, IL-3, IL-18 Rb, IL-21, leptin, matrix metalloproteinase-1 ("MMP-1"), matrix metalloproteinase-2 ("MMP-2"), matrix metalloproteinase- 3 ("MMP-3"), matrix metalloproteinase-8 ("MMP-8"), matrix metalloproteinase Enzyme-9 ("MMP-9"), Matrix Metalloproteinase-10 ("MMP-10"), Matrix Metalloproteinase-13 ("MMP-13"), Neural Cell Adhesion Molecule ("NCAM-1"), Nest Protein ("Nestin-1"), Neuron Specific Enolase ("NSE"), Oncostatin M ("OSM"), Procalcitonin, Prolactin, Prostate Specific Antigen ("PSA") , Sialic acid-binding Ig-like lectin 9 ("Siglec-9"), ADAM 17 endopeptidase ("TACE"), thyroglobulin, metalloproteinase inhibitor 4 ("TIMP-4"), TSH2B4, with integrated Protein and metalloproteinase domain protein 9 ("ADAM-9"), angiopoietin 2, tumor necrosis factor ligand superfamily member 13/acid leucine-rich nucleophosphoprotein 32 family member B ("APRIL "), Bone Morphogenetic Protein 2 ("BMP-2"), Bone Morphogenetic Protein 9 ("BMP-9"), Complement Component 5a ("C5a"), Cathepsin L, CD200, CD97, Chemoattractants , Tumor Necrosis Factor Receptor Superfamily Member 6B ("DcR3"), Fatty Acid Binding Protein 2 ("FABP2"), Fibroblast Activation Protein, α ("FAP"), Fibroblast Growth Factor 19 ("FGF-19 "), Galectin-3, Hepatocyte Growth Factor Receptor ("HGF R"), IFN-γ/βR2, Insulin-like Growth Factor 2 ("IGF-2"), Insulin-like Growth Factor 2 Receptor ( "IGF-2 R"), interleukin-1 receptor 6 ("IL-1R6"), interleukin 24 ("IL-24"), interleukin 33 ("IL-33", kallikrein Enzyme 14, aspartame-based endopeptidase ("pod protein"), oxidized low-density lipoprotein receptor 1 ("LOX-1"), mannose-binding lectin ("MBL"), enkephalinase ("NEP"), Notch homologue 1, translocation related (Drosophila) ("Notch-1"), Wilms tumor overexpression ("NOV"), Osteoactivin, planned cell death protein 1 ("PD-1"), N-Acetyl muralyl-L-alanine glycidase ("PGRP-5"), serine protease inhibitor A4, secreted frizzled-related protein 3 (" sFRP-3"), thrombomodulin, Toll-like receptor 2 ("TLR2"), tumor necrosis factor receptor superfamily member 10A ("TRAIL R1"), transferrin ("TRF"), WIF-LACE- 2. Albumin, AMICA, angiopoietin 4, B cell activating factor ("BAFF"), carbohydrate antigen 19-9 ("CA19-9"), CD 163, clusterin, CRT AM, chemokine ( CXC motif) Ligand 14 ("CXCL14"), Cystatin C, Decorin ("DCN" ), Dickkopf-related protein 3 ("Dkk-3"), delta-like protein 1 ("DLL1"), fetuin A, heparin-binding growth factor 1 ("aFGF"), folate receptor alpha ("FOLR1"), Furin, GPCR-related sorting protein 1 ("GASP-1"), GPCR-related sorting protein 2 ("GASP-2"), granular leukocyte community stimulating factor receptor ("GCSF R"), silk The amino acid protease hepsin ("HAI-2"), interleukin-17B receptor ("IL-17B R"), interleukin 27 ("IL-27"), lymphocyte priming gene 3 ("LAG-3 "), Apolipoprotein AV ("LDL R"), Pepsinogen I, Retinol Binding Protein 4 ("RBP4"), SOST, Acethaparin Sulfate Proteoglycan ("Multi-ligand Proteoglycan- 1"), tumor necrosis factor receptor superfamily member 13B ("TACI"), tissue factor pathway inhibitor ("TFPI"), TSP-1, tumor necrosis factor receptor superfamily member 10b ("TRAIL R2"), TRANCE, troponin I, urokinase plasminogen activator ("uPA"), cadherin type 5, 2 or VE-cadherin (vascular endothelial cells) (also known as CD144 ("VE-cadherin)) "Su")), WNT1 induced signaling pathway protein 1 ("WISP-1"), and nuclear factor kappa B receptor promoter ("RANK").

在一些實施方式中，癌症治療劑係抗癌症化合物。示例性抗癌症化合物包括但不限於阿侖單抗（Campath®）、阿利維A酸（Panretin®）、阿那曲唑（Arimidex®）、貝伐單抗（Avastin®）、貝沙羅汀（Targretin®）、硼替佐米（Velcade®）、博舒替尼（Bosulif®）、本妥昔單抗（Adcetris®）、卡巴坦尼（Cometriq™）、卡菲佐米（Kyprolis™）、西妥昔單抗（Erbitux®）、克裡唑蒂尼（Xalkori®）、達沙替尼（Sprycel®）、地尼介白素（Ontak®）、鹽酸埃羅替尼（Tarceva®）、依維莫司（Afinitor®）、依西美坦（Aromasin®）、氟維司群（Faslodex®）、吉非替尼（Iressa®）、替坦異貝莫單抗（Zevalin®）、甲磺酸伊馬替尼（Gleevec®）、伊匹單抗（Yervoy™）、二對甲苯磺酸拉帕替尼（Tykerb®）、來曲唑（Femara®）、尼洛替尼（Tasigna®）、奧法木單抗（Arzerra®）、帕尼單抗（Vectibix®）、鹽酸帕唑帕尼（Votrient®）、帕妥珠單抗（Perjeta™）、普拉曲沙（Folotyn®）、瑞戈非尼（Stivarga®）、利妥昔單抗（Rituxan®）、羅米地辛（Istodax®）、甲苯磺酸索拉非尼（Nexavar®）、蘋果酸舒尼替尼（Sutent®）、他莫昔芬、西羅莫司（Torisel®）、托瑞米芬（Fareston®）、托西莫單抗及131I-托西莫單抗（Bexxar®）、曲妥珠單抗（Herceptin®）、維甲酸（Vesanoid®）、凡德他尼（Caprelsa®）、威羅菲尼（Zelboraf®）、伏立諾他（Zolinza®）及阿柏西普（Zaltrap®）。In some embodiments, the cancer therapeutic agent is an anti-cancer compound. Exemplary anti-cancer compounds include, but are not limited to, alemtuzumab (Campath®), aliretin (Panretin®), anastrozole (Arimidex®), bevacizumab (Avastin®), bexarotene (Targretin®) ), Bortezomib (Velcade®), Bosutinib (Bosulif®), Bentuximab (Adcetris®), Carbatanyl (Cometriq™), Kafizomib (Kyprolis™), Cetuximab Anti-(Erbitux®), Crizotinib (Xalkori®), Dasatinib (Sprycel®), Dinileukin (Ontak®), Erlotinib Hydrochloride (Tarceva®), Everolimus ( Afinitor®), exemestane (Aromasin®), fulvestrant (Faslodex®), gefitinib (Iressa®), titan isibemozumab (Zevalin®), imatinib mesylate ( Gleevec®), Ipilimumab (Yervoy™), Lapatinib Dip-toluenesulfonate (Tykerb®), Letrozole (Femara®), Nilotinib (Tasigna®), Ofatumumab ( Arzerra®), Panitumumab (Vectibix®), Pazopanib Hydrochloride (Votrient®), Pertuzumab (Perjeta™), Pratroxa (Folotyn®), Regorafenib (Stivarga®) , Rituximab (Rituxan®), romidepsin (Istodax®), sorafenib tosylate (Nexavar®), sunitinib malate (Sutent®), tamoxifen, siroline Moss (Torisel®), toremifene (Fareston®), tositumomab and 131I-tositumomab (Bexxar®), trastuzumab (Herceptin®), retinoic acid (Vesanoid®) , Vandetanib (Caprelsa®), Verofinil (Zelboraf®), Vorinostat (Zolinza®) and Aflibercept (Zaltrap®).

修飾調節基因表現及其他細胞功能的蛋白質的功能的示例性抗癌症化合物（例如，HDAC抑制劑，類視黃醇受體配位基）係伏立諾他（Zolinza®）、貝沙羅汀（Targretin®）及羅米地辛（Istodax®）、阿利維A酸（Panretin®）及維甲酸（Vesanoid®）。Exemplary anti-cancer compounds (eg, HDAC inhibitors, retinoid receptor ligands) that modify the functions of proteins that regulate gene expression and other cellular functions are vorinostat (Zolinza®), bexarotene (Targretin) ®) and romidepsin (Istodax®), alitretinoin (Panretin®) and retinoic acid (Vesanoid®).

誘導細胞凋亡的示例性抗癌症化合物（例如，蛋白酶體抑制劑，葉酸拮抗劑）係硼替佐米（Velcade®）、卡菲佐米（Kyprolis™）及普拉曲沙（Folotyn®）。Exemplary anti-cancer compounds (eg, proteasome inhibitors, folic acid antagonists) that induce apoptosis are bortezomib (Velcade®), kafizomib (Kyprolis™), and pratroxa (Folotyn®).

增加抗腫瘤免疫應答的示例性抗癌化合物（例如抗CD20、抗CD52；抗細胞毒性T淋巴細胞相關抗原-4）為利妥昔單抗（Rituxan®）、阿侖單抗（Campath®）、奧法木單抗（Arzerra®）及伊匹單抗（Yervoy™）。Exemplary anti-cancer compounds that increase the anti-tumor immune response (for example, anti-CD20, anti-CD52; anti-cytotoxic T lymphocyte-associated antigen-4) are rituximab (Rituxan®), alemtuzumab (Campath®), Ofatumumab (Arzerra®) and Ipilimumab (Yervoy™).

將毒劑遞送至癌細胞的示例性抗癌症化合物（例如，抗CD20-放射性核素融合物；IL-2-白喉毒素融合物；抗CD30-單甲基澳瑞他汀E（MMAE）-融合物）係托西莫單抗及131I-托西莫單抗（Bexxar®）及替坦異貝莫單抗（Zevalin®）、地尼介白素（Ontak®）及本妥昔單抗（Adcetris®）。Exemplary anti-cancer compounds that deliver toxins to cancer cells (eg, anti-CD20-radionuclide fusion; IL-2-diphtheria toxin fusion; anti-CD30-monomethylaustatin E (MMAE)-fusion) It is tositumomab and 131I-tositumomab (Bexxar®) and titan and isibemozumab (Zevalin®), denisikin (Ontak®) and Bentuximab (Adcetris®) .

其他示例性抗癌症化合物係小分子抑制劑及其結合物，例如，Janus激酶、ALK、Bcl-2、PARP、PI3K、VEGF受體、Braf、MEK、CDK及HSP90。Other exemplary anti-cancer compounds are small molecule inhibitors and their conjugates, for example, Janus kinase, ALK, Bcl-2, PARP, PI3K, VEGF receptor, Braf, MEK, CDK, and HSP90.

示例性基於鉑的抗癌症化合物包括（例如）順鉑、卡鉑、奧沙利鉑、賽特鉑、吡鉑、奈達鉑、三鉑（Triplatin）及脂鉑（Lipoplatin）。適用於治療的其他基於金屬的藥物包括但不限於基於釕的化合物、二茂鐵衍生物、基於鈦的化合物及基於鎵的化合物。Exemplary platinum-based anti-cancer compounds include, for example, cisplatin, carboplatin, oxaliplatin, sattraplatin, picoplatin, nedaplatin, triplatin, and lipoplatin. Other metal-based drugs suitable for treatment include, but are not limited to, ruthenium-based compounds, ferrocene derivatives, titanium-based compounds, and gallium-based compounds.

在一些實施方式中，癌症治療劑係包括放射性核素的放射性部分。示例性放射性核素包括但不限於Cr-51、Cs-131、Ce-134、Se-75、Ru-97、I-125、Eu-149、Os-189m、Sb-119、I-123、Ho-161、Sb-117、Ce-139、In-111、Rh-103m、Ga-67、Tl-201、Pd-103、Au-195、Hg-197、Sr-87m、Pt-191、P-33、Er-169、Ru-103、Yb-169、Au-199、Sn-121、Tm-167、Yb-175、In-113m、Sn-113、Lu-177、Rh-105、Sn-117m、Cu-67、Sc-47、Pt-195m、Ce-141、I-131、Tb-161、As-77、Pt-197、Sm-153、Gd-159、Tm-173、Pr-143、Au-198、Tm-170、Re-186、Ag-111、Pd-109、Ga-73、Dy-165、Pm-149、Sn-123、Sr-89、Ho-166、P-32、Re-188、Pr-142、Ir-194、In-114m/In-114及Y-90。In some embodiments, the cancer therapeutic agent system includes a radioactive portion of a radionuclide. Exemplary radionuclides include but are not limited to Cr-51, Cs-131, Ce-134, Se-75, Ru-97, I-125, Eu-149, Os-189m, Sb-119, I-123, Ho -161, Sb-117, Ce-139, In-111, Rh-103m, Ga-67, Tl-201, Pd-103, Au-195, Hg-197, Sr-87m, Pt-191, P-33 , Er-169, Ru-103, Yb-169, Au-199, Sn-121, Tm-167, Yb-175, In-113m, Sn-113, Lu-177, Rh-105, Sn-117m, Cu -67, Sc-47, Pt-195m, Ce-141, I-131, Tb-161, As-77, Pt-197, Sm-153, Gd-159, Tm-173, Pr-143, Au-198 , Tm-170, Re-186, Ag-111, Pd-109, Ga-73, Dy-165, Pm-149, Sn-123, Sr-89, Ho-166, P-32, Re-188, Pr -142, Ir-194, In-114m/In-114 and Y-90.

在一些實施方式中，額外治療劑係抗生素。例如，如果檢測疾病相關細菌和/或疾病相關微生物組特徵存在，則可投與抗生素例如以從受試者消除疾病相關細菌。在一些實施方式中，癌症治療劑係抗生素。例如，如果根據本文提供之方法來檢測癌症相關細菌和/或癌症相關微生物組特徵的存在，則可投與抗生素以從受試者消除癌症相關細菌。「抗生素」在廣義上係指能夠抑制或預防細菌感染的化合物。抗生素可以諸多方式（包含根據其用於特定感染的用途、其作用機制、其生物可用性或其靶微生物範圍（例如革蘭氏陰性細菌對革蘭氏陽性細菌、需氧細菌對厭氧細菌等））進行分類且可使用該等方式來殺死宿主的特定區域（「生態位」）中的特定細菌（Leekha等人, 2011. General Principles of Antimicrobial Therapy [抗微生物療法的一般原則]. Mayo Clin Proc. [梅歐醫院院刊] 86 (2): 156-167）。在某些實施方式中，可使用抗生素來選擇性靶向特定生態位的細菌。在一些實施方式中，可使用已知治療包括疾病（例如癌症）生態位的特定感染的抗生素來靶向疾病相關微生物（包括該生態位中的疾病相關細菌）。在其他實施方式中，在固體劑型之後投與抗生素。在一些實施方式中，在固體劑型之前投與抗生素。In some embodiments, the additional therapeutic agent is an antibiotic. For example, if disease-related bacteria and/or disease-related microbiome characteristics are detected, antibiotics can be administered, for example, to eliminate disease-related bacteria from the subject. In some embodiments, the cancer therapeutic agent is an antibiotic. For example, if the presence of cancer-related bacteria and/or cancer-related microbiome characteristics is detected according to the methods provided herein, antibiotics can be administered to eliminate cancer-related bacteria from the subject. "Antibiotics" in a broad sense refer to compounds that can inhibit or prevent bacterial infections. Antibiotics can be used in many ways (including according to their use for a specific infection, their mechanism of action, their bioavailability or their target microbial range (for example, Gram-negative bacteria vs. Gram-positive bacteria, aerobic bacteria vs. anaerobic bacteria, etc.) ) To classify and use these methods to kill specific bacteria in a specific area ("niche") of the host (Leekha et al., 2011. General Principles of Antimicrobial Therapy [General Principles of Antimicrobial Therapy]. Mayo Clin Proc . [Journal of Mayo Clinic] 86 (2): 156-167). In certain embodiments, antibiotics can be used to selectively target bacteria in a specific niche. In some embodiments, antibiotics known to treat specific infections including disease (eg, cancer) niches can be used to target disease-related microorganisms (including disease-related bacteria in that niche). In other embodiments, the antibiotic is administered after the solid dosage form. In some embodiments, the antibiotic is administered before the solid dosage form.

在一些方面，可基於殺細菌或細菌抑制性質來選擇抗生素。殺細菌抗生素包含破壞細胞壁（例如β-內醯胺）、細胞膜（例如達托黴素（daptomycin））或細菌DNA（例如氟喹啉酮（fluoroquinolone））的作用機制。細菌抑制劑抑制細菌複製且包含磺醯胺、四環素（tetracycline）及巨環內酯並藉由抑制蛋白質合成來發揮作用。另外，儘管一些藥物可在某些生物體中具有殺細菌性且在其他生物體中具有細菌抑制性，但知曉靶生物體使得熟悉該項技術者可選擇具有適當性質的抗生素。在某些治療條件中，細菌抑制抗生素抑制殺細菌抗生素的活性。因此，在某些實施方式中，並不組合殺細菌抗生素及細菌抑制抗生素。In some aspects, antibiotics can be selected based on bactericidal or bacteriostatic properties. Bactericidal antibiotics include mechanisms of action that destroy cell walls (such as β-lactam), cell membranes (such as daptomycin), or bacterial DNA (such as fluoroquinolone). Bacterial inhibitors inhibit bacterial replication and contain sulfonamides, tetracyclines and macrolides and act by inhibiting protein synthesis. In addition, although some drugs may have bactericidal properties in certain organisms and bacterial inhibitory properties in other organisms, knowing the target organism allows those skilled in the art to choose antibiotics with appropriate properties. In certain treatment conditions, bacterial inhibitory antibiotics inhibit the activity of bactericidal antibiotics. Therefore, in some embodiments, bactericidal antibiotics and bacteriostatic antibiotics are not combined.

抗生素包括但不限於胺基糖苷、安莎黴素（ansamycin）、碳頭孢烯（carbacephem）、碳青黴烯（carbapenem）、頭孢菌素（cephalosporin）、糖肽、林可醯胺（lincosamide）、脂肽、巨環內酯、單醯胺菌素（monobactam）、硝基呋喃、㗁唑啶酮、青黴素（penicillin）、多肽抗生素、喹啉酮（quinolone）、氟喹啉酮、磺醯胺、四環素及抗分枝桿菌化合物及其組合。Antibiotics include, but are not limited to, aminoglycosides, ansamycin, carbacephem, carbapenem, cephalosporin, glycopeptides, lincosamide, lipids Peptides, macrolides, monobactam, nitrofurans, azolidinone, penicillin, peptide antibiotics, quinolone, fluoroquinolone, sulfonamide, tetracycline And anti-mycobacterial compounds and combinations thereof.

胺基糖苷包括但不限於阿米卡星（Amikacin）、建它黴素（Gentamicin）、康黴素（Kanamycin）、新黴素（Neomycin）、奈替米星（Netilmicin）、妥布黴素（Tobramycin）、巴龍黴素（Paromomycin）及大觀黴素（Spectinomycin）。胺基糖苷可有效抵抗例如革蘭氏陰性細菌（例如大腸桿菌、克雷伯氏菌屬、銅綠假單胞菌（Pseudomonas aeruginosa）及土倫病法蘭西斯氏菌（Francisella tularensis））且抵抗某些需氧細菌，但對於專性/兼性厭氧菌具有較小有效性。據信，胺基糖苷結合至細菌30S或50S核糖體亞基，由此抑制細菌蛋白合成。Amino glycosides include but are not limited to Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin ( Tobramycin), Paromomycin (Paromomycin) and Spectinomycin (Spectinomycin). Aminoglycosides can effectively resist, for example, Gram-negative bacteria (such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa and Francisella tularensis) and some Aerobic bacteria, but less effective against obligate/facultative anaerobes. It is believed that aminoglycosides bind to bacterial 30S or 50S ribosomal subunits, thereby inhibiting bacterial protein synthesis.

安莎黴素包括但不限於格爾德黴素（Geldanamycin）、除莠黴素（Herbimycin）、利福黴素（Rifamycin）及曲張鏈菌素（Streptovaricin）。據信，格爾德黴素及除莠黴素抑制或改變熱休克蛋白90的功能。Ansamycin includes but is not limited to Geldanamycin, Herbimycin, Rifamycin, and Streptovaricin. It is believed that geldanamycin and herbimycin inhibit or alter the function of heat shock protein 90.

碳頭孢烯包括但不限於氯碳頭孢（Loracarbef）。據信，碳頭孢烯抑制細菌細胞壁合成。Carbocephem includes, but is not limited to, Loracarbef (Loracarbef). It is believed that carbocephem inhibits bacterial cell wall synthesis.

碳青黴烯包括但不限於厄他培南（Ertapenem）、多尼培南（Doripenem）、亞胺培南（Imipenem）/西司他丁（Cilastatin）及美羅培南（Meropenem）。碳青黴烯作為寬譜抗生素對革蘭氏陽性細菌及革蘭氏陰性細菌均具有殺細菌性。據信，碳青黴烯抑制細菌細胞壁合成。Carbapenems include, but are not limited to, Ertapenem, Doripenem, Imipenem/Cilastatin, and Meropenem. As a broad-spectrum antibiotic, carbapenem has bactericidal properties against both gram-positive bacteria and gram-negative bacteria. It is believed that carbapenem inhibits bacterial cell wall synthesis.

頭孢菌素包括但不限於頭孢羥胺苄（Cefadroxil）、頭孢唑啉（Cefazolin）、頭孢噻吩（Cefalotin）、頭孢金素（Cefalothin）、頭孢胺苄（Cefalexin）、頭孢克洛（Cefaclor）、頭孢孟多（Cefamandole）、頭孢西丁（Cefoxitin）、頭孢丙烯（Cefprozil）、頭孢呋辛（Cefuroxime）、頭孢克肟（Cefixime）、頭孢地尼（Cefdinir）、頭孢托侖（Cefditoren）、頭孢哌酮（Cefoperazone）、頭孢噻肟（Cefotaxime）、頭孢泊肟（Cefpodoxime）、頭孢他啶（Ceftazidime）、頭孢布烯（Ceftibuten）、頭孢唑肟（Ceftizoxime）、頭孢曲松（Ceftriaxone）、頭孢吡肟（Cefepime）、頭孢他洛林酯（Ceftaroline fosamil）及頭孢比普（Ceftobiprole）。所選頭孢菌素可效抵抗（例如）革蘭氏陰性細菌及革蘭氏陽性細菌（包含假單胞菌（Pseudomonas）），某些頭孢菌素可有效抵抗甲氧西林（methicillin）抗性金黃色葡萄球菌（Staphylococcus aureus）（MRSA）。據信，頭孢菌素藉由破壞細菌細胞壁的肽聚糖層的合成來抑制細菌細胞壁合成。Cephalosporins include but are not limited to Cefadroxil (Cefadroxil), Cefazolin (Cefazolin), Cefalotin (Cefalotin), Cefalotin (Cefalothin), Cefalexin, Cefaclor (Cefaclor), Cefazolin Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil and Ceftobiprole. The selected cephalosporins are effective against (for example) Gram-negative bacteria and Gram-positive bacteria (including Pseudomonas), and certain cephalosporins can effectively resist methicillin resistance gold Staphylococcus aureus (MRSA). It is believed that cephalosporins inhibit bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

糖肽包括但不限於替考拉寧（Teicoplanin）、萬古黴素（Vancomycin）及特拉萬星（Telavancin）。糖肽可有效抵抗（例如）好氧及厭氧革蘭氏陽性細菌（包含MRSA及艱難梭菌）。據信，糖肽藉由破壞細菌細胞壁的肽聚糖層的合成來抑制細菌細胞壁合成。Glycopeptides include but are not limited to Teicoplanin, Vancomycin, and Telavancin. Glycopeptides can effectively resist (for example) aerobic and anaerobic Gram-positive bacteria (including MRSA and Clostridium difficile). It is believed that glycopeptides inhibit bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

林可醯胺包括但不限於克林達黴素（Clindamycin）及林可黴素（Lincomycin）。林可醯胺可有效抵抗（例如）厭氧細菌以及葡萄球菌（Staphylococcus）及鏈球菌（Streptococcus）。據信，林可醯胺結合至細菌50S核糖體亞基，由此抑制細菌蛋白合成。Lincomycin includes but is not limited to Clindamycin and Lincomycin. Lincoramide is effective against (for example) anaerobic bacteria, Staphylococcus and Streptococcus. It is believed that Lincoramide binds to the bacterial 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

脂肽包括但不限於達托黴素。脂肽可有效抵抗例如革蘭氏陽性細菌。據信，脂肽結合至細菌膜並引起快速去極化。Lipopeptides include but are not limited to daptomycin. Lipopeptides are effective against, for example, Gram-positive bacteria. It is believed that lipopeptides bind to bacterial membranes and cause rapid depolarization.

巨環內酯包括但不限於阿奇黴素（Azithromycin）、克拉黴素（Clarithromycin）、地紅黴素（Dirithromycin）、紅黴素（Erythromycin）、羅紅黴素（Roxithromycin）、醋竹桃黴素（Troleandomycin）、泰利黴素（Telithromycin）及螺旋黴素（Spiramycin）。巨環內酯可有效抵抗例如鏈球菌屬及支原體屬（Mycoplasma）。據信，巨環內酯結合至細菌或50S核糖體亞基，由此抑制細菌蛋白合成。Macrolides include but are not limited to Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin ), Telithromycin and Spiramycin. Macrolides are effective against, for example, Streptococcus and Mycoplasma. It is believed that macrolide binds to bacteria or 50S ribosomal subunits, thereby inhibiting bacterial protein synthesis.

單醯胺菌素包括但不限於胺曲南（Aztreonam）。單醯胺菌素可有效抵抗例如革蘭氏陰性細菌。據信，單醯胺菌素藉由破壞細菌細胞壁的肽聚糖層的合成來抑制細菌細胞壁合成。Monoamides include but are not limited to Aztreonam (Aztreonam). Monoamides are effective against, for example, Gram-negative bacteria. It is believed that monoamidoxin inhibits bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

硝基呋喃包括但不限於呋喃唑酮（Furazolidone）及呋喃妥因（Nitrofurantoin）。Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.

㗁唑啶酮包括但不限於利奈唑胺（Linezolid）、潑斯唑來（Posizolid）、雷得唑來（Radezolid）及特地唑胺（Torezolid）。據信，㗁唑啶酮係蛋白質合成抑制劑。Zazolidone includes but is not limited to Linezolid, Posizolid, Radezolid and Torezolid. It is believed that azolidinone is a protein synthesis inhibitor.

青黴素包括但不限於阿莫西林（Amoxicillin）、安比西林（Ampicillin）、阿洛西林（Azlocillin）、羧苄青黴素（Carbenicillin）、氯噻青黴素（Cloxacillin）、二氯噻青黴素（Dicloxacillin）、氟氯西林（Flucloxacillin）、美洛西林（Mezlocillin）、甲氧西林、萘夫西林（Nafcillin）、苯唑西林（Oxacillin）、青黴素G、青黴素V、哌拉西林（Piperacillin）、替莫西林（Temocillin）及替凱西林（Ticarcillin）。青黴素可有效抵抗例如革蘭氏陽性細菌、兼性厭氧菌（例如鏈球菌屬、包柔氏螺旋體屬（Borrelia）及密螺旋體屬（Treponema））。據信，青黴素藉由破壞細菌細胞壁的肽聚糖層的合成來抑制細菌細胞壁合成。Penicillins include but are not limited to Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin (Flucloxacillin), Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin and Temocillin Ticarcillin. Penicillin is effective against, for example, Gram-positive bacteria and facultative anaerobes (such as Streptococcus, Borrelia and Treponema). It is believed that penicillin inhibits bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

青黴素組合包括但不限於阿莫西林/克拉維酸鹽（clavulanate）、安比西林/舒巴坦（sulbactam）、哌拉西林/三唑巴坦（tazobactam）及替凱西林/克拉維酸鹽。Penicillin combinations include, but are not limited to, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and ticexillin/clavulanate.

多肽抗生素包括但不限於桿菌肽（Bacitracin）、黏菌素（Colistin）及多黏菌素（Polymyxin）B及E。多肽抗生素可有效抵抗（例如）革蘭氏陰性細菌。據信，某些多肽抗生素抑制涉及細菌細胞壁的肽聚糖層的合成的焦磷酸異戊二烯基酯，而其他多肽抗生素藉由置換細菌相對離子來去穩定細菌外膜。Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and Polymyxin B and E. Polypeptide antibiotics are effective against (for example) Gram-negative bacteria. It is believed that certain polypeptide antibiotics inhibit the synthesis of isoprenyl pyrophosphate involved in the peptidoglycan layer of the bacterial cell wall, while other polypeptide antibiotics destabilize the bacterial outer membrane by displacing the relative ions of the bacteria.

喹啉酮及氟喹啉酮包括但不限於環丙沙星（Ciprofloxacin）、依諾沙星（Enoxacin）、加替沙星（Gatifloxacin）、吉米沙星（Gemifloxacin）、左氧氟沙星（Levofloxacin）、洛美沙星（Lomefloxacin）、莫西沙星（Moxifloxacin）、萘啶酮酸（Nalidixic acid）、諾氟沙星（Norfloxacin）、氧氟沙星（Ofloxacin）、曲伐沙星（Trovafloxacin）、格帕沙星（Grepafloxacin）、司帕沙星（Sparfloxacin）及替馬沙星（Temafloxacin）。喹啉酮/氟喹啉酮可有效抵抗（例如）鏈球菌屬及奈瑟菌屬（Neisseria ）。據信，喹啉酮/氟喹啉酮抑制細菌DNA旋轉酶或拓撲異構酶IV，由此抑制DNA複製及轉錄。Quinolinones and fluoroquinolinones include but are not limited to Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin Star (Lomefloxacin), Moxifloxacin (Moxifloxacin), Nalidixic acid (Nalidixic acid), Norfloxacin, Ofloxacin (Ofloxacin), Travafloxacin (Trovafloxacin), Gapafloxacin ( Grepafloxacin), Sparfloxacin (Sparfloxacin) and Temafloxacin (Temafloxacin). Quinolinone / fluoro effective against quinolone (e.g.) of Neisseria and Streptococcus (Neisseria). It is believed that quinolinone/fluoroquinolinone inhibits bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.

磺醯胺包括但不限於磺胺米隆（Mafenide）、磺胺醋醯（Sulfacetamide）、磺胺嘧啶（Sulfadiazine）、磺胺嘧啶銀、磺胺地索辛（Sulfadimethoxine）、磺胺甲噻二唑（Sulfamethizole）、磺胺甲㗁唑（Sulfamethoxazole）、磺胺亞胺基（Sulfanilimide）、柳氮磺胺吡啶（Sulfasalazine）、磺胺異㗁唑（Sulfisoxazole）、甲氧苄啶-磺胺甲㗁唑（Trimethoprim-Sulfamethoxazole）（複方磺胺甲㗁唑（Co-trimoxazole））及磺醯胺基柯衣汀（Sulfonamidochrysoidine）。據信，磺醯胺藉由競爭性抑制二氫蝶酸合成酶來抑制葉酸合成，由此抑制核酸合成。Sulfadiazines include but are not limited to Mafenide, Sulfacetamide, Sulfadiazine, Silver Sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethizole Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (compound sulfamethoxazole) (Co-trimoxazole)) and Sulfonamidochrysoidine (Sulfonamidochrysoidine). It is believed that sulfonamides inhibit folic acid synthesis by competitively inhibiting dihydropteroate synthase, thereby inhibiting nucleic acid synthesis.

四環素類包括但不限於地美環素（Demeclocycline）、強力黴素（Doxycycline）、米諾環素（Minocycline）、土黴素（Oxytetracycline）及四環素。四環素類可有效抵抗例如革蘭氏陰性細菌。據信，四環素結合至細菌30S核糖體亞基，由此抑制細菌蛋白合成。Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, and tetracycline. Tetracyclines are effective against, for example, Gram-negative bacteria. It is believed that tetracycline binds to the bacterial 30S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

抗分枝桿菌化合物包括但不限於氯法齊明（Clofazimine）、胺苯碸（Dapsone）、卷麯黴素（Capreomycin）、環絲胺酸（Cycloserine）、乙胺丁醇（Ethambutol）、乙硫異菸醯胺（Ethionamide）、異菸酸肼（Isoniazid）、吡𠯤醯胺（Pyrazinamide）、利福平（Rifampicin）、利福布汀（Rifabutin）、利福噴丁（Rifapentine）及鏈黴素（Streptomycin）。Anti-mycobacterial compounds include but are not limited to Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethion Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine and Streptomycin Streptomycin).

合適的抗生素還包含胂凡納明（arsphenamine）、氯黴素（chloramphenicol）、磷黴素（fosfomycin）、夫西地酸（fusidic acid）、甲硝唑（metronidazole）、莫匹羅星（mupirocin）、平板黴素（platensimycin）、奎奴普汀（quinupristin）/達福普汀（dalfopristin）、替吉環素（tigecycline）、替硝唑（tinidazole）、甲氧苄啶-阿莫西林（trimethoprim amoxicillin）/克拉維酸鹽、安比西林/舒巴坦、安福黴素-利托菌素（amphomycin ristocetin）、阿奇黴素、桿菌肽、卜福林（buforin）II、卡波黴素（carbomycin）、殺菌肽（cecropin）Pl、克拉黴素、紅黴素、呋喃唑酮、夫西地酸、夫西地鈉、短桿菌素（gramicidin）、亞胺培南、吲哚菌素（indolicidin）、交沙黴素（josamycin）、馬蓋納尼（magainan）II、甲硝唑（metronidazole）、硝基咪唑、米卡黴素（mikamycin）、變鏈素（mutacin）B-Ny266、變鏈素B-JHl 140、變鏈素J-T8、乳鏈球菌素（nisin）、乳鏈球菌素A、新生黴素（novobiocin）、竹桃黴素（oleandomycin）、奧斯立星（ostreogrycin）、哌拉西林/三唑巴坦、普那黴素（pristinamycin）、雷莫拉寧（ramoplanin）、牛蛙皮膚抗菌肽（ranalexin）、羅伊氏素（reuterin）、利福昔明（rifaximin）、薔薇黴素（rosamicin）、羅沙米星（rosaramicin）、大觀黴素、螺旋黴素、葡萄黴素（staphylomycin）、鏈黴殺陽素（streptogramin）、鏈黴殺陽素A、協同菌素（synergistin）、牛磺羅定（taurolidine）、替考拉寧、泰利黴素、替凱西林/克拉維酸（clavulanic acid）、三乙醯基竹桃黴素（triacetyloleandomycin）、泰洛星（tylosin）、短桿菌酪肽（tyrocidin）、短桿菌素（tyrothricin）、萬古黴素、維馬黴素（vemamycin）及維吉黴素（virginiamycin）。Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin , Platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin )/Clavulanate, ampicillin/sulbactam, amphomycin-ristocetin (amphomycin ristocetin), azithromycin, bacitracin, buforin II, carbomycin, cecropin ) Pl, clarithromycin, erythromycin, furazolidone, fusidic acid, fusidic sodium, gramicidin, imipenem, indolicidin, josamycin , Magainan II, Metronidazole, Nitroimidazole, Mikamycin, Mutacin B-Ny266, Mutacin B-JHl 140, Mutacin J-T8, nisin, nisin, novobiocin, oleandomycin, ostreogrycin, piperacillin/tazobactam, Pristinamycin, ramoplanin, ranalexin, reuterin, rifaximin, rosamicin, rosamid Star (rosaramicin), spectinomycin, spiramycin, staphylomycin, streptogramin, streptogramin A, synergistin, taurolidine , Teicoplanin, telithromycin, teccillin/clavulanic acid, triacetyloleandomycin, tylosin, tyrocidin, short Tyrothricin (tyrothricin), vancomycin, vemamycin (vemamycin) and virginiamycin (virginiamycin).

在一些實施方式中，另外的治療劑係免疫抑制劑、DMARD、止痛藥、類固醇、非類固醇抗炎藥（NSAID）或細胞介素拮抗劑，及其組合。代表性藥劑包括但不限於環孢素、類視黃醇、皮質類固醇、丙酸衍生物、乙酸衍生物、烯醇酸衍生物、芬那酸衍生物、Cox-2抑制劑、魯美昔布（lumiracoxib）、伊布洛芬（ibuprophen）、水楊酸膽鹼鎂（cholin magnesium salicylate）、非諾洛芬（fenoprofen）、雙水楊酯（salsalate）、二氟苯水楊酸（difunisal）、托美汀（tolmetin）、酮洛芬（ketoprofen）、氟比洛芬（flurbiprofen）、奧沙普秦（oxaprozin）、吲哚美辛（indomethacin）、舒林酸（sulindac）、依託度酸（etodolac）、酮咯酸（ketorolac）、萘丁美酮（nabumetone）、萘普生（naproxen）、伐地考昔（valdecoxib）、依託考昔（etoricoxib）、MK0966；羅非昔布（rofecoxib）、對乙醯胺基酚（acetominophen）、塞來昔布（Celecoxib）、雙氯芬酸（Diclofenac）、曲馬多（tramadol）、吡羅昔康（piroxicam）、美洛昔康（meloxicam）、替諾昔康（tenoxicam）、屈昔康（droxicam）、氯諾昔康（lornoxicam）、伊索昔康（isoxicam）、甲芬那酸（mefanamic acid）、甲氯芬那酸（meclofenamic acid）、氟芬那酸（flufenamic acid）、托芬那酸（tolfenamic）、伐地考昔（valdecoxib）、帕瑞昔布（parecoxib）、依託度酸（etodolac）、吲哚美辛（indomethacin）、阿司匹林（aspirin）、伊布洛芬（ibuprophen）、非羅考昔（firocoxib）、胺甲喋呤（methotrexate（MTX））、抗瘧疾藥物（例如，羥基氯喹（hydroxychloroquine）及氯喹（chloroquine））、柳氮磺胺吡啶（sulfasalazine）、來氟米特（Leflunomide）、硫唑嘌呤（azathioprine）、環孢素（cyclosporin）、金鹽（gold salt）、米諾環素（minocycline）、環磷醯胺（cyclophosphamide）、D-青黴胺（D-penicillamine）、米諾環素（minocycline）、金諾芬（auranofin）、他克莫司（tacrolimus）、硫代苯酸金鈉（myocrisin）、苯丁酸氮芥（chlorambucil）、TNF α拮抗劑（例如，TNF α拮抗劑或TNF α受體拮抗劑），例如，阿達木單抗（Humira®）、依那西普（Enbrel®）、英夫利昔單抗（Remicade®；TA-650）、聚乙二醇賽妥珠單抗（Cimzia®；CDP870）、戈利木單抗（Simpom®；CNTO 148）、阿那白滯素（Kineret®）、利妥昔單抗（Rituxan®；MabThera®）、阿巴西普（Orencia®）、托珠單抗（RoActemra /Actemra®）、整合素拮抗劑（TYSABRI®（那他珠單抗））、IL-1拮抗劑（ACZ885（Ilaris））、阿那白滯素（Kineret®））、CD4拮抗劑、IL-23拮抗劑、IL-20拮抗劑、IL-6拮抗劑、BLyS拮抗劑（例如，阿塞西普、Benlysta®/LymphoStat-B®（貝利木單抗））、p38抑制劑、CD20拮抗劑（奧瑞珠單抗（Ocrelizumab）、奧法木單抗（Arzerra®））、干擾素γ拮抗劑（芳妥珠單抗（Fontolizumab））、普賴蘇穠（prednisolone）、強體松（Prednisone）、地塞米松（dexamethasone）、皮質醇（Cortisol）、可體松（cortisone）、氫化可體松（hydrocortisone）、甲基普賴蘇穠（methylprednisolone）、倍他米松（betamethasone）、曲安奈德（triamcinolone）、倍氯米松（beclometasome）、氟氫可體松（fludrocortisone）、去氧皮質酮（deoxycorticosterone）、醛固酮（aldosterone）、強力黴素（Doxycycline）、萬古黴素（vancomycin）、吡格列酮（pioglitazone）、SBI-087、SCIO-469、Cura-100、Oncoxin + Viusid、TwHF、甲氧沙林（Methoxsalen）、維生素D-麥角鈣化醇（Vitamin D - ergocalciferol）、米那普侖（Milnacipran）、紫杉醇（Paclitaxel）、羅西格塔松（rosig tazone）、他克莫司（Tacrolimus）（Prograf®）、RADOOl、拉帕蒙（rapamune）、雷帕黴素（rapamycin）、福斯馬替尼（fostamatinib）、芬太尼（Fentanyl）、XOMA 052、福斯馬替尼二鈉（Fostamatinib disodium）、羅格列酮（rosightazone）、薑黃素（Curcumin）（Longvida™）、瑞舒伐他汀（Rosuvastatin）、馬拉韋羅（Maraviroc）、雷米普利（ramipnl）、米那普侖（Milnacipran）、考前列酮（Cobiprostone）、生長激素（somatropin）、tgAAC94基因治療媒劑、MK0359、GW856553、埃索美拉唑（esomeprazole）、依維莫司（everolimus）、曲妥珠單抗（trastuzumab）、JAKl及JAK2抑制劑、泛JAK抑制劑，例如，四環吡啶酮6（P6）、325、PF-956980、狄諾塞麥（denosumab）、IL-6拮抗劑、CD20拮抗劑、CTLA4拮抗劑、IL-8拮抗劑、IL-21拮抗劑、IL-22拮抗劑、整合素拮抗劑（Tysarbri®（那他珠單抗））、VGEF拮抗劑、CXCL拮抗劑、MMP拮抗劑、防禦素拮抗劑、IL-1拮抗劑（包括IL-1 β拮抗劑），及IL-23拮抗劑（例如，受體誘捕物、拮抗性抗體等）。In some embodiments, the additional therapeutic agent is an immunosuppressant, DMARD, analgesic, steroid, non-steroidal anti-inflammatory drug (NSAID) or cytokine antagonist, and combinations thereof. Representative agents include but are not limited to cyclosporine, retinoids, corticosteroids, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumincoxib (Lumiracoxib), ibuprophen, cholin magnesium salicylate, fenoprofen, salsalate, difunisal, Tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac ), ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, p-acetamide Acetominophen, Celecoxib, Diclofenac, Tramadol, Piroxicam, Meloxicam, Tenoxicam, Tenoxicam Droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, Tolfenamic, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprophen, non Rocoxib (firocoxib), methotrexate (MTX), antimalarial drugs (for example, hydroxychloroquine and chloroquine), sulfasalazine, Leflunomide ), azathioprine, cyclosporin, gold salt, minocycline, cyclophosphamide, D-penicillamine, rice Nocycline (minoc ycline), auranofin, tacrolimus, myocrisin, chlorambucil, TNF α antagonist (for example, TNF α antagonist or TNF Alpha receptor antagonists), such as adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®; TA-650), polyethylene glycol certuzumab (Cimzia®; CDP870), golimumab (Simpom®; CNTO 148), anakinra (Kineret®), rituximab (Rituxan®; MabThera®), abatacept (Orencia®) , Tocilizumab (RoActemra /Actemra®), Integrin antagonist (TYSABRI® (natalizumab)), IL-1 antagonist (ACZ885 (Ilaris)), Anakinra (Kineret®)) , CD4 antagonist, IL-23 antagonist, IL-20 antagonist, IL-6 antagonist, BLyS antagonist (for example, Asazecept, Benlysta®/LymphoStat-B® (belimumab)), p38 inhibitor, CD20 antagonist (Ocrelizumab, Ofatumumab (Arzerra®)), interferon gamma antagonist (Fontolizumab), prednisolone ), Prednisone, dexamethasone, Cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone (Betamethasone), triamcinolone, beclometasome, fludrocortisone, deoxycorticosterone, aldosterone, doxycycline, vancomycin (Vancomycin), pioglitazone, SBI-087, SCIO-469, Cura-100, Oncoxin + Viusid, TwHF, Methoxsalen, Vitamin D-ergocalciferol (Vitamin D-ergocalciferol), rice Nacipran (Milnacipran), paclitaxel (Paclitaxel), rosig tazone (rosig tazone), Tacrolimus (Prograf®), RADOOl, rapamune, rapamycin, fostamatinib, fentanyl, XOMA 052, fosmartin Fostamatinib disodium, rosightazone, curcumin (Longvida™), rosuvastatin, Maraviroc, ramipril, Milnacipran (Milnacipran), cobiprostone (Cobiprostone), growth hormone (somatropin), tgAAC94 gene therapy vehicle, MK0359, GW856553, esomeprazole (esomeprazole), everolimus (everolimus), triturate Touzumab (trastuzumab), JAK1 and JAK2 inhibitors, pan-JAK inhibitors, for example, tetracycline 6 (P6), 325, PF-956980, denosumab, IL-6 antagonist, CD20 antagonist, CTLA4 antagonist, IL-8 antagonist, IL-21 antagonist, IL-22 antagonist, integrin antagonist (Tysarbri® (natalizumab)), VGEF antagonist, CXCL antagonist, MMP antagonists, defensin antagonists, IL-1 antagonists (including IL-1 β antagonists), and IL-23 antagonists (for example, receptor traps, antagonistic antibodies, etc.).

在一些實施方式中，另外的療法可以包含JAK抑制劑，例如巴瑞替尼、盧梭替尼、托法替尼和/或帕利替尼。In some embodiments, the additional therapy may include a JAK inhibitor, such as baritinib, russotinib, tofacitinib, and/or palitinib.

在一些實施方式中，另外的治療劑係免疫抑制劑。免疫抑制劑的實例包括但不限於皮質類固醇激素、美沙拉𠯤（mesalazine）、美沙拉明（mesalamine）、柳氮磺胺吡啶（sulfasalazine）、柳氮磺胺吡啶衍生物、免疫抑制藥物、環孢素A、巰基嘌呤、硫唑嘌呤（azathiopurine）、強體松、胺甲喋呤、抗組胺藥、糖皮質激素、腎上腺素、茶鹼、色甘酸鈉、抗白三烯、用於鼻炎的抗膽鹼能藥物、TLR拮抗劑、發炎體抑制劑、抗膽鹼能解充血劑、肥大細胞穩定劑、單株抗IgE抗體、疫苗（例如，用於其中使過敏原的量逐漸增加的接種疫苗的疫苗）、細胞介素抑制劑（諸如抗IL-6抗體）、TNF抑制劑（諸如英夫利昔單抗、阿達木單抗、聚乙二醇賽妥珠單抗、戈利木單抗或依那西普）及其組合。In some embodiments, the additional therapeutic agent is an immunosuppressive agent. Examples of immunosuppressive agents include, but are not limited to, corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporine A , Mercaptopurine, azathiopurine (azathiopurine), prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotriene, anti-biliary for rhinitis Alkalinergic drugs, TLR antagonists, inflammasome inhibitors, anticholinergic decongestants, mast cell stabilizers, monoclonal anti-IgE antibodies, vaccines (for example, for vaccination in which the amount of allergens is gradually increased Vaccines), cytokine inhibitors (such as anti-IL-6 antibodies), TNF inhibitors (such as infliximab, adalimumab, polyethylene glycol certuzumab, golimumab, or Nasipp) and its combination.

在一些實施方式中，另外的治療劑係RNA分子，例如雙股RNA。In some embodiments, the additional therapeutic agent is an RNA molecule, such as double-stranded RNA.

在一些實施方式中，另外的治療劑係反義寡核苷酸。 投與In some embodiments, the additional therapeutic agent is an antisense oligonucleotide. Invest in

在某些方面中，本文提供向受試者遞送本文描述的固體劑型之方法。在本文提供之方法的一些實施方式中，包含細菌和/或mEV的固體劑型與另外的治療劑的投與一起投與。在一些實施方式中，固體劑型包含與另外的治療劑共同配製的藥劑。在一些實施方式中，固體劑型與另外的治療劑共同投與。在一些實施方式中，在投與固體劑型之前（例如之前約1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50或55分鐘，之前約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23小時，或之前約1、2、3、4、5、6、7、8、9、10、11、12、13或14天），向受試者投與另外的治療劑。在一些實施方式中，在投與固體劑型之後（例如之後約1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50或55分鐘，之後約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23小時，或之後約1、2、3、4、5、6、7、8、9、10、11、12、13或14天），向受試者投與另外的治療劑。在一些實施方式中，使用相同遞送模式來遞送固體劑型及另外的治療劑。在一些實施方式中，使用不同遞送模式來投與固體劑型及另外的治療劑。例如，在一些實施方式中，經口投與固體劑型，而經由注射（例如靜脈內、肌內和/或腫瘤內注射）投與另外的治療劑。In certain aspects, provided herein are methods of delivering the solid dosage forms described herein to a subject. In some embodiments of the methods provided herein, a solid dosage form comprising bacteria and/or mEV is administered with the administration of an additional therapeutic agent. In some embodiments, the solid dosage form contains an agent co-formulated with another therapeutic agent. In some embodiments, the solid dosage form is co-administered with another therapeutic agent. In some embodiments, prior to administration of the solid dosage form (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes, before about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 Or 23 hours, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days before), another therapeutic agent is administered to the subject. In some embodiments, after administration of the solid dosage form (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes, then about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 Or 23 hours, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days later), the subject is administered an additional therapeutic agent. In some embodiments, the same delivery mode is used to deliver the solid dosage form and the additional therapeutic agent. In some embodiments, different delivery modes are used to administer the solid dosage form and the additional therapeutic agent. For example, in some embodiments, the solid dosage form is administered orally, while the additional therapeutic agent is administered via injection (eg, intravenous, intramuscular, and/or intratumor injection).

在某些實施方式中，本文描述的固體劑型可與任一其他常規抗癌治療（例如諸如放射療法及腫瘤手術切除術）聯合投與。該等治療可在需要和/或指示時應用且可發生於投與本文描述的固體劑型之前、同時或之後。In certain embodiments, the solid dosage forms described herein can be administered in combination with any other conventional anti-cancer treatments such as, for example, radiotherapy and surgical resection of tumors. Such treatments can be applied when needed and/or indicated and can occur before, at the same time or after administration of the solid dosage forms described herein.

劑量方案可為各種方法及量中的任一者，且可藉由熟悉該項技術者根據已知臨床因素來確定。如醫學技術中已知，任一患者的劑量可取決於許多因素，包含受試者物種、大小、體表面積、年齡、性別、免疫活性及總體健康狀況、有待投與的特定微生物、持續時間及投與途徑、疾病種類及階段（例如腫瘤大小）及其他化合物（例如同時或近乎同時投與的藥物）。除上述因素外，該等水平可受微生物感染性及微生物性質影響，如可由熟悉該項技術者所測定。在本發明之方法中，微生物的適當最小劑量程度可為足夠使微生物存活、生長及複製的程度。可根據劑型、投與途徑、靶疾病的程度或階段等來適當地設定或調節本文描述的藥劑（例如呈固體劑型）的劑量。例如，藥劑的一般有效劑量範圍可為0.01 mg/kg體重/天至1000 mg/kg體重/天、0.1 mg/kg體重/天至1000 mg/kg體重/天、0.5 mg/kg體重/天至500 mg/kg體重/天、1 mg/kg體重/天至100 mg/kg體重/天或5 mg/kg體重/天至50 mg/kg體重/天。有效劑量可為0.01、0.05、0.1、0.5、1、2、3、5、10、20、30、40、50、60、70、80、90、100、200、500或1000 mg/kg體重/天或更高，但劑量並不限於此。The dosage regimen can be any of various methods and amounts, and can be determined by those skilled in the art based on known clinical factors. As is known in medical technology, the dosage of any patient can depend on many factors, including the subject species, size, body surface area, age, sex, immune activity and general health, the specific microorganisms to be administered, duration and The route of administration, the type and stage of the disease (for example, tumor size), and other compounds (for example, drugs administered at the same time or nearly at the same time). In addition to the above factors, these levels can be affected by microbial infectivity and microbial properties, as can be determined by those familiar with the technology. In the method of the present invention, the appropriate minimum dosage level of the microorganisms may be sufficient to allow the microorganisms to survive, grow, and replicate. The dosage of the medicament described herein (for example, in a solid dosage form) can be appropriately set or adjusted according to the dosage form, the route of administration, the degree or stage of the target disease, and the like. For example, the general effective dose range of the drug may be 0.01 mg/kg body weight/day to 1000 mg/kg body weight/day, 0.1 mg/kg body weight/day to 1000 mg/kg body weight/day, 0.5 mg/kg body weight/day to 500 mg/kg body weight/day, 1 mg/kg body weight/day to 100 mg/kg body weight/day, or 5 mg/kg body weight/day to 50 mg/kg body weight/day. The effective dose can be 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500 or 1000 mg/kg body weight/ Days or higher, but the dosage is not limited to this.

在一些實施方式中，向受試者投與的劑量足以預防疾病（例如，自體免疫性疾病、炎性疾病、代謝性疾病、菌群失調或癌症）、延遲其發作或減緩或停止其進展，或減輕疾病的一個或多個症狀。熟悉該項技術者將認識到，劑量將取決於多種因素，包含所採用特定藥用劑（例如藥劑）的強度以及受試者的年齡、物種、病症及體重。還根據以下因素來確定劑量大小：投與途徑、時機及頻率以及可伴隨投與特定藥劑的任何不良副作用的存在、性質及程度及期望的生理學效果。In some embodiments, the dose administered to the subject is sufficient to prevent a disease (eg, autoimmune disease, inflammatory disease, metabolic disease, dysbacteriosis, or cancer), delay its onset or slow or stop its progression , Or alleviate one or more symptoms of the disease. Those skilled in the art will recognize that the dosage will depend on a variety of factors, including the strength of the particular medicinal agent (e.g., medicament) used and the age, species, condition, and weight of the subject. The dosage is also determined based on the following factors: the route of administration, timing and frequency, and the existence, nature and extent of any adverse side effects that may accompany the administration of a specific agent, and the desired physiological effect.

可藉由熟悉該項技術者已知的常規範圍探測技術來確定合適的劑量及劑量方案。通常，以不超過化合物最佳劑量的較小劑量開始治療。然後，以小增量增加劑量直至達到該狀況下的最佳效果為止。有效劑量及治療方案可藉由常規及常規方式來確定，例如，其中在實驗室動物中以低劑量開始且然後增加劑量，同時監測效果，且還系統地改變劑量方案。通常使用動物研究來測定每公斤重量的生物活性藥劑的最大可耐受劑量（「MTD」）。熟悉該項技術者通常在其他物種（包含人）中外推劑量以達到功效，同時避免毒性。The appropriate dose and dosage regimen can be determined by conventional range detection techniques known to those skilled in the art. Generally, treatment is started with a smaller dose that does not exceed the optimal dose of the compound. Then, increase the dose in small increments until the best effect under the condition is reached. Effective doses and treatment regimens can be determined by conventional and conventional methods, for example, where starting with a low dose in laboratory animals and then increasing the dose, while monitoring the effect, and also systematically changing the dosage regimen. Animal studies are often used to determine the maximum tolerable dose ("MTD") of a biologically active agent per kilogram of weight. Those familiar with the technology usually extrapolate the dose in other species (including humans) to achieve efficacy while avoiding toxicity.

根據上文，在治療應用中，與影響所選劑量的其他因素相比，用於本發明之藥劑的劑量尤其取決於以下因素有所變化：活性劑、年齡、體重及接受患者的臨床狀況及投與療法的臨床醫師或從業人員的經歷及判斷。例如，對於癌症治療，劑量應足以導致減緩腫瘤的生長，較佳的是使腫瘤的生長消退，並且最較佳的是導致癌症的完全消退，或者轉移的大小或數目的減小。作為另一個實例，劑量應足以導致減緩受試者正在治療的疾病的進展，較佳的是改善受試者正在治療的疾病的一個或多個症狀。Based on the above, in therapeutic applications, compared with other factors that affect the selected dose, the dose of the medicament used in the present invention varies particularly depending on the following factors: the active agent, age, weight, and the clinical condition of the receiving patient and The experience and judgment of the clinician or practitioner who administered the therapy. For example, for cancer treatment, the dose should be sufficient to slow down the growth of the tumor, preferably to cause the growth of the tumor to recede, and most preferably to cause the complete regression of the cancer, or a reduction in the size or number of metastases. As another example, the dosage should be sufficient to result in slowing the progression of the disease being treated by the subject, preferably ameliorating one or more symptoms of the disease being treated by the subject.

分開投與可包括任何數量的兩次或更多次投與，包括二、三、四、五或六次投與。熟悉該項技術者可容易地根據本領域中已知的用於監測治療方法之方法及本文提供的其他監測方法確定進行投與的次數或進行一或多次額外投與的期望。因此，本文提供之方法包括向受試者提供固體劑型的一或多次投與之方法，其中投與次數可藉由監測受試者確定，且基於監測的結果，判定是否需提供一或多次另外投與。可基於各種監測結果決定是否需提供一或多次另外投與。Separate administrations can include any number of two or more administrations, including two, three, four, five, or six administrations. Those skilled in the art can easily determine the number of administrations or the expectation of one or more additional administrations based on methods known in the art for monitoring treatment methods and other monitoring methods provided herein. Therefore, the method provided herein includes one or more administration methods of providing a solid dosage form to a subject, wherein the number of administrations can be determined by monitoring the subject, and based on the results of the monitoring, it is determined whether one or more doses need to be provided. Another vote. It can be determined based on various monitoring results whether one or more additional injections are required.

投與間的時間段可為各個時間段中的任一者。投與間的時間段可隨各種因素中的任一者而變化，包括監測步驟（如關於投與數量所描述）、受試者建立免疫應答的時間段。在一個實例中，時間段可隨受試者建立免疫應答的時間段而變化；例如，時間段可大於受試者建立免疫應答的時間段，例如大於約一週、大於約10天、大於約兩週或大於約一個月；在另一個實例中，時間段可不大於受試者建立免疫應答的時間段，例如不大於約一週、不大於約十天、不大於約兩週或不大於約一個月。The time period between the investment can be any of the various time periods. The time period between administrations can vary with any of a variety of factors, including monitoring steps (as described with regard to the number of administrations), and the time period for the subject to establish an immune response. In one example, the time period may vary with the time period during which the subject establishes an immune response; for example, the time period may be greater than the time period during which the subject establishes an immune response, such as greater than about one week, greater than about 10 days, or greater than about two. Week or greater than about one month; in another example, the time period may be no greater than the time period during which the subject establishes an immune response, such as no greater than about one week, no greater than about ten days, no greater than about two weeks, or no greater than about one month .

在一些實施方式中，另外的治療劑與本文描述的固體劑型的組合的遞送減少另外的治療劑的不利影響和/或改善另外的治療劑的功效。In some embodiments, the delivery of the combination of the additional therapeutic agent and the solid dosage form described herein reduces the adverse effects of the additional therapeutic agent and/or improves the efficacy of the additional therapeutic agent.

本文描述的另外的治療劑的有效劑量係針對特定受試者、組成物及投與模式有效達成所需治療劑應答且對受試者的毒性最小的另外的治療劑的量。可使用本文描述之方法來鑒別有效劑量水平且將取決於多種藥物動力學因素，包含所投與特定組成物或藥劑的活性、投與途徑、投與時間、所採用特定化合物的排泄速率、治療持續時間、與所採用特定組成物組合使用的其他藥物、化合物和/或材料、所治療受試者的年齡、性別、體重、病症、總體健康狀況及先前醫學史以及醫學技術中熟知的類似因素。一般而言，另外的治療劑的有效劑量將是該另外的治療劑的量，其為有效產生治療效應的最低劑量。通常這樣的有效劑量將取決於上文所述之該等因素。The effective dose of the additional therapeutic agent described herein is the amount of the additional therapeutic agent that is effective for the specific subject, composition, and mode of administration to achieve the desired therapeutic agent response with minimal toxicity to the subject. The methods described herein can be used to identify effective dosage levels and will depend on a variety of pharmacokinetic factors, including the activity of the specific composition or agent administered, the route of administration, the time of administration, the excretion rate of the specific compound used, and the treatment Duration, other drugs, compounds and/or materials used in combination with the specific composition used, age, gender, weight, illness, general health of the subject to be treated, and previous medical history and similar factors well known in medical technology . In general, the effective dose of the additional therapeutic agent will be the amount of the additional therapeutic agent, which is the lowest dose effective to produce a therapeutic effect. Generally such effective doses will depend on the factors mentioned above.

另外的治療劑的毒性係受試者在治療期間及治療之後經受的不利影響的程度。與另外的治療劑毒性相關的不良事件可以包括但不限於：腹痛、酸消化不良、酸回流、過敏反應、禿髮、全身性過敏反應、貧血、焦慮、食欲不振、關節痛、乏力、運動失調、氮質血症、失去平衡、骨痛、出血、血凝塊、低血壓、血壓升高、呼吸困難、支氣管炎、淤血、白血球計數降低、紅血球計數降低、血小板計數降低、心臟毒性、膀胱炎、出血性膀胱炎、心律不整、心瓣膜疾病、心肌病、冠狀動脈疾病、白內障、中樞神經毒性、認知障礙、意識模糊、結膜炎、便秘、咳嗽、痙攣、膀胱炎、深層靜脈栓塞、脫水、抑鬱、腹瀉、眩暈、口乾、皮膚乾燥、消化不良、呼吸困難（dyspnea）、水腫、電解質不平衡、食道炎、疲乏、生育力喪失、發燒、胃腸積氣、面紅、胃逆流、胃食道逆流病、生殖器疼痛、粒細胞減少症、男子女乳症、青光眼、脫髮、手足綜合症、頭痛、聽覺損失、心臟衰竭、心悸、胃灼熱、血腫、出血性膀胱炎、肝毒性、高澱粉酶血症、高鈣血症、高氯血症、高糖血症、高鉀血症、高脂血症、高鎂血症、高鈉血症、高磷酸鹽血症、色素過多、高三酸甘油酯血症、高尿酸血症、低白蛋白血症、低鈣血症、低氯血症、低血糖症、低鉀血症、低鎂血症、低鈉血症、低磷酸鹽血症、陽萎、感染、注射部位反應、失眠、缺鐵、瘙癢、關節痛、腎衰竭、白血球減少症、肝功能障礙、失憶、閉經、口瘡、黏膜炎、肌肉痛、肌痛、骨髓抑制、心肌炎、嗜中性白血球減少性發燒、噁心、腎毒性、嗜中性白血球減少症、流鼻血、麻木、耳毒性、疼痛、手足綜合症（palmar-plantar erythrodysesthesia）、全部血球減少症、心包炎、周邊神經病變、咽炎、畏光、光敏感、肺炎（pneumonia）、局限性肺炎（pneumonitis）、蛋白尿、肺血栓、肺性纖維化、肺毒性、皮疹、心跳加快、直腸出血、坐立不安、鼻炎、癲癇、呼吸短促、鼻竇炎、血小板減少症、耳鳴、泌尿道感染、陰道出血、陰道乾燥、眩暈、水滯留（water retention）、無力、體重減輕、體重增加及口乾症（xerostomia）。一般而言，如果經由療法所達到的受試者益處勝過受試者因療法所經歷的不良事件，則毒性係可接受的。 免疫障礙The toxicity of another therapeutic agent is the degree of adverse effects experienced by the subject during and after treatment. Adverse events related to the toxicity of another therapeutic agent may include, but are not limited to: abdominal pain, acid indigestion, acid reflux, allergic reactions, baldness, anaphylaxis, anemia, anxiety, loss of appetite, arthralgia, fatigue, ataxia , Azotemia, loss of balance, bone pain, bleeding, blood clots, hypotension, increased blood pressure, dyspnea, bronchitis, congestion, decreased white blood cell count, decreased red blood cell count, decreased platelet count, cardiotoxicity, cystitis , Hemorrhagic cystitis, arrhythmia, heart valve disease, cardiomyopathy, coronary artery disease, cataract, central nervous system toxicity, cognitive impairment, confusion, conjunctivitis, constipation, cough, spasm, cystitis, deep vein embolism, dehydration, depression , Diarrhea, dizziness, dry mouth, dry skin, indigestion, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue, loss of fertility, fever, gastrointestinal gas, flushing, gastric reflux, gastroesophageal reflux Disease, genital pain, neutropenia, gynecomastia, glaucoma, hair loss, hand-foot syndrome, headache, hearing loss, heart failure, palpitations, heartburn, hematoma, hemorrhagic cystitis, liver toxicity, hyperamylase blood Symptoms, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hyperlipidemia, hypermagnesemia, hypernatremia, hyperphosphatemia, hyperpigmentation, hypertriglycerides Hyperemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, positive Wilt, infection, injection site reaction, insomnia, iron deficiency, itching, arthralgia, renal failure, leukopenia, liver dysfunction, amnesia, amenorrhea, aphthous, mucositis, myalgia, myalgia, bone marrow suppression, myocarditis, addiction Neutropenic fever, nausea, nephrotoxicity, neutropenia, nosebleeds, numbness, ototoxicity, pain, palmar-plantar erythrodysesthesia, total hypocytopenia, pericarditis, peripheral neuropathy , Pharyngitis, photophobia, photosensitivity, pneumonia (pneumonia), localized pneumonia (pneumonitis), proteinuria, pulmonary thrombosis, pulmonary fibrosis, pulmonary toxicity, rash, rapid heartbeat, rectal bleeding, restlessness, rhinitis, epilepsy, breathing Shortness, sinusitis, thrombocytopenia, tinnitus, urinary tract infection, vaginal bleeding, vaginal dryness, dizziness, water retention, weakness, weight loss, weight gain, and xerostomia. Generally speaking, if the benefit of the subject through the therapy outweighs the adverse events experienced by the subject due to the therapy, then the toxicity is acceptable. Immune disorders

在一些實施方式中，本文描述之方法及固體劑型涉及治療或預防與病理學免疫應答相關的疾病或障礙（如自體免疫性疾病、過敏反應和/或炎性疾病）。在一些實施方式中，疾病或障礙係炎性腸病（例如，克羅恩氏病或潰瘍性結腸炎）。在一些實施方式中，疾病或障礙係牛皮癬。在一些實施方式中，疾病或障礙係特應性皮炎。In some embodiments, the methods and solid dosage forms described herein involve the treatment or prevention of diseases or disorders associated with pathological immune responses (such as autoimmune diseases, allergic reactions, and/or inflammatory diseases). In some embodiments, the disease or disorder is inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis). In some embodiments, the disease or disorder is psoriasis. In some embodiments, the disease or disorder is atopic dermatitis.

本文描述之方法和固體劑型可用以治療有需要的任何受試者。如本文中所使用，「有需要的受試者」包括患有與病理學免疫應答相關的疾病或障礙（例如，炎性腸病）的任何受試者，及具有增加獲得此疾病或障礙的可能性的任何受試者。The methods and solid dosage forms described herein can be used to treat any subject in need. As used herein, "subjects in need" include any subject suffering from a disease or disorder related to a pathological immune response (for example, inflammatory bowel disease), and those who have increased acquisition of the disease or disorder The possibility of any subject.

本文描述的固體劑型可例如用作預防或治療（部分或完全減少以下疾病的不利影響）自體免疫性疾病，如慢性炎性腸病、全身性紅斑狼瘡、牛皮癬、穆-韋二氏綜合症、類風濕性關節炎、多發性硬化或橋本病（Hashimoto's disease）；過敏性疾病，如食物過敏、花粉熱或氣喘；傳染性疾病，如艱難梭菌感染；炎性疾病，如TNF介導的炎性疾病（例如，胃腸道炎性疾病，如結腸袋炎（pouchitis）；心血管炎性疾病，如動脈粥樣硬化；或炎性肺病，如慢性阻塞性肺疾病）的藥物組成物；用作用於抑制器官移植中的排斥或其中可能發生組織排斥的其他情況的藥物組成物；用作用於改善免疫功能的補充物、食物或飲料；或用作用於抑制免疫細胞的增殖或功能的試劑。The solid dosage forms described herein can be used, for example, to prevent or treat (partially or completely reduce the adverse effects of the following diseases) autoimmune diseases, such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, Mu-Wei’s syndrome , Rheumatoid arthritis, multiple sclerosis or Hashimoto's disease; allergic diseases such as food allergy, hay fever or asthma; infectious diseases such as Clostridium difficile infection; inflammatory diseases such as TNF-mediated Pharmaceutical compositions for inflammatory diseases (for example, gastrointestinal inflammatory diseases, such as pouchitis; cardiovascular inflammatory diseases, such as atherosclerosis; or inflammatory lung diseases, such as chronic obstructive pulmonary disease); use A pharmaceutical composition that acts to suppress rejection in organ transplantation or other situations in which tissue rejection may occur; used as a supplement, food or beverage for improving immune function; or used as an agent for inhibiting the proliferation or function of immune cells.

在一些實施方式中，本文提供之方法和固體劑型適用於治療炎症。在某些實施方式中，身體的任何組織及器官的炎症，包括肌肉骨骼炎症、血管炎症、神經炎症、消化系統炎症、眼部炎症、生殖系統炎症及其他炎症，如下文討論。In some embodiments, the methods and solid dosage forms provided herein are suitable for treating inflammation. In certain embodiments, inflammation of any tissue and organ of the body includes musculoskeletal inflammation, vascular inflammation, neuroinflammation, digestive system inflammation, ocular inflammation, reproductive system inflammation, and other inflammations, as discussed below.

肌肉骨骼系統的免疫障礙包括但不限於那些影響骨骼關節（包括手、手腕、肘部、肩部、下巴、脊柱、頸部、臀部、膝蓋、踝部及足部的關節）的病症，及影響將肌肉連接至骨頭的組織（如肌腱）的病症。可用本文描述之方法及組成物治療的這類免疫障礙的實例包括但不限於關節炎（包括，例如，骨關節炎、類風濕性關節炎、牛皮癬關節炎、強直性脊柱炎、急性及慢性感染性關節炎、與痛風和假痛風相關的關節炎及幼年特發性關節炎）、肌腱炎、滑膜炎、腱鞘炎、滑囊炎、纖維組織炎（纖維肌痛）、上髁炎、肌炎及骨炎（包括，例如，佩吉特氏病（Paget's disease）、恥骨炎及囊性纖維性骨炎）。Immune disorders of the musculoskeletal system include but are not limited to those that affect bone joints (including joints of hands, wrists, elbows, shoulders, chin, spine, neck, hips, knees, ankles and feet), and affect A condition of the tissues (such as tendons) that connect muscles to bones. Examples of such immune disorders that can be treated with the methods and compositions described herein include, but are not limited to, arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic infections) Arthritis, arthritis related to gout and pseudogout, and juvenile idiopathic arthritis), tendinitis, synovitis, tenosynovitis, bursitis, fibromyalgia (fibromyalgia), epicondylitis, myositis And osteitis (including, for example, Paget's disease, osteitis pubis, and cystic fibrous osteitis).

眼部免疫障礙係指影響眼睛的任何結構（包括眼瞼）的免疫障礙。可用本文描述之方法及組成物治療的眼部免疫障礙的實例包括但不限於瞼緣炎、眼瞼皮膚松垂症、結膜炎、淚腺炎、角膜炎、乾燥性角膜結膜炎（乾眼症）、鞏膜炎、倒睫及眼色素層炎。Ocular immune disorder refers to an immune disorder that affects any structure of the eye (including the eyelids). Examples of ocular immune disorders that can be treated with the methods and compositions described herein include, but are not limited to, blepharitis, eyelid skin ptosis, conjunctivitis, lacrimal gland inflammation, keratitis, keratoconjunctivitis sicca (dry eye), scleritis , Trichiasis and uveitis.

可用本文描述之方法及固體劑型治療的神經系統免疫障礙的實例包括但不限於腦炎、格林-巴厘綜合症（Guillain-Barre syndrome）、腦膜炎、神經性肌強直、發作性睡病、多發性硬化、脊髓炎及精神分裂症。可用本文描述之方法及組成物治療的脈管系統或淋巴系統炎症的實例包括但不限於關節硬化、關節炎、靜脈炎、血管炎及淋巴管炎。Examples of immune disorders of the nervous system that can be treated with the methods and solid dosage forms described herein include, but are not limited to, encephalitis, Guillain-Barre syndrome, meningitis, neuromuscular rigidity, narcolepsy, and multiple Sclerosis, myelitis and schizophrenia. Examples of inflammations of the vasculature or lymphatic system that can be treated with the methods and compositions described herein include, but are not limited to, arthritis, arthritis, phlebitis, vasculitis, and lymphangitis.

可用本文描述之方法及固體劑型治療的消化系統免疫障礙的實例包括但不限於膽管炎、膽囊炎、腸炎、小腸結腸炎、胃炎、腸胃炎、炎性腸病、回腸炎及直腸炎。炎性腸病包括（例如）一組相關病症的某些本領域公認的形式。已知炎性腸病的幾種主要形式，這類障礙中最常見的為克羅恩氏病（區域性腸病，例如，非活性及活性形式）及潰瘍性結腸炎（例如，非活性及活性形式）。另外，炎性腸病涵蓋腸易激綜合症、顯微鏡下結腸炎、淋巴細胞性-漿細胞性腸炎、乳糜瀉、膠原性結腸炎、淋巴細胞性結腸炎及嗜酸性小腸結腸炎。IBD的其他不常見形式包括不確定性結腸炎、假膜性結腸炎（壞死性結腸炎）、缺血性炎性腸病、白塞氏病（Behcet’s disease）、類肉瘤病、硬皮病、IBD相關性發育不良、與發育不良相關的腫塊或病變及原發性硬化性膽管炎。Examples of immune disorders of the digestive system that can be treated with the methods and solid dosage forms described herein include, but are not limited to, cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease, ileitis, and proctitis. Inflammatory bowel disease includes, for example, certain art-recognized forms of a group of related disorders. Several major forms of inflammatory bowel disease are known. The most common of these disorders are Crohn’s disease (regional bowel disease, for example, inactive and active forms) and ulcerative colitis (for example, inactive and active forms). Active form). In addition, inflammatory bowel disease covers irritable bowel syndrome, microscopic colitis, lymphocytic-plasma cell enteritis, celiac disease, collagenous colitis, lymphocytic colitis, and eosinophilic enterocolitis. Other uncommon forms of IBD include indeterminate colitis, pseudomembranous colitis (necrotizing colitis), ischemic inflammatory bowel disease, Behcet's disease, sarcoidosis, scleroderma, IBD-related dysplasia, lumps or lesions related to dysplasia, and primary sclerosing cholangitis.

可用本文描述之方法及固體劑型治療的生殖系統免疫障礙的實例包括但不限於子宮頸炎、絨毛膜羊膜炎、子宮內膜炎、附睾炎、臍炎、卵巢炎、睾丸炎、輸卵管炎、輸卵管卵巢膿腫、尿道炎、陰道炎、外陰炎及外陰痛。Examples of immune disorders of the reproductive system that can be treated with the methods and solid dosage forms described herein include, but are not limited to, cervicitis, chorioamnionitis, endometritis, epididymitis, umbilitis, ovarian inflammation, orchitis, salpingitis, fallopian tube Ovarian abscess, urethritis, vaginitis, vulvitis and vulvar pain.

本文描述之方法及固體劑型可用以治療具有發炎成分的自體免疫性疾病。此病症包括但不限於全身性急性播散性禿頭症、白塞氏病、恰加斯氏病（Chagas' disease）、慢性疲勞綜合症、自主神經失調、腦脊髓炎、強直性脊柱炎、再生障礙性貧血、化膿性汗腺炎、自體免疫性肝炎、自體免疫性卵巢炎、乳糜瀉、克羅恩氏病、1型糖尿病、巨細胞動脈炎、古德帕斯丘綜合症、格雷夫斯病、格林-巴厘綜合症、橋本病、亨諾-許蘭二氏紫斑症（Henoch-Schonlein purpura）、川崎病（Kawasaki's disease）、紅斑狼瘡、顯微鏡下結腸炎、顯微鏡下多動脈炎、混合結締組織病、穆-韋二氏綜合症（Muckle-Wells syndrome）、多發性硬化、重症肌無力、眼陣攣肌陣攣綜合症、視神經炎、奧德氏甲狀腺炎、天皰瘡、結節性多動脈炎、多肌痛、類風濕性關節炎、萊特爾氏綜合症（Reiter's syndrome）、休葛籣氏綜合症（Sjogren's syndrome）、顳動脈炎、韋格納肉芽腫病（Wegener's granulomatosis）、溫熱自體免疫性溶血性貧血、間質性膀胱炎、萊姆病（Lyme disease）、局限性硬皮病、牛皮癬、類肉瘤病、硬皮病、潰瘍性結腸炎及白斑病。The methods and solid dosage forms described herein can be used to treat autoimmune diseases with inflammatory components. This condition includes but is not limited to systemic acute disseminated alopecia, Behcet's disease, Chagas' disease, chronic fatigue syndrome, autonomic disorders, encephalomyelitis, ankylosing spondylitis, regeneration Obstructive anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes, giant cell arteritis, Goodpasture syndrome, Grave S disease, Guillain-Bali syndrome, Hashimoto’s disease, Henoch-Schonlein purpura, Kawasaki’s disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed Connective tissue disease, Muckle-Wells syndrome, multiple sclerosis, myasthenia gravis, ocular clonic myoclonus syndrome, optic neuritis, Odder's thyroiditis, pemphigus, nodular Polyarteritis, polymyalgia, rheumatoid arthritis, Reiter’s syndrome, Sjogren’s syndrome, temporal arteritis, Wegener’s granulomatosis, temperature Heat autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, localized scleroderma, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and leukoplakia.

本文描述之方法及固體劑型可用以治療具有發炎成分的T細胞介導的超敏性疾病。此類病症包括但不限於接觸性超敏反應、接觸性皮炎（包括由於毒葛引起的接觸性皮炎）、蕁麻疹、皮膚過敏、呼吸道過敏（花粉熱、過敏性鼻炎、屋塵蟎過敏）及麩膠敏感性腸病（乳糜瀉）。The methods and solid dosage forms described herein can be used to treat T cell-mediated hypersensitivity diseases with inflammatory components. Such conditions include but are not limited to contact hypersensitivity, contact dermatitis (including contact dermatitis caused by poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis, house dust mite allergy) and Gluten-sensitive enteropathy (celiac disease).

可用本發明之方法及固體劑型治療的其他免疫病症包括例如闌尾炎、皮炎、皮肌炎、心內膜炎、纖維組織炎、齒齦炎、舌炎、肝炎、化膿性汗腺炎、虹膜炎、喉炎、乳腺炎、心肌炎、腎炎、耳炎、胰臟炎、腮腺炎、心包炎、腹膜炎（peritonoitis）、咽炎、胸膜炎、局限性肺炎、前列腺增生症（prostatistis）、腎盂腎炎及口炎（stomatisi）、移植排斥（涉及如腎、肝、心臟、肺、胰臟（例如，胰島細胞）、骨髓、角膜、小腸的器官，同種異體皮膚移植、皮膚同種移植物及心臟瓣膜異種移植、血清病及移植物抗宿主病）、急性胰臟炎、慢性胰臟炎、急性呼吸窘迫綜合症、西紮利氏綜合症（Sexary's syndrome）、先天性腎上腺增生、非化膿性甲狀腺炎、高鈣血症相關癌症、天皰瘡、大皰性皰疹樣皮炎、重度多形紅斑、剝脫性皮炎、脂溢性皮炎、季節性或常年性過敏性鼻炎、支氣管氣喘、接觸性皮炎、特應性皮炎、藥物超敏反應、過敏性結膜炎、角膜炎、眼帶狀皰疹、虹膜炎及虹膜睫狀體炎、脈絡膜視網膜炎、視神經炎、症狀性類肉瘤病（symptomatic sarcoidosis）、暴發性或散播性肺結核化學療法、成人特發性血小板減少性紫癜、成人繼發性血小板減少症、獲得性（自體免疫性）溶血性貧血症、成人白血病及淋巴瘤、兒童急性白血病、局限性腸炎、自體免疫性血管炎、多發性硬化、慢性阻塞性肺疾病、實體器官移植排斥反應、敗血症。較佳的治療包括以下的治療：移植排斥、類風濕性關節炎、牛皮癬關節炎、多發性硬化、1型糖尿病、氣喘、炎性腸病、全身性紅斑狼瘡、牛皮癬、慢性阻塞性肺疾病及伴隨感染病症的炎症（例如，敗血症）。 代謝失調Other immune disorders that can be treated with the method and solid dosage form of the present invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis , Mastitis, myocarditis, nephritis, otitis, pancreatitis, mumps, pericarditis, peritonitis (peritonoitis), pharyngitis, pleurisy, localized pneumonia, prostate hyperplasia (prostatistis), pyelonephritis and stomatitis (stomatisi), Transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (eg, pancreatic islet cells), bone marrow, cornea, small intestine, allogeneic skin transplantation, skin allograft and heart valve xenograft, serum sickness and transplant Anti-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, sexary's syndrome, congenital adrenal hyperplasia, non-suppurative thyroiditis, hypercalcemia-related cancers, Pemphigus, bullous herpetiform dermatitis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug super Allergic reactions, allergic conjunctivitis, keratitis, ocular herpes zoster, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated tuberculosis chemotherapy , Adult idiopathic thrombocytopenic purpura, adult secondary thrombocytopenia, acquired (autoimmune) hemolytic anemia, adult leukemia and lymphoma, childhood acute leukemia, localized enteritis, autoimmune blood vessels Inflammation, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis. Preferred treatments include the following treatments: transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic obstructive pulmonary disease, and Inflammation that accompanies infectious conditions (for example, sepsis). Metabolic disorders

在一些實施方式中，本文描述之方法和固體劑型涉及治療或預防代謝性疾病或障礙，例如II型糖尿病、糖耐量受損、胰島素抵抗、肥胖、高血糖、高胰島素血症、脂肪肝、非酒精性脂肪性肝炎、高膽固醇血症、高血壓、高脂蛋白血症、高脂血症、高甘油三酯血症、酮酸中毒、低血糖、血栓性疾病、血脂異常、非酒精性脂肪性肝病（NAFLD）、非酒精性脂肪性肝炎（NASH）或相關疾病。在一些實施方式中，相關疾病係心血管疾病、動脈粥樣硬化、腎臟疾病、腎病、糖尿病性神經病、糖尿病性視網膜病變、性功能障礙、皮膚病、消化不良或水腫。在一些實施方式中，本文描述之方法和藥物組成物涉及非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）的治療。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of metabolic diseases or disorders, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non- Alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, ketoacidosis, hypoglycemia, thrombotic diseases, dyslipidemia, non-alcoholic fat Liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or related diseases. In some embodiments, the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, or edema. In some embodiments, the methods and pharmaceutical compositions described herein relate to the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

本文描述之方法和固體劑型可用以治療有需要的任何受試者。如本文所使用的，「有需要的受試者」包括具有代謝性疾病或障礙的任何受試者，以及具有獲得這種疾病或障礙的增加的可能性的任何受試者。The methods and solid dosage forms described herein can be used to treat any subject in need. As used herein, "subject in need" includes any subject who has a metabolic disease or disorder, as well as any subject who has an increased likelihood of obtaining such disease or disorder.

本文描述的固體劑型可用於例如預防或治療代謝性疾病（部分或完全地減少代謝性疾病的不利影響），該代謝性疾病係例如II型糖尿病、糖耐量受損、胰島素抵抗、肥胖、高血糖、高胰島素血症、脂肪肝、非酒精性脂肪性肝炎、高膽固醇血症、高血壓、高脂蛋白血症、高脂血症、高甘油三酯血症、酮酸中毒、低血糖、血栓性疾病、血脂異常、非酒精性脂肪性肝病（NAFLD）、非酒精性脂肪性肝炎（NASH）或相關疾病。在一些實施方式中，相關疾病係心血管疾病、動脈粥樣硬化、腎臟疾病、腎病、糖尿病性神經病、糖尿病性視網膜病變、性功能障礙、皮膚病、消化不良或水腫。 癌症The solid dosage forms described herein can be used, for example, to prevent or treat metabolic diseases (partially or completely reduce the adverse effects of metabolic diseases) such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia , Hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, ketoacidosis, hypoglycemia, thrombosis Diseases, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or related diseases. In some embodiments, the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, or edema. cancer

在一些實施方式中，本文描述之方法及固體劑型涉及癌症治療。在一些實施方式中，任何癌症可使用本文描述之方法治療。可藉由本文描述之方法及固體劑型治療的癌症的實例包括但不限於來自以下的癌細胞：膀胱、血液、骨頭、骨髓、腦、乳房、結腸、食道、胃腸、牙齦、頭、腎、肝、肺、鼻咽、頸、卵巢、前列腺、皮膚、胃、睪丸、舌頭或子宮。另外，該癌症可特定地是下列組織學類型，但其不限於該等類型：贅瘤，惡性；癌；癌，未分化；巨大及梭細胞癌；小細胞癌；乳頭狀癌；鱗狀細胞癌；淋巴上皮癌；基底細胞癌（basal cell carcinoma）；毛髮基質（pilomatrix）癌；移行細胞癌；乳頭狀移行細胞癌；腺癌；胃泌素瘤，惡性；膽管癌；肝細胞癌；肝細胞癌合併膽管癌；小梁腺癌；腺樣囊性癌；腺瘤息肉的腺癌；腺癌，家族性結腸息肉；實體癌；類癌瘤，惡性；細支氣管肺泡（branchiolo-alveolar）腺癌；乳頭狀腺癌；嫌色細胞癌；嗜酸性細胞癌；嗜酸性腺癌；嗜鹼性粒細胞癌；透明細胞腺癌；顆粒細胞癌；濾泡性腺癌；乳頭狀及濾泡性腺癌；非包膜性硬化性癌；腎上腺皮質癌；子宮內膜樣癌；皮膚附器癌；頂漿（apocrine）腺癌；皮脂腺癌；耵聹（ceruminous）腺癌；黏液表皮樣癌；囊腺癌；乳頭狀囊腺癌；乳頭狀漿液性囊腺癌；黏液性囊腺癌；黏液性腺癌；戒環細胞癌；浸潤性管狀癌；髓樣癌；小葉癌；發炎癌；佩吉特氏病，乳房；腺泡細胞癌；腺鱗癌；腺癌與鱗狀轉移瘤（adenocarcinoma w/squamous metaplasia）；胸腺瘤，惡性；卵巢間質瘤，惡性；卵泡膜細胞瘤（thecoma），惡性；粒層細胞瘤，惡性；及成釉細胞瘤，惡性；賽特利氏（sertoli）細胞癌；睾丸間質細胞（leydig cell）瘤，惡性；脂質細胞瘤，惡性；副神經節瘤，惡性；乳房外副神經節瘤，惡性；嗜鉻細胞瘤；血管球肉瘤（glomangiosarcoma）；惡性黑色素瘤；無色素性黑色素瘤；淺表擴散黑色素瘤；巨大色素痣中的惡性黑色素瘤；上皮樣細胞黑色素瘤；藍痣，惡性；肉瘤；纖維肉瘤；纖維組織細胞瘤，惡性；黏液肉瘤；脂肉瘤（liposarcoma）；平滑肌肉瘤；橫紋肌肉瘤；胚胎性橫紋肌肉瘤；肺泡橫紋肌肉瘤；基質肉瘤；混合瘤，惡性；苗勒氏混合瘤（mullerian mixed tumor）；腎母細胞瘤；肝母細胞瘤；癌肉瘤；間質瘤，惡性；布倫納瘤（brenner tumor），惡性；葉狀瘤，惡性；滑膜肉瘤；間皮瘤，惡性；無性細胞瘤；胚胎性癌；畸胎瘤，惡性；卵巢甲狀腺瘤，惡性；絨毛膜癌；中腎瘤，惡性；血管肉瘤；血管內皮瘤，惡性；卡波西氏肉瘤（kaposi's sarcoma）；血管外皮細胞瘤，惡性；淋巴管肉瘤；骨肉瘤；近皮質骨肉瘤；軟骨肉瘤；軟骨胚細胞瘤，惡性；間葉細胞軟骨肉瘤；骨巨細胞瘤；尤因肉瘤（ewing's sarcoma）；齒源性腫瘤，惡性；釉質母細胞齒源性瘤；釉質母細胞瘤，惡性；釉質母細胞纖維肉瘤；松果體瘤，惡性；脊索瘤；神經膠質瘤，惡性；室管膜瘤；星形細胞瘤；原漿性星形細胞瘤；纖維性星形細胞瘤；星形母細胞瘤；膠質母細胞瘤；少突神經膠質瘤；少突膠質母細胞瘤；原始神經外胚葉腫瘤；小腦肉瘤；節細胞母細胞瘤；神經母細胞瘤；視網膜母細胞瘤；嗅神經源性腫瘤；腦膜瘤，惡性；神經纖維肉瘤；神經鞘瘤，惡性；顆粒細胞瘤，惡性；惡性淋巴瘤；霍奇金病（Hodgkin’s Disease）；何杰金氏淋巴瘤；副肉芽腫；小淋巴細胞性惡性淋巴瘤；彌漫性大細胞惡性淋巴瘤；濾泡型惡性淋巴瘤；蕈樣真菌病；其他指定非何杰金氏淋巴瘤；惡性組織細胞增生症；多發性骨髓瘤；肥大細胞肉瘤；免疫增殖性小腸病；白血病；淋巴樣白血病；漿細胞白血病；紅白血病；淋巴肉瘤細胞白血病；髓樣白血病；嗜鹼性白血病；嗜酸性球性白血病；單核細胞白血病；肥大細胞白血病；巨核細胞性白血病；髓樣肉瘤；及毛細胞白血病。In some embodiments, the methods and solid dosage forms described herein relate to cancer treatment. In some embodiments, any cancer can be treated using the methods described herein. Examples of cancers that can be treated by the methods and solid dosage forms described herein include, but are not limited to, cancer cells from the following: bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal, gums, head, kidney, liver , Lungs, nasopharynx, neck, ovaries, prostate, skin, stomach, testicles, tongue or uterus. In addition, the cancer may specifically be the following histological types, but it is not limited to these types: neoplastic, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell Carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; liver Cell carcinoma with cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma of adenoma polyps; adenocarcinoma, familial colon polyp; solid carcinoma; carcinoid tumor, malignant; bronchiolo-alveolar gland Carcinoma; papillary adenocarcinoma; chromophobe cell carcinoma; eosinophilic carcinoma; eosinophilic adenocarcinoma; basophilic granular cell carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma ; Non-encapsulated sclerosing carcinoma; adrenal cortex carcinoma; endometrioid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cyst gland Carcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; ring cell carcinoma; invasive tubular carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; Paget's Disease, breast; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia (adenocarcinoma w/squamous metaplasia); thymoma, malignant; ovarian stromal tumor, malignant; follicular cell tumor (thecoma), malignant; Granulocytoma, malignant; and ameloblastoma, malignant; Sertoli cell carcinoma; Leydig cell tumor, malignant; Lipid cell tumor, malignant; Paraganglioma, malignant; Extramammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; achromatic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevi; epithelioid cell melanoma Blue nevi, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma (liposarcoma); leiomyosarcoma; rhabdomyosarcoma; embryonic rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; Mullerian mixed tumor; Wilms tumor; Hepatoblastoma; Carcinosarcoma; Stromal tumor, malignant; Brenner tumor, malignant; Phylloma, malignant; Synovial sarcoma Mesothelioma, malignant; dysgerminoma; embryonic carcinoma; teratoma, malignant; ovarian thyroid tumor, malignant; choriocarcinoma; mesorenoma, malignant; angiosarcoma; hemangioendothelioma, malignant; Kaposi Kaposi's sarcoma (kaposi's sarcoma); Hemangiopericytoma, malignant; Lymphangiosarcoma; Osteosarcoma; Subcortical osteosarcoma; Chondrosarcoma; Chondrosarcoma , Malignant; Mesenchymal chondrosarcoma; Giant cell tumor of bone; Ewing's sarcoma; Dental tumor, malignant; Ameloblastic dental tumor; Ameloblastoma, malignant; Ameloblastic fibrosarcoma; Pineal tumor, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrous astrocytoma; astroblastoma; glioblastoma Tumor; Oligodendrocyte Glioma; Oligodendrocyte Glioblastoma; Primitive Neuroectodermal Tumor; Cerebellar Sarcoma; Ganglioblastoma; Neuroblastoma; Retinoblastoma; Olfactory Neurogenic Tumor; Meningioma, Malignant Neurofibrosarcoma; Neurilemmoma, malignant; Granulosa cell tumor, malignant; Malignant lymphoma; Hodgkin's Disease; Hodgkin's disease; Hodgkin's lymphoma; Paragranulomatosis; Small lymphocytic malignant lymphoma; Diffuse Large cell malignant lymphoma; follicular malignant lymphoma; mycosis fungoides; other designated non-Hodgkin’s lymphoma; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small bowel disease; Leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryocytic leukemia; myeloid sarcoma ; And hairy cell leukemia.

在一些實施方式中，癌症包括乳癌（例如三陰性乳癌）。In some embodiments, the cancer includes breast cancer (eg, triple-negative breast cancer).

在一些實施方式中，癌症包括結直腸癌（例如，微衛星穩定（MSS）結直腸癌）。In some embodiments, the cancer includes colorectal cancer (eg, microsatellite stable (MSS) colorectal cancer).

在一些實施方式中，癌症包括腎細胞癌。In some embodiments, the cancer comprises renal cell carcinoma.

在一些實施方式中，癌症包括肺癌（例如，非小細胞肺癌）。In some embodiments, the cancer includes lung cancer (eg, non-small cell lung cancer).

在一些實施方式中，癌症包括膀胱癌。In some embodiments, the cancer comprises bladder cancer.

在一些實施方式中，癌症包括胃食管癌。In some embodiments, the cancer comprises gastroesophageal cancer.

在一些實施方式中，本文提供之方法及固體劑型涉及白血病的治療。術語「白血病」在廣義上包括造血器官/系統的進展性、惡性疾病且其特徵通常在於白血球及其先質在血液及骨髓中的異常增殖及發育。白血病疾病的非限制性實例包含急性非淋巴細胞性白血病、慢性淋巴細胞性白血病、急性粒細胞性白血病、慢性粒細胞性白血病、急性前骨髓細胞性白血病、成人T細胞白血病、非白血性白血病、白血球增多性白血病、嗜鹼粒細胞白血病、胚細胞白血病、牛白血病、慢性骨髓細胞性白血病、皮膚白血病、胚細胞性白血病、嗜酸性球性性白血病、格羅斯氏白血病（Gross' leukemia）、裡德爾細胞白血病（Rieder cell leukemia）、希林氏白血病（Schilling's leukemia）、幹細胞白血病、亞白血病性白血病、未分化細胞白血病、毛細胞白血病、成血細胞性白血病（hemoblastic leukemia）、成血胚細胞性白血病（hemocytoblastic leukemia）、組織細胞性白血病、幹細胞白血病、急性單核細胞性白血病、白血球減少性白血病、淋巴性白血病、淋巴母細胞性白血病、淋巴細胞性白血病、淋巴源性白血病、淋巴樣白血病、淋巴肉瘤細胞白血病、肥大細胞白血病、巨核細胞性白血病、小骨髓母細胞性白血病、單核細胞性白血病、骨髓母細胞性白血病、骨髓細胞性白血病、骨髓性粒細胞性白血病、骨髓單核細胞性白血病、內格利白血病（Naegeli leukemia）、漿細胞白血病、漿細胞性白血病及前骨髓細胞性白血病。In some embodiments, the methods and solid dosage forms provided herein relate to the treatment of leukemia. The term "leukemia" broadly includes progressive, malignant diseases of hematopoietic organs/systems and is usually characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Non-limiting examples of leukemia diseases include acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, Leukemia, basophilic leukemia, blastoblastic leukemia, bovine leukemia, chronic myelogenous leukemia, skin leukemia, blastic leukemia, eosinophilic leukemia, Gross' leukemia, Li Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia ( hemocytoblastic leukemia), histocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenia leukemia, lymphoid leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphoid leukemia, lymphosarcoma Cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelogenous leukemia, myelogenous leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasma cell leukemia and premyelogenous leukemia.

在一些實施方式中，本文提供之方法及固體劑型涉及癌治療。術語「癌」係指上皮細胞的惡性生長，該等上皮細胞往往浸潤環繞組織和/或抑制生理學及非生理學細胞死亡信號並產生轉移。癌的非限制性示例性類型包含腺泡癌、腺泡樣癌、腺囊樣癌、腺樣囊性癌、腺癌（carcinoma adenomatosum）、腎上腺皮質癌、肺泡癌、肺泡細胞癌、基底細胞癌（basal cell carcinoma）、基底細胞癌（carcinoma basocellulare）、基底細胞樣癌、基底鱗狀細胞癌、支氣管肺泡癌、細支氣管癌、支氣管癌、腦狀癌、膽管細胞癌、絨毛膜癌、膠狀癌、粉刺癌、子宮體癌、篩狀癌、鎧甲狀癌、皮膚癌、柱狀癌、柱狀細胞癌、導管癌、硬癌（carcinoma durum）、胚胎性癌、腦狀癌（encephaloid carcinoma）、表皮樣癌、腺樣上皮細胞癌、外植癌、潰瘍性癌、纖維癌、膠狀癌（gelatiniform carcinoma）、膠樣癌（gelatinous carcinoma）、巨細胞癌（giant cell carcinoma）、印戒細胞癌（signet-ring cell carcinoma）、單純癌、小細胞癌、馬鈴薯狀癌、球狀細胞癌、梭形細胞癌、髓狀癌、鱗狀癌、鱗狀細胞癌、繩捆癌（string carcinoma）、毛細管擴張癌（carcinoma telangiectaticum）、毛細管擴張性癌（carcinoma telangiectodes）、移行細胞癌、塊狀癌、結節性皮癌、疣狀癌、絨毛狀癌、巨細胞癌（carcinoma gigantocellulare）、腺體癌（glandular carcinoma）、粒層細胞癌、毛基質細胞癌（hair-matrix carcinoma）、血樣癌、肝細胞癌、許特耳細胞癌（Hurthle cell carcinoma）、玻質狀癌、腎上腺樣癌、幼稚型胚胎性癌、原位癌、表皮內癌、上皮內癌、克羅姆佩柯赫爾氏腫瘤（Krompecher's carcinoma）、庫爾契茨基氏細胞癌（Kulchitzky-cell carcinoma）、大細胞癌、豆狀癌（lenticular carcinoma）、豆樣癌（carcinoma lenticulare）、脂瘤樣癌、淋巴上皮癌、髓樣癌、髓質癌、黑色素癌、軟癌、黏液性癌（mucinous carcinoma）、黏液癌（carcinoma muciparum）、黏液細胞癌（carcinoma mucocellulare）、黏液表皮樣癌、黏膜癌（carcinoma mucosum）、黏膜性癌（mucous carcinoma）、黏液瘤樣癌、鼻咽癌、燕麥狀細胞癌、骨化性癌、骨質癌（osteoid carcinoma）、乳頭狀癌、門靜脈周癌、浸潤前癌、棘細胞癌、糜爛性癌、腎臟的腎細胞癌、儲備細胞癌、肉瘤樣癌、施奈德氏癌（schneiderian carcinoma）、硬性癌（scirrhous carcinoma）及陰囊癌（carcinoma scroti）。In some embodiments, the methods and solid dosage forms provided herein relate to cancer treatment. The term "carcinoma" refers to the malignant growth of epithelial cells, which often infiltrate surrounding tissues and/or inhibit physiological and non-physiological cell death signals and produce metastasis. Non-limiting exemplary types of cancers include acinar carcinoma, acinoid carcinoma, adenoid cystoid carcinoma, adenoid cystic carcinoma, adenocarcinoma (carcinoma adenomatosum), adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma (Basal cell carcinoma), basal cell carcinoma (carcinoma basocellulare), basal cell carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, brain cancer, cholangiocarcinoma, choriocarcinoma, colloid Cancer, acne cancer, uterine body cancer, cribriform carcinoma, thyroid carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, carcinoma durum, embryonic carcinoma, encephaloid carcinoma , Epidermoid carcinoma, adenoid epithelial cell carcinoma, explant carcinoma, ulcerative carcinoma, fibrous carcinoma, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, signet ring cell Carcinoma (signet-ring cell carcinoma), simple carcinoma, small cell carcinoma, potato-like carcinoma, spheroid cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous carcinoma, squamous cell carcinoma, string carcinoma , Carcinoma telangiectaticum (carcinoma telangiectaticum), telangiectodes (carcinoma telangiectodes), transitional cell carcinoma, massive carcinoma, nodular skin carcinoma, verrucous carcinoma, villous carcinoma, giant cell carcinoma (carcinoma gigantocellulare), glandular carcinoma (Glandular carcinoma), granular cell carcinoma, hair-matrix carcinoma, blood-like carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, vitreous carcinoma, adrenal carcinoma, naive Embryonic carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, legume Lenticular carcinoma, carcinoma lenticulare, lipoma-like carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinoma muciparum ), mucocellular carcinoma (carcinoma mucocellulare), mucoepidermoid carcinoma, mucosal carcinoma (carcinoma mucosum), mucosal carcinoma (mucous carcinoma), myxoma-like carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, spine Cell carcinoma, erosive carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma and carcinoma scroti.

在一些實施方式中，本文提供之方法及固體劑型涉及肉瘤的治療。術語「肉瘤」通常是指如胚胎結締組織等物質組成的腫瘤且通常由包埋於原纖維、異質或均質物質中的緊密堆積細胞構成。肉瘤包括但不限於軟骨肉瘤、纖維肉瘤、淋巴肉瘤、黑色素肉瘤、黏液肉瘤、骨肉瘤、子宮內膜肉瘤、基質肉瘤、尤文氏肉瘤（Ewing' s sarcoma）、筋膜肉瘤、成纖維細胞性肉瘤、巨細胞肉瘤、艾伯內西氏肉瘤（Abemethy's sarcoma）、脂肪肉瘤、脂肉瘤、軟組織腺泡狀肉瘤、釉質母細胞肉瘤、葡萄形肉瘤、綠色肉瘤、絨毛膜癌、胚胎性肉瘤、維爾姆斯氏腫瘤肉瘤（Wilms' tumor sarcoma）、粒細胞肉瘤、何傑金氏肉瘤（Hodgkin's sarcoma）、特發性多發性色素沈著出血性肉瘤、B細胞免疫母細胞肉瘤、淋巴瘤、T細胞免疫母細胞肉瘤、晏森氏肉瘤（Jensen's sarcoma）、卡波西氏肉瘤（Kaposi's sarcoma）、庫普弗細胞肉瘤（Kupffer cell sarcoma）、血管肉瘤、白血病性肉瘤、惡性間葉瘤肉瘤、骨周肉瘤、網狀細胞肉瘤、勞斯肉瘤（Rous sarcoma）、漿液囊性肉瘤、滑膜肉瘤及毛細血管擴張性肉瘤。In some embodiments, the methods and solid dosage forms provided herein relate to the treatment of sarcoma. The term "sarcoma" generally refers to a tumor composed of materials such as embryonic connective tissue and is usually composed of tightly packed cells embedded in fibrils, heterogeneous or homogeneous materials. Sarcomas include but are not limited to chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma , Giant cell sarcoma, Abemethy's sarcoma (Abemethy's sarcoma), liposarcoma, liposarcoma, soft tissue acinar sarcoma, ameloblastic sarcoma, botryoid sarcoma, green sarcoma, choriocarcinoma, embryonal sarcoma, Wilms Wilms' tumor sarcoma (Wilms' tumor sarcoma), granulocytic sarcoma, Hodgkin's sarcoma (Hodgkin's sarcoma), idiopathic multiple pigmented hemorrhagic sarcoma, B cell immunoblastic sarcoma, lymphoma, T cell immunoblast Cell sarcoma, Jensen’s sarcoma, Kaposi’s sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, periosteal sarcoma, Reticular cell sarcoma, Rous sarcoma (Rous sarcoma), serous cystic sarcoma, synovial sarcoma and telangiectatic sarcoma.

可使用本文描述之方法及固體劑型治療的另外的示例性腫瘤包括霍奇金病（Hodgkin’s Disease）、非何杰金氏淋巴瘤、多發性骨髓瘤、神經母細胞瘤、乳癌、卵巢癌、肺癌、橫紋肌肉瘤、原發性血小板增多症、原發性巨球蛋白血症、小細胞肺腫瘤、原發性腦腫瘤、胃癌、大腸癌、惡性胰臟胰島素瘤、惡性類癌、癌前皮膚病變、睪丸癌、淋巴瘤、甲狀腺癌、神經母細胞瘤、食道癌、泌尿生殖道癌、惡性高鈣血症、宮頸癌、子宮內膜癌、漿細胞瘤、結直腸癌、直腸癌及腎上腺皮質癌。Additional exemplary tumors that can be treated using the methods and solid dosage forms described herein include Hodgkin's Disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer , Rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small cell lung tumors, primary brain tumors, gastric cancer, colorectal cancer, malignant pancreatic insulinoma, malignant carcinoid, precancerous skin lesions , Testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, plasmacytoma, colorectal cancer, rectal cancer and adrenal cortex cancer.

在一些實施方式中，所治療的癌症係黑色素瘤。術語「黑色素瘤」意指源自皮膚及其他器官的黑色素細胞系統的腫瘤。黑色素瘤的非限制性實例係哈-巴二氏黑色素瘤（Harding-Passey melanoma）、幼年型黑色素瘤、惡性小痣性痣黑色素瘤、惡性黑色素瘤、肢端小痣性黑色素瘤、無黑色素性黑色素瘤、良性幼年型黑色素瘤、克勞德曼氏黑色素瘤（Cloudman's melanoma）、S91黑色素瘤、結節性黑色素瘤甲下黑色素瘤及淺表擴展性黑色素瘤。In some embodiments, the cancer being treated is melanoma. The term "melanoma" means a tumor derived from the melanocyte system of the skin and other organs. Non-limiting examples of melanoma are Harding-Passey melanoma (Harding-Passey melanoma), juvenile melanoma, malignant mole melanoma, malignant melanoma, acral mole melanoma, non-melanoma Melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma subungual melanoma, and superficial expanded melanoma.

可使用本文描述之方法及固體劑型治療的腫瘤的特定類別包括淋巴組織增生性疾病、乳癌、卵巢癌、前列腺癌、宮頸癌、子宮內膜癌、骨癌、肝癌、胃癌、大腸癌、胰臟癌、甲狀腺癌、頭頸癌、中樞神經系統的癌症、外周神經系統的癌症、皮膚癌、腎癌、及所有上述的轉移。特定類型的腫瘤包含肝細胞癌、肝細胞瘤、肝母細胞瘤、橫紋肌肉瘤、食管癌、甲狀腺癌、惡性神經節瘤、纖維肉瘤、黏液肉瘤、脂肉瘤、軟骨肉瘤、成骨性肉瘤、脊索瘤、血管肉瘤、內皮肉瘤、尤文氏腫瘤、平滑肌肉瘤、橫紋肌內皮肉瘤、侵襲性導管癌、乳頭狀腺癌、黑色素瘤、肺鱗狀細胞癌、基底細胞癌、腺癌（充分分化、中等分化、分化不良或未分化）、支氣管肺泡癌、腎細胞癌、腎上腺樣瘤、腎上腺樣腺癌、膽管癌、絨毛膜癌、精原細胞瘤、胚胎性癌、維爾姆斯氏腫瘤、睾丸腫瘤、肺癌（包含小細胞肺癌、非小細胞肺癌及大細胞肺癌）、膀胱癌、神經膠質瘤、星形細胞瘤、髓母細胞瘤、顱咽管瘤、室管膜瘤、松果體瘤、視網膜母細胞瘤、神經母細胞瘤、大腸癌、直腸癌、血液系統惡性腫瘤（包含所有類型的白血病及淋巴瘤，包含：急性髓性白血病、急性髓細胞性白血病、急性淋巴細胞性白血病、慢性髓性白血病、慢性淋巴球性白血病、肥大細胞白血病、多發性骨髓瘤、髓樣淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、漿細胞瘤、結直腸癌及直腸癌。Specific categories of tumors that can be treated using the methods and solid dosage forms described herein include lymphoproliferative diseases, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, gastric cancer, colorectal cancer, and pancreas. Cancer, thyroid cancer, head and neck cancer, central nervous system cancer, peripheral nervous system cancer, skin cancer, kidney cancer, and all the above-mentioned metastases. Specific types of tumors include hepatocellular carcinoma, hepatocytoma, hepatoblastoma, rhabdomyosarcoma, esophageal cancer, thyroid cancer, malignant ganglioma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, notochord Tumor, angiosarcoma, endothelial sarcoma, Ewing’s tumor, leiomyosarcoma, rhabdomyoendothelioma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, lung squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (fully differentiated, moderately differentiated , Poorly differentiated or undifferentiated), bronchoalveolar carcinoma, renal cell carcinoma, adrenoid tumor, adrenal adenocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonic carcinoma, Wilms’ tumor, testicular tumor, Lung cancer (including small cell lung cancer, non-small cell lung cancer and large cell lung cancer), bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, retina Blastoma, neuroblastoma, colorectal cancer, rectal cancer, hematological malignancies (including all types of leukemia and lymphoma, including: acute myeloid leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia Leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, medullary lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, plasmacytoma, colorectal cancer and rectal cancer.

某些實施方式中所治療的癌症還包含癌症前期病灶，例如光化性角化病（日光性角化病）、莫耳痣（發育異常痣）、光化性唇炎（農夫唇）、皮角、巴瑞特氏食管症（Barrett's esophagus）、萎縮性胃炎、先天性角化不良、缺鐵性咽下困難、扁平苔蘚、口腔黏膜下纖維化、光化性（日光性）彈性組織變性及子宮頸發育不良。The cancer treated in some embodiments also includes precancerous lesions, such as actinic keratosis (actinic keratosis), moles (dysplastic nevi), actinic cheilitis (farmers’ lips), skin Angle, Barrett’s esophagus, atrophic gastritis, congenital dyskeratosis, iron-deficiency dysphagia, lichen planus, oral submucosal fibrosis, actinic (sun-induced) elastic tissue degeneration, and Cervical dysplasia.

一些實施方式中所治療的癌症包含非癌性或良性腫瘤，例如內胚層、外胚層或間質起源的腫瘤，包括但不限於膽管瘤、結腸息肉、腺瘤、乳頭瘤、囊腺瘤、肝細胞腺瘤、葡萄胎、腎小管腺瘤、鱗狀細胞乳頭瘤、胃息肉、血管瘤、骨瘤、軟骨瘤、脂肪瘤、纖維瘤、淋巴管瘤、平滑肌瘤、橫紋肌瘤、星形細胞瘤、痣、腦膜瘤及神經節瘤。 其他疾病及障礙The cancer to be treated in some embodiments includes non-cancerous or benign tumors, such as tumors of endoderm, ectoderm, or mesenchymal origin, including but not limited to cholangiomas, colon polyps, adenomas, papillomas, cystadenoma, liver Cell adenoma, hydatidiform mole, renal tubular adenoma, squamous cell papilloma, gastric polyp, hemangioma, osteoma, chondroma, lipoma, fibroma, lymphangioma, leiomyoma, rhabdomyomas, astrocytes Tumors, moles, meningiomas and gangliomas. Other diseases and disorders

在一些實施方式中，本文描述之方法及固體劑型涉及肝疾病的治療。此疾病包括（但不限於）阿拉吉爾綜合症（Alagille Syndrome）、酒精相關肝病、α-1抗胰蛋白酶缺乏症、自體免疫性肝炎、良性肝腫瘤、膽管閉鎖、肝硬化、半乳糖血症、吉伯特綜合症、血色素沈著病、A型肝炎、B型肝炎、C型肝炎、肝性腦病、妊娠期肝內膽汁淤積症（ICP）、溶酶體酸脂肪酶缺乏症（LAL-D）、肝囊腫、肝癌、新生兒黃疸、原發性膽汁性膽管炎（PBC）、原發性硬化性膽管炎（PSC）、雷氏綜合症（Reye Syndrome）、I型糖原貯積病及威爾森病（Wilson Disease）。In some embodiments, the methods and solid dosage forms described herein relate to the treatment of liver disease. This disease includes (but is not limited to) Alagille Syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, benign liver tumors, bile duct atresia, liver cirrhosis, galactosemia , Gilbert syndrome, hemochromatosis, hepatitis A, hepatitis B, hepatitis C, hepatic encephalopathy, intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D) ), liver cysts, liver cancer, neonatal jaundice, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Reye Syndrome, type I glycogen storage disease and Wilson Disease.

本文描述之方法及固體劑型可用以治療神經退化性及神經性疾病。在某些實施方式中，神經退化性和/或神經性疾病係巴金森氏病、阿爾茲海默症、普里昂疾病、亨廷頓病、運動神經元疾病（MND）、脊髓小腦共濟失調、脊髓性肌萎縮症、肌張力障礙、特發性顱內高壓、癲癇、神經系統疾病、中樞神經系統疾病、運動障礙、多發性硬化、腦病、周圍神經病變或術後認知功能障礙。 菌群失調The methods and solid dosage forms described herein can be used to treat neurodegenerative and neurological diseases. In certain embodiments, the neurodegenerative and/or neurological disease is Parkinson’s disease, Alzheimer’s disease, Prion’s disease, Huntington’s disease, motor neuron disease (MND), spinocerebellar ataxia, spinal cord Muscular dystrophy, dystonia, idiopathic intracranial hypertension, epilepsy, neurological disease, central nervous system disease, dyskinesia, multiple sclerosis, encephalopathy, peripheral neuropathy, or postoperative cognitive dysfunction. Dysbacteriosis

近年來，越來越清楚的是，腸道微生物組（也稱為「腸道微生物群」）可藉由微生物對宿主的免疫細胞和其它細胞的活性以及影響（局部和/或遠端）對個體健康產生顯著影響（Walker, W.A., Dysbiosis [菌群失調]. The Microbiota in Gastrointestinal Pathophysiology [胃腸道病理生理學中的微生物.] 第二十五章. 2017；Weiss和Thierry, Mechanisms and consequences of intestinal dysbiosis[腸道菌群失調的機制和後果].Cellular and Molecular Life Sciences [細胞與分子生命科學]. (2017) 74 (16): 2959-2977. Zurich Open Repository and Archive[蘇黎世開放存儲庫和檔案館], doi: https://doi.org/10.1007/s00018-017-2509-x)）。In recent years, it has become increasingly clear that the intestinal microbiome (also known as the "gut microbiota") can affect the host's immune cells and other cell activity and influence (local and/or remote) by microorganisms. Individual health has a significant impact (Walker, WA, Dysbiosis [Bacterial imbalance]. The Microbiota in Gastrointestinal Pathophysiology [Gastrointestinal Pathophysiology.] Chapter 25. 2017; Weiss and Thierry, Mechanisms and consequences of intestinal dysbiosis[Mechanisms and consequences of intestinal flora imbalance]. Cellular and Molecular Life Sciences [Cell and Molecular Life Sciences]. (2017) 74 (16): 2959-2977. Zurich Open Repository and Archive[ Zurich Open Repository and Archive Hall], doi: https://doi.org/10.1007/s00018-017-2509-x)).

健康的宿主腸道微生物組穩態有時被稱為「生態平衡」或「正常微生物」，而宿主微生物組的組成和/或其多樣性的有害變化可能導致微生物組的不健康失衡，或「菌群失調」（Hooks和O'Malley.Dysbiosis and its discontents [菌群失調及其不滿]. American Society for Microbiology [美國微生物學會]. 2017年10月. 第8卷. 第5期. mBio 8: e01492-17. https://doi.org/10.1128/mBio.01492-17）。當微生物組穩態喪失或減弱時，可能會發生菌群失調以及相關的局部或遠端宿主發炎或免疫效應，從而導致：對病原體的敏感性增加；宿主細菌代謝活性改變；誘導宿主促炎活性和/或降低宿主抗炎活性。此類效應部分地由宿主免疫細胞（例如，T細胞、樹突細胞、肥大細胞、NK細胞、腸上皮淋巴細胞（IEC）、巨噬細胞和吞噬細胞）和細胞介素，以及由此類細胞和其它宿主細胞釋放的其他物質之間的相互作用介導。The homeostasis of a healthy host's gut microbiome is sometimes referred to as "ecological balance" or "normal microorganisms", and harmful changes in the composition and/or diversity of the host microbiome may lead to unhealthy imbalances in the microbiome, or "bacteria Dysbiosis and its discontents " (Hooks and O'Malley. Dysbiosis and its discontents). American Society for Microbiology [American Society for Microbiology]. October 2017. Vol. 8, No. 5. mBio 8: e01492 -17. https://doi.org/10.1128/mBio.01492-17). When the microbiome homeostasis is lost or weakened, flora imbalance and related local or remote host inflammation or immune effects may occur, resulting in: increased sensitivity to pathogens; changes in host bacterial metabolic activity; induction of host pro-inflammatory activity And/or reduce the host's anti-inflammatory activity. Such effects are partly determined by host immune cells (eg, T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (IEC), macrophages and phagocytes) and cytokines, as well as by such cells Interactions with other substances released by other host cells are mediated.

菌群失調可能發生在胃腸道內（「胃腸道菌群失調」或「腸道菌群失調」），或者可能發生在胃腸道內腔外（「遠端菌群失調」）。胃腸菌群失調通常與腸上皮屏障完整性降低、緊密連接完整性降低和腸通透性增加有關。Citi, S. Intestinal Barriers protect against disease [腸屏障可預防疾病],Science [科學] 359: 1098-99 (2018); Srinivasan等人., TEER measurement techniques for in vitro barrier model systems [用於體外屏障模型系統的TEER測量技術].J. Lab. Autom. [實驗室自動化雜誌] 20: 107-126 (2015)。胃腸道菌群失調可以在胃腸道內外產生生理和免疫作用。Bacterial dysbiosis may occur in the gastrointestinal tract ("gastrointestinal dysbacteriosis" or "intestinal dysbiosis"), or it may occur outside the lumen of the gastrointestinal tract ("distal dysbacteriosis"). Disorders of gastrointestinal flora are usually associated with decreased integrity of the intestinal epithelial barrier, decreased integrity of tight junctions, and increased intestinal permeability. Citi, S. Intestinal Barriers protect against disease [Intestinal Barriers protect against disease], Science [Science] 359: 1098-99 (2018); Srinivasan et al., TEER measurement techniques for in vitro barrier model systems [For in vitro barrier model systems Systematic TEER measurement technology]. J. Lab. Autom. [Journal of Laboratory Automation] 20: 107-126 (2015). The imbalance of the gastrointestinal flora can produce physiological and immune effects inside and outside the gastrointestinal tract.

菌群失調的存在已與多種疾病和病症相關，包括：感染、癌症、自體免疫失調症（例如全身性紅斑狼瘡（SLE））或炎性失調症（例如功能性胃腸道疾病，例如炎性腸病（IBD）、潰瘍性結腸炎和克羅恩氏病）、神經炎性疾病（例如多發性硬化症）、移植失調症（例如移植物抗宿主病）、脂肪肝疾病、I型糖尿病、類風濕性關節炎、乾燥綜合症、乳糜瀉、囊性纖維化，慢性阻塞性肺病（COPD）以及其他與免疫功能障礙相關的疾病和病症。Lynch等人, The Human Microbiome in Health and Disease [健康與疾病中的人類微生物組],N. Engl. J. Med. 375: 2369-79 (2016)，Carding等人, Dysbiosis of the gut microbiota in disease [疾病中腸道微生物的菌群失調].Microb. Ecol. Health Dis. [微生物生態與健康疾病] (2015); 26: 10: 3402/mehd.v26.2619; Levy等人, Dysbiosis and the Immune System [菌群失調和免疫系統],Nature Reviews Immunology [自然評論免疫學] 17: 219 (2017年4月)。The presence of dysbacteriosis has been associated with a variety of diseases and conditions, including: infection, cancer, autoimmune disorders (such as systemic lupus erythematosus (SLE)) or inflammatory disorders (such as functional gastrointestinal diseases, such as inflammatory Bowel disease (IBD), ulcerative colitis and Crohn’s disease), neuroinflammatory diseases (such as multiple sclerosis), transplant disorders (such as graft-versus-host disease), fatty liver disease, type I diabetes, Rheumatoid arthritis, Sjogren’s syndrome, celiac disease, cystic fibrosis, chronic obstructive pulmonary disease (COPD) and other diseases and disorders related to immune dysfunction. Lynch et al., The Human Microbiome in Health and Disease, N. Engl. J. Med. 375: 2369-79 (2016), Carding et al., Dysbiosis of the gut microbiota in disease [Dysbiosis of gut microbes in diseases]. Microb. Ecol. Health Dis. [Microbial Ecology and Health Diseases] (2015); 26: 10: 3402/mehd.v26.2619; Levy et al., Dysbiosis and the Immune System [Bacterial imbalance and immune system], Nature Reviews Immunology [Nature Reviews Immunology] 17: 219 (April 2017).

本文所揭露的示例性藥物組成物和/或固體劑型可以藉由修飾存在於菌群失調部位的免疫活性來治療菌群失調及其影響。如本文所述，此類組成物可藉由對宿主免疫細胞的作用（導致例如抗炎細胞介素的分泌增加和/或促炎細胞介素的分泌減少，從而減輕受試接受者的炎症）或藉由代謝產物生產的變化來修飾菌群失調。The exemplary pharmaceutical composition and/or solid dosage form disclosed herein can treat the dysbacteriosis and its effects by modifying the immune activity present at the site of the dysbacteriosis. As described herein, such compositions can act on the host's immune cells (resulting in, for example, increased secretion of anti-inflammatory cytokines and/or decreased secretion of pro-inflammatory cytokines, thereby reducing inflammation in the subject) Or modify the imbalance of the flora by changes in the production of metabolites.

本文揭露的可用於治療與菌群失調相關的障礙的示例性藥物組成物和/或固體劑型包含一種或多種類型的免疫調節細菌（例如抗炎細菌）和/或由此類細菌產生的mEV（微生物胞外囊泡）。這樣的組成物能夠影響接受者宿主在胃腸道中的免疫功能，和/或在受試者胃腸道外的遠端部位產生系統性作用。The exemplary pharmaceutical compositions and/or solid dosage forms disclosed herein that can be used to treat disorders related to flora disorders include one or more types of immunomodulatory bacteria (such as anti-inflammatory bacteria) and/or mEVs produced by such bacteria ( Microbial extracellular vesicles). Such a composition can affect the immune function of the recipient host in the gastrointestinal tract, and/or produce a systemic effect at the remote site outside the gastrointestinal tract of the subject.

本文揭露的可用於治療與菌群失調相關的障礙的示例性藥物組成物和/或固體劑型包含單一細菌物種（例如，單一菌株）的免疫調節細菌（例如，抗炎細菌）的群體和/或由此類細菌產生的mEV。這樣的組成物能夠影響接受者宿主在胃腸道中的免疫功能，和/或在受試者胃腸道外的遠端部位產生系統性作用。The exemplary pharmaceutical compositions and/or solid dosage forms disclosed herein that can be used to treat disorders related to flora disorders include a population of immunomodulatory bacteria (eg, anti-inflammatory bacteria) of a single bacterial species (eg, a single strain) and/or MEV produced by such bacteria. Such a composition can affect the immune function of the recipient host in the gastrointestinal tract, and/or produce a systemic effect at the remote site outside the gastrointestinal tract of the subject.

在一個實施方式中，將包含經分離的免疫調節細菌（例如抗炎細菌細胞）群體或由此類細菌產生的mEV的藥物組成物和/或固體劑型以有效治療哺乳動物接受者的菌群失調和其一種或多種影響的量投與（例如口服）給該接受者。該菌群失調可以是胃腸道菌群失調或遠端菌群失調。In one embodiment, a pharmaceutical composition and/or solid dosage form comprising an isolated population of immunomodulatory bacteria (for example, anti-inflammatory bacterial cells) or mEV produced by such bacteria is used to effectively treat dysbacteriosis in a mammalian recipient And one or more of its effects are administered (for example, orally) to the recipient. The microflora disorder can be a gastrointestinal microflora disorder or a distal microflora disorder.

在另一個實施方式中，本發明之藥物組成物和/或固體劑型可以治療胃腸道菌群失調及其對宿主免疫細胞的一種或多種影響，導致抗炎細胞介素的分泌增加和/或促炎細胞介素的分泌減少，從而減輕受試接受者的炎症。In another embodiment, the pharmaceutical composition and/or solid dosage form of the present invention can treat gastrointestinal flora imbalance and one or more of its effects on host immune cells, leading to increased secretion of anti-inflammatory cytokines and/or promoting The secretion of inflammatory cytokines is reduced, thereby reducing inflammation in the test recipient.

在另一個實施方式中，藥物組成物和/或固體劑型可以藉由以下來治療胃腸道菌群失調及其一種或多種影響：經由細胞和細胞介素調節來調節接受者的免疫應答，以藉由增加腸上皮屏障的完整性來降低腸道通透性。In another embodiment, the pharmaceutical composition and/or solid dosage form can treat gastrointestinal flora imbalance and one or more of its effects by regulating the recipient’s immune response through cell and cytokine regulation, thereby Reduce intestinal permeability by increasing the integrity of the intestinal epithelial barrier.

在另一個實施方式中，藥物組成物和/或固體劑型可以藉由以下來治療遠端菌群失調及其一種或多種影響：經由調節宿主免疫細胞來調節菌群失調部位的接受者免疫應答。In another embodiment, the pharmaceutical composition and/or solid dosage form can treat the remote dysbacteriosis and one or more of its effects by regulating the immune response of the recipient at the site of the dysbacteriosis by regulating host immune cells.

其他示例性藥物組成物和/或固體劑型可用於治療與菌群失調有關的失調症，該等組成物包含一種或多種類型的細菌或mEV，該等細菌和/或mEV能夠改變接受者中的宿主免疫細胞亞群（例如T細胞、免疫淋巴樣細胞、樹突細胞、NK細胞和其他免疫細胞的亞群）相對比例或其功能。Other exemplary pharmaceutical compositions and/or solid dosage forms can be used to treat disorders related to flora disorders. These compositions include one or more types of bacteria or mEVs that can change the recipient’s The relative proportion of host immune cell subpopulations (such as T cells, immune lymphoid cells, dendritic cells, NK cells, and other immune cell subpopulations) or their functions.

其他示例性藥物組成物和/或固體劑型可用於治療與菌群失調有關的障礙，組成物包含單一細菌物種（例如，單一菌株）的免疫調節細菌和/或mEV的群體，其能夠改變接受者中免疫細胞亞群（例如T細胞亞群、免疫淋巴樣細胞、NK細胞和其他免疫細胞）的相對比例或其功能。Other exemplary pharmaceutical compositions and/or solid dosage forms can be used to treat disorders related to flora imbalance. The composition includes a population of immunomodulatory bacteria of a single bacterial species (eg, a single strain) and/or mEV, which can change the recipient The relative proportion of immune cell subpopulations (such as T cell subpopulations, immune lymphoid cells, NK cells and other immune cells) or their functions.

在一個實施方式中，本發明提供了藉由以下來治療胃腸道菌群失調及其一種或多種影響之方法：向有需要的受試者口服投與藥物組成物和/或固體劑型，該藥物組成物和/或固體劑型改變存在於菌群失調部位的微生物組群體。藥物組成物和/或固體劑型可以包含一種或多種類型的免疫調節細菌或mEV或單一細菌物種（例如，單一菌株）的免疫調節細菌和/或mEV的群體。In one embodiment, the present invention provides a method for treating gastrointestinal flora imbalance and one or more of its effects by: orally administering a pharmaceutical composition and/or solid dosage form to a subject in need, the drug The composition and/or solid dosage form changes the microbiome population present at the site of the dysbacteriosis. The pharmaceutical composition and/or solid dosage form may comprise one or more types of immunomodulatory bacteria or mEV or a population of immunomodulatory bacteria and/or mEV of a single bacterial species (for example, a single strain).

在一個實施方式中，本發明提供了藉由以下來治療遠端菌群失調及其一種或多種影響之方法：向有需要的受試者口服投與藥物組成物和/或固體劑型，該藥物組成物和/或固體劑型改變受試者的胃腸道外的免疫應答。藥物組成物和/或固體劑型可以包含一種或多種類型的免疫調節細菌或mEV或單一細菌物種（例如，單一菌株）的免疫調節細菌和/或mEV的群體。In one embodiment, the present invention provides a method for treating distal dysbacteriosis and one or more of its effects by: orally administering a pharmaceutical composition and/or solid dosage form to a subject in need, the drug The composition and/or solid dosage form alters the subject's immune response outside the gastrointestinal tract. The pharmaceutical composition and/or solid dosage form may comprise one or more types of immunomodulatory bacteria or mEV or a population of immunomodulatory bacteria and/or mEV of a single bacterial species (for example, a single strain).

在示例性實施方式中，可用於治療與菌群失調有關的障礙的藥物組成物和/或固體劑型刺激宿主免疫細胞分泌一種或多種抗炎細胞介素。抗炎細胞介素包括但不限於IL-10、IL-13、IL-9、IL-4、IL-5、TGFβ及其組合。在其他示例性實施方式中，可用於治療與菌群失調有關的障礙的藥物組成物和/或固體劑型減少（例如抑制）宿主免疫細胞分泌一種或多種促炎細胞介素。促炎細胞介素包括但不限於IFNγ、IL-12p70、IL-1α、IL-6、IL-8、MCP1、MIP1α、MIP1β、TNFα及其組合。其他示例性細胞介素係本領域已知的並且在本文中描述。In an exemplary embodiment, the pharmaceutical composition and/or solid dosage form that can be used to treat disorders related to the imbalance of the flora stimulate the host immune cells to secrete one or more anti-inflammatory cytokines. Anti-inflammatory cytokines include, but are not limited to, IL-10, IL-13, IL-9, IL-4, IL-5, TGFβ, and combinations thereof. In other exemplary embodiments, the pharmaceutical composition and/or solid dosage form that can be used to treat disorders related to dysbacteriosis reduces (for example, inhibits) the secretion of one or more pro-inflammatory cytokines by the host's immune cells. Pro-inflammatory cytokines include, but are not limited to, IFNγ, IL-12p70, IL-1α, IL-6, IL-8, MCP1, MIP1α, MIP1β, TNFα, and combinations thereof. Other exemplary cytokines are known in the art and described herein.

在另一方面，本發明提供了在有需要的受試者中治療或預防與菌群失調有關的障礙之方法，該方法包括向受試者投與（例如口服投與）益生菌食品或醫療食品形式的治療組成物，該治療組成物包含的細菌和/或mEV的數量足以改變菌群失調部位的微生物組，從而治療與菌群失調有關的障礙。In another aspect, the present invention provides a method for treating or preventing disorders related to dysbacteriosis in a subject in need thereof, the method comprising administering (eg orally administering) a probiotic food or medical treatment to the subject A therapeutic composition in the form of a food, the therapeutic composition contains bacteria and/or mEV in an amount sufficient to change the microbiome at the site of the dysbiosis, thereby treating disorders related to the dysbiosis.

在另一個實施方式中，益生菌食品或醫療食品形式的本發明之治療組成物可用於預防或延遲處於發展為菌群失調風險的受試者中菌群失調的發作。 製造增強的細菌之方法In another embodiment, the therapeutic composition of the present invention in the form of a probiotic food or medical food can be used to prevent or delay the onset of dysbacteriosis in subjects who are at risk of developing a dysbacteriosis. Method of making enhanced bacteria

在某些方面中，本文提供製造用於產生本文描述的細菌和/或mEV（例如smEV和/或pmEV）的工程改造的細菌之方法。在一些實施方式中，該等工程改造的細菌經修飾以增強某些所需性質。例如，在一些實施方式中，對工程改造的細菌進行修飾以增強細菌和/或mEV（例如smEV和/或pmEV）的免疫調節作用和/或治療效果（例如，單獨或與另一種治療劑組合），以降低毒性和/或改善細菌和/或mEV（例如smEV和/或pmEV）製造（例如更高的耐氧性、更高的抗凍融性、更短的產生時間）。工程改造的細菌可使用本領域中已知的任何技術產生，包括（但不限於）定點誘變、轉座子誘變、敲除、敲入、聚合酶鏈反應誘變、化學誘變、紫外線誘變、轉形（化學或藉由電穿孔）、噬菌體轉導、定向演化、CRISPR/Cas9或其任何組合。In certain aspects, provided herein are methods of making engineered bacteria used to produce the bacteria and/or mEVs described herein (eg, smEV and/or pmEV). In some embodiments, the engineered bacteria are modified to enhance certain desired properties. For example, in some embodiments, the engineered bacteria are modified to enhance the immunomodulatory effect and/or therapeutic effect of the bacteria and/or mEV (e.g., smEV and/or pmEV) (e.g., alone or in combination with another therapeutic agent) ) To reduce toxicity and/or improve the manufacture of bacteria and/or mEV (such as smEV and/or pmEV) (such as higher oxygen resistance, higher freeze-thaw resistance, shorter production time). The engineered bacteria can be produced using any technique known in the art, including (but not limited to) site-directed mutagenesis, transposon mutagenesis, knockout, knock-in, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light Mutagenesis, transformation (chemically or by electroporation), phage transduction, directed evolution, CRISPR/Cas9 or any combination thereof.

在本文提供之方法的一些實施方式中，細菌藉由定向演化進行修飾。在一些實施方式中，該定向演化包含將細菌暴露於環境條件並選擇在環境條件下具有經改善的存活和/或生長的細菌。在一些實施方式中，該方法包括使用識別增強的細菌的分析篩選誘變細菌。在一些實施方式中，該方法還包括誘變細菌（例如，藉由暴露於化學誘變劑和/或UV輻射），或將它們暴露於治療劑（例如抗生素），接著進行分析以檢測具有所需表型的細菌（例如，體內分析、離體分析或體外分析）。 感染In some embodiments of the methods provided herein, the bacteria are modified by directed evolution. In some embodiments, the directed evolution includes exposing bacteria to environmental conditions and selecting bacteria that have improved survival and/or growth under environmental conditions. In some embodiments, the method includes screening for mutagenized bacteria using an assay that recognizes enhanced bacteria. In some embodiments, the method further includes mutagenizing bacteria (for example, by exposure to chemical mutagens and/or UV radiation), or exposing them to therapeutic agents (for example antibiotics), followed by analysis to detect Bacteria requiring phenotype (for example, in vivo analysis, in vitro analysis, or in vitro analysis). Infect

炎症可以是對有害刺激（例如入侵病原體、受損細胞、有毒化合物或癌細胞）的保護性應答。但是，對這種刺激的過度炎性應答會導致嚴重的不利影響，包括組織損傷甚至死亡。例如，產生促炎性細胞介素（例如白血球介素8（IL-8）、白血球介素6（IL-6）、白血球介素1β（IL-1β）和腫瘤壞死因子α（TNFα））以應答許多病毒感染係與感染相關的不良症狀（在某些情況下包括死亡）的主要原因之一。例如，炎性細胞介素的釋放與多種病毒感染（包括冠狀病毒（例如，SARS-CoV-2、導致冠狀病毒病2019（COVID-19）的病毒、流感病毒和呼吸道合胞病毒）感染）引起的疾病嚴重程度有關。例如，患有嚴重COVID-19的患者經常在肺部表現出升高水平的炎性細胞介素，其促成COVID-19患者經歷的肺損傷。Inflammation can be a protective response to harmful stimuli, such as invading pathogens, damaged cells, toxic compounds, or cancer cells. However, an excessive inflammatory response to this stimulus can cause serious adverse effects, including tissue damage and even death. For example, the production of pro-inflammatory cytokines (such as interleukin 8 (IL-8), interleukin 6 (IL-6), interleukin 1β (IL-1β) and tumor necrosis factor α (TNFα)) Responding to many viral infections is one of the main causes of infection-related adverse symptoms (including death in some cases). For example, the release of inflammatory cytokines is caused by a variety of viral infections (including coronavirus (eg, SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), influenza virus, and respiratory syncytial virus)) Related to the severity of the disease. For example, patients with severe COVID-19 often show elevated levels of inflammatory cytokines in the lungs, which contribute to the lung damage experienced by COVID-19 patients.

在一些實施方式中，本文描述之方法和固體劑型涉及細菌性敗血症性休克、細胞介素風暴和/或病毒感染的治療或預防。在一些實施方式中，固體劑型包含棲組織普雷沃菌細菌（例如，普雷沃菌屬菌株B 50329（NRRL登錄號B 50329））。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of bacterial septic shock, interleukin storm, and/or viral infection. In some embodiments, the solid dosage form comprises Prevotella histobialis bacteria (eg, Prevotella strain B 50329 (NRRL accession number B 50329)).

在一些實施方式中，本文描述之方法和固體劑型涉及治療或預防病毒感染，例如呼吸道病毒感染，例如冠狀病毒感染（例如，MERS（中東呼吸綜合症），嚴重急性呼吸綜合症（SARS）感染，例如SARS-CoV-2感染），流感感染和/或呼吸道合胞病毒感染。在一些實施方式中，本文提供的本文描述之方法和固體劑型用於治療冠狀病毒感染（例如，MERS感染，嚴重急性呼吸綜合症（SARS）感染，例如SARS-CoV-2感染）。在一些實施方式中，本文提供了用於治療COVID-19之方法和固體劑型。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of viral infections, such as respiratory viral infections, such as coronavirus infections (eg, MERS (Middle East Respiratory Syndrome), Severe Acute Respiratory Syndrome (SARS) infections, Such as SARS-CoV-2 infection), influenza infection and/or respiratory syncytial virus infection. In some embodiments, the methods and solid dosage forms described herein provided herein are used to treat coronavirus infections (eg, MERS infection, severe acute respiratory syndrome (SARS) infection, such as SARS-CoV-2 infection). In some embodiments, methods and solid dosage forms for the treatment of COVID-19 are provided herein.

在一些實施方式中，本文描述之方法和固體劑型涉及病毒感染的治療或預防。在一些實施方式中，感染係冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染。在一些實施方式中，病毒感染係SARS-CoV-2感染。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of viral infections. In some embodiments, the infection is a coronavirus infection, influenza infection, and/or respiratory syncytial virus infection. In some embodiments, the viral infection is SARS-CoV-2 infection.

在一些實施方式中，向受試者投與另外的療法。在一些實施方式中，另外的療法包含抗病毒藥物。在一些實施方式中，另外的療法包含抗病毒藥物，例如利巴韋林、神經胺酸酶抑制劑、蛋白酶抑制劑、重組干擾素、抗體、奧司他韋、紮那米韋、帕拉米韋或巴羅薩韋瑪波酯。在一些實施方式中，另外的療法包含羥氯喹和/或氯喹。在一些實施方式中，另外的療法包含瑞德西韋。在一些實施方式中，另外的療法包含從感染受試者的相同病毒的感染中恢復的受試者的血漿（例如，從SARS-CoV-2感染中恢復的受試者的血漿）。在一些實施方式中，另外的療法包含抗炎劑，例如NSAID或抗炎類固醇。在一些實施方式中，另外的療法包括地塞米松。In some embodiments, additional therapies are administered to the subject. In some embodiments, the additional therapy comprises antiviral drugs. In some embodiments, the additional therapy comprises antiviral drugs, such as ribavirin, neuraminidase inhibitors, protease inhibitors, recombinant interferons, antibodies, oseltamivir, zanamivir, peramid Wei or Barossa Weimaporpate. In some embodiments, the additional therapy comprises hydroxychloroquine and/or chloroquine. In some embodiments, the additional therapy comprises remdesivir. In some embodiments, the additional therapy comprises the plasma of a subject that has recovered from an infection of the same virus that infected the subject (eg, the plasma of a subject that has recovered from a SARS-CoV-2 infection). In some embodiments, the additional therapy includes anti-inflammatory agents, such as NSAIDs or anti-inflammatory steroids. In some embodiments, the additional therapy includes dexamethasone.

在一些實施方式中，另外的療法包含對IL-6和/或IL-6受體具有特異性的抗體。在一些實施方式中，另外的療法包含托珠單抗（Actemra®）。在一些實施方式中，另外的療法包含薩瑞魯單抗（Kevzara®）。In some embodiments, the additional therapy comprises antibodies specific for IL-6 and/or IL-6 receptor. In some embodiments, the additional therapy comprises tocilizumab (Actemra®). In some embodiments, the additional therapy comprises sareruzumab (Kevzara®).

在一些實施方式中，另外的療法可以包含抗病毒療法。例如，抗病毒療法可包含核苷酸類似物，例如瑞德西韋、伽利德韋或克拉夫定；病毒RNA聚合酶抑制劑，例如法匹雷韋或伽利德韋；蛋白酶抑制劑，如利托那韋、達盧那韋或丹諾普韋；病毒膜融合抑制劑，如烏芬諾韋；和/或抗SARS-CoV-2血漿。In some embodiments, the additional therapy may include antiviral therapy. For example, antiviral therapy may include nucleotide analogs, such as remdesivir, galidevir, or clavudine; viral RNA polymerase inhibitors, such as fapirevir or galidevir; protease inhibitors, Such as ritonavir, dalunavir, or danoprevir; viral membrane fusion inhibitors, such as ufenovir; and/or anti-SARS-CoV-2 plasma.

在一些實施方式中，另外的療法可以包含係抗炎療法。例如，抗炎治療可以包含皮質類固醇；西羅莫司；阿那白滯素；filamod；或抗體。在一些實施方式中，抗體可以包含GMSF抑制劑，例如侖茲魯單抗或瑾司魯單抗；和抗IL1 β抑制劑，例如卡那單抗；IL-6抑制劑，例如托珠單抗或司妥昔單抗；IL-6R抑制劑，例如薩瑞魯單抗；和/或CCR5拮抗劑，例如leronlimab。In some embodiments, the additional therapy may include an anti-inflammatory therapy. For example, anti-inflammatory treatment may include corticosteroids; sirolimus; anakinra; filamod; or antibodies. In some embodiments, the antibody may comprise a GMSF inhibitor, such as renzrumumab or jinsrumumab; and an anti-IL1 β inhibitor, such as kanazumab; an IL-6 inhibitor, such as tocilizumab Or stuximab; IL-6R inhibitors, such as sareruzumab; and/or CCR5 antagonists, such as leronlimab.

在一些實施方式中，另外的療法可以包含JAK抑制劑，例如巴瑞替尼、盧梭替尼、托法替尼和/或帕利替尼。In some embodiments, the additional therapy may include a JAK inhibitor, such as baritinib, russotinib, tofacitinib, and/or palitinib.

在一些實施方式中，另外的療法可以包含TLR7促效劑，例如咪喹莫特或reisquimod。In some embodiments, the additional therapy may include a TLR7 agonist, such as imiquimod or reisquimod.

在一些實施方式中，另外的療法可以包含基於細胞的療法。例如，基於細胞的療法可以包含Remestemcel-L；骨髓幹細胞療法，例如MultiStem或Bm-Allo-MSC；間充質基質細胞；和/或脂肪衍生的間充質幹細胞，例如AstroStem。In some embodiments, additional therapies may include cell-based therapies. For example, cell-based therapy may include Remestemcel-L; bone marrow stem cell therapy, such as MultiStem or Bm-Allo-MSC; mesenchymal stromal cells; and/or adipose-derived mesenchymal stem cells, such as AstroStem.

在一些實施方式中，另外的療法可以包含ACE受體抑制劑。In some embodiments, the additional therapy may include an ACE receptor inhibitor.

在一些實施方式中，另外的療法可以包含σ1和/或σ2受體的調節劑。γ 照射：樣本方案： In some embodiments, the additional therapy may include modulators of sigma 1 and/or sigma 2 receptors. γ Irradiation: Sample plan:

粉末可以在環境溫度下以17.5 kGy輻射單位進行γ照射。冷凍生物量可以在乾冰存在下以25 kGy輻射單位進行γ照射。冷凍生物質製備：樣本方案 The powder can be gamma irradiated with 17.5 kGy radiation units at ambient temperature. Frozen biomass can be gamma irradiated with 25 kGy radiation units in the presence of dry ice. Frozen biomass preparation: sample plan

在達到所需水平的細菌培養物生長後，離心培養物，棄去上清液，使沈澱盡可能乾燥。渦旋沈澱以使生物質疏鬆。將沈澱重懸於所需的冷凍保護劑溶液中，轉移至低溫管中，並在液氮中速凍。儲存在-80攝氏度的冰箱中。粉末製備：樣本方案 After the bacterial culture has grown to the desired level, the culture is centrifuged, the supernatant is discarded, and the pellet is as dry as possible. Vortex the pellet to loosen the biomass. Resuspend the pellet in the desired cryoprotectant solution, transfer to a cryotube, and snap freeze in liquid nitrogen. Store in a refrigerator at -80 degrees Celsius. Powder preparation: sample plan

在達到所需水平的細菌培養物生長後，離心培養物，棄去上清液，使沈澱盡可能乾燥。將沈澱重懸於所需的冷凍保護劑溶液中，製成配製的細胞糊。冷凍保護劑可包含例如麥芽糊精、抗壞血酸鈉、麩胺酸鈉和/或氯化鈣。將配製的細胞糊裝載到不銹鋼託盤上，然後裝載到冷凍乾燥機中，例如以定義的循環參數以自動模式運行。將冷凍乾燥的產品送入研磨機中，並收集所得粉末。After the bacterial culture has grown to the desired level, the culture is centrifuged, the supernatant is discarded, and the pellet is as dry as possible. The pellet is resuspended in the desired cryoprotectant solution to prepare a prepared cell paste. The cryoprotectant may include, for example, maltodextrin, sodium ascorbate, sodium glutamate, and/or calcium chloride. The prepared cell paste is loaded on a stainless steel tray, and then loaded into a freeze dryer, for example, to run in an automatic mode with defined cycle parameters. The freeze-dried product is sent to the grinder, and the resulting powder is collected.

將粉末在2-8攝氏度（例如在4攝氏度）下，儲存於例如乾燥器中（例如真空密封袋中）。實例 實例1：製備具有更快崩散過程的固體劑型Store the powder at 2-8 degrees Celsius (for example, at 4 degrees Celsius), for example in a desiccator (for example, in a vacuum sealed bag). Examples Example 1: Preparation of solid dosage forms with faster disintegration process

製備表5中的以下核心配方，並且然後進行測試： [表 5 ]： 核心配方 組成 %（w/w） 乳酸乳球菌乳脂亞種粉末 25 甘露醇SD200 20 L-HPC（LH-B1） 32 交聯羧甲基纖維素鈉 （Ac-Di-Sol SD-711） 6 交聚維酮 15 硬脂酸鎂 1 膠體二氧化矽（Aerosil 200） 1 The following core formulas in Table 5 were prepared, and then tested: [ Table 5 ] : Core formulas composition %(W/w) Lactococcus lactis subsp. crema powder 25 Mannitol SD200 20 L-HPC (LH-B1) 32 Sodium Croscarmellose (Ac-Di-Sol SD-711) 6 Crospovidone 15 Magnesium stearate 1 Colloidal silica (Aerosil 200) 1

上面提到的乳酸乳球菌乳脂亞種菌株已經保藏為乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）。The aforementioned strain of Lactococcus lactis subsp. crema has been deposited as strain A of Lactococcus lactis subsp. crema (ATCC designation number PTA-125368).

進行了崩散研究，以查看該配方的18 mm片劑崩散的速度。這係針對750 mg的長18 mm的橢圓形片劑。將片劑在pH 1.2緩衝液中放置約2小時，然後將緩衝液轉變為pH 6.8緩衝液並測量崩散時間。A disintegration study was conducted to see how quickly the 18 mm tablets of this formulation disintegrated. This is for a 750 mg oval tablet with a length of 18 mm. The tablets were placed in a pH 1.2 buffer for about 2 hours, then the buffer was changed to a pH 6.8 buffer and the disintegration time was measured.

下表6中所示的所得平均崩散時間係平均時間。下表中的DT代表崩散時間（以分鐘:秒計）。 [表 6 ] 壓實力（kN） 生產速率（RPM） 厚度（mm） DT（mm:ss） TS（MPa） 重量（std） 脆性（%） 脫模力（N） 13.6 10.8 6.87 5:55 0.86 759.8 (3.4) 6.73 278 18.0 10.8 6.6 7:27 1.47 769.8 (6.1) 0.06 304 17.6 20.6 6.6 5:54 1.1 754.3 (1.8) 0.04 324 實例2: 製備包含小韋榮氏球菌的固體劑型The obtained average disintegration time shown in Table 6 below is the average time. DT in the table below stands for collapse time (in minutes: seconds). [ Table 6 ] Compressive strength (kN) Production rate (RPM) Thickness (mm) DT (mm:ss) TS (MPa) Weight (std) brittleness(%) Demoulding force (N) 13.6 10.8 6.87 5:55 0.86 759.8 (3.4) 6.73 278 18.0 10.8 6.6 7:27 1.47 769.8 (6.1) 0.06 304 17.6 20.6 6.6 5:54 1.1 754.3 (1.8) 0.04 324 Example 2: Preparation of solid dosage form containing Veillonella parvum

製備表7中的以下配方。 [表 7 ]： 小韋榮氏球菌片劑組成 組分 商品名稱/等級 % w/w       低劑量 高劑量 小韋榮氏球菌粉末 小韋榮氏球菌 8.0* 25.0* 甘露醇 Pearlitol 200SD 36.5* 19.5*             膠體二氧化矽 Aerosil 200P 1 1             交聚維酮 科利當CL-F 15 15             低取代的羥丙基纖維素 LH-B1 32 32             硬脂酸鎂 Ligamed MF-2V 1.5 1.5             交聯羧甲基纖維素鈉 Ac-Di-Sol SD-711 6 6 目標核心片劑重量（mg）    75 750             *根據DS（藥物物質）的效力進行了調整。這兩種組分的總百分比應占混合物的44.5% w/w。 The following formula in Table 7 was prepared. [ Table 7 ] : Composition of Veillonella minor tablets Component Product name/rank % w/w Low dose High dose Veillonella minor powder Veillonella parvum 8.0* 25.0* Mannitol Pearlitol 200SD 36.5* 19.5* Colloidal silica Aerosil 200P 1 1 Crospovidone Collidom CL-F 15 15 Low-substituted hydroxypropyl cellulose LH-B1 32 32 Magnesium stearate Ligamed MF-2V 1.5 1.5 Croscarmellose Sodium Ac-Di-Sol SD-711 6 6 Target core tablet weight (mg) 75 750 *Adjusted based on the effectiveness of DS (drug substance). The total percentage of these two components should account for 44.5% w/w of the mixture.

上面提到的小韋榮氏球菌菌株已被保藏為小韋榮氏球菌（ATCC指定編號PTA-125691）。The aforementioned strain of Veillonella parvum has been deposited as Veillonella parvum (ATCC designation number PTA-125691).

表7的低劑量組成物以5.5 mm圓形片劑提供。表7的高劑量組成物以18 mm x 8.5 mm橢圓形片劑提供。實例 3 ： 製備包含棲組織普雷沃菌的固體劑型The low-dose composition of Table 7 is provided in 5.5 mm round tablets. The high-dose composition of Table 7 is provided in 18 mm x 8.5 mm oval tablets. Example 3 : Preparation of solid dosage form containing Prevotella tissue

進行壓片，並且首先用歐巴代QX藍對製造的批次進行底包衣，然後再用Kollicoat MAE100P進行用於腸溶釋放的頂包衣。 [表 8 ]： 棲組織普雷沃菌片劑組成 材料 活性劑量（ % w/w ） 棲組織普雷沃菌菌株B（NRRL登錄號B 50329）粉末 25.0 甘露醇200 SD 19.5 L-HPC（LH-B1） 32.0 交聚維酮（科利當CL-F） 15.0 交聯羧甲基纖維素鈉（Ac-Di-Sol SD-711） 6.0 膠體二氧化矽（Aerosil 200） 1.0 硬脂酸酯鎂 1.5 總計 100.0 Compression is performed, and the manufactured batch is first coated with Opadry QX Blue and then top coated with Kollicoat MAE100P for enteric release. [ Table 8 ] : Composition of Prevotella tissue tablets Material Active dose ( % w/w ) Prevotella histosporum strain B (NRRL accession number B 50329) powder 25.0 Mannitol 200 SD 19.5 L-HPC (LH-B1) 32.0 Crospovidone (Colidan CL-F) 15.0 Sodium Croscarmellose (Ac-Di-Sol SD-711) 6.0 Colloidal silica (Aerosil 200) 1.0 Magnesium stearate 1.5 total 100.0

上面提到的棲組織普雷沃菌菌株已被保藏為棲組織普雷沃菌菌株B（NRRL登錄號B 50329）。The above-mentioned strain of Prevotella histosporum has been deposited as strain B of Prevotella histologica (NRRL accession number B 50329).

表8的劑量組成物以17.4 mm x 7.1 mm的片劑提供。 [表 9 ]： 底包衣組成物 材料 （ % w/w ） 歐巴代QX藍 15.00 WFI 85.00 總計 100.00 [表 10 ]頂包衣組成物 材料 （ % w/w ） Kollicoat MAE 100P 15.00 TEC 2.25 滑石 3.00 水 79.75 總計 100 The dosage composition of Table 8 is provided in 17.4 mm x 7.1 mm tablets. [ Table 9 ] : Bottom coating composition Material ( % w/w ) Opadry QX Blue 15.00 WFI 85.00 total 100.00 [ Table 10 ] Top coating composition Material ( % w/w ) Kollicoat MAE 100P 15.00 TEC 2.25 talc 3.00 water 79.75 total 100

每片劑的目標重量為650 mg（劑量強度為162.5 mg）。The target weight of each tablet is 650 mg (dose strength is 162.5 mg).

測試了二十四個以15%包衣重量的樣本（%係相對於片劑核心）在兩種介質（0.1 M HCl和pH 6.8磷酸鹽緩衝液）中的崩散，並且所得數據匯總於表11中。 [表 11 ]： N = 24 時活性片劑的崩散數據 包衣 % 片劑編號 0.1 M HCl pH 6.8 磷酸鹽緩衝液 第一失敗 失敗數 第一單元 最後單元 15% 1-6 DND 0 15 : 08 18 : 36 6-12 DND 0 16 : 29 19 : 39 13-18 DND 0 16 : 34 19 : 14 19-24 DND 0 14 : 29 17 : 53 DND: 沒有崩散 實例4：作為EV來源的代表性菌株Twenty-four samples with 15% coating weight (% relative to the tablet core) were tested for disintegration in two media (0.1 M HCl and pH 6.8 phosphate buffer), and the data obtained are summarized in the table 11 in. [ Table 11 ] : Disintegration data of active tablets when N = 24 Coating % Tablet number 0.1 M HCl pH 6.8 phosphate buffer First failure Number of failures The first unit Last unit 15% 1-6 DND 0 15: 08 18: 36 6-12 DND 0 16: 29 19: 39 13-18 DND 0 16: 34 19: 14 19-24 DND 0 14: 29 17: 53 DND: No disintegration. Example 4: A representative strain as a source of EV

從表J中列出的菌株中分離出分泌型微生物胞外囊泡（smEV）。表J中還提供了每種菌株的革蘭氏染色、細胞壁結構和分類學分類的資訊。Secretory microbial extracellular vesicles (smEV) were isolated from the strains listed in Table J. Table J also provides information on the Gram stain, cell wall structure and taxonomic classification of each strain.

表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌可以用於本文描述的固體劑型中。Bacteria from the taxonomic groups (eg, class, order, family, genus, species, or strain) listed in Table J can be used in the solid dosage forms described herein.

表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌的mEV可以用於本文描述的固體劑型中。 [表 J ]：胞外囊泡（ EV ）由其分離出的菌株 菌株 革蘭氏染色 細胞被膜結構 門 綱 目 科 狄氏副擬桿菌DRLU022118 A ILEUM-6 革蘭氏染色陰性 雙層 擬桿菌門 擬桿菌綱 擬桿菌目 卟啉單胞菌科 古氏副擬桿菌S4 革蘭氏染色陰性 雙層 擬桿菌門 擬桿菌綱 擬桿菌目 卟啉單胞菌科 棲組織普雷沃菌 革蘭氏染色陰性 雙層 擬桿菌門 擬桿菌綱 擬桿菌目 普雷沃菌科 棲組織普雷沃菌 革蘭氏染色陰性 雙層 擬桿菌門 擬桿菌綱 擬桿菌目 普雷沃菌科 Fournierella massiliensis S10 GIMucosa-297 革蘭氏染色陰性 單層 厚壁菌門 梭菌綱 真細菌目 顫螺旋菌科（以前為瘤胃菌科） Harryflintia acetispora S4-M5 革蘭氏染色陰性 單層 厚壁菌門 梭菌綱 真細菌目 顫螺旋菌科 馬賽布勞特氏菌S1046-4A5 革蘭氏染色陰性 單層 厚壁菌門 梭菌綱 真細菌目 毛螺菌科 地中海桿菌/活潑[瘤胃球菌] S10 GIMucosa-412 革蘭氏染色陰性 單層 厚壁菌門 梭菌綱 真細菌目 毛螺菌科 艱難梭菌S10 GImucosa-525 革蘭氏染色陽性 單層 厚壁菌門 梭菌綱 真細菌目 消化鏈球菌科 Aminipila 屬物種S16-M4 革蘭氏染色陽性 單層 厚壁菌門 梭菌綱 真細菌目 梭菌目XIII科/地位未定41/[真細菌目，無科] 巨型球菌屬物種S29-N3 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 巨型球菌屬物種S1007 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 菲利克斯月形單胞菌S34N-300R 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes Selenomonadales目 月形單孢菌科 小韋榮氏球菌S14Ileum-201 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 Propionispora 屬物種DSM100705-1A 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes Selenomonadales目 Sporomusaceae Rarimicrobium hominis S24RS2-T2-5 革蘭氏染色陰性 雙層 互養菌門 互養菌綱 互養菌目 互養菌科 埃夫裡氯酸桿菌S29-M8 革蘭氏染色陰性 雙層 互養菌門 互養菌綱 互養菌目 互養菌科 小韋榮氏球菌S14-205 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 韋榮氏球菌屬物種/殊異ECD01-DP-201 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 小韋榮氏球菌/殊異ECD01-DP-223 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 小韋榮氏球菌S16 GIMucosa-95 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 實例5：製備包含棲組織普雷沃菌的片劑The mEV of bacteria of the taxonomic groups (eg, class, order, family, genus, species, or strain) listed in Table J can be used in the solid dosage forms described herein. [ Table J ] : Strains isolated from extracellular vesicles ( EV) Strains s Cell envelope structure door Class Item division Parabacteroides dieni DRLU022118 A ILEUM-6 Gram stain negative Double layer Bacteroides Bacteroides Bacteroides Porphyromonaceae Parabacteroides greekii S4 Gram stain negative Double layer Bacteroides Bacteroides Bacteroides Porphyromonaceae Prevotella histobialis Gram stain negative Double layer Bacteroides Bacteroides Bacteroides Prevotaceae Prevotella histobialis Gram stain negative Double layer Bacteroides Bacteroides Bacteroides Prevotaceae Fournierella massiliensis S10 GIMucosa-297 Gram stain negative Single layer Firmicutes Clostridium Eubacteriales Oscillatoriaceae (formerly Rumenaceae) Harryflintia acetispora S4-M5 Gram stain negative Single layer Firmicutes Clostridium Eubacteriales Oscillospiraceae Blautella marseilles S1046-4A5 Gram stain negative Single layer Firmicutes Clostridium Eubacteriales Laospirillaceae Mediterranean Bacillus/Lively [Rumen Cocci] S10 GIMucosa-412 Gram stain negative Single layer Firmicutes Clostridium Eubacteriales Laospirillaceae Clostridium difficile S10 GImucosa-525 Gram stain positive Single layer Firmicutes Clostridium Eubacteriales Peptostreptococcaceae Aminipila species S16-M4 Gram stain positive Single layer Firmicutes Clostridium Eubacteriales Clostridial Order XIII Family/Status Undecided 41/[Eu Bacterial Order, No Family] Megacoccus species S29-N3 Gram stain negative Double layer Firmicutes Negativicutes Veillonella Veillonellaceae Megacoccus species S1007 Gram stain negative Double layer Firmicutes Negativicutes Veillonella Veillonellaceae Lunamonas felix S34N-300R Gram stain negative Double layer Firmicutes Negativicutes Selenomonadales Lunamonaceae Veillonella minor S14Ileum-201 Gram stain negative Double layer Firmicutes Negativicutes Veillonella Veillonellaceae Propionispora species DSM100705-1A Gram stain negative Double layer Firmicutes Negativicutes Selenomonadales Sporomusaceae Rarimicrobium hominis S24RS2-T2-5 Gram stain negative Double layer Syntrophic bacteria Syntrophic Bacteria Syntrophicles Syntrophicaceae Chlorobacter effrii S29-M8 Gram stain negative Double layer Syntrophic bacteria Syntrophic Bacteria Syntrophicles Syntrophicaceae Veillonella minor S14-205 Gram stain negative Double layer Firmicutes Negativicutes Veillonella Veillonellaceae Veillonella species/unique ECD01-DP-201 Gram stain negative Double layer Firmicutes Negativicutes Veillonella Veillonellaceae Veillonella minor/Special ECD01-DP-223 Gram stain negative Double layer Firmicutes Negativicutes Veillonella Veillonellaceae Veillonella minor S16 GIMucosa-95 Gram stain negative Double layer Firmicutes Negativicutes Veillonella Veillonellaceae Example 5: Preparation of tablets containing Prevotella tissue

製備表K中的以下配方。 [表 K ]：棲組織普雷沃菌片劑組成 材料 活性劑量（ % w/w ） 棲組織普雷沃菌菌株B （NRRL 登錄號 B 50329 ）粉末 23.0 甘露醇200 SD 21.5 L-HPC（LH-B1） 32.0 交聚維酮（科利當CL-F） 15.0 交聯羧甲基纖維素鈉（Ac-Di-Sol SD-711） 6.0 膠體二氧化矽（Aerosil 200） 1.0 硬脂酸酯鎂 1.5 總計 100.0 Prepare the following formula in Table K. [ Table K ] : Composition of Prevotella tissue tablets Material Active dose ( % w/w ) Prevotella histosporum strain B ( NRRL accession number B 50329 ) powder 23.0 Mannitol 200 SD 21.5 L-HPC (LH-B1) 32.0 Crospovidone (Colidan CL-F) 15.0 Sodium Croscarmellose (Ac-Di-Sol SD-711) 6.0 Colloidal silica (Aerosil 200) 1.0 Magnesium stearate 1.5 total 100.0

該片劑被製備為17.4 mm x 7.1 mm的片劑。The tablet was prepared as a 17.4 mm x 7.1 mm tablet.

該片劑被腸溶包衣。The tablets are enteric coated.

該片劑包含棲組織普雷沃菌菌株B（NRRL登錄號B 50329）的3.2 x 1011 TCC。 The tablet contains 3.2 x 10 11 TCC of Prevotella histosporum strain B (NRRL accession number B 50329).

上面提到的棲組織普雷沃菌菌株已被保藏為棲組織普雷沃菌菌株B（NRRL登錄號B 50329）。 藉由引用併入The above-mentioned strain of Prevotella histosporum has been deposited as strain B of Prevotella histologica (NRRL accession number B 50329). Incorporated by reference

在本文中提及的所有出版物、專利申請都藉由引用以其全文特此併入，如同各個單獨的出版物或專利申請被確切地並且單獨地指明為藉由引用併入。如果出現衝突，則以本申請（包含本文的任何定義）為准。 等效形式All publications and patent applications mentioned in this text are hereby incorporated by reference in their entirety, as if each individual publication or patent application is specifically and individually indicated as being incorporated by reference. In the event of a conflict, this application (including any definitions herein) shall prevail. Equivalent form

熟悉該項技術者僅使用常規實驗將認識到或能確定本文所述本發明之具體實例的許多等效形式。此類等效形式旨在為下列請求項所涵蓋。Those skilled in the art will recognize or be able to ascertain many equivalent forms of the specific examples of the invention described herein using only routine experimentation. Such equivalent forms are intended to be covered by the following claims.

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Claims (117)

一種藥物組成物的固體劑型，該固體劑型包含： 藥劑，其具有的藥劑總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的35%，其中該藥劑包含細菌和/或微生物胞外囊泡（mEV）； 低取代的羥丙基纖維素（L-HPC），其具有的L-HPC總質量係該藥物組成物總質量的至少22%且不超過該藥物組成物總質量的42%； 交聯羧甲基纖維素鈉，其具有的交聯羧甲基纖維素鈉總質量係該藥物組成物總質量的至少0.01%且不超過該藥物組成物總質量的16%；以及 交聚維酮，其具有的交聚維酮總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的25%。A solid dosage form of a pharmaceutical composition, the solid dosage form comprising: A medicament, which has a total mass of at least 5% of the total mass of the pharmaceutical composition and no more than 35% of the total mass of the pharmaceutical composition, wherein the medicament contains bacteria and/or microbial extracellular vesicles (mEV); Low-substituted hydroxypropyl cellulose (L-HPC), which has a total mass of L-HPC that is at least 22% of the total mass of the pharmaceutical composition and does not exceed 42% of the total mass of the pharmaceutical composition; Croscarmellose sodium, which has a total mass of croscarmellose sodium that is at least 0.01% of the total mass of the pharmaceutical composition and does not exceed 16% of the total mass of the pharmaceutical composition; and Crospovidone has a total mass of crospovidone that is at least 5% of the total mass of the pharmaceutical composition and does not exceed 25% of the total mass of the pharmaceutical composition. 如請求項1所述之固體劑型，其中該L-HPC總質量加上該交聯羧甲基纖維素鈉總質量加上該交聚維酮總質量係該藥物組成物總質量的至少40%。The solid dosage form according to claim 1, wherein the total mass of the L-HPC plus the total mass of the croscarmellose sodium plus the total mass of the crospovidone is at least 40% of the total mass of the pharmaceutical composition . 如請求項1所述之固體劑型，其中該L-HPC總質量加上該交聯羧甲基纖維素鈉總質量加上該交聚維酮總質量係該藥物組成物總質量的至少50%。The solid dosage form according to claim 1, wherein the total mass of the L-HPC plus the total mass of the croscarmellose sodium plus the total mass of the crospovidone is at least 50% of the total mass of the pharmaceutical composition . 如請求項1至3中任一項所述之固體劑型，其中該L-HPC係LH-B1級的L-HPC。The solid dosage form according to any one of claims 1 to 3, wherein the L-HPC is LH-B1 grade L-HPC. 如請求項1至4中任一項所述之固體劑型，其中該交聯羧甲基纖維素鈉係SD-711級的Ac-Di-Sol。The solid dosage form according to any one of claims 1 to 4, wherein the croscarmellose sodium is SD-711 grade Ac-Di-Sol. 如請求項1至5中任一項所述之固體劑型，其中 該L-HPC總質量係該藥物組成物總質量的至少27%且不超過該藥物組成物總質量的37%； 該交聯羧甲基纖維素鈉總質量係該藥物組成物總質量的至少1%且不超過該藥物組成物總質量的11%；並且 該交聚維酮總質量係該藥物組成物總質量的至少10%且不超過該藥物組成物總質量的20%。The solid dosage form according to any one of claims 1 to 5, wherein The total mass of the L-HPC is at least 27% of the total mass of the pharmaceutical composition and does not exceed 37% of the total mass of the pharmaceutical composition; The total mass of croscarmellose sodium is at least 1% of the total mass of the pharmaceutical composition and does not exceed 11% of the total mass of the pharmaceutical composition; and The total mass of crospovidone is at least 10% of the total mass of the pharmaceutical composition and does not exceed 20% of the total mass of the pharmaceutical composition. 如請求項1至6中任一項所述之固體劑型，其中 該L-HPC總質量係該藥物組成物總質量的至少31%且不超過該藥物組成物總質量的33%； 該交聯羧甲基纖維素鈉總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的7%；並且 該交聚維酮總質量係該藥物組成物總質量的至少14%且不超過該藥物組成物總質量的16%。The solid dosage form according to any one of claims 1 to 6, wherein The total mass of the L-HPC is at least 31% of the total mass of the pharmaceutical composition and does not exceed 33% of the total mass of the pharmaceutical composition; The total mass of croscarmellose sodium is at least 5% of the total mass of the pharmaceutical composition and does not exceed 7% of the total mass of the pharmaceutical composition; and The total mass of crospovidone is at least 14% of the total mass of the pharmaceutical composition and does not exceed 16% of the total mass of the pharmaceutical composition. 如請求項1至7中任一項所述之固體劑型，其中 該L-HPC總質量係該藥物組成物總質量的約32%； 該交聯羧甲基纖維素鈉總質量係藥物組成物總質量的約6%；並且 該交聚維酮總質量係該藥物組成物總質量的約15%。The solid dosage form according to any one of claims 1 to 7, wherein The total mass of the L-HPC is about 32% of the total mass of the pharmaceutical composition; The total mass of croscarmellose sodium is about 6% of the total mass of the pharmaceutical composition; and The total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. 一種藥物組成物的固體劑型，該固體劑型包含藥劑和一種或多種崩散劑，其中該一種或多種崩散劑的總質量係該藥物組成物總質量的至少40%，並且其中該藥劑包含細菌和/或微生物胞外囊泡（mEV）。A solid dosage form of a pharmaceutical composition, the solid dosage form comprising a medicament and one or more disintegrating powders, wherein the total mass of the one or more disintegrating powders is at least 40% of the total mass of the pharmaceutical composition, and wherein the medicament contains bacteria and/ Or microbial extracellular vesicles (mEV). 如請求項9所述之固體劑型，其中該一種或多種崩散劑包含L-HPC。The solid dosage form according to claim 9, wherein the one or more disintegrating agents comprise L-HPC. 如請求項10所述之固體劑型，其中該L-HPC係LH-B1級的L-HPC。The solid dosage form according to claim 10, wherein the L-HPC is LH-B1 grade L-HPC. 如請求項10或11所述之固體劑型，其中該L-HPC總質量係該藥物組成物總質量的至少22%且不超過該藥物組成物總質量的42%。The solid dosage form according to claim 10 or 11, wherein the total mass of the L-HPC is at least 22% of the total mass of the pharmaceutical composition and does not exceed 42% of the total mass of the pharmaceutical composition. 如請求項9至12中任一項所述之固體劑型，其中該一種或多種崩散劑包含交聯羧甲基纖維素鈉。The solid dosage form according to any one of claims 9 to 12, wherein the one or more disintegrating agents comprise croscarmellose sodium. 如請求項13所述之固體劑型，其中該交聯羧甲基纖維素鈉係SD-711級的Ac-Di-Sol。The solid dosage form according to claim 13, wherein the croscarmellose sodium is SD-711 grade Ac-Di-Sol. 如請求項13或14所述之固體劑型，其中該交聯羧甲基纖維素鈉總質量係該藥物組成物總質量的至少1%且不超過該藥物組成物總質量的16%。The solid dosage form according to claim 13 or 14, wherein the total mass of croscarmellose sodium is at least 1% of the total mass of the pharmaceutical composition and does not exceed 16% of the total mass of the pharmaceutical composition. 如請求項9至15中任一項所述之固體劑型，其中該一種或多種崩散劑包含交聚維酮。The solid dosage form according to any one of claims 9 to 15, wherein the one or more disintegrating agents comprise crospovidone. 如請求項16所述之固體劑型，其中該交聚維酮總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的25%。The solid dosage form according to claim 16, wherein the total mass of the crospovidone is at least 5% of the total mass of the pharmaceutical composition and does not exceed 25% of the total mass of the pharmaceutical composition. 如請求項9至17中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的35%。The solid dosage form according to any one of claims 9 to 17, wherein the total mass of the medicament is at least 5% of the total mass of the pharmaceutical composition and does not exceed 35% of the total mass of the pharmaceutical composition. 如請求項1至18中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的至少15%且不超過該藥物組成物總質量的35%。The solid dosage form according to any one of claims 1 to 18, wherein the total mass of the drug is at least 15% of the total mass of the drug composition and does not exceed 35% of the total mass of the drug composition. 如請求項1至18中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的至少20%且不超過該藥物組成物總質量的30%。The solid dosage form according to any one of claims 1 to 18, wherein the total mass of the drug is at least 20% of the total mass of the pharmaceutical composition and does not exceed 30% of the total mass of the pharmaceutical composition. 如請求項1至18中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的至少24%且不超過該藥物組成物總質量的26%。The solid dosage form according to any one of claims 1 to 18, wherein the total mass of the drug is at least 24% of the total mass of the drug composition and does not exceed 26% of the total mass of the drug composition. 如請求項1至18中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的約25%。The solid dosage form according to any one of claims 1 to 18, wherein the total mass of the medicament is about 25% of the total mass of the pharmaceutical composition. 如請求項1至22中任一項所述之固體劑型，該固體劑型進一步包含甘露醇，其具有的甘露醇總質量係該藥物組成物總質量的至少10%且不超過該藥物組成物總質量的40%。The solid dosage form according to any one of claims 1 to 22, the solid dosage form further comprising mannitol, which has a total mass of mannitol that is at least 10% of the total mass of the pharmaceutical composition and does not exceed the total mass of the pharmaceutical composition 40% of the quality. 如請求項1至23中任一項所述之固體劑型，該固體劑型進一步包含硬脂酸鎂，其具有的硬脂酸鎂總質量係該藥物組成物總質量的至少0.01%且不超過該藥物組成物總質量的10%。The solid dosage form according to any one of claims 1 to 23, the solid dosage form further comprising magnesium stearate, which has a total mass of magnesium stearate that is at least 0.01% of the total mass of the pharmaceutical composition and does not exceed the 10% of the total mass of the pharmaceutical composition. 如請求項1至24中任一項所述之固體劑型，該固體劑型進一步包含膠體二氧化矽，其具有的膠體二氧化矽總質量係該藥物組成物總質量的至少0.01%且不超過該藥物組成物總質量的10%。The solid dosage form according to any one of claims 1 to 24, the solid dosage form further comprising colloidal silica, the total mass of colloidal silica having at least 0.01% of the total mass of the pharmaceutical composition and not exceeding the 10% of the total mass of the pharmaceutical composition. 如請求項1至25中任一項所述之固體劑型，其中該藥劑包含細菌。The solid dosage form according to any one of claims 1 to 25, wherein the agent contains bacteria. 如請求項26所述之固體劑型，其中該細菌係凍乾的細菌。The solid dosage form according to claim 26, wherein the bacteria are freeze-dried bacteria. 如請求項1至27中任一項所述之固體劑型，其中該藥劑包含分離的細菌（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量））。The solid dosage form according to any one of claims 1 to 27, wherein the medicament comprises isolated bacteria (for example, from one or more bacterial strains (for example, bacteria of interest) (for example, a therapeutically effective amount thereof)). 如請求項1至28中任一項所述之固體劑型，其中該藥劑包含細菌，該細菌已經經γ照射、UV照射、熱滅活、酸處理或氧噴射。The solid dosage form according to any one of claims 1 to 28, wherein the medicament contains bacteria that have been γ-irradiated, UV-irradiated, heat-inactivated, acid-treated, or oxygen sprayed. 如請求項1至28中任一項所述之固體劑型，其中該藥劑包含活細菌。The solid dosage form according to any one of claims 1 to 28, wherein the medicament comprises live bacteria. 如請求項1至28中任一項所述之固體劑型，其中該藥劑包含死細菌。The solid dosage form according to any one of claims 1 to 28, wherein the medicament contains dead bacteria. 如請求項1至28中任一項所述之固體劑型，其中該藥劑包含非複製型細菌。The solid dosage form according to any one of claims 1 to 28, wherein the agent contains non-replicating bacteria. 如請求項1至32中任一項所述之固體劑型，其中該藥劑包含來自一種細菌菌株的細菌。The solid dosage form according to any one of claims 1 to 32, wherein the agent comprises bacteria derived from a bacterial strain. 如請求項1至33中任一項所述之固體劑型，其中該細菌被凍乾（例如，凍乾的產物還包含藥學上可接受的賦形劑）（例如，粉末形式）。The solid dosage form according to any one of claims 1 to 33, wherein the bacteria are lyophilized (for example, the lyophilized product further contains a pharmaceutically acceptable excipient) (for example, in powder form). 如請求項1至34中任一項所述之固體劑型，其中該細菌經γ照射。The solid dosage form according to any one of claims 1 to 34, wherein the bacteria are gamma-irradiated. 如請求項1至34中任一項所述之固體劑型，其中該細菌經UV照射。The solid dosage form according to any one of claims 1 to 34, wherein the bacteria are irradiated with UV. 如請求項1至34中任一項所述之固體劑型，其中該細菌經熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。The solid dosage form according to any one of claims 1 to 34, wherein the bacteria are heat-inactivated (for example, at 50°C for two hours or at 90°C for two hours). 如請求項1至34中任一項所述之固體劑型，其中該細菌經酸處理。The solid dosage form according to any one of claims 1 to 34, wherein the bacteria are acid-treated. 如請求項1至34中任一項所述之固體劑型，其中該細菌經氧噴射（例如，以0.1 vvm持續兩小時）。The solid dosage form according to any one of claims 1 to 34, wherein the bacteria are sprayed with oxygen (for example, at 0.1 vvm for two hours). 如請求項1至39中任一項所述之固體劑型，其中該細菌係革蘭氏陽性細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are Gram-positive bacteria. 如請求項1至39中任一項所述之固體劑型，其中該細菌係革蘭氏陰性細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are Gram-negative bacteria. 如請求項1至39中任一項所述之固體劑型，其中該細菌係需氧細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are aerobic bacteria. 如請求項1至39中任一項所述之固體劑型，其中該細菌係厭氧細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are anaerobic bacteria. 如請求項1至39中任一項所述之固體劑型，其中該細菌係嗜酸細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are acidophilic bacteria. 如請求項1至39中任一項所述之固體劑型，其中該細菌係嗜鹼細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacterium is an alkaliphilic bacterium. 如請求項1至39中任一項所述之固體劑型，其中該細菌係嗜中性細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are neutrophils. 如請求項1至39中任一項所述之固體劑型，其中該細菌係難養細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacterium is a refractory bacterium. 如請求項1至39中任一項所述之固體劑型，其中該細菌係非難養細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are non-difficult bacteria. 如請求項1至40中任一項所述之固體劑型，其中該細菌來自表1、表2或表3中列出的分類學組（例如，綱、目、科、屬、種或菌株）。The solid dosage form according to any one of claims 1 to 40, wherein the bacteria are from the taxonomic group listed in Table 1, Table 2 or Table 3 (for example, class, order, family, genus, species or strain) . 如請求項1至40中任一項所述之固體劑型，其中該細菌來自表1、表2或表3中列出的細菌菌株。The solid dosage form according to any one of claims 1 to 40, wherein the bacteria are from the bacterial strains listed in Table 1, Table 2 or Table 3. 如請求項1至40中任一項所述之固體劑型，其中該細菌來自表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。The solid dosage form according to any one of claims 1 to 40, wherein the bacteria are from the taxonomic group (for example, class, order, family, genus, species, or strain) listed in Table J. 如請求項1至40中任一項所述之固體劑型，其中該細菌來自表J中列出的細菌菌株。The solid dosage form according to any one of claims 1 to 40, wherein the bacteria are from the bacterial strains listed in Table J. 如請求項1至52中任一項所述之固體劑型，其中該藥劑包含微生物胞外囊泡（mEV）。The solid dosage form according to any one of claims 1 to 52, wherein the agent comprises microbial extracellular vesicles (mEV). 如請求項1至53中任一項所述之固體劑型，其中該藥劑包含分離的mEV（例如，來自一種或多種細菌菌株（例如，目的細菌））（例如，其治療有效量）。The solid dosage form according to any one of claims 1 to 53, wherein the medicament comprises isolated mEV (for example, from one or more bacterial strains (for example, bacteria of interest)) (for example, a therapeutically effective amount thereof). 如請求項1至54中任一項所述之固體劑型，其中該藥劑包含mEV，並且該mEV包含分泌型mEV（smEV）。The solid dosage form according to any one of claims 1 to 54, wherein the medicament comprises mEV, and the mEV comprises secreted mEV (smEV). 如請求項1至54中任一項所述之固體劑型，其中該藥劑包含mEV，並且該mEV包含經處理的mEV（pmEV）。The solid dosage form according to any one of claims 1 to 54, wherein the medicament comprises mEV, and the mEV comprises processed mEV (pmEV). 如請求項1至54中任一項所述之固體劑型，其中該藥劑包含pmEV，並且該pmEV由已經γ照射、UV照射、熱滅活、酸處理或氧噴射的細菌產生。The solid dosage form according to any one of claims 1 to 54, wherein the medicament contains pmEV, and the pmEV is produced by bacteria that have been gamma-irradiated, UV-irradiated, heat-inactivated, acid-treated, or oxygen-sprayed. 如請求項1至54中任一項所述之固體劑型，其中該藥劑包含pmEV，並且該pmEV由活細菌產生。The solid dosage form according to any one of claims 1 to 54, wherein the medicament comprises pmEV, and the pmEV is produced by live bacteria. 如請求項1至54中任一項所述之固體劑型，其中該藥劑包含pmEV，並且該pmEV由死細菌產生。The solid dosage form according to any one of claims 1 to 54, wherein the medicament comprises pmEV, and the pmEV is produced by dead bacteria. 如請求項1至54中任一項所述之固體劑型，其中該藥劑包含pmEV，並且該pmEV由非複製型細菌產生。The solid dosage form according to any one of claims 1 to 54, wherein the medicament comprises pmEV, and the pmEV is produced by non-replicating bacteria. 如請求項1至60中任一項所述之固體劑型，其中該藥劑包含mEV，並且該mEV來自一種細菌菌株。The solid dosage form according to any one of claims 1 to 60, wherein the medicament comprises mEV, and the mEV is derived from a bacterial strain. 如請求項1至61中任一項所述之固體劑型，其中該mEV被凍乾（例如，凍乾的產物還包含藥學上可接受的賦形劑）。The solid dosage form according to any one of claims 1 to 61, wherein the mEV is lyophilized (for example, the lyophilized product further contains a pharmaceutically acceptable excipient). 如請求項1至62中任一項所述之固體劑型，其中該mEV經γ照射。The solid dosage form according to any one of claims 1 to 62, wherein the mEV is irradiated with gamma. 如請求項1至62中任一項所述之固體劑型，其中該mEV經UV照射。The solid dosage form according to any one of claims 1 to 62, wherein the mEV is irradiated with UV. 如請求項1至62中任一項所述之固體劑型，其中該mEV經熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。The solid dosage form according to any one of claims 1 to 62, wherein the mEV is heat-inactivated (for example, two hours at 50°C or two hours at 90°C). 如請求項1至62中任一項所述之固體劑型，其中該mEV經酸處理。The solid dosage form according to any one of claims 1 to 62, wherein the mEV is acid-treated. 如請求項1至66中任一項所述之固體劑型，其中該mEV經氧噴射（例如，以0.1 vvm持續兩小時）。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is injected with oxygen (for example, at 0.1 vvm for two hours). 如請求項1至66中任一項所述之固體劑型，其中該mEV來自革蘭氏陽性細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from Gram-positive bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自革蘭氏陰性細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from Gram-negative bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自需氧細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from aerobic bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自厭氧細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from anaerobic bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自嗜酸細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from acidophilic bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自嗜鹼細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from alkaliphilic bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自嗜中性細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from neutrophilic bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自難養細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from refractory bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自非難養細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is derived from non-difficult bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自表1、表2或表3中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is from a taxonomic group listed in Table 1, Table 2 or Table 3 (for example, class, order, family, genus, species or strain) Bacteria. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自表1、表2或表3中列出的細菌菌株。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is from a bacterial strain listed in Table 1, Table 2 or Table 3. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is from a bacteria of a taxonomic group (for example, class, order, family, genus, species, or strain) listed in Table J. 如請求項1至66中任一項所述之固體劑型，其中該mEV來自表J中列出的細菌菌株。The solid dosage form according to any one of claims 1 to 66, wherein the mEV is from a bacterial strain listed in Table J. 如請求項1至52中任一項所述之固體劑型，其中該藥劑包含細菌並且細菌的劑量為約1 x 107 至約2 x 1012 （約3 x 1010 或約1.5 x 1011 或約1.5 x 1012 ）個細胞，其中該劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。The solid dosage form according to any one of claims 1 to 52, wherein the medicament contains bacteria and the dose of the bacteria is from about 1 x 10 7 to about 2 x 10 12 (about 3 x 10 10 or about 1.5 x 10 11 or Approximately 1.5 x 10 12 ) cells, where the dose is the dose per capsule or tablet or the dose of all mini-tablets in the capsule. 如請求項1至52中任一項所述之固體劑型，其中該藥劑包含細菌並且細菌的劑量為約1 x 109 、約3 x 109 、約5 x 109 、約1.5 x 1010 、約3 x 1010 、約5 x 1010 、約1.5 x 1011 、約1.5 x 1012 、或約2 x 1012 個細胞，其中該劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。The solid dosage form according to any one of claims 1 to 52, wherein the medicament contains bacteria and the dose of the bacteria is about 1 x 10 9 , about 3 x 10 9 , about 5 x 10 9 , about 1.5 x 10 10 , About 3 x 10 10 , about 5 x 10 10 , about 1.5 x 10 11 , about 1.5 x 10 12 , or about 2 x 10 12 cells, wherein the dose is the dose per capsule or tablet or the total number of cells in the capsule The dosage of the tablet. 如請求項1至82中任一項所述之固體劑型，其中該藥劑包含細菌和/或mEV，並且該藥劑（例如細菌和/或mEV）的劑量為約10 mg至約1500 mg，其中該劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。The solid dosage form according to any one of claims 1 to 82, wherein the medicament comprises bacteria and/or mEV, and the dose of the medicament (for example, bacteria and/or mEV) is about 10 mg to about 1500 mg, wherein The dosage is the dosage of each capsule or tablet or the dosage of all the mini-tablets in the capsule. 如請求項1至82中任一項所述之固體劑型，其中該藥劑包含細菌和/或mEV，並且該藥劑（例如細菌和/或mEV）的劑量為約30 mg至約1300 mg（按細菌和/或mEV的重量計）（約25、約30、約35、約50、約75、約100、約120、約150、約250、約300、約350、約400、約500、約600、約700、約750、約800、約900、約1000、約1100、約1200、約1250、約1300、約2000、約2500、約3000、或約3500 mg，其中該劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。The solid dosage form according to any one of claims 1 to 82, wherein the medicament contains bacteria and/or mEV, and the dose of the medicament (for example, bacteria and/or mEV) is about 30 mg to about 1300 mg (according to bacteria And/or the weight of mEV) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600 , About 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg, wherein the dose is per capsule or tablet The dose of the drug is the dose of all the mini-tablets in the capsule. 如請求項1至82中任一項所述之固體劑型，其中該藥劑包含細菌和/或mEV，並且該藥劑（例如細菌和/或mEV）的劑量為約2 x 106 至約2 x 1016 個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中該劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。The solid dosage form according to any one of claims 1 to 82, wherein the medicament comprises bacteria and/or mEV, and the dosage of the medicament (for example, bacteria and/or mEV) is about 2 x 10 6 to about 2 x 10 16 particles (for example, the particle count is determined by NTA (Nanoparticle Tracking Analysis)), where the dose is the dose of each capsule or tablet or the dose of all mini-tablets in the capsule. 如請求項1至82中任一項所述之固體劑型，其中該藥劑包含細菌和/或mEV，並且該藥劑（例如細菌和/或mEV）的劑量為約5 mg至約900 mg總蛋白（例如，其中總蛋白藉由布拉德福德測定或BCA確定），其中該劑量係每膠囊或片劑的劑量或係膠囊中全部微型片劑的劑量。The solid dosage form according to any one of claims 1 to 82, wherein the medicament contains bacteria and/or mEV, and the dose of the medicament (for example, bacteria and/or mEV) is about 5 mg to about 900 mg total protein ( For example, where the total protein is determined by Bradford assay or BCA), where the dose is the dose per capsule or tablet or the dose of all mini-tablets in the capsule. 如請求項1至86中任一項所述之固體劑型，其中該固體劑型還包含一種或多種另外的治療劑。The solid dosage form according to any one of claims 1 to 86, wherein the solid dosage form further comprises one or more additional therapeutic agents. 如請求項1至87中任一項所述之固體劑型，其中該固體劑型還包含賦形劑（例如，本文描述的賦形劑，例如稀釋劑、黏結劑和/或黏合劑、崩散劑、潤滑劑和/或助流劑、著色劑、調味劑和/或甜味劑）。The solid dosage form according to any one of claims 1 to 87, wherein the solid dosage form further comprises excipients (for example, the excipients described herein, such as diluents, binders and/or binders, disintegrating agents, Lubricants and/or glidants, coloring agents, flavoring agents and/or sweetening agents). 如請求項1至88中任一項所述之固體劑型，其中該固體劑型係片劑。The solid dosage form according to any one of claims 1 to 88, wherein the solid dosage form is a tablet. 如請求項89所述之固體劑型，其中片劑係5 mm、5.5 mm、6 mm、6.5 mm、7 mm、7.5 mm、8 mm、8.5 mm、9 mm、9.5 mm、10 mm、11 mm、12 mm、13 mm、14 mm、15 mm、16 mm、17 mm或18 mm片劑。The solid dosage form described in claim 89, wherein the tablets are 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm or 18 mm tablets. 如請求項1至88中任一項所述之固體劑型，其中該固體劑型係微型片劑。The solid dosage form according to any one of claims 1 to 88, wherein the solid dosage form is a microtablet. 如請求項88所述之固體劑型，其中該微型片劑係1 mm微型片劑、1.5 mm微型片劑、2 mm微型片劑、3 mm微型片劑或4 mm微型片劑。The solid dosage form according to claim 88, wherein the mini-tablet is a 1 mm mini-tablet, 1.5 mm mini-tablet, 2 mm mini-tablet, 3 mm mini-tablet or 4 mm mini-tablet. 如請求項91或92所述之固體劑型，其中多個微型片劑包含於膠囊中。The solid dosage form according to claim 91 or 92, wherein a plurality of micro-tablets are contained in a capsule. 如請求項1至93中任一項所述之固體劑型，該固體劑型還包含腸溶衣。The solid dosage form according to any one of claims 1 to 93, which further comprises an enteric coating. 如請求項94所述之固體劑型，其中該腸溶衣係單腸溶衣或多於一個腸溶衣。The solid dosage form according to claim 94, wherein the enteric coating is a single enteric coating or more than one enteric coating. 如請求項94或95所述之固體劑型，其中該腸溶衣包含內部腸溶衣和外部腸溶衣，並且其中該內部和外部腸溶衣不相同。The solid dosage form according to claim 94 or 95, wherein the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are different. 如請求項94至96中任一項所述之固體劑型，其中該腸溶衣包含甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1 : 1）。The solid dosage form according to any one of claims 94 to 96, wherein the enteric coating comprises ethyl methacrylate acrylate (MAE) copolymer (1:1). 如請求項94至97中任一項所述之固體劑型，其中該腸溶衣包含鄰苯二甲酸乙酸纖維素（CAP）、偏苯三酸乙酸纖維素（CAT）、聚醋酸乙烯鄰苯二甲酸酯（PVAP）、羥丙基甲基纖維素鄰苯二甲酸酯（HPMCP）、脂肪酸、蠟、蟲膠（紫膠桐酸的酯）、塑膠、植物纖維、玉米醇溶蛋白、Aqua-Zein（不含醇的水性玉米醇溶蛋白配製物）、直鏈澱粉、澱粉衍生物、糊精、丙烯酸甲酯-甲基丙烯酸共聚物、醋酸琥珀酸纖維素、羥丙基甲基醋酸琥珀酸纖維素（醋酸羥丙甲纖維素琥珀酸酯）、甲基丙烯酸甲酯-甲基丙烯酸共聚物、或海藻酸鈉。The solid dosage form according to any one of claims 94 to 97, wherein the enteric coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate Formate (PVAP), Hydroxypropyl Methyl Cellulose Phthalate (HPMCP), Fatty Acid, Wax, Shellac (Ester of Shellac), Plastic, Vegetable Fiber, Zein, Aqua -Zein (aqueous zein formulation without alcohol), amylose, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl acetate succinate Acid cellulose (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, or sodium alginate. 如請求項94至97中任一項所述之固體劑型，其中該腸溶衣包含陰離子聚合物材料。The solid dosage form according to any one of claims 94 to 97, wherein the enteric coating comprises an anionic polymer material. 一種預防或治療受試者的疾病之方法，該方法包括向該受試者投與如請求項1至99中任一項所述之固體劑型。A method for preventing or treating a disease in a subject, the method comprising administering the solid dosage form according to any one of claims 1 to 99 to the subject. 如請求項1至99中任一項所述之固體劑型用於治療或預防受試者的疾病的用途。Use of the solid dosage form according to any one of claims 1 to 99 for treating or preventing diseases in a subject. 如請求項1至99中任一項所述之固體劑型用於製備藥物的用途，該藥物用於治療或預防受試者的疾病。The use of the solid dosage form according to any one of claims 1 to 99 for the preparation of a medicament for the treatment or prevention of a disease in a subject. 如請求項1至99中任一項所述之固體劑型，用於治療或預防受試者的疾病。The solid dosage form according to any one of claims 1 to 99 is used for treating or preventing diseases in a subject. 如請求項100至103中任一項所述之方法/固體劑型/用途，其中該固體劑型經口服投與（例如用於口服投與）。The method/solid dosage form/use according to any one of claims 100 to 103, wherein the solid dosage form is administered orally (for example, for oral administration). 如請求項100至104中任一項所述之方法/固體劑型/用途，其中該固體劑型空腹（例如，進食前一小時或進食後兩小時）投與。The method/solid dosage form/use according to any one of claims 100 to 104, wherein the solid dosage form is administered on an empty stomach (for example, one hour before eating or two hours after eating). 如請求項100至105中任一項所述之方法/固體劑型/用途，其中該固體劑型（例如，片劑或多個微型片劑（例如，包含在膠囊中））被投與（例如，用於投與）每天1、2、3或4次。The method/solid dosage form/use according to any one of claims 100 to 105, wherein the solid dosage form (for example, a tablet or a plurality of microtablets (for example, contained in a capsule)) is administered (for example, For administration) 1, 2, 3 or 4 times a day. 如請求項100至106中任一項所述之方法/固體劑型/用途，其中該固體劑型包含片劑或多個微型片劑（例如，包含在膠囊中）並且每天1、2、3或4次投與（例如，用於投與）1、2、3或4個固體劑型（例如，片劑或多個微型片劑（例如，包含在膠囊中）。The method/solid dosage form/use according to any one of claims 100 to 106, wherein the solid dosage form comprises a tablet or a plurality of mini-tablets (for example, contained in a capsule) and 1, 2, 3, or 4 per day One administration (eg, for administration) 1, 2, 3, or 4 solid dosage forms (eg, tablets or multiple mini-tablets (eg, contained in capsules). 如請求項100至107中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）癌症。The method/solid dosage form/use according to any one of claims 100 to 107, wherein the subject needs to treat (and/or prevent) cancer. 如請求項100至107中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）自體免疫性疾病。The method/solid dosage form/use according to any one of claims 100 to 107, wherein the subject needs to treat (and/or prevent) an autoimmune disease. 如請求項100至107中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）炎性疾病。The method/solid dosage form/use according to any one of claims 100 to 107, wherein the subject needs to treat (and/or prevent) an inflammatory disease. 如請求項100至107中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）代謝性疾病。The method/solid dosage form/use according to any one of claims 100 to 107, wherein the subject needs to treat (and/or prevent) a metabolic disease. 如請求項100至107中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）菌群失調。The method/solid dosage form/use according to any one of claims 100 to 107, wherein the subject needs treatment (and/or prevention) of dysbacteriosis. 如請求項100至112中任一項所述之方法/固體劑型/用途，其中該固體劑型與治療劑組合投與。The method/solid dosage form/use according to any one of claims 100 to 112, wherein the solid dosage form is administered in combination with a therapeutic agent. 一種製備藥物組成物的固體劑型之方法，該方法包括： (a) 將以下組合成藥物組成物： (i) 藥劑，其具有的藥劑總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的35%，其中該藥劑包含細菌和/或微生物胞外囊泡（mEV）； (ii) 低取代的羥丙基纖維素（L-HPC），其具有的L-HPC總質量係該藥物組成物總質量的至少22%且不超過該藥物組成物總質量的42%； (iii) 交聯羧甲基纖維素鈉，其具有的交聯羧甲基纖維素鈉總質量係該藥物組成物總質量的至少0.01%且不超過該藥物組成物總質量的16%；以及 (iv) 交聚維酮，其具有的交聚維酮總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的25%；並且 (b) 將該藥物組成物壓製成固體劑型。A method for preparing a solid dosage form of a pharmaceutical composition, the method comprising: (a) Combine the following into a pharmaceutical composition: (i) A medicament, which has a total mass of at least 5% of the total mass of the pharmaceutical composition and no more than 35% of the total mass of the pharmaceutical composition, wherein the medicament contains bacteria and/or microbial extracellular vesicles (mEV ); (ii) Low-substituted hydroxypropyl cellulose (L-HPC), which has a total mass of L-HPC that is at least 22% of the total mass of the pharmaceutical composition and does not exceed 42% of the total mass of the pharmaceutical composition; (iii) Croscarmellose sodium, which has a total mass of croscarmellose sodium that is at least 0.01% of the total mass of the pharmaceutical composition and does not exceed 16% of the total mass of the pharmaceutical composition; and (iv) Crospovidone, which has a total mass of crospovidone that is at least 5% of the total mass of the pharmaceutical composition and does not exceed 25% of the total mass of the pharmaceutical composition; and (b) Compress the pharmaceutical composition into a solid dosage form. 如請求項114所述之方法，該方法還包括將該固體劑型進行腸溶包衣以獲得經腸溶包衣的固體劑型的步驟。According to the method described in claim 114, the method further comprises the step of enteric coating the solid dosage form to obtain an enteric-coated solid dosage form. 如請求項114或115所述之方法，其中該固體劑型係片劑。The method according to claim 114 or 115, wherein the solid dosage form is a tablet. 如請求項114或115所述之方法，其中該固體劑型係微型片劑。The method according to claim 114 or 115, wherein the solid dosage form is a microtablet.
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