WO2022061123A1

WO2022061123A1 - Solid dosage forms with improved disintegration profiles

Info

Publication number: WO2022061123A1
Application number: PCT/US2021/050886
Authority: WO
Inventors: Syed Altaf; Jiannan LU
Original assignee: Evelo Biosciences, Inc.
Priority date: 2020-09-21
Filing date: 2021-09-17
Publication date: 2022-03-24
Also published as: TW202227111A

Abstract

Methods and compositions related to solid dosage forms that facilitate the oral delivery of Prevotella histicola bacteria are provided herein.

Description

SOLID DOSAGE FORMS WITH IMPROVED DISINTEGRATION

PROFILES

Cross-Reference to Related Applications

[001] This application claims the benefit of the following U.S. Provisional Application serial numbers 63/081,108, filed September 21, 202.0, and 63/161,528, filed March 16, 2021, the entire contents of each of which are incorporated herein by reference.

Background

[002] The formulation of the solid dosage form of a pharmaceutical product can have a significant impact on the bioavailability of its active pharmaceutical ingredients. To improve bioavailability, a disintegration agent can be included in the solid dosage form. However, there are many potential disintegration agents available to choose from, each possessing its own properties. As the solid formulation disintegration process is complex and not well- understood, the effectiveness of any particular disintegration agent to facilitate the disintegration of a specific solid dose formulation is unpredictable. As a consequence, even with the addition of a disintegration agent, the disintegration rate of many solid dosage forms of pharmaceutical products can remain slow, adversely affecting active ingredient bioavailability.

Summary

[003] This disclosure is based, in part, on the discovery of certain improved solid dosage forms that facilitate the oral delivery of Prevote Ila histicola bacteria. For example, in certain embodiments the solid dosage forms disclosed herein include certain combinations and/or amounts of disintegration agents, resulting in a decrease in the disintegration time of the composition (e.g., 2-fold, 3-fold, 4-fold, 5-fold, 6-fokl, 7-fold, 8-fold, 9-fold) as compared to conventional solid dosage forms (e.g., solid dosage forms containing conventional amounts of disintegration agents). In certain embodiments, the solid dosage forms provided herein result in an increase in therapeutic efficacy and/or physiological effect as compared to a pharmaceutical product having conventional solid dosage forms.

[004] In certain aspects provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, the solid dosage form comprises a pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria, (e.g., bacteria and/or a powder comprising bacteria). In some embodiments, the solid dosage forms maintain their stability, e.g., for three, six, twelve, eighteen and/or twenty-four months under long-term (2-8°C) and/or accelerated (25 °C / 60% RH) storage conditions, e.g., as determined by total cell count (TCC), e.g., as determined by Quantom Tx and described herein. For example, as described herein, stability is maintained for a solid dosage form wherein a TCC range is set at 50% to 150% of a target amount, e.g., at a given time point (e.g., at a three, six, twelve, eighteen and/or twenty-four month time point, e.g., under long-term (2-8°C) and/or accelerated (25 "C / 60% RH) storage conditions), and the solid dosage form comprises a TCC within the set TCC range. For example, for a target amount of 3.2x10¹¹ TCC, the acceptable TCC range is set at 1.6x10¹¹ to 4.8x10¹¹, and stability is maintained wherein the solid dosage form comprises a TCC within the set TCC range. For example, as described herein, stability is maintained (e.g., as determined by being within a TCC range of 50% to 150% of the target, amount) at three months under long-term (2-8 °C) and/or accelerated (25 °C / 60% RH) storage conditions). For example, as described herein, stability is maintained (e.g., as determined by being within a TCC range of 50% to 150% of the target amount) at twelve months under long-term (2-8°C) and/or accelerated (25°C I 60%) RH) storage conditions).

[005] In certain aspects provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, the solid dosage form comprises a pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella hislicola bacteria (e.g., bacteria and/or a powder comprising bacteria). In some embodiments, the water content of the solid dosage forms is between about 3% and about. 6% (e.g., about 4.5% to about 5.5%, e.g., about 5 %), e.g., as determined by the Karl-Fischer method for water content analysis provided in Ph. Ear. method 2.5.32, and as described herein. In some embodiments, the solid dosage forms maintain their water content, e.g., for three, six, twelve, eighteen and/or twenty- four months under long-term (2-8°C) and/or accelerated (25°C / 60% RH) storage conditions. In some embodiments, the solid dosage forms maintain their water content, e.g., for three months under long-term (2-8°C) and/or accelerated (25 °C / 60% RH) storage conditions. In some embodiments, the solid dosage forms maintain their water content, e.g., for twelve months under long-term (2-8°C) and/or accelerated (25 C / 60% RH) storage conditions.

[006] In certain aspects provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, the solid dosage form comprises a pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria), and one or more disintegration agents (e.g., one, two or three disintegration agents). In certain embodiments, the solid dosage form comprises a pharmaceutical agent, wherein the pharmaceutical agent comprises Prevolella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria), and three disintegration agents. In certain embodiments, the total pharmaceutical agent mass is at least 20% of the total mass of the pharmaceutical composition. In some embodiments, the total pharmaceutical agent mass is no more than 25?% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the one or more disintegrating agents 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 the one or more disintegrating agents is no more than 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition. In some embodiments, the one or more disintegration agents comprise low-substituted hydroxypropyl cellulose (L-HPC, e.g., LH-B1), croscarmellose sodium (Ac-Di-Sol, e.g., Ac-Di-Sol SD-711), and/or crospovidone (PVPP, e.g., Koliidon, e.g., Koliidon CL-F).

[007] In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is of grade LH-B1. In certain embodiments, the total L-HPC mass 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% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass is no more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, or 42% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass is about 29% to about 35% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC (e.g., LH- Bl) mass is about 32% of the total mass of the pharmaceutical composition.

[008] In certain embodiments, the solid dosage forms provided herein comprise Croscarmellose Sodium (e.g., Ac-Di-Sol). In some embodiments, the Croscarmellose Sodium (e.g., Ac-Di-Sol) is Ac-Di-Sol of grade SD-711. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is at least 0.01%, 0.1 %, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of tire total mass of the pharmaceutical composition. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is about 3% to about 9 % of the total mass of the pharmaceutical composition. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) (e.g., Ac-Di-Sol SD-711) mass is about 6 % of the total mass of the pharmaceutical composition , [009] In certain embodiments, the solid dosage forms provided herein comprise PVPP (crospovidone, e.g., Koliidon, e.g., Kollidon CL-F). In certain embodiments, the total PVPP mass is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is no more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition , In certain embodiments, the total PVPP mass is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is about 12% to about 18% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is about 15% of the total mass of the pharmaceutical composition.

[010] In certain embodiments, the solid dosage forms provided herein comprise: (i) a pharmaceutical agent having a total pharmaceutical agent mass that is at least 20% and no more than 25% of the total mass of the pharmaceutical composition, (ii) L-HPC (e.g., L-HPC of grade LH-B1) having a total L-HPC mass that is at least 22% (e.g., at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%) and no more than 42% (e.g., no more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%) of tire total mass of the pharmaceutical composition; (iii) Croscarmellose Sodium (e.g., Ac-Di-Sol) (e.g., Ac-Di-Sol of grade SD-711) having a total Croscarmellose Sodium (e.g,, Ac-Di-Sol) mass that is at least. 0.01 % (e.g., at least 0.01%, 0.1%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%) and no more than 16% (e.g., no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%) of the total mass of the pharmaceutical composition; and (iv) PVPP having a total PVPP mass that is at least 5% (e.g., 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 no more than 25% (no more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%) of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass plus the total Croscarmeliose Sodium (e.g., Ac-Di-Sol) mass plus the total PVPP mass is at least 35%, 40%, 45%, or 50% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: a total L-HPC mass is about 32% of the total mass of the pharmaceutical composition; a total Croscarmeliose Sodium (e.g., Ac-Di-Sol) mass is about 6% of the total mass of the pharmaceutical composition; and a total PVPP mass is about 15% of the total mass of the pharmaceutical composition.

[011] In certain embodiments, the solid dosage forms provided herein further comprise mannitol. In some embodiments, the mannitol is mannitol SD200. In certain embodiments, tlie total mannitol mass is at least 18% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol mass is no more than 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol mass is about 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 18% to about 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 22% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 21.5% of the total mass of the pharmaceutical composition.

[012] In certain embodiments, the solid dosage forms provided herein comprise magnesium stearate. In certain embodiments, the total magnesium stearate mass is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is no more than 0.01%, 0.1%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, tire total magnesium stearate mass is about 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%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 1% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 1 .5% of the total mass of the pharmaceutical composition. [013] In certain embodiments, the solid dosage forms provided herein comprise colloidal silica. In some embodiments, the colloidal silica is Aerosil 2.00. In certain embodiments, the total colloidal silica mass is at least 0.01%, 0.1%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11 % of the total mass of the pharmaceutical composition. In certain embodiments, tlie total colloidal silica mass is no more than 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is about 0.01 %, 0, 1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica (e.g., Aerosil 200) mass is about 1 % of the total mass of the pharmaceutical composition.

[014] In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g,, bacteria and/or a powder comprising bacteria); about 22% mannitol (e.g,, mannitol SD200); about 32% L-HPC (e.g., L-HPC LH-Bl ); about 6% croscarmellose sodium (e.g., Ac-Di-Sol SD-7I1); about 15% crospovidone (e.g., PVPP); about 1% magnesium stearate; and about 1% colloidal silica (e.g., Aerosil 200).

[015] In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria); about 21.5% mannitol; about 32% L-HPC (e.g., L-HPC LH-Bl); about 6% croscarmellose sodium (e.g., Ac-Di-Sol SD- 711); about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silica (e.g., Aerosil 200P).

[016] In certain embodiments, the solid dosage forms of a pharmaceutical agent as described herein include tablets and minitablets. In some embodiments, the solid dosage form is enterically coated (e.g., comprises an enteric coating; e.g., is coated with an enteric coating). The tablets or minitablets are coated with one layer of enteric coating or with two layers of enteric coatings (e.g., an inner enteric coating and an outer enteric coating). The enterically-coated minitablets (with one layer of enteric coating or with two layers of enteric coatings (e.g., an inner enteric coating and an outer enteric coating)) can be loaded into a capsule; e.g., the capsule is not enterically coated.

[017] In some embodiments, the solid dosage form comprises a tablet. In some embodiments, the tablet (e.g., enterically coated tablet) is a 5mm, 5,5mm, 6mm, 6.5mm, 7mm, 7.5mm, 8mm, 8.5mm, 9mm, 9.5mm, 10mm, 11mm, I2mm, 13mm, 14mm, 15mm, 16mm, 17mm, or 18mm tablet. In some embodiments, die tablet (e.g., enterically coated tablet) is a 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, or 18mm tablet. In some embodiments, the tablet (e.g., enterically coated tablet) is a 17mm tablet.

[018] In some embodiments, the solid dosage form comprises a minitablet. In some embodiments, the minitablet (e.g., enterically coated minitablet) is a 1mm minitablet, 1.5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet. In some embodiments, a plurality of enterically coated minitablets are contained in a capsule (e.g., a size 0 capsule can contain about 31 to about 35 (e.g., 33) minitablets, wherein the minitablets are 3mm in size). In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. In some embodiments, the capsule comprises HPMC (hydroxyl propyl methyl cellulose) or gelatin.

[019] In some embodiments, the enteric coating comprises one enteric coating.

[020] In some embodiments, the enteric coating comprises 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 identical (e.g., the inner and outer enteric coatings do not contain identical components in identical amounts).

[021 ] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a polymethacrylate-based copolymer.

[022] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1 : 1).

[023] In some embodiments, the one enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1 : 1) (such as Kollicoat MAE 100P).

[024] In some embodiments, the one enteric coating comprises a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g,, Eudragit FS 30 D).

[025] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methyl cellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate -methacrylic acid copolymer, or sodium alginate. [026] In some embodiments, the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) comprises an anionic polymeric material. [027] In some embodiments, the solid dosage form comprises a sub-coating, e.g., in addition to the enteric coating, e.g., the sub-coating is beneath the enteric coating (e.g., between the solid dosage form and the enteric coating). In some embodiments, the sub- coating comprises Opadry QX, e.g., Opadry QX Blue.

[028] The pharmaceutical agent can be a powder that comprises the Prevotella histicola bacteria, and, can comprise additional agents such as, e.g., cryoprotectant. For example, in some embodiments, the pharmaceutical agent is a lyophilized powder of Prevotella histicola bacteria that optionally, further comprises additional agents, such as a cryoprotectant.

[029] In some embodiments, the pharmaceutical agent has one or more beneficial immune effects outside the gastrointestinal tract, e.g,, when the solid dosage form is orally administered.

[030] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract in the subject, e.g., when the solid dosage form is orally administered.

[031] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when the solid dosage form is orally administered.

[032] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine (e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when tire solid dosage form is orally administered.

[033] In some embodiments, the pharmaceutical agent comprises isolated Prevotella histicola bacteria (e.g., from one or more strains of bacteria (e.g., bacteria of interest) (e.g., a therapeutically effective amount thereof)). E.g., wherein 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 pharmaceutical agent is the isolated Prevotella histicola bacteria (e.g., bacteria of interest). [034[ In some embodiments, the pharmaceutical agent comprises live bacteria.

[035] In some embodiments, the pharmaceutical agent comprises dead bacteria.

[036] In some embodiments, the pharmaceutical agent comprises non-replicating bacteria.

[037] In some embodiments, the pharmaceutical agent comprises bacteria that have been gamma-irradiated (e.g., at 17.5 or 25 kGy). [038] In some embodiments, the pharmaceutical agent comprises bacteria from one strain of bacteria.

[039] In some embodiments, the bacteria are lyophilized (e.g,, the lyophilized product further comprises a pharmaceutically acceptable excipient, e.g., such as a cryoprotectant) (e.g., a powder form).

[040] In some embodiments, the Prevotella histicola bacteria are from a strain comprising at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are from a strain comprising at least 99% genomic, 16S and/or CRISPR sequence i dentity to the nucleoti de sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacteria are from Prevotella Strain B 50329 (NRRL accession number B 50329).

[0411 In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 2.4 x 10¹¹ to about 4,0 x 10¹¹ cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per tablet or per total number of minitablets in a capsule.

[042] In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 2.8 x 10¹¹ to about 3.6 x 10¹¹ cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per tablet or per total number of minitablets m a capsule.

[043] In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 2.4 x 10¹¹, about 2.8 x 10¹¹, about 3.2 x 10¹¹, about 3.6 x 10¹¹, or about 4.0 x 10¹¹, cells, wherein the dose is per tablet or per total number of minitablets in a capsule.

[044] In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 3.2 x 10¹¹ cels, wherein the dose is per tablet or per total number of minitablets in a capsule.

[045] In some aspects, the disclosure provides a method of treating a subject (e.g,, human) (e.g., a subject in need of treatment), the method comprising administering to the subject a solid dosage form provided herein.

[046] In some aspects, the disclosure provides use of a solid dosage form provided herein for the preparation of a medicament for treating a subject (e.g,, human) (e.g., a subject in need of treatment). [047] In some embodiments, the solid dosage form is orally administered (e.g., is for oral administration).

[048] In some embodiments, the solid dosage form is administered to a subject that is in a fed or fasting state. In some embodiments, the solid dosage form is administered to a subject on an empty stomach (e.g., one hour before eating or two hours after eating). In some embodiments, the solid dosage form is administered to a subject one hour before eating. In some embodiments, the solid dosage form is administered to a subject two hours after eating. [049] In some embodiments, the solid dosage form is administered (e.g., is for administration) 1, 2, 3, or 4 times a day. In some embodiments, 1, 2, 3, 4 or 5 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 , 2, 3, or 4 times a day. In some embodiments, 2, 4, 6, 8, or 10 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) I, 2, 3, or 4 times a day. In some embodiments, 1 solid dosage form (e.g., tablet) is administered (e.g., is for administration) 1 or 2 times a day. In some embodiments, 2 solid dosage forms (e.g,, tablets) are administered (e.g., are for administration) 1 or 2 times a day. In some embodiments, 3 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day. In some embodiments, 4 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day. In some embodiments, 5 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day.

[050] In some embodiments, 1 solid dosage form (e.g., tablet) is administered (e.g., is for administration) 1 or 2 times a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 101 Icells. In some embodiments, 2 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 3.2. x 10¹¹cells. In some embodiments, 3 solid dosage forms (e.g,, tablets) are administered (e.g., are for administration) 1 or 2 times a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10”cells. In some embodiments, 4 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2. times a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹cells. In some embodiments, 5 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) I or 2 times a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹cells.

[051] In some embodiments, 1 solid dosage form (e.g., tablet.) is administered (e.g., is for administration) per day, w'herein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹cells. In some embodiments, 2 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) per day, wherein the soiid dosage form comprises a dose of bacteria of about 3.2. x 10¹¹cells. In some embodiments, 3 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹cells. In some embodiments, 4 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2. x 10¹¹cells. In some embodiments, 5 solid dosage forms (e.g,, tablets) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹cells.

[052[ In some embodiments, the solid dosage form provides release of the pharmaceutical agent in the small intestine, e.g., in the upper small intestine, of the pharmaceutical agent contained in the solid dosage form.

[053 j In some embodiments, the solid dosage form delivers the pharmaceutical agent to the small intestine, wherein the pharmaceutical agent can act on immune cells and/or epithelial cells in the small intestine, e.g., in the upper small intestine, e.g., to cause effects throughout the body (e.g., systemic effect).

[054 [ In some embodiments, the pharmaceutical agent provides one or more beneficial immune effects outside the gastrointestinal tract, e.g., when orally administered,

[055] In some embodiments, the pharmaceutical agent modulates immune effects outside die gastrointestinal tract in the subject, e.g., when orally administered.

[056] In some embodiments, the pharmaceutical agent causes a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when orally administered.

[057] In some embodiments, the pharmaceutical agent acts on immune cells and/or epithelial cells in the small intestine (e.g., upper small intestine) (e.g., causing a systemic effect (e.g., an effect outside of the gastrointestinal tract), e.g., when orally administered. [058] In some embodiments, the solid dosage form is administered orally and has one or more beneficial immune effects outside the gastrointestinal tract (e.g., interaction between the agent and cells in tire small intestine modulates a sy stemic immune response).

[059] In some embodiments, the solid dosage form is administered orally and modulates immune effects outside the gastrointestinal tract (e.g., interaction between agent and cells in the small intestine (e.g., upper small intestine) modulates a systemic immune response).

[060] In some embodiments, the solid dosage form is administered orally and activates innate antigen presenting cells (e.g., in the small intestine, e.g., upper small intestine), [061] In some embodiments, the subject is in need of treatment (and/or prevention) of an autoimmune disease. [062] In some embodiments, the subject is in need of treatment (and/or prevention) of an inflammatory disease. In some embodiments, the inflammatory disease is a Thl, T112, or Thl 7 inflammatory disease.. In some embodiments, the inflammatory' disease is a Thl inflammatory disease. In some embodiments, the inflammatory' disease is a Th2 inflammatory disease. In some embodiments, the inflammatory disease is a Thl 7 inflammatory disease.

[063] In some embodiments, the subject is in need of treatment (and/or prevention) of a metabolic disease.

[064] In some embodiments, the subject is in need of treatment (and/or prevention) of a dysbiosis.

[065] In some embodiments, the subject is in need of treatment (and/or prevention) of psoriasis.

[066] In some embodiments, the subject is in need of treatment (and/or prevention) of psoriatic arthritis.

[067] In some embodiments, the subject is in need of treatment (and/or prevention) of atopic dermatitis.

[068] In some embodiments, the subject is in need of decreased inflammatory' cytokine expression (e.g., decreased IL-8, IL-6, IL-lβ, and/or TNFa expression levels).

[069] In some embodiments, the subject is in need of treatment (and/or prevention) of bacterial septic shock, cytokine storm and/or viral infection.

[070] In some embodiments, the subject is in need of treatment (and/or prevention) of a viral infection.

[071] In some embodiments, the viral infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.

[072] In some embodiments the viral infection is a SARS-CoV-2 infection.

[073] In some embodiments, the solid dosage form is administered in combination with a therapeutic agent (e.g., additional therapeutic agent).

[074] In certain aspects, provided herein are methods of preparing a solid dosage form of a pharmaceutical composition, the method comprising combining into a pharmaceutical composition a pharmaceutical agent, wherein the pharmaceutical agent comprises Prevolella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria), and one or more (e.g., one, two or three) disintegration agents. In certain embodiments, the total pharmaceutical agent mass is at least 20% of the total mass of the pharmaceutical composition. In some embodiments the total pharmaceutical agent mass is no more than 25% of tire total mass of the pharmaceutical composition. In some embodiments, the total mass of the one or more disintegrating agents 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 the one or more disintegrating agents is no more than 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition.

[075] In some embodiments, the one or more disintegration agents comprise 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 of grade LH-B 1. In certain embodiments, the total L-HPC mass 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% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass is no more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% of the total mass of the pharmaceutical composition. In certain embodiments, the solid dosage forms provided herein comprise Croscarmellose Sodium (e.g., Ac-Di-Sol). In some embodiments, the Croscarmellose Sodium (e.g., Ac-Di-Sol) is Ac-Di-Sol of grade SD-711. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is about 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the solid dosage forms provided herein comprise PVPP, In certain embodiments, the total PVPP mass is at least 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is no more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition.

[076] In certain embodiments, the method further comprises combining mannitol. In some embodiments, the mannitol is mannitol SD200. In certain embodiments, the total mannitol mass is at least 18% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol mass is no more than 25% of tire total mass of the pharmaceutical composition. In certain embodiments, the total mannitol mass is about 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 18% to about 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 22% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 21.5% of the total mass of the pharmaceutical composition.

[077] In certain embodiments, the method further comprises combining magnesium stearate. In certain embodiments, the total magnesium stearate mass is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is no more than 0.01%, 0.1%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, tire total magnesium stearate mass is about 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%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 1 % of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 1 .5% of the total mass of the pharmaceutical composition.

[078] In certain embodiments, the method further comprises combining comprise colloidal silica. In some embodiments, the colloidal silica is Aerosil 200. In certain embodiments, the total colloidal silica mass is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is no more than 0.01%, 0.1 %, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11 % of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%. or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica (e.g., Aerosil 200) mass is about 1 % of the total mass of the pharmaceutical composition.

[079] In certain embodiments, the method further comprises combining about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g,, bacteria and/or a powder comprising bacteria); about 22% mannitol (e.g,, mannitol SD200); about 32% L-HPC (e.g., L-HPC LH-B1 ); about 6% croscarmellose sodium (e.g., Ac-Di-Sol SD-711); about 15% crospovidone (e.g., PVPP); about 1% magnesium stearate; and about 1% colloidal silica (e.g., Aerosil 200).

[080] In certain embodiments, the method further comprises combining about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria); about 21.5% mannitol; about 32% L-HPC (e.g., L-HPC LH-B1); about 6% croscarmellose sodium (e.g., Ac-Di-Sol SD- 711); about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silica (e.g., Aerosil 200P).

[081] In certain embodiments, the method further comprises compressing the pharmaceutical composition, thereby forming a tablet or a minitablet. In some embodiments, the method further comprises enterically coating the tablet or minitablet, thereby preparing the enterically coated tablet. In certain embodiments, the method further comprises loading the minitablets into a capsule.

Brief Description of the Drawings

[082] Figure 1 is a graph showing a Total Celis/T ablet Stability Profile over 3 months long- term (2-8°C) and accelerated (25°C / 60% RH) storage conditions. The lower trace (diamonds) in the graph provides values for accelerated (25 °C / 60% RH) storage conditions. The upper trace (circles) in the graph provides values for long-term (2-8°C) storage conditions. Total Cell Count (TCC) was determined by Quantom Tx.

[083] Figure 2 is a graph showing a Water Content Stability Profile over 3 months long-term (2 -8 °C) and accelerated (25 °C / 60% RH) storage conditions. The lower trace (diamonds) in the graph provides values for accelerated (25 °C / 60% RH) storage conditions. The upper trace (circles) in the graph provides values for long-term (2-8°C) storage conditions. Water content was determined by the Karl Fisher method . [084] Figure 3 is a graph showing a Total Cells/Tablet Stability Profile over 12 months long- term (2-8°C) and accelerated (25 C / 60% RH) storage conditions. Total Cell Count (TCC) was determined by Quantom Tx.

[0851 Figure 4 is a graph showing a Water Content Stability Profile over 12 months long- term (2-8 °C) and accelerated (25 °C / 60% RH) storage conditions. Water content was determined by the Karl Fisher method.

Detailed Description

[086 j The disclosure provides solid dosage forms that comprise Prevotella histicola (e.g., Prevotella histicola powder) that maintain their stability, e.g., for three, six, twelve, eighteen and/or twenty-four months under long-term (2-8°C) and/or accelerated (25 C / 60% RH) storage conditions. Stability can be determined by total ceil count (TCC), e.g., as determined by Quantom Tx and described herein.

[087] The disclosure provides solid dosage forms that comprise Prevotella histicola (e.g,, Prevotella histicola powder) that have the water content between about 3% and about 6% (e.g., about 4.5% to about 5.5%, e.g., about 5%), e.g., as determined by the Karl-Fischer method for water content analysis provided in Ph. Eur. method 2.5.32, and as described herein. In some embodiments, the solid dosage forms maintain their water content, e.g., for three, six, twelve, eighteen and/or twenty-four months under long-term (2-8 °C) and/or accelerated (25°C / 60% RH) storage conditions.

[088 ] This disclosure is based, in part, on the discovery' that an amount of one or more disintegration agents (e.g., one, two or three disintegration agents) can improve the disintegration times of solid dosage forms that contain Prevotella histicola pow der. For example, for a solid dosage form to contain a given amount (e.g., dose) of active ingredient (e.g., Prevotella histicola powder), the amount of pharmaceutical agent (that contains the active ingredient) incorporated into a solid dosage form may be adjusted depending on the amount of active ingredient contained in a given preparation (e.g., batch) of pharmaceutical agent. The amount of diluent (such as mannitol) is then adjusted accordingly. For example, if the amount of pharmaceutical agent is increased, the amount of diluent is decreased; and vice versa. As described herein, adjustments can be made to the amounts of pharmaceutical agent and diluent, yet the amount of one or more disintegration agents (e.g., one, two or three disintegration agents) remains constant, e.g., batch to batch for a given solid dosage form recipe. Similarly, the amounts of magnesium stearate and colloidal silica can also remain constant, e.g., batch to batch for a given solid dosage form recipe. [089] .As tin example, in the working examples provided herein, pharmaceutical agent containing Prevotella histicola powder was used to prepare two tablet solid dosage forms. In both preparations, the three disintegrants totaled 53% (w7w) of the tablet, specifically: 32% low substituted hydroxypropyl cellulose; 15% crospovidone; and 6% croscarmellose sodium. Also, the magnesium stearate and colloidal silica were each 1.5% and 1%, respectively in both preparations. Yet in one preparation, tire pharmaceutical agent was used at 25%. In the other, it was used at 23%. To adjust for the differing amounts of pharmaceutical agent, the amount of mannitol was differed: 19.5% mannitol when 25% pharmaceutical agent was used; 21.5% mannitol when 23% pharmaceutical agent was used.

Definitions

[090] “Adjuvant” or “Adjuvant therapy” broadly refers to an agent that affects an immunological or physiological response in a subject (e.g., human). For example, an adjuvant might help absorb an antigen presenting cell antigen, activate macrophages and lymphocytes and support the production of cytokines. By changing an immune response, an adjuvant might permit a smaller dose of an immune interacting agent to increase the effectiveness or safety of a particular dose of the immune interacting agent. For example, an adjuvant might prevent T cell exhaustion and thus increase the effectiveness or safety of a particular immune interacting agent.

[091] “Administration” broadly refers to a route of administration of a composition (e.g., a pharmaceutical composition such as a solid dosage form of a pharmaceutical agent as described herein) to a subject. Examples of routes of administration include oral administration, rectal administration, topical administration, inhalation (nasal) or injection. Administration by injection includes intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration. A pharmaceutical composition described herein can be administered in any form by any effective route, including but not limited to oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), intradermal, ophthalmic, (intra)nasally, local, non -oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, vaginal, intra-arterial, and intrathecal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), implanted, intravesical, intrapulmonary, intraduodenal, intragastrical, and intrabronchial. In preferred embodiments, a pharmaceutical composition described herein is administered orally, rectally, topically, mtravesically, by injection into or adjacent to a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously. In another preferred embodiment, a pharmaceutical composition described herein is administered orally, or intravenously. In another embodiment, a pharmaceutical composition described herein is administered orally.

[092] A “carbohydrate” refers to a sugar or polymer of sugars. The terms “saccharide,” ‘‘polysaccharide,” ‘'carbohydrate,” and “oligosaccharide” may be used interchangeably. Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually one on each carbon atom of the molecule. Carbohydrates generally have the molecular formula CnH2nOn. A carbohydrate may be a monosaccharide, a disaccharide, trisaccharide, oligosaccharide, or polysaccharide. The most basic carbohydrate is a monosaccharide, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose, and fructose.

Disaccharides are two joined monosaccharides. Exemplar}' disaccharides include sucrose, maltose, cellobiose, and lactose. Typically, an oligosaccharide includes between three and six monosaccharide units (e.g., raffinose, stachyose), and polysaccharides include six or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified saccharide units such as 2 ’-deoxyribose wherein a hydroxyl group is removed, 2 ’-fluororibose wherein a hydroxyl group is replaced with a fluorine, or N-acetylglucosamine, a nitrogen-containing form of glucose (e.g., 2’- fluororibose, deoxyribose, and hexose). Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.

[093] “Cellular augmentation” broadly refers to the influx of cells or expansion of cells in an environment that are not substantially present in the environment prior to administration of a composition and not present in the composition itself. Cells that augment the environment include immune cells, stromal cells, bacterial and fungal cells.

[094] “Clade” refers to the OTUs or members of a phylogenetic tree that are downstream of a statistically valid node in a phylogenetic tree. The clade comprises a set of terminal leaves in the phylogenetic tree that is a distinct monophyletic evolutionary unit and that share some extent of sequence similarity .

[095] A “combination” of bacteria from two or more strains includes the physical co- existence of the bacteria, either in the same material or product or in physically connected products, as w ell as the temporal co-admimstration or co-localization of the bacteria from the two or more strains.

[096] The term “decrease” or “deplete” means a change, such that the difference is, depending on circumstances, 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 after treatment when compared to a pre-treatment state. Properties that may be decreased include tire number of immune cells, bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites; the level of a cytokine; or another physical parameter (such as ear thickness (e.g., in a DTH animal model) or tumor size).

[097] ‘’Dysbiosis” refers to a state of the microbiota or microbiome of the gut or other body area, including, e.g., mucosal or skin surfaces (or any other microbiome niche) in which the normal diversity and/or function of the host gut microbiome ecological networks ■‘microbiome”) are disrupted. A state of dysbiosis may result in a diseased state, or it may be unhealthy under only certain conditions or only if present for a prolonged period. Dysbiosis may be due to a variety of factors, including, environmental factors, infectious agents, host genotype, host diet and/or stress. A dysbiosis may result in: a change (e.g., increase or decrease) in the prevalence of one or more bacteria types (e.g., anaerobic), species and/or strains, change (e.g., increase or decrease) in diversity of the host microbiome population composition; a change (e.g., increase or reduction) of one or more populations of symbiont organisms resulting in a reduction or loss of one or more beneficial effects; overgrowth of one or more populations of pathogens (e.g. , pathogenic bacteria); and/or the presence of, and/or overgrowth of, symbiotic organisms that cause disease only when certain conditions are present.

[098] lire term “ecological consortium” is a group of bacteria which trades metabolites and positively co-regulates one another, in contrast to two bacteria which induce host synergy through activating complementary host pathways for improved efficacy.

[099] As used herein, “engineered bacteria” are any bacteria that have been genetically altered from their natural state by human activities, and the progeny of any such bacteria. Engineered bacteria include, for example, the products of targeted genetic modification, the products of random mutagenesis screens and the products of directed evolution.

[100] lire term “gene” is used broadly to refer to any nucleic acid associated with a biological function. The term “gene” applies to a specific genomic sequence, as well as to a cDNA or an mRNA encoded by that genomic sequence.

[101] “Identity” as between nucleic acid sequences of two nucleic acid molecules can be determined as a percentage of identity using known computer algorithms such as the “FASTA” program, using for example, the default parameters as in Pearson et. al. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F., et al., J Molec Biol 215:403 (1990); Guide to Huge Computers, Mrtin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo et al. (1988) SIAM J Applied Math 48: 1073). For example, the BLAST function of the National Center for Biotechnology Information database can be used to determine identity. Other commercially or publicly available programs include, DNAStar “MegAlign” program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG) “Gap” program (Madison Wis.)).

[102] As used herein, the term “immune disorder” refers to any disease, disorder or disease symptom caused by an activity of the immune system, including autoimmune diseases, inflammatory diseases and allergies. Immune disorders include, but are not limited to, autoimmune diseases (e.g., psoriasis, atopic dermatitis, lupus, scleroderma, hemolytic anemia, vasculitis, type one 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, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis and/or interstitial cystitis), and/or an allergies (e.g., food allergies, drag allergies and/or environmental allergies).

[103] “Immunotherapy” is treatment that uses a subject’s immune system to treat disease (e.g., immune disease, inflammatory disease, metabolic disease) and includes, tor example, cytokines, cell therapy, CAR-T cells, and dendritic cell therapy.

[104] lire term “increase” means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 4-fold, 10- fold, 100-fold, 10^{^}3 fold, 10^{^}4 fold, 10^{^}5 fold, 10^{^}6 fold, and/or 10^{^}7 told greater after treatment when compared to a pre-treatment state. Properties that may be increased include the number of immune cells, bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites; the level of a cytokine; or another physical parameter (such as ear thickness (e.g., in a DTH animal model) or tumor size).

[105] “Innate immune agonists” or “immuno-adjuvants” are small molecules, proteins, or other agents that specifically target innate immune receptors including Toll-Like Receptors (TLR), NOD receptors, RLRs, C-type lectin receptors, STING-cGAS Pathway components, inflammasome complexes. For example, LPS is a TLR-4 agonist that is bacterially derived or synthesized and aluminum can be used as an immune stimulating adjuvant, immuno- adjuvants are a specific class of broader adjuvant or adjuvant therapy. 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, Sp-isomers of the bis-phosphorothioate analog of 2'3'-cGAMP). Examples of TLR agonists include, but are not limited to, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, Tl RIO and TLRI 1. Examples of NOD agonists include, but are not limited to, N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyldipeptide (MDP)), gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), and desmuramylpeptides (DMP) .

[106] The ’‘internal transcribed spacer” or “ITS” is a piece of non-functional RNA located between structural ribosomal RN As (rRN A ) on a common precursor transcript often used for identification of eukaryotic species in particular fungi. The rRNA of fungi that forms the core of the ribosome is transcribed as a signal gene and consists of the 8S, 5.8S and 28S regions with ITS4 and 5 between the 8S and 5.8S and 5.8S and 2.8S regions, respectively. These two intercistronic segments between the 18S and 5.8S and 5.8S and 28S regions are removed by splicing and contain significant variation between species for barcoding purposes as previously described (Schoch et al Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DN A barcode marker for Fungi. PNAS 109:6241 -6246. 2012). 18S rDNA is traditionally used for phylogenetic reconstruction however the ITS can serve this function as it is generally highly conserved but contains hypervariable regions that harbor sufficient nucleotide diversity to differentiate genera and species of most fungus.

[107] The term “isolated” or “enriched” encompasses a microbe (such as a bacterium) or oilier entity or substance that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting), and/or (2.) produced, prepared, purified, and/or manufactured by the hand of man. In some embodiments, isolated microbes are more 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 more than about 99% pure. As used herein, a substance is “pure” if it is substantially free of other components. The terms “purify,” “purifying” and “purified” refer to a microbe or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether m nature or in an experimental setting), or during any time after its initial production. A microbe or a microbial population may be considered purified if it is isolated at or after production, such as from a material or environment containing the microbe or microbial population, and a purified microbe or microbial population 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 above about 90% and still be considered “isolated.” In some embodiments, purified microbes or microbial population are more 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 more than about 99% pure. In the instance of microbial compositions provided herein, the one or more microbial types present in the composition can be independently purified from one or more other microbes produced and/or present in the material or environment containing the microbial type. Microbial compositions thereof are generally purified from residual habitat products.

[108] As used herein a "lipid” includes fats, oils, triglycerides, cholesterol, phospholipids, fatty acids in any form including free fatty acids. Fats, oils and fatty acids can be saturated, unsaturated (cis or trans) or partially unsaturated (cis or trans).

[109] The term “LPS mutant or lipopolysaccharide mutant” broadly refers to selected bacteria that comprises loss of LPS. Loss of LPS might be due to mutations or disruption to genes involved in lipid A biosynthesis, such as IpxA, IpxC, and IpxD. Bacteria comprising LPS mutants can be resistant to aminoglycosides and polymyxins (polymyxin B and colistin).

[110] “Metabolite” as used herein refers to any and all molecular compounds, compositions, molecules, ions, co-factors, catalysts or nutrients used as substrates in any cellular or microbial metabolic reaction or resulting as product compounds, compositions, molecules, ions, co-factors, catalysts or nutrients from any cellular or microbial metabolic reaction.

[111] “Microbe” refers to any natural or engineered organism characterized as a archaeaon, parasite, bacterium, fungus, microscopic alga, protozoan, and the stages of development or life cycle stages (e.g., vegetative, spore (including sporulation, dormancy, and germination), latent, biofilm) associated with the organism. Examples of gut microbes include: Actinomyces graevenitzii, Actinomyces odontolyticus, AJdcermansia muciniphila, Bacteroides caccae, Bacteroides fragilis, Bacteroides putredinis, Bacteroides thetaiotaomicron, Bacteroides vultagus, Bifidobacterium adolescentis, Bifidobacterium bifidum, Bilophila wadsworthia, Blautia, Butyrivibrio Campylobacter gracilis, Clostridia cluster 111, Clostridia cluster IV, Clostridia cluster IX (Acidaminococcaceae group), Clostridia cluster XI, Clostridia cluster XIII (Peptostreptococcus group), Clostridia cluster XIV Clostridia cluster XV, Collinsella aerofaciens, Coprococcus, Corynebacterium sunsvallense, Desulfomonas pigra, Dorea formicigenerans, Dorea longicatena, Escherichia coli, Eubacterium hadrum, Eubacterium rectale, Faecalibacteria prausnitzii, Gemella, Lactococcus, Lanchnospira, Mollicutes cluster XVI, Mollicutes cluster XVIII, Prevote Ila, Ro thia mudlaginosa, Ruminococcus callidus, Ruminococcus gnavus, Ruminococcus torques, and Streptococcus.

[112] “Microbiome” broadly refers to the microbes residing on or in body si te of a subject or patient. Microbes in a microbiome may include bacteria, viruses, eukaryotic microorganisms, and/or viruses. Individual microbes in a microbiome may be metabolically active, dormant, latent, or exist as spores, may exist planktonically or in biofilms, or may be present in the microbiome in sustainable or transient manner. The microbiome may be a commensal or healthy-state microbiome or a disease-state microbiome. The microbiome may be native to the subject or patient, or components of the microbiome may be modulated, introduced, or depleted due to changes m health state or treatment conditions (e.g., antibiotic treatment, exposure to different microbes). In some aspects, the microbiome occurs at a mucosal surface. In some aspects, the microbiome is a gut microbiome.

[113j A “microbiome profile” or a “microbiome signature” of a tissue or sample refers to an at least partial characterization of the bacterial makeup of a microbiome. In some embodiments, a 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 or absent in a microbiome.

[114] “Modified” in reference to a bacteria broadly refers to a bacteria that has undergone a change from its wild-type form. Bacterial modification can result from engineering bacteria. Examples of bacterial modifications inc hide genetic modification, gene expression modification, phenotype modification, formulation modification, chemical modification, and dose or concentration. Examples of improved properties are described throughout this specification and include, e.g., attenuation, auxotrophy, homing, or antigenicity. Phenotype modification might include, by way of example, bacteria growth in media that modify the phenotype of a bacterium such that it increases or decreases virulence.

[115] “Operational taxonomic units” and “OTU(s)” refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g., the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species. In some embodiments the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence. In other embodiments, the entire genomes of two entities are sequenced and compared. In another embodiment, select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared. For 16S, OTUs that share > 97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU. See e.g., Claesson MJ, Wang Q, O’Sullivan O, Greene-Dmiz R, Cole JR, Ross RP, and O'Toole PW. 2.010.

Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res 38: e200. Konstantinidis KT, Raniette A, and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361 : 1929-1940. For complete genomes, MLSTs, specific genes, other than 16S, or sets of genes OTUs that share > 95% average nucleotide identity are considered the same OTU. See e.g., Achtman M, and Wagner M. 2008. Microbial diversity and the genetic nature of microbial species. Nat. Rev. Microbiol. 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 361: 1929-1940. OTUs are frequently 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. OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g., “house-keeping” genes), or a combination thereof. Operational Taxonomic Units (OTUs) with taxonomic assignments made to, e.g., genus, species, and phylogenetic clade are provided herein.

[116] As used herein, a gene is “overexpressed” in a bacteria if it is expressed at a higher level in an engineered bacteria under at least some conditions than it is expressed by a wdld- type bacteria of the same species under the same conditions. Similarly, a gene is “underexpressed” in a bacteria if it is expressed at a lower level in an engineered bacteria under at least some conditions than it is expressed by a wild-type bacteria of the same species under the same conditions.

[117] The terms “polynucleotide,” and “nucleic acid” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxy ribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), micro RNA (miRNA), silencing RNA (siRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. A polynucleotide may be further modified, such as by conjugation with a labeling component. In ali nucleic acid sequences provided herein, L^! nucleotides are interchangeable with T nucleotides.

[118] As used herein, the term “preventing” a disease or condition in a subject refers to administering to the subject to a pharmaceutical treatment, e.g., the administration of one or more agents (e.g., pharmaceutical agent), such that onset of at least one symptom of the disease or condition is delayed or prevented.

[119] As used herein, a substance is “'pure” if it is substantially free of other components. [1201 “Residual habitat products” refers to material derived from the habitat for microbiota within or on a subject. For example, fermentation cultures of microbes can contain contaminants, e.g., other microbe strains or forms (e.g., bacteria, virus, niycopiasm, and/or fungus). For example, microbes live in feces in the gastrointestinal tract, on the skin itself, in saliva, mucus of the respiratory tract, or secretions of the genitourinary' tract (i.e., biological matter associated with the microbial community'). Substantially free of residual habitat products means that the microbial composition no longer contains the biological matter associated with the microbial environment on or in the culture or human or animal subject and is 100% free, 99% free, 98% free, 97% free, 96% free, or 95% free of any contaminating biological matter associated with the microbial community. Residual habitat products can include abiotic materials (including undigested food) or it can include unwanted microorganisms. Substantially free of residual habitat products may also mean that the microbial composition contains no detectable cells from a culture contaminant or a human or animal and that only- microbial cells are detectable. In one embodiment, substantially' free of residual habitat products may also mean that the microbial composition contains no detectable viral (including bacteria, viruses (e.g., phage)), fungal, mycoplasmal contaminants. In another embodiment, it means that fewer than 1x10^-2%, 1x10^-3%, 1x10^-4%, 1x10^-5%, 1x10- ⁶%, 1x10^-7%, 1x10^-8% of the viable cells in the microbial composition are human or animal, as compared to microbial cells. There are multiple ways to accomplish this degree of purity, none of w hich are limiting. Thus, contamination may be reduced by isolating desired constituents through multiple steps of streaking to single colonies on solid media until replicate (such as, but not limited to, two) streaks from serial single colonies have showm only a single colony morphology. Alternatively, reduction of contamination can be accomplished by multiple rounds of serial dilutions to single desired cells (e.g., a dilution of 10^-8 or 10^-9), such as through multiple 10-fold serial dilutions. This can further be confirmed by showing that multiple isolated colonies have similar cell shapes and Gram staining behavior. Other methods for confirming adequate purity include genetic analysis (e.g., PCR, DNA sequencing), serology and antigen analysis, enzymatic and metabolic analysis, and methods using instrumentation such as flow cytometry' with reagents that distinguish desired constituents from contaminants. [121] “Strain” refers to a member of a bacterial species with a genetic signature such that it may be differentiated from closely-related members of the same bacterial species, the genetic signature may be the absence of all or part of at least one gene, the absence of all or part of at least on regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the absence (“curing”) of at least one native plasmid, the presence of at least one recombinant gene, the presence of at least one mutated gene, the presence of at least one foreign gene (a gene derived from another species), the presence at least one mutated regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the presence of at least one non-native plasmid, the presence of at least one antibiotic resistance cassette, or a combination thereof. Genetic signatures between different strains may be identified by PCR amplification optionally followed by DNA sequencing of the genomic region(s) of interest or of the whole genome. In the case in which one strain (compared with another of the same species) has gained or lost antibiotic resistance or gained or lost a biosynthetic capability (such as an auxotrophic strain), strains may be differentiated by selection or counter-selection using an antibiotic or nutrient/metabolite, respectively.

[122j The terms “subject” or “patient” refers to any mammal. A subject or a patient described as “in need thereof” refers to one in need of a treatment (or prevention) for a disease. Mammals (i.e., mammalian animals) include humans, laboratory' animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs), and household pets (e.g., dogs, cats, rodents). The subject may be a human. The subject may' be a non-human mammal including but. not limited to of a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a. guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee. The subject may be healthy, or may be suffering from a disease or disorder at any developmental stage. [123] As used herein, a “systemic effect” in a subject treated with a pharmaceutical composition containing bacteria (e.g., a pharmaceutical agent comprising bacteria) of the instant invention means a physiological effect occurring at one or more sites outside the gastrointestinal tract. Systemic effect(s) can result from immune modulation (e.g., via an increase and/or a reduction of one or more immune cell types or subtypes and/or one or more cytokines). Such systemic effect(s) may be the result of the modulation by bacteria of the instant invention on immune or other cells (such as epithelial cells) in the gastrointestinal tract which then, directly or indirectly, result in the alteration of activity' (activation and/or deactivation) of one or more biochemical pathways outside the gastrointestinal tract. The systemic effect may include treating or preventing a disease or condition in a subject. [124] As used herein, the term “treating” a disease in a subject or “treating” a subject having or suspected of having a disease refers to administering to the subject to a pharmaceutical treatment, e.g., the administration of one or more agents, such that at least one symptom of the disease is decreased or prevented from worsening. Tirus, in one embodiment, “treating” refers inter alia to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof,

[125] As used herein, a value is “greater than” another value if it is higher by any amount (e.g., each of 100, 50, 20, 12, 11, 10.6, 10.1, 10.01, and 10.001 is at least 10). Similarly, as used herein, a value is “less than” another value if it is lower by any amount (e.g., each of 1, 2, 4, 6, 8, 9, 9.2, 9.4, 9.6, 9.8, 9.9, 9.99, 9.999 is no more than 10). In contrast, as used herein, a test value “is” an anchor value when the test value rounds to the anchor value (e.g., if “an ingredient mass is 10% of a total mass,” in which case 10% is the anchor value, the test values of 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10,3, and 10.4 would also meet the “ingredient mass is 10% of the total mass” feature).

Bacteria

[126] The pharmaceutical agent of tire pharmaceutical composition s di sclosed herein comprise Prevotella histicola bacteria. For example, the pharmaceutical agent of the pharmaceutical compositions disclosed herein can comprise a powder comprising Prevotella histicola bacteria.

[127] In some embodiments, the bacteria of the pharmaceutical agent are lyophilized.

[128] The phase of growth can affect the amount or properties of Prevotella histicola bacteria. For example, bacteria can be isolated, e.g., from a culture, at the start of the log phase of growth, midway through the log phase, and/or once stationary phase growth has been reached.

[129] In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria therefrom, e.g., from a strain comprising 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% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the pharmaceutical agent comprises Prevotella bacteria from Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the pharmaceutical agent comprises one strain of Prevotella bacteria. Solid Dosage Form Compositions

[130] In certain embodiments, provided herein are solid dosage forms (e.g., pharmaceutical products having a solid dosage form) comprising a pharmaceutical agent that contains Prevotella histicola bacteria. In some embodiments, the pharmaceutical agent can optionally contain one or more additional components, such as a cryoprotectant. The pharmaceutical agent can be lyophilized (e.g., resulting in a powder). The pharmaceutical agent can be combined with one or more excipients (e.g., pharmaceutically acceptable excipients) in the solid dose form.

[131] In certain aspects provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, the solid dosage form comprises a pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria), and one or more disintegration agents (e.g.. one, two or three disintegration agents). In certain embodiments, the solid dosage form comprises a. pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g, bacteria and/or a powder comprising bacteria), and three disintegration agents. In certain embodiments, the total pharmaceutical agent mass is at least 20% of the total mass of the pharmaceutical composition. In some embodiments, the total pharmaceutical agent mass is no more than 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the one or more disintegrating agents 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 the one or more disintegrating agents is no more than 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition. In some embodiments, the one or more disintegration agents comprise low-substituted hydroxypropyl cellulose (L-HPC, e.g, LH-B1), croscarmellose sodium (Ac-Di-Sol, <-.g, Ac-Di-Sol SD-711), and/or crospovidone (PVPP, e.g, Kollidon, e.g, Kollidon CL-F).

[132] In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is of grade LH-B1. In certain embodiments, the total L-HPC mass 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% of tire total mass of tire pharmaceutical composition. In certain embodiments, the total L-HPC mass is no more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass is about 29% to about 35% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC (e.g., LH- Bl) mass is about 32% of the total mass of the pharmaceutical composition.

[133] In certain embodiments, the solid dosage forms provided herein comprise Croscarmellose Sodium (e.g., Ac-Di-Sol). In some embodiments, the Croscarmellose Sodium (e.g., Ac-Di-Sol) is Ac-Di-Sol of grade SD-711. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is at least 0,01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total Ac-Di-Sol mass is about 3% to about 9 % of the total mass of the pharmaceutical composition. In certain embodiments, tlie total Croscarmellose Sodium (e.g., Ac-Di-Sol) (e.g., Ac-Di-Sol SD-711) mass is about 6 % of the total mass of the pharmaceutical composition.

[134] In certain embodiments, the solid dosage forms provided herein comprise PVPP (crospovidone, e.g., Kollidon, e.g., Kollidon CL-F). In certain embodiments, the total PVPP mass is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is no more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is about 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is about 12% to about 18% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is about 15% of the total mass of the pharmaceutical composition.

[135] In certain embodiments, the solid dosage forms provided herein comprise: (i) a pharmaceutical agent having a total pharmaceutical agent mass that is at least 20% and no more than 25% of the total mass of the pharmaceutical composition, (ii) L-HPC (e.g., L-HPC of grade LH-B1) having a total L-HPC mass that is at least 22% (e.g., at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%) and no more than 42% (e.g., no more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%) of the total mass of the pharmaceutical composition; (iii) Croscarmellose Sodium (e.g., Ac-Di-Sol) (eg., Ac-Di-Sol of grade SD-711) having a total Croscarmellose Sodium (e.g,, Ac-Di-Sol) mass that is at least 0.01 % (e.g., at least 0.01%, 0.1%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%) and no more than 16% (e.g., no more than 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%) of the total mass of the pharmaceutical composition; and (iv) PVPP having a total PVPP mass that is at least 5% (e.g., 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 no more than 25% (no more than 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, or 25%) of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass plus the total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass plus the total PVPP mass is at least 35%, 40%, 45%, or 50% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: a total L-HPC mass is about 32% of the total mass of the pharmaceutical composition; a total Croscarmellose Sodium (e.g., Ac-Di-Sol) mass is about 6% of the total mass of the pharmaceutical composition; and a total PVPP mass is about 15% of the total mass of the pharmaceutical composition.

[136| In certain embodiments, the solid dosage forms provided herein further comprise mannitol. In some embodiments, the mannitol is mannitol SD200. In certain embodiments, the total mannitol mass is at least 18% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol mass is no more than 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol mass is about 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24,5%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 18% to about 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD2.00) mass is about 22% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 21 .5% of the total mass of the pharmaceutical composition. [137] In certain embodiments, the solid dosage forms provided herein comprise magnesium stearate. In certain embodiments, the total magnesium stearate mass is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is no more than 0.01%, 0.1%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, tire total magnesium stearate mass is about 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%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 0.5% to about 1 .5% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 1 % of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 1 .5% of the total mass of the pharmaceutical composition.

[138] In certain embodiments, the solid dosage forms provided herein comprise colloidal silica. In some embodiments, the colloidal silica is Aerosil 200. In certain embodiments, the total colloidal silica mass is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11 % of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is no more than 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11 % of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is about 0.5% to about I .5% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica (e.g., Aerosil 200) mass is about 1% of the total mass of the pharmaceutical composition.

[139] In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria); about 22% mannitol (e.g., mannitol SD200); about 32% L-HPC (e.g,, L-HPC LH-B1); about 6% croscarmellose sodium (e.g., Ac-Di-Sol SD-711); about 15% crospovidone (e.g., PVPP); about 1% magnesium stearate; and about 1% colloidal silica (e.g., Aerosd 200).

[140] In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria); about 21.5% mannitol; about 32% L-HPC (e.g., L-HPC LH-B1); about 6% croscarmellose sodium (e.g., Ac-Di-Sol SD- 711); about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silica (e.g., Aerosil 200P).

[141] Thus, in certain embodiments, provided herein are solid dosage forms comprising a pharmaceutical agent that contains Prevotella histicola bacteria. The bacteria can be live bacteria (e.g., powder or biomass thereof); non-live (dead) bacteria (e.g., powder or biomass thereof); non replicating bacteria (e.g., powder or biomass thereof); gamma-irradiated bacteria (e.g,, powder or biomass thereof); and/or lyophilized bacteria (e.g., powder or biomass thereof).

[142] In some embodiments, the pharmaceutical agents comprise lyophilized Prevotella histicola bacteria.

[143] In some embodiments, total cell count (TCC) can be used to quantify the numbers of Prevotella histicola bacteria present in a sample. In some embodiments, to quantify the numbers of Prevotella histicola bacteria present in a sample, electron microscopy (e.g., EM of ultrathin frozen sections) can be used to visualize the bacteria and count their relative numbers.

[144] In certain aspects, provided herein are solid dosage forms comprising pharmaceutical agents that comprise Prevotella histicola bacteria useful for the treatment and/or prevention of disease (e.g., an autoimmune disease, an inflammatory disease, a metabolic disease, or a dysbiosis); or treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection); or to decrease inflammatory cytokine expression (e.g.. decreased IL-8, IL-6, IL-lfy and/or TNFa expression levels), as well as methods of making and/or identifying such bacteria, and methods of using pharmaceutical agents and solid dosage forms thereof (e.g., for the treatment of an autoimmune disease, an inflammatory disease, or a metabolic disease, dysbiosis, bacterial septic shock, cytokine storm and/or viral infection, or to decrease inflammatory cytokine expression) either alone or in combination with other therapeutics. In some embodiments, the pharmaceutical agents comprise Prevotella histicola bacteria (e.g,, whole bacteria) (e.g., live bacteria, dead (e.g,, killed) bacteria, non-replicating bacteria, gamma-irradiated bacteria; attenuated bacteria).

[145] In certain aspects, provided are pharmaceutical agents for administration to a subject (e.g., human subject). In some embodiments, the pharmaceutical agents are combined with additional active and/or inactive materials in order to produce a final product, which may be in single dosage unit or in a multi-dose fonnat. In some embodiments, the pharmaceutical agent is combined with an adjuvant such as an immuno-adjuvant (e.g., a STING agonist, a TLR agonist, or a NOD agonist).

[146] In some embodiments, the solid dosage form comprises at least one carbohydrate.

[147] In some embodiments, the solid dosage form comprises at least one lipid. In some embodiments, the lipid comprises at least one fatty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16: 1), margaric acid (17:0), heptadecenoic acid (17: 1), stearic acid (18:0), oleic acid (18: 1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20: 1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EP A), docosanoic acid (22:0), docosenoic acid (22: 1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and tetracosanoic acid (24:0).

[148] In some embodiments, the solid dosage form comprises at least one mineral or mineral source. Examples of minerals include, without limitation: 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.

[149] In some embodiments, the solid dosage form comprises at least one vitamin. The at least one vitamin can be fat-soluble or water-soluble vitamins. 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 are salts of the vitamin, derivatives of the vitamin, compounds having tire same or similar activity of the vitamin, and metabolites of the vitamin.

[150] In some embodiments, the solid dosage form comprises an excipient. Non-limiting examples of suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, and a coloring agent.

[151 ] 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, eds., Handbook of Pharmaceutical Excipients, sixth ed.: 2009; Pharmaceutical Press and American Pharmacists Association. Solid Dosage Forms

[152] The solid dosage form described herein can be, e.g., a tablet or a minitablet. Further, a plurality of minitablets can be in (e.g., loaded into) a capsule.

[153] In some embodiments, the solid dosage form comprises a tablet (> 4mm) (e.g., 5mm- 17mm). For example, the tablet is a 5mm, 5.5mm, 6mm, 6.5mm, 7mm, 7.5mm, 8mm, 8.5mm, 9mm, 9.5mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm or 18mm tablet. In some embodiments, the tablet is a 13mm, 14mm, 15mm, 16mm, 17mm or 18mm tablet. In some embodiments, the tablet is a 17mm tablet. The size refers to the diameter of the tablet, as is known in the art. As used herein, the size of the tablet refers to the size of the tablet prior to application of an enteric coating.

[154] In some embodiments, the solid dosage form comprises a minitablet. The minitablet can be in the size range of lmm-4 mm range. E.g., the minitablet can be a 1mm minitablet, 1.5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet. The size refers to the diameter of the minitablet, as is known in the art. As used herein, the size of the minitablet refers to the size of the minitablet prior to application of an enteric coating.

[155] The minitablets can be in a capsule. The capsule can be a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. The capsule that contains the minitablets can comprise HPMC (hydroxyl propyl methyl cellulose) or gelatin. The minitablets can be inside a capsule: tlie number of minitablets inside a capsule will depend on the size of the capsule and the size of the minitablets. As an example, a size 0 capsule can contain 31-35 (an average of 33) minitablets that are 3mm minitablets.

Coating

[156] The solid dosage form (e.g., tablet or minitablet) described herein can be enterically coated, e.g., with one enteric coating layer or with two layers of enteric coating, e.g,, an inner enteric coating and an outer enteric coating. The inner enteric coating and outer enteric coating are not identical (e.g., the inner enteric coating and outer enteric coating do not contain the same components in the same amounts). The enteric coating allows for release of the pharmaceutical agent, e.g., in the small intestine, e.g., upper small intestine, e.g., duodenum and/or jejunum .

[157] Release of the pharmaceutical agent in the small intestine, e.g., in the upper small intestine, e.g., in the duodenum, or in the jejunum, allows the pharmaceutical agent to target and affect cells (e.g., epithelial cells and/or immune cells) located at these specific locations, e.g., which can cause a local effect in the small intestine and/or cause a systemic effect (e.g., an effect outside of the gastrointestinal tract).

[158] EUDRAGIT is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.

[159] Examples of other materials that can be used in the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) include cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly( vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (esters of aleurtic acid), plastics, plant fibers, zein, AQUA-ZEIN® (an aqueous zein formulation containing no alcohol), amylose starch, starch derivatives, dextrins, methyl acrylate-methacrylic acid copolymers, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate- methacrylic acid copolymers, and/or sodium alginate,

[160] The enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) can include a methacrylic acid ethyl acrylate (MAE) copolymer ( 1:1).

[161] The one enteric coating can include methacrylic acid ethyl acrylate (MAE) copolymer ( 1:1) (such as Kollicoat MAE 100P).

[162] lire one enteric coating can include a Eudragit copolymer, e.g., a Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), a Eudragit S, a Eudragit RL, a Eudragit RS, a Eudragit E, or a Eudragit FS (e.g., Eudragit FS 30 D).

[163[ Other examples of materials that can be used in the enteric coating (e.g., the one enteric coating or the inner enteric coating and/or the outer enteric coating) include those described in, e.g., 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. 2.004/0028737; WO 2005/044240.

[164] See also, e.g., U.S. 9233074, which provides pH dependent, enteric polymers that can be used with the solid dosage forms provided herein, including methacrylic acid copolymers, polyvinylacetate phthalate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate and cellulose acetate phthalate; suitable methacrylic acid copolymers include: poly(methacry1ic acid, methyl methacrylate) 1: 1 sold, for example, under the Eudragit LI 00 trade name; poly(methacrylic acid, ethyl acrylate) 1: 1 sold, for example, under the Eudragit L100-55 trade name; partially-neutralized poly(methacrylic acid, ethyl acrylate) 1: 1 sold, for example, under the Kollicoat MAE-100P trade name; and poly(methacrylic acid, methyl methacrylate) 1:2 sold, for example, under the Eudragit SI 00 trade name.

[165] In certain aspects, the solid dosage form (e.g., tablet or minitablet) described herein further comprises a sub-coating. In some embodiments, the solid dosage form comprises a sub-coating, e.g., in addition to the enteric coating, e.g., the sub-coating is beneath the enteric coating (e.g., between the solid dosage form and the enteric coating). In some embodiments, the sub-coating comprises Opadry QX, e.g., Opadry QX Blue.

Dose

[166] The dose of the pharmaceutical agent (e.g., for human subjects) is the dose per tablet or per total number of minitablets (e.g., total number of minitablets in a capsule).

[167] In embodiments where dose is determined by total cell count (TCC), total cell count can be determined by Coulter counter,

[168] In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 2.4 x 10¹¹ to about 4.0 x 10¹¹ cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 2.8 x 10¹¹ to about 3.6 x 10¹¹ ceils (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 3.2 x 10¹¹ cells (e.g., wherein cell number is determined by total cell count, which is determined by Coulter counter), wherein the dose is per tablet or per total number of minitablets in a capsule.

[169] In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 2.4 x 10^!1, about 2.8 x 10¹¹, about 3,2 x 10¹¹, about 3.6 x 10¹¹, or about 4.0 x 10¹¹, cells, wherein the dose is per tablet or per total number of minitablets in a capsule. In some embodiments, the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of bacteria is about 3.2 x 10¹¹ cells, wherein the dose is per tablet or per total number of minitablets in a capsule. [170] In some aspects, the disclosure provides a method of treating a subject (e.g., human) (e.g., a subject in need of treatment), the method comprising administering to the subject a solid dosage form provided herein.

[171] In some aspects, the disclosure provides use of a solid dosage form provided herein for the preparation of a medicament for treating a subject (e.g., human) (e.g., a subject in need of treatment).

[172] In some embodiments, the solid dosage form is orally administered (e.g., is for oral administration).

[173] In some embodiments, the solid dosage form is administered (e.g., is for administration) 1 , 2, 3, or 4 times a day. In some embodiments, 1 , 2, 3, 4 or 5 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 , 2, 3, or 4 times a day. In some embodiments, 2, 4, 6, 8, or 10 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1, 2, 3, or 4 times a day. In some embodiments, 1 solid dosage form (e.g., tablet) is administered (e.g., is for administration) 1 or 2 times a day. In some embodiments, 2 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day. In some embodiments, 3 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) I or 2 times a day. In some embodiments, 4 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day. In some embodiments, 5 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day.

[174] In some embodiments, 1 solid dosage form (e.g., tablet) is administered (e.g., is for administration) 1 or 2 times a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ cells. In some embodiments, 2 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day, wherein the solid dosage form comprises a. dose of bacteria of about 3.2 x 10¹¹ cells. In some embodiments, 3 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ cells. In some embodiments, 4 solid dosage forms (e.g,, tablets) are administered (e.g., are for administration) 1 or 2 times a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ cells. In some embodiments, 5 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) 1 or 2 times a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ cells,

[175] In some embodiments, I solid dosage form (e.g., tablet) is administered (e.g., is for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ cells (e.g., resulting in a total of about 3.2 x 10¹¹ cells being administered). In some embodiments, 2 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ cells (e.g., resulting in a total of about 6.4 x 10¹¹ cells being administered with the 2 tablets). In some embodiments, 3 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ cells (e.g., resulting in a total of about 9.6 x 10¹¹ cells being administered with the 3 tablets). In some embodiments, 4 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3,2 x 10¹¹ cells (e.g., resulting in a total of about 12.8 x 10¹¹ cells being administered with the 4 tablets). In some embodiments, 5 solid dosage forms (e.g., tablets) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ cells (e.g., resulting in a total of about 16 x 10¹¹ cells being administered with the 5 tablets).

[176] A human dose can be calculated appropriately based on allometric scaling of a dose administered to a model organism (e.g., mouse).

[177] In some embodiments, the solid dosage form is administered orally. In some embodiments, the administration to the subject once daily. In some embodiments, the solid dosage form is administered in 2 or more doses (e.g., 3 or more, 4 or more or 5 or more doses). In some embodiments, the administration to the subject of the two or more doses are separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, I day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days.

[178] In some embodiments, the solid dosage form is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 2.6 days, 27 days, 2.8 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.

[179] In some embodiments, the solid dosage form is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the solid dosage form is administered once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. [180] In some embodiments, the solid dosage form is administered twice daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.

[181] In some embodiments, the solid dosage form is administered twice daily for 1, 2, 3, 4,

5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the solid dosage form is administered once daily for at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks.

[182] In some embodiments, one or two solid dosage forms (e.g., tablets) can be administered one or two times a day.

[183] In some embodiments, one or two solid dosage forms can be administered daily.

[184] In some embodiments, 3, 4, or 5 solid dosage forms can be administered one or two times a day.

[185] In some embodiments, 3, 4, or 5 solid dosage forms can be administered daily.

[186] In some embodiments, 4 solid dosage forms can be administered one or two times a day.

[187] In some embodiments, 4 solid dosages form can be administered daily.

[188] The pharmaceutical agent contains the Prevotella histicola bacteria or contains a powder comprising Prevotella histicola bacteria, and can also contain one or more additional components, such as a cryoprotectant.

Methods of Use

[189] The solid dosage forms having the disclosed combinations and/or amounts of disintegration agents provide a decrease in disintegration times (e.g., 2. -fold, 4-fold, 6-fold, 8- fold), which can further result in an increase in therapeutic efficacy and/or physiological effect as compared to the same solid dosage forms that do not have the disclosed combinations of the disintegration agents,

[190] The solid dosage forms described herein allow, e.g., for oral administration of a pharmaceutical agent contained therein.

[191] The solid dosage forms described herein can be used in the treatment and/or prevention of inflammation, autoimmunity, a metabolic condition, or a dysbiosis. [192] The solid dosage forms described herein can be used in the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection).

[193] The solid dosage forms described herein can be used to decrease inflammatory' cytokine expression (e.g., decreased IL-8, IL-6, IL- Iβ, and/or TNFa expression levels).

[194] Methods of using a solid dosage form (e.g., for oral administration) (e.g., for pharmaceutical use) comprising a pharmaceutical agent (e.g,, a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises Prevotella histicola bacteria, and wherein the solid dosage form further comprises the disclosed components are described herein.

[195] The methods and administered solid dosage forms described herein allow', e.g., for oral administration of a pharmaceutical agent contained therein. The solid dosage form can be administered to a subject is a fed or fasting state. The solid dosage form can be administered, e.g., on an empty stomach (e.g., 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.

[196] A solid dosage form for use in the treatment and/or prevention of inflammation, autoimmunity, a metabolic condition, or a dysbiosis is provided herein.

[197] A solid dosage form for use in the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory' syncytial virus infection) is provided herein.

[198] A solid dosage form for use in decrease inflammatory cytokine expression (e.g.. decreased IL-8, IL-6, IL- Iβ, and/or TNFa expression levels) is provided herein.

[199] Use of a solid dosage form for the preparation of a medicament for the treatment and/or prevention of inflammation, autoimmunity, a metabolic condition, or a dysbiosis is provided herein.

[200] Use of a solid dosage form for the preparation of a medicament for the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory' syncytial virus infection) is provided herein.

[201] Use of a solid dosage form for the preparation of a medicament for decreasing inflammatory cytokine expression (e.g., decreased IL-8, IL-6, IL- Iβ, and/or TNFa expression levels) is provided herein. Method of Making Solid Dosage Forms

[202] In certain aspects, provided herein are methods of preparing a solid dosage form of a pharmaceutical composition, the method comprising combining into a pharmaceutical composition a pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria), and one or more (e.g., one, two or three) disintegration agents. In certain embodiments, the total pharmaceutical agent mass is at least 20% of the total mass of the pharmaceutical composition. In some embodiments the total pharmaceutical agent mass is no more than 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the one or more disintegrating agents 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 tlie one or more disintegrating agents is no more than 70%, 65%, 60%, or 55% of the total mass of the pharmaceutical composition.

[203] In some embodiments, the one or more disintegration agents comprise 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 of grade LH-B1 . In certain embodiments, the total L-HPC mass 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% of the total mass of the pharmaceutical composition. In certain embodiments, the total L-HPC mass is no more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% of the total mass of the pharmaceu tical composition. In certain embodiments, the total L-HPC mass is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42% of the total mass of the pharmaceutical composition. In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (Ac-Di-Sol). In some embodiments, the croscarmellose sodium (Ac-Di-Sol) is Ac-Di-Sol of grade SD-711. In certain embodiments, the total croscarmellose sodium (Ac-Di-Sol) mass is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total croscarmellose sodium (Ac- Di-Sol) mass is no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the total croscarmellose sodium (Ac-Di-Sol) mass is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16% of the total mass of the pharmaceutical composition. In certain embodiments, the solid dosage forms provided herein comprise PVPP. In certain embodiments, tire total PVPP mass is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is no more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total PVPP mass is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% of the total mass of the pharmaceutical composition.

[204] In certain embodiments, the method further comprises combining mannitol. In some embodiments, the mannitol is mannitol SD200. In certain embodiments, the total mannitol mass is at least 18% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol mass is no more than 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol mass is about 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, or 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (<?.g, mannitol SD200) mass is about 18% to about 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 22% of the total mass of the pharmaceutical composition. In certain embodiments, the total mannitol (e.g., mannitol SD200) mass is about 21.5% of the total mass of the pharmaceutical composition.

[205] In certain embodiments, the method further comprises combining magnesium stearate. In certain embodiments, the total magnesium stearate mass is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is no more than 0.01%, 0.1%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 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%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 1 % of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium stearate mass is about 1 .5% of the total mass of the pharmaceutical composition. [ 206] In certain embodiments, the method further comprises combining comprise colloidal silica. In some embodiments, the colloidal silica is Aerosil 2.00. In certain embodiments, the total colloidal silica mass is at least 0.01%, 0.1%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11 % of the total mass of the pharmaceutical composition. In certain embodiments, tlie total colloidal silica mass is no more than 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is about 0.01 %, 0, 1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 11% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica mass is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total colloidal silica (e.g., Aerosil 200) mass is about 1 % of the total mass of the pharmaceutical composition.

[207] In certain embodiments, the method further comprises combining about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g,, bacteria and/or a powder comprising bacteria); about 22% mannitol (e.g,, mannitol SD200); about 32% L-HPC (e.g., L-HPC LH-B1 ); about 6% croscarmellose sodium (e.g., Ac-Di-Sol SD-7I1); about 15% crospovidone (e.g., PVPP); about 1% magnesium stearate; and about 1% colloidal silica (e.g., Aerosil 200).

[ 208] In certain embodiments, the method further comprises combining about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria (e.g., bacteria and/or a powder comprising bacteria); about 21.5% mannitol; about 32% L-HPC (e.g., L-HPC LH-B1); about 6% croscarmellose sodium (e.g., Ac-Di-Sol SD- 711); about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silica (e.g., Aerosil 200P).

[209] In certain embodiments, the method further comprises compressing the pharmaceutical composition, thereby forming a tablet or a minitablet. In some embodiments, the method further comprises enterically coating the tablet or minitablet, thereby preparing the enterically coated tablet. In certain embodiments, the method further comprises loading the minitablets into a capsule.

Additional Aspects of the Solid Dosage Forms

[210] The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent

(e.g,, a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises

Prevotella histicola bacteria, and wherein the solid dosage form further comprises the described components, can provide a therapeutically effective amount of the pharmaceutical agent to a subject, e.g., a human.

[211] The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises Prevotella histicola bacteria, and wherein the solid dosage form further comprises the described components, can provide a non-natural amount of the therapeutically effective components (e.g., present in the pharmaceutical agent) to a subject, e.g., a human.

[212j The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises Prevotella histicola bacteria, and wherein the solid dosage form further comprises the described components, can provide an unnatural quantity of the therapeutically effective components (e.g., present in the pharmaceutical agent) to a subject, e.g., a human.

[ 213 ] lire solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises Prevotella histicola bacteria, and wherein the solid dosage form further comprises the described components, can bring about one or more changes to a subject, e.g., human, e.g., to treat or prevent a disease or a health disorder.

[214j The solid dosage forms, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises Prevotella histicola bacteria, and wherein the solid dosage form further comprises the described components, has potential for significant utility, e.g,, to affect a subject, e.g., a human, e.g., to treat or prevent a disease or a health disorder.

Additional Therapeutic Agents

[215] In certain aspects, the methods provided herein include the administration to a subject of a solid dosage form described herein either alone or in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunosuppressant, an anti-inflammatory agent, and/or a steroid.

[216] In some embodiments, the solid dosage form is administered to the subject before the additional therapeutic agent is administered (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 before 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 before).

In some embodiments , the solid dosage form is administered to the subject after the additional therapeutic agent is administered (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 after 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 after). In some embodiments, the solid dosage form and the additional therapeutic agent are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other).

[217] In some embodiments, an antibiotic is administered to the subject before 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 before 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 before). In some embodiments, an antibiotic is administered to the subject 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 before 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 after). In some embodiments, the solid dosage form and the antibiotic are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other).

[218] In some embodiments, the additional therapeutic is an antibiotic. For example, if the presence of a disease-associated bacteria and/or a disease-associated microbiome profile is detected, antibiotics can be administered, e.g., to eliminate the disease-associated bacteria from the subject. “Antibiotics” broadly refers to compounds capable of inhibiting or preventing a bacterial infection , Antibiotics can be classified in a number of ways, including their use for specific infections, their mechanism of action, their bi oava.il ability, or their spectrum of target microbe (e.g.. Gram-negative vs. Gram-positive bacteria, aerobic vs. anaerobic bacteria, etc.) and these may be used to kill specific bacteria in specific areas of the host (“niches”) (Leekha, et al 2011. General Principles of Antimicrobial Therapy. Mayo Clin Proc. 86(2): 156-167). In certain embodiments, antibiotics can be used to selectively target bacteria of a specific niche. In some embodiments, antibiotics know n to treat a particular infection that includes a disease niche may be used to target disease-associated microbes, including disease-associated bacteria in that niche. In other embodiments, antibiotics are administered after the solid dosage form. In some embodiments, antibiotics are administered before the solid dosage form.

[219] In some aspects, antibiotics can be selected based on their bactericidal or bacteriostatic properties. Bactericidal antibiotics include mechanisms of action that disrupt tire cell wall (e.g., p-lactams), the cell membrane (e.g., daptomycin), or bacterial DNA (e.g,, fluoroquinolones). Bacteriostatic agents inhibit bacterial replication and include sulfonamides, tetracyclines, and macrolides, and act by inhibiting protein synthesis. Furthermore, while some drugs can be bactericidal in certain organisms and bacteriostatic in others, knowing the target organism allows one skilled in the art to select an antibiotic with tlie appropriate properties. In certain treatment conditions, bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics. Thus, in certain embodiments, bactericidal and bacteriostatic antibiotics are not combined.

[220] Antibiotics include, but are not limited to aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, and anti -mycobacterial compounds, and combinations thereof.

[221] Aminoglycosides include, but are not limited to Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, and Spectinomycin. Aminoglycosides are effective, e.g., against Gram-negative bacteria, such as Escherichia coll, Klebsiella, Pseudomonas aeruginosa, and Francisella tularensis, and against certain aerobic bacteria but less effective against obligate/facultative anaerobes. Aminoglycosides are believed to bind to the bacterial 30S or 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[222] Ansamycins include, but are not limited to, Geldanamycin, Herbimycin, Rifamycin, and Streptovaricin. Geldanamycin and Herbimycin are believed to inhibit or alter the function of Heat Shock Protein 90.

[223] Carbacephems include, but are not limited to, Loracarbef. Carbacephems are believed to inhibit bacterial cell wall synthesis.

[224] Carbapenems include, but are not limited to, Ertapenem, Doripenem, Imipenem/Cilastatin, and Meropenem. Carbapenems are bactericidal for both Gram-positive and Gram-negative bacteria as broad-spectrum antibiotics. Carbapenems are believed to inhibit bacterial cell wall synthesis.

[225] Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin, Cefalotin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil, and Ceftobiprole. Selected Cephalosporins are effective, e.g., against Gram-negative bacteria and against Gram-positive bacteria, including Pseudomonas, certain Cephalosporins are effective against methicillin resistant Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wail synthesis by disrupting synthesis of the peptidoglycan layer of bacterial ceil wails.

[226] Glycopeptides include, but are not limited to, Teicopianin, Vancomycin, and Telavancin. Glycopeptides are effective, e.g., against aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile. Glycopeptides are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[227] Lincosamides include, but are not limited to, Clindamycin and Lincomycin. Lincosamides are effective, e.g., against anaerobic bacteria, as well as Staphylococcus, and Streptococcus. Lincosamides are believed to bind to the bacterial 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[ 228] Lipopeptides include, but are not limited to, Daptomycin. Lipopeptides are effective, e.g., against Gram-positive bacteria. Lipopeptides are believed to bind to the bacterial membrane and cause rapid depolarization,

[229] Macrolides include, but are not limited to, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, and Spiramycin. Macrolides are effective, e.g., against Streptococcus and Mycoplasma. Macrolides are believed to bind to the bacterial or 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

[230] Monobactams include, but are not limited to, Aztreonam. Monobactams are effective, e.g., against Gram-negative bacteria. Monobactams are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[231] Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.

[232] Oxazolidonones include, but are not limited to, Linezolid, Posizolid, Radezolid, and Torezolid. Oxazolidonones are believed to be protein synthesis inhibitors.

[233] Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxaciltin, Dicloxacillin, Flucioxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin and Ticarcillin. Penicillins are effective, e.g., against Gram-positive bacteria, facultative anaerobes, e.g., Streptococcus, Borrelia, and Treponema. Penicillins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[234] Penicillin combinations include, but are not. limited to, Amoxicillin/clavulanate, Ampicillin/sulbactam, Piperacillin/tazobactam, and Ticarcillin/clavulanate. [235] Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and Polymyxin B and E. Polypeptide Antibiotics are effective, e.g., against Gram-negative bacteria. Certain polypeptide antibiotics are believed to inhibit isoprenyl pyrophosphate involved in synthesis of the peptidoglycan layer of bacterial cell walls, while others destabilize the bacterial outer membrane by displacing bacterial counter-ions.

[236] Quinolones and Fluoroquinolone include, but are not limited to, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, and Temafloxacin. Qumolones/Fluoroquinolone are effective, e.g., against Streptococcus and Neisseria. Quinolones/Fluoroquinolone are believed to inhibit the bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.

[237] Sulfonamides include, but are not limited to, Mafenide, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfametlnzole, Sulfamethoxazole, Sulfamlimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), and Sulfonamidochrysoidine. Sulfonamides are believed to inhibit folate synthesis by competitive inhibition of dihydropteroate synthetase, thereby inhibiting nucleic acid synthesis.

[238] Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, and Tetracycline. Tetracyclines are effective, e.g., against Gram-negative bacteria. Tetracyclines are believed to bind to the bacterial 30S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[239] Anti-mycobacterial compounds include, but are not limited to, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine, and Streptomycin.

[240] Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocm, platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin Pl, clarithromycin, erythromycins, furazolidone, fusidic acid, Na fusidate, gramicidin, imipenem, indolicidin, josamycin, magainan II, metronidazole, nitroimidazoles, mikamycin, mutacin B-Ny266, mutacin B-JH1 140, mutacin J-T8, nisin, nisin A, novobiocin, oleandomycin, ostreogrycin, piperacillin/tazobactam, pristinamycin, ramoplanin, ranalexin, reutenn, rifaximin, rosamicin, rosaramicin, spectinomycin, spiramycin, staphylomycin, streptogramin, streptogramin A, synergistin, taurolidine, teicoplanin, telithromycin, ticarcillin/clavulanic acid, triacetyloieandomycin, tylosin, tyrocidin, tyrothricin, vancomycin, vemamycin, and virginiamycm.

[241] In some embodiments, the additional therapeutic agent is an immunosuppressive agent, a DMARD, a pain-control drag, a steroid, a non-steroidal anti-inflammatory drag (NS AID), or a cytokine antagonist, and combinations thereof. Representative agents include, but are not limited to, cyclosporin, retinoids, corticosteroids, propionic acid derivative, acetic acid derivative, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib, ibuprophen, cholin magnesium salicylate, fenoprofen, salsalate, difiinisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetominophen, Celecoxib, Diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, tolfenamic, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprophen, firocoxib, methotrexate (MTX), antimalarial drags (e.g., hydroxychloroquine and chloroquine), sulfasalazine, Leflunomide, azathioprine, cyclosporin, gold salts, minocycline, cyclophosphamide, D-penicillamine, minocycline, auranofm, tacrolimus, myocrisin, chlorambucil, TNF alpha antagonists (e.g., TNF alpha antagonists or TNF alpha receptor antagonists), e.g., ADALIMUMAB (Humira®), ETANERCEPT (Enbrel®), INFLIXIMAB (Remicade®; TA-650), CERTOLIZUMAB PEGOL (Cimzia®; CDP870), GOLIMUMAB (Simpom®: CNTO 148), ANAKINRA (Kmeret®), RITUXIMAB (Rituxan®; MabThera®), ABATACEPT (Orencia®), TOCILIZUMAB (RoActemra /Actemra®), integrin antagonists (TYSABRI® (natalizumab)), IL-1 antagonists (ACZ885 (Haris)), Anakinra (Kineret®)), CD4 antagonists, IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, BLyS antagonists (e.g., Atacicept, Benlysta®/ LymphoStat-B® (belimumab)), p38 Inhibitors, CD20 antagonists (Ocrelizumab, Ofatumumab (Arzerra®)), interferon gamma antagonists (Fontolizumab), prednisolone, Prednisone, dexamethasone, Cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone, triamcinolone, beclometasome, fludrocortisone, deoxycorticosterone, aldosterone, Doxycycline, vancomycin, pioglitazone, SBI-087, SCIO-469, Cura-100, Oncoxin + Viusid, TwIIF, Methoxsalen, Vitamin D - ergocalciferol, Milnacipran, Paclitaxel, rosig tazone, Tacrolimus (Prograf®), RADOO1, rapamune, rapamycin, fostamatinib, Fentanyl, XOMA 052, Fostamatinib disodium, rosightazone, Curcumin (Longvida™), Rosuvastatin, Maraviroc, ramipril, Milnacipran, Cobiprostone, somatropin, tgAAC94 gene therapy vector, MK0359, GW856553, esomeprazole, everolimus, trastuzumab, JAK1 and JAK2 inhibitors, pan JAK inhibitors, e.g., tetracyclic pyridone 6 (P6), 325, PF-956980, denosumab, IL-6 antagonists, CD20 antagonistis, CTLA4 antagonists, IL-8 antagonists, IL- 21 antagonists, IL-22 antagonist, integrin antagonists (Tysarbri® (natalizumab)), VGEF antagnosits, CXCL antagonists, MMP antagonists, defensin antagonists, IL-1 antagonists (including IL-1 beta antagonsits), and IL-23 antagonists (e.g., receptor decoys, antagonistic antibodies, etc.).

[242] In some embodiments, the additional therapy can comprise a JAK inhibitor such as baricitinib, ruxolitinib, tofacitinib, and/or pacritinib.

[243] 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, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti- cholinergic drugs for rhinitis, TLR antagonists, inflammasome inhibitors, anti-cholinergic decongestants, mast-cell stabilizers, monoclonal anti-lgE antibodies, vaccines (e.g., vaccines used for vaccination where the amount of an allergen is gradually increased), cytokine inhibitors, such as ant i-IL-6 antibodies, TNF inhibitors such as infliximab, adalirnumab, certolizumab pegol, golimumab, or etanercept, and combinations thereof.

[244] In some embodiments, the additional therapeutic agent is an RNA molecule, such as a double stranded RNA.

[245] In some embodiments, the additional therapeutic agent is an anti-sense oligonucleotide.

Administration

[246] In certain aspects, provided herein is a method of delivering a solid dosage form described herein to a subject. In some embodiments of the methods provided herein, the solid dosage form is administered in conjunction with the administration of an additional therapeutic agent. In some embodiments, the solid dosage form comprises a pharmaceutical agent co-fonnulated with the additional therapeutic agent. In some embodiments, the solid dosage form is co-administered with the additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered to the subject before administration of the solid dosage form (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 2.0, 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 before, or about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13 or 14 days before). In some embodiments, the additional therapeutic agent is administered to the subject 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 after, 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 after, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after). In some embodiments, the same mode of delivery' is used to deliver both the solid dosage form and the additional therapeutic agent. In some embodiments, different modes of delivery 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 (e.g., an intravenous and/or intramuscular).

[247] The dosage regimen can be any of a variety of methods and amounts, and can be determined by one skilled in the art according to known clinical factors. As is known in the medical arts, dosages for any one patient can depend on many factors, including the subject's species, size, body surface area, age, sex, immunocompetence, and general health, the particular microorganism to be administered, duration and route of administration, the kind and stage of the disease, and other compounds such as drugs being administered concurrently or near-concurrently . In addition to the above factors, such levels can be affected by the infectivity' of the microorganism, and the nature of the microorganism, as can be determined by one skilled in the art. In the present methods, appropriate minimum dosage levels of microorganisms can be levels sufficient for the microorganism to survive, grow and replicate. The dose of a pharmaceutical agent (e.g., in a solid dosage form) described herein may be appropriately set or adjusted in accordance with the dosage form, the route of administration, the degree or stage of a target disease, and the like. For example, the general effective dose of the agents may range between 0.01 rng/kg body weight/day and 1000 mg/kg body weight/day, between 0.1 mg/kg body weight/day and 1000 mg/kg body weight/day, 0.5 mg/kg body weight/day and 500 mg/kg body weight/day, 1 mg/kg body weight/day and 100 mg/kg body weight/day, or between 5 mg/kg body weight/day and 50 mg/kg body weight/day. The effective dose may be 0.01, 0.05, 0.1, 0.5, I, 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, or 1000 mg/kg body weight/day or more, but the dose is not limited thereto.

[248] In some embodiments, the dose administered to a subject is sufficient to prevent disease (e.g., autoimmune disease, inflammatory disease, or metabolic disease), delay its onset, or slow or stop its progression, or relieve one or more symptoms of the disease. One skilled in the art w ill recognize that dosage will depend upon a variety of factors including the strength of the particular agent (e.g., pharmaceutical agent) employed, as well as the age, species, condition, and body weight of the subject. The size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular pharmaceutical agent and the desired physiological effect.

[249] Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are no more than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. An effective dosage and treatment protocol can be determined by routine and conventional means, starting e.g., with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Animal studies are commonly used to determine the maximal tolerable dose ("MTD") of bioactive agent per kilogram weight. Those skilled m the art regularly extrapolate doses for efficacy, while avoiding toxicity, in other species, including humans.

[250] In accordance with the above, in therapeutic applications, the dosages of the pharmaceutical agents used in accordance with the invention vary depending on the active agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage. As another example, the dose should be sufficient to result in slowing of progression of the disease for which the subject is being treated, and preferably amelioration of one or more symptoms of the disease for which the subject is being treated.

[251] Separate administrations can include any number of two or more administrations, including two, three, four, five or six administrations. One skilled in the art can readily determine the number of administrations to perform or the desirability of performing one or more additional administrations according to methods known in the art for monitoring therapeutic methods and other monitoring methods provided herein. Accordingly, the methods provided herein include methods of providing to the subject one or more administrations of a solid dosage form, where the number of administrations can be determined by monitoring the subject, and, based on the results of the monitoring, determining whether or not to provide one or more additional administrations. Deciding on whether or not to provide one or more additional administrations can be based on a variety of monitoring results,

[252] The time period between administrations can be any of a variety of time periods. The time period between administrations can be a function of any of a variety of factors, including monitoring steps, as described in relation to the number of administrations, the time period for a subject to mount an immune response. In one example, the time period can be a function of the time period for a subject to mount an immune response; for example, the time period can be more than the time period for a subject to mount an immune response, such as more than about one week, more than about ten days, more than about two weeks, or more than about a month; in another example, the time period can be no more than tire time period for a subject to mount an immune response, such as no more than about one week, no more than about ten days, no more than about two weeks, or no more than about a month.

[253] In some embodiments, the delivery of an additional therapeutic agent in combination with the solid dosage form described herein reduces the adverse effects and/or improves the efficacy of the additional therapeutic agent.

[254] Tire effective dose of an additional therapeutic agent described herein is the amount of tire additional therapeutic agent that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, with the least toxicity to the subject. The effective dosage level can be identified using the methods described herein and will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions or agents administered, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employ ed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts. In general, an effective dose of an additional therapeutic agent will be the amount of the additional therapeutic agent which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[255] The toxicity of an additional therapeutic agent is the level of adverse effects experienced by the subject during and following treatment. Adverse events associated with additional therapy toxicity can include, but are not limited to, abdominal pain, acid indigestion, acid reflux, allergic reactions, alopecia, anaphylaxis, anemia, anxiety, lack of appetite, arthralgias, asthenia, ataxia, azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, elevated blood pressure, difficulty breathing, bronchitis, bruising, low white blood cell count, low red blood cell count, low platelet count, cardio toxicity, cystitis, hemorrhagic cystitis, arrhythmias, heart valve disease, cardiomyopathy, coronary artery' disease, cataracts, central neurotoxicity, cognitive impairment, confusion, conjunctivitis, constipation, coughing, cramping, cystitis, deep vein thrombosis, dehydration, depression, diarrhea, dizziness, dry mouth, dry skin, dyspepsia, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue, loss of fertility, fever, flatulence, flushing, gastric reflux, gastroesophageal reflux disease, genital pain, granulocytopenia, gynecomastia, glaucoma, hair loss, hand-foot syndrome, headache, hearing loss, heart failure, heart palpitations, heartbum, hematoma, hemorrhagic cystitis, hepatotoxicity, hyperamylasemia, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hyperlipasemia, hypermagnesemia, hypernatremia, hyperphosphatemia, hyperpigmentation, hypertriglyceridemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, impotence, infection, injection site reactions, insomnia, iron deficiency, itching, joint pain, kidney failure, leukopenia, liver dysfunction, memory loss, menopause, mouth sores, mucositis, muscle pain, myalgias, myelosuppression, myocarditis, neutropenic fever, nausea, nephrotoxicity, neutropenia, nosebleeds, numbness, ototoxicity, pain, palmar-plantar erythrodysesthesia, pancytopenia, pericarditis, peripheral neuropathy, pharyngitis, photophobia, photosensitivity, pneumonia, pneumonitis, proteinuria, pulmonary embolus, pulmonary' fibrosis, pulmonary' toxicity, rash, rapid heartbeat, rectal bleeding, restlessness, rhinitis, seizures, shortness of breath, sinusitis, thrombocytopenia, tinnitus, urinary tract infection, vaginal bleeding, vaginal dryness, vertigo, water retention, weakness, weight loss, weight gain, and xerostomia. In general, toxicity is acceptable if the benefits to the subject achieved through the therapy outweigh the adverse events experienced by the subject due to the therapy.

Immune Disorders

[256] In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of a disease or disorder associated a pathological immune response, such as an autoimmune disease, an allergic reaction and/or an inflammatory disease. In some embodiments, the disease or disorder is an inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis).

[257] In some embodiments, the disease or disorder is psoriasis.

[258] In some embodiments, the disease or disorder is psoriatic arthritis.

[259] In some embodiments, the disease or disorder is atopic dermatitis.

[260] The methods and solid dosage forms described herein can be used to treat any subject in need thereof. As used herein, a “subject in need thereof” includes any subject that has a disease or disorder associated with a pathological immune response (e.g., an inflammatory bowel disease), as w ell as any subject with an increased likelihood of acquiring a such a disease or disorder.

[261] The solid dosage forms described herein can be used, for example, as a pharmaceutical composition for preventing or treating (reducing, partially or completely, the adverse effects of) an autoimmune disease, such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, muckle-wells syndrome, rheumatoid arthritis, multiple sclerosis, or Hashimoto's disease; an allergic disease, such as a food allergy, pollenosis, or asthma; an infectious disease, such as an infection with Clostridium difficile; an inflammatory disease such as a TNF-mediated inflammatory disease (e.g., an inflammatory disease of the gastrointestinal tract, such as pouchitis, a cardiovascular inflammatory condition, such as atherosclerosis, or an inflammatory lung disease, such as chronic obstructive pulmonary disease); a pharmaceutical composition for suppressing rejection in organ transplantation or other situations in which tissue rejection might occur; a supplement, food, or beverage for improving immune functions; or a reagent for suppressing the proliferation or function of immune cells.

[262] In some embodiments, the methods and solid dosage forms provided herein are useful for the treatment of inflammation. In certain embodiments, the inflammation of any tissue and organs of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation, as discussed below.

[263] Immune disorders of the musculoskeletal system include, but are not limited, to those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulderjaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons. Examples of such immune disorders, which may 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 infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic).

[264] Ocular immune disorders refers to a immune disorder that affects any structure of the eye, including the eye lids. Examples of ocular immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis.

[265] Examples of nervous system immune disorders which may be treated with the methods and solid dosage forms described herein include, but are not limited to, encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis and schizophrenia. Examples of inflammation of the vasculature or lymphatic sy stem which may be treated with the methods and compositions described herein include, but are not limited to, arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

[266] Examples of digestive system immune disorders which may 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 diseases include, for example, certain art- recognized forms of a group of related conditions. Several major forms of inflammatory bowel diseases are known, with Crohn's disease (regional bowel disease, e.g., inactive and active forms) and ulcerative colitis (e.g., inactive and active forms) the most common of these disorders. In addition, the inflammatory bowel disease encompasses irritable bowel syndrome, microscopic colitis, lymphocytic-plasmocytic enteritis, coeliac disease, collagenous colitis, lymphocytic colitis and eosinophilic enterocolitis. Other less common forms of IBD include indeterminate colitis, pseudomembranous colitis (necrotizing colitis), ischemic inflammatory bowel disease, Behcet’s disease, sarcoidosis, scleroderma, IBD- associated dysplasia, dysplasia associated masses or lesions, and primary sclerosing cholangitis.

[267] Examples of reproductive system immune disorders which may be treated with the methods and solid dosage forms described herein include, but are not limited to, cervicitis, chori oamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[268] lire methods and solid dosage forms described herein may be used to treat autoimmune conditions having an inflammatory’ component. Such conditions include, but are not limited to, acute disseminated alopecia uni versalise, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonornia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1, giant cell arteritis, Goodpasture's syndrome, Grave's disease, Guillain-Barre 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, opsoclonus myoclonus syndrome, optic neuritis, Ord’s thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[269] The methods and solid dosage forms described herein may be used to treat T-cell mediated hypersensitivity diseases having an inflammatory component. Such conditions include, but are not limited to, contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis, house dustmite allergy) and gluten-sensitive enteropathy (Celiac disease).

[270] Other immune disorders which may be treated with the methods and solid dosage forms include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis, pleuritis, pneumonitis, prostatistis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xengrafts, sewrum sickness, and graft vs host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sexary’s syndrome, congenital adrenal hyperplasis, nonsuppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensistivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and oiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) haemolytic anemia, leukaemia and lymphomas in adults, acute leukaemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary' disease, solid organ transplant rejection, sepsis. Preferred treatments include treatment of 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 accompanying infectious conditions (e.g., sepsis). Metabolic Disorders

[271] In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of a metabolic disease or disorder a, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty' liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) or a related disease. In some embodiments, the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, or edema. In some embodiments, the methods and pharmaceutical compositions described herein relate to the treatment of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH).

[272] The methods and solid dosage forms described herein can be used to treat any’ subject in need thereof. As used herein, a “subject in need thereof’ includes any subject that has a metabolic disease or disorder, as well as any subject with an increased likelihood of acquiring a such a disease or disorder.

[273] The solid dosage forms described herein can be used, for example, for preventing or treating (reducing, partially or completely, the adverse effects of) a metabolic disease, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), Nonalcoholic Steatohepatitis (NASH), or a related disease. In some embodiments, the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, or edema.

Other Diseases and Disorders

[274] In some embodiments, the methods and solid dosage forms described herein relate to the treatment of liver diseases. Such diseases include, but are not limited to, Alagille Syndrome, Alcohol -Related Liver Disease, Alpha- 1 Antitrypsin Deficiency, Autoimmune Hepatitis, Benign Liver Tumors, Bihary' Atresia, 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, Newborn Jaundice, Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Reye Syndrome, Type I Glycogen Storage Disease, and Wilson Disease.

[275] The methods and solid dosage forms described herein may 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 diseas<

Huntington’s disease, motor neuron diseases (MND), spinocerebellar ataxia, spinal muscular atrophy, dystonia, idiopathicintracranial hypertension, epilepsy, nervous system disease, central nervous system disease, movement disorders, multiple sclerosis, encephalopathy, peripheral neuropathy or post-operative cognitive dysfunction.

Dysbiosis

[276] In recent years, it has become increasingly clear that the gut microbiome (also called the “gut microbiota”) can have a significant impact on an individual’s health through microbial activity and influence (local and/or distal) on immune and other cells of the host (Walker, W.A., Dysbiosis. The Microbiota in Gastrointestinal Pathophysiology. Chapter 25. 2017; Weiss and Thierry, Mechanisms and consequences of intestinal dysbiosis. Cellular and Molecular Life Sciences. (2017) 74(16):2959-2977. Zurich Open Repository and Archive, doi: https://doi.org/10. 1007/s00018-017-2509-x)).

[277] A healthy host-gut microbiome homeostasis is sometimes referred to as a “eubiosis” or “normobiosis,” whereas a detrimental change in the host microbiome composition and/or its diversity can lead to an unhealthy imbalance in the microbiome, or a “dysbiosis” (Hooks and O’Malley . Dysbiosis and its discontents . American Society for Microbiology . Oct 2017. Vol. 8. Issue 5. mBio 8:e01492-17. https://doi.org/10.1128/mBio.01492-r7). Dysbiosis, and associated local or distal host inflammatory or immune effects, may occur where microbiome homeostasis is lost or diminished, resulting in: increased susceptibility to pathogens; altered host bacterial metabolic activity; induction of host proinflammatory activity and/or reduction of host anti-inflammatory activity. Such effects are mediated in part by interactions between host immune cells (e.g., T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (IEC), macrophages and phagocytes) and cytokines, and other substances released by such cells and other host cells.

[278] A dysbiosis may occur within the gastrointestinal tract (a “gastrointestinal dysbiosis” or “gut dysbiosis”) or may occur outside the lumen of the gastrointestinal tract (a “distal dysbiosis”). Gastrointestinal dysbiosis is often associated with a reduction in integrity of the intestinal epithelial barrier, reduced tight junction integrity and increased intestinal permeability. Citi, S. Intestinal Barriers protect against disease, Science 359: 1098-99 (2018); Srinivasan et al., TEER measurement techniques for in vitro barrier model systems. J Lab. Autorn. 20: 107-126 (2015). A gastrointestinal dysbiosis can have physiological and immune effects within and outside the gastrointestinal tract.

[279] The presence of a dysbiosis has been associated with a wide variety of diseases and conditions including: infection, cancer, autoimmune disorders (e.g., systemic lupus erythematosus (SLE)) or inflammatory disorders (e.g., functional gastrointestinal disorders such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn’s disease), neuroinflammatory diseases (e.g., multiple sclerosis), transplant disorders (e.g., graft-versus- host disease), fatty liver disease, type I diabetes, rheumatoid arthritis, Sjogren’s syndrome, celiac disease, cystic fibrosis, chronic obstructive pulmonary disorder (COPD), and other diseases and conditions associated with 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. Microb. Ecol. Health Dis. (2015); 26: 10: 3402/mehd.v26.2619; Levy et al, Dysbiosis and the Immune System, Nature Reviews Immunology 17:219 (April 2017)

[280] Exemplary pharmaceutical compositions (e.g., solid dosage forms) disclosed herein can treat a dysbiosis and its effects by modifying tire immune activity present at the site of dysbiosis. As described herein, such compositions can modify a dysbiosis via effects on host immune cells, resulting in, e.g., an increase in secretion of anti-inflammatory cytokines and/or a decrease in secretion of pro-inflammatory cytokines, reducing inflammation in the subject recipient or via changes in metabolite production.

[281] Exemplary' pharmaceutical compositions (e.g., solid dosage forms) disclosed herein that are useful for treatment of disorders associated with a dysbiosis contain one or more types of immunomodulatory bacteria (e.g., anti-inflammatory bacteria) derived from such bacteria. Such compositions are capable of affecting the recipient host’s immune function, in the gastrointestinal tract, and/or a systemic effect at distal sites outside the subject’s gastrointestinal tract.

[282[ Exemplary' pharmaceutical compositions (e.g., solid dosage forms) disclosed herein that are usefill for treatment of disorders associated with a dysbiosi s contain a population of immunomodulatory' bacteria of a single bacterial species (e.g., a single strain) (e.g., anti- inflammatory bacteria). Such compositions are capable of affecting the recipient host’s immune function, in the gastrointestinal tract, and /or a systemic effect at distal sites outside the subject’s gastrointestinal tract.

[283] In one embodiment, pharmaceutical compositions (e.g., solid dosage forms) containing an isolated population of Prevotella histicola bacteria are administered (e.g., orally) to a mammalian recipient in an amount effective to treat a dysbiosis and one or more of its effects in the recipient. The dysbiosis may be a gastrointestinal tract dysbiosis or a distal dysbiosis.

[284] In another embodiment, pharmaceutical compositions (e.g., solid dosage forms) of the instant invention can treat a gastrointestinal dysbiosis and one or more of its effects on host immune cells, resulting in an increase in secretion of anti-inflammatory cytokines and/or a decrease in secretion of pro-inflammatory cytokines, reducing inflammation in the subject recipient.

[285] In another embodiment, the pharmaceutical compositions (e.g., solid dosage forms) can treat a gastrointestinal dysbiosis and one or more of its effects by modulating the recipient immune response via cellular and cytokine modulation to reduce gut permeability by increasing the integrity of the intestinal epithelial barrier.

[286] In another embodiment, the pharmaceutical compositions (e.g,, solid dosage forms) can treat a distal dysbiosis and one or more of its effects by modulating the recipient immune response at the site of dysbiosis via modulation of host immune cells.

[287] Other exemplary pharmaceutical compositions (e.g., solid dosage forms) are useful for treatment of disorders associated with a dysbiosis, which compositions contain one or more types of bacteria capable of altering the relative proportions of host immune cell subpopulations, e.g., subpopulations of T cells, immune lymphoid cells, dendritic cells, NK cells and other immune cells, or the function thereof, in the recipient.

[288] Other exemplary pharmaceutical compositions are useful for treatment of disorders associated with a dysbiosis, which compositions contain a population of immunomodulatory bacteria of a single bacterial species e.g., a single strain) capable of altering the relative proportions of immune cell subpopulations, e.g., T cell subpopulations, immune lymphoid cells, NK cells and other immune cells, or the function thereof, in the recipient subject.

[289] In one embodiment, the invention provides methods of treating a gastrointestinal dysbiosis and one or more of its effects by orally administering to a subject in need thereof a pharmaceutical composition which alters the microbiome population existing at the site of the dysbiosis. The pharmaceutical composition can contain one or more types of immunomodulatory bacteria or a population of immunomodulatory bacteria of a single bacterial species (e.g., a single strain).

[290] In one embodiment, the invention provides methods of treating a distal dysbiosis and one or more of its effects by orally administering to a subject in need thereof a pharmaceutical composition (e.g., solid dosage forms) which alters the subject’s immune response outside the gastrointestinal tract. The pharmaceutical composition can contain one or more topes of immunomodulatory bacteria or a population of immunomodulatory bacteria of a single bacterial species (e.g., a single strain).

[291] In exemplary embodiments, pharmaceutical compositions useful for treatment of disorders associated with a dysbiosis stimulate secretion of one or more anti-inflammatory cytokines by host immune cells. 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, pharmaceutical compositions useful for treatment of disorders associated with a dysbiosis that decrease (e.g., inhibit) secretion of one or more pro-inflammatory cytokines by host immune cells. Pro-inflammatory' cytokines include, but are not limited to, IFNy, IL- 12p70, IL-la, IL-6, IL-8, MCP1, MIPla, MIP Iβ, TNFa, and combinations thereof. Other exemplary' cytokines are known in the art and are described herein,

[292] In another aspect, the invention provides a method of treating or preventing a disorder associated with a dysbiosis in a subject in need thereof, comprising administering (e.g., orally administering) to the subject a therapeutic composition in the form of a probiotic or medical food comprising bacteria an amount sufficient to alter the microbiome at a site of the dysbiosis, such that the disorder associated with the dysbiosis is treated.

[293] In another embodiment, a therapeutic composition of the instant invention in the form of a probiotic or medical food may be used to prevent or delay the onset of a dysbiosis in a subject at risk for developing a dysbiosis.

Infection

[294] Inflammation can be a protective response to harmful stimuli, such as invading pathogens, damaged cells, toxic compounds, or cancerous cells. However, excessive inflammatory responses to such stimuli can result in serious adverse effects, including tissue damage and even death. For example, production of pro-inflammatory cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin- 1 beta (IL- Iβ), and tumor necrosis factor alpha (TNFά) in response to many viral infections is one of the primary causes of the adverse symptoms associated with infection (including, in some cases, death). For example, release of inflammatory cytokines has been associated with disease severity resulting from infection by a number of viruses, including infection by coronaviruses (e.g, SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19)), influenza viruses, and respiratory' syncytial viruses. For example, patients with severe COVID-19 often exhibit elevated levels of inflammatory cytokines in their lungs, w hich contributes to lung damage experienced by tire COVID-19 patients.

[295] In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of bacterial septic shock, cytokine storm and/or viral infection.

[296] In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of a viral infection such as a respiratory' viral infection, such as a coronavirus infection (e.g., a MERS (Middle East Respiratory Syndrome) infection, a severe acute respiratory' syndrome (SARS) infection, such as a SARS-CoV-2 infection), an influenza infection, and/or a respiratory' syncytial virus infection. In some embodiments, the methods and solid dosage forms described herein provided herein are for the treatment, of a coronavirus infection (e.g., a MERS infection, a severe acute respiratory syndrome (SARS) infection, such as a SARS-CoV-2 infection). In some embodiments, provided herein are methods and solid dosage forms for treating COVID-19.

[297] In some embodiments, the methods and solid dosage forms described herein relate to tiie treatment or prevention of a viral infection. In some embodiments, the infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection. In some embodiments the viral infection is a SARS-CoV-2 infection.

[298] In some embodiments, an additional therapy is administered to the subject. In some embodiments, the additional therapy comprises an antiviral medication. In some embodiments, the additional therapy comprises an antiviral medication such as ribavirin, neuraminidase inhibitor, protease inhibitor, recombinant interferons, antibodies, oseltamivir, zanamivir, peramivir or baloxavir marboxil. In some embodiments, the additional therapy comprises hydroxychloroquine and/or chloroquine. In some embodiments, tire additional therapy comprises remdesivir. In some embodiments, the additional therapy' comprises plasma from a subject who has recovered from infection by the same virus that is infecting the subject (e.g., plasma from a subject who has recovered from SARS-CoV-2 infection). In some embodiments, the additional therapy comprises an anti-inflammatory' agent such as NSAIDs or anti-inflammatory steroids. In some embodiments, the additional therapy' comprises dexamethasone. [299] In some embodiments, the additional therapy comprises an antibody specific for IL-6 and/or the IL-6 receptor. In some embodiments, the additional therapy comprises tocilizumab (Actemra®). In some embodiments, the additional therapy comprises sarilumab (Kevzara®).

[300] In some embodiments, the additional therapy can comprise an anti-viral therapy. For example, the anti-viral therapy can comprise a nucleotide analog, such as rerndesivir, galidesivir or clevudine; a viral RNA polymerase inhibitor such as favipiravir or galidesivir; a protease inhibitor such as ritonavi r, darunavir, or danoprevir; an inhibitor of viral membrane fusion such as umifenovir; and/or anti-SARS-CoV-2 plasma.

[301] In some embodiments, the additional therapy can comprise an anti-inflammatory therapy. For example, the anti -inflammatory therapy can comprise a corticosteroid; sirolimus; anakmra; filamod; or an antibody. In some embodiments, the antibody can comprise a GMSF inhibitor, such as lenzilumab or gimsilurnab; an anti-ILl beta inhibitor such as canakinumab; an IL-6 inhibitor such as tocilizumab or siltuximab; an 1L-6R inhibitor such as sarilumab; and/or a CCR5 antagonist such as leronlimab.

[302] In some embodiments, the additional therapy can comprise a JAK inhibitor such as baricitinib, ruxolitinib, tofacitinib, and/or pacritinib.

[303] In some embodiments, the additional therapy can comprise a TLR7 agonist such as imiquimod or reisquimod.

[304] In some embodiments, the additional therapy can comprise a cell-based therapy. For example, the cell based therapy can comprise Remestemcel- L; bone marrow stem cell therapy, such as MultiStem or Bm-Allo-MSC; mesenchymal stromal cells; and/or adiopose derived mesenchymal stem cells such as AstroStem.

[305] In some embodiments, the additional therapy can comprise an ACE receptor inhibitor.

[306] In some embodiments, the additional therapy can comprise a regulator of tire Sigma 1 and/or Sigma 2 receptor.

Examples

Example 1 : Powder Preparation Sample Protocol

[307] After desired level of bacterial culture growth is achieved, centrifuge cultures, discard the supernatant, leaving the pellet as dry as possible. Resuspend pellet in desired cryoprotectant solution to create a formulated cell paste. The cryoprotectant may contain, e.g., maltodextrin, sodium ascorbate, sodium glutamate, and/or calcium chloride. Load the formulated cell paste onto stainless steel trays and load into a freeze drier, e.g., operating in automated mode with defined cycle parameters. The freeze dried product is fed into a milling machine and tire resulting powder is collected.

[308] Powders are stored (e.g,, in vacuum sealed bags) at 2-8 degrees C (e.g., at. 4 degrees

C), e.g., in a desiccator.

Example 2: Gamma-Irradiation: Sample Protocol:

[309] Powders are gamma-irradiated at 17.5 kGy radiation unit at ambient temperature.

Frozen biomasses are gamma-irradiated at 25 kGy radiation unit in the presence of dry ice.

Example 3: Preparation of a Tablet Comprising Prevotella histicola

[310] The following recipe in Table 1 is prepared.

Table 1: Prevotella histicola Tablet Composition

[311] lire tablet is prepared as a 17.4mm x 7.1 mm tablet. The tablet is enteric coated. The tablet contains 3.2 x 10¹¹ TCC of Prevotella histicola Strain B (NRRL accession number B 50329).

[312] The Prevotella histicola strain referred to above has been deposited as Prevotella histicola Strain B (NRRL accession number B 50329).

Example 4: Preparation of a Solid Dosage Form comprising Prevotella histicola

[313] Tablets according to the recipe in Table 2 were prepared. Tableting was performed and manufactured batches were first sub-coated with Opadry QX blue before top-coating for enteric release with Kollicoat MAE 1 OOP. Table 2: Prevotella histicola Tablet Composition, 3.2x 10¹¹ cells/tablet

[314] The Prevotella histicola strain referred to above has been deposited as Prevotella histicola Strain B (NRRL accession number B 50329).

[315] The dose composition of Table 2 was provided in a 17.4mm x 7. 1 mm tablet.

Table 3: Sab-coating Composition

Table 4: Top-coating Composition

[316] The target weight per tablet is 650 mg (dose strength 162.5mg).

Example 5: Preparation of a Tablet Comprising Prevotella histicola

[317] Tablets of the recipe in Table 5 were prepared. Table 5: Composition of Prevotella histicola Coated Tablets, 3.2 10¹¹

a Amount adjusted based on the potency of drug substance to ensure targeted strength

[318] Total coated tablet weight was 777 mg .

Example 6: Tablet Total Cell Count

[319] I.: The Total Cell Count (TCC) of tablets prepared according to the recipe in Example 5 was determined.

[320] Total Cell Count (TCC) was measured by Fluorescence Microscopy by Quantom Tx. The acceptable range is set at 1.6x 10¹¹ - 4.8x 10¹¹ total cells /tablet.

[321] Total cell count (TCC) method using Fluorescence Microscopy by Quantom Tx™ is developed and qualified for drug product release and stability studies along with coulter counter method. It counts fluorescence-stained microbial cells through fluorescence imaging and analysis to produce accurate and objective bacterial cell counts.

[322] The sample is diluted in pH 6.8 buffer in presence of glass beads and vortexed. Additional dilutions are prepared as needed and sample is placed into the cell counting chamber and counted under a microscope. The result is reported as TCC/tablet. [323] The following formula (Quantom Tx formula) is used to calculate the TCC/tablet: [(Q x 2. x D) / QCF] x W

Where:

Q = the average number of cells across the 10 images.

QCF (Quantom Tx™ correction factor) - 0.00000864,

D is the dilution factor of the sample, which is IE-4 dilution = 1/0.0001 W is weight of the single coated tablet.

[324] Result: The TCC of the tablet by this was calculated to be 2.8 x 10ⁿ cells/tablet.

[325] II.: The Total Cell Count (TCC) of tablets prepared according to the recipe in Example 4 was determined.

[326] Total Cell Count (TCC) was measured by Fluorescence Microscopy by Quantom Tx. The acceptable range is set at 1.6x10¹¹ - 4.8x10¹¹ total cells /tablet.

[327] Total cell count (TCC) method using Fluorescence Microscopy by Quantom Tx™ is developed and qualified for drug product release and stability studies along with coulter counter method. It counts fluorescence-stained microbial cells through fluorescence imaging and analysis to produce accurate and objective bacterial cell counts.

[328] The sample is diluted in pH 6.8 buffer in presence of glass beads and vortexed. Additional dilutions are prepared as needed and sample is placed into the cell counting chamber and counted under a microscope. The result is reported as TCC/tablet.

[329] The following formula is used to calculate the TCC/tablet:

[(Q x 2 x D) / QCF] x w

Where:

Q ^:=: the average number of cells across the 10 images.

QCF (Quantom Tx™ correction factor) = 0.00000864,

D is the dilution factor of the sample, which is IE-4 dilution= 1/0.0001 W is weight of the single coated tablet.

[330] Result: The TCC of the tablet by this was calculated to be 3.76 x10¹¹ cells/tablet.

Example 7: Water Content

[331] 1.: The water content of tablets prepared according to the recipe in Example 5 was assessed.

[332] Water content (%) was determined by Karl-Fischer (Ph. Eur. 2.5.32). [333] The Karl-Fischer method for water content analysis followed Ph. Eur. method 2.5.32 and its suitability is confirmed.

[334] Result: The water content by this method was calculated to be 4.9%.

[335] II.: The water content of tablets prepared according to the recipe in Example 4 was assessed.

[336] Water content (%) was determined by Karl-Fischer (Ph. Eur. 2.5.32).

[337] The Karl-Fischer method for water content analysis followed Ph. Eur. method 2.5.32 and its suitability is confirmed.

[338] Result: The water content by this method was calculated to be 4.8%.

Example 8: Stability Data

[339] The stability of tablets prepared according to the recipe in Example 4 was assessed.

[340] The stability data available to date for Prevotella histicola drug product stored under long-term (up to 3 months) and accelerated storage (up to 3 months) conditions.

[341] Tablet Content and Potency: Total Cells/Tablet:

[342[ The total cells/tablet for the feasibility batch tested for up to 3 months till date showed comparable total cells count: at long-term (2-8°C) and accelerated (25°C / 60% RH (relative humidity)) storage conditions. TCC was determined by Quantom Tx. There were no apparent trends in real time and accelerated temperature condition data for up to 3 months. The data are presented in Figure 1.

[343] The total cells/tablet for the feasibility batch tested for up to 12 months showed comparable total cells count till date at long-term (2-8°C) and accelerated (25°C / 60% RH (relative humidity)) storage conditions. TCC was determined by Quantom Tx. There were no apparent trends in real time and accelerated temperature condition data for up to 12 months. Tlie data are presented in Figure 3.

[344] Water Content:

[345] The water content was within the stability specification for both long-term (2-8°C) and accelerated (25°C / 60% RH) storage conditions for up to 3 months. The results are shown in Figure 2. There were no apparent trends for up to 3 months per real time and accelerated data.

[346] The water content was measured using Karl Fisher method (Karl Fisher titration). The data was within the stability specification for both long-term (2-8°C) and accelerated (25°C / 60% RH) storage conditions for up to 12 months. The results are shown in Figure 4. There were no apparent trends for up to 12. months per real time and accelerated data.

Incorporation by Reference

[347] All publications patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents

[348] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

Claims What is claimed is:

1 . A solid dosage form of a pharmaceutical composition comprising: a pharmaceutical agent having a total pharmaceutical agent mass that is at least 20% and no more than 25% of the total mass of the pharmaceutical composition, wherein the pharmaceutical agent comprises Prevotella kisticoia bacteria; low-substituted hydroxypropyl cellulose (L-HPC) having a total L-HI’C mass that is at least 22% and no more than 42% of the total mass of the pharmaceutical composition; croscarmellose sodium (Ac-Di-Sol) having a total Ac-Di-Sol mass that is at least 0.01 % and no more than 16% of the total mass of the pharmaceutical composition; and crospovidone (PVPP) having a total PVPP mass that is at least 5% and no more than 25% of the total mass of the pharmaceutical composition.

2. The solid dosage form of claim 1, wherein the total L-HPC mass plus the total croscarmellose sodium (Ac-Di-Sol) mass plus the total PVPP mass is at least 40% of the total mass of the pharmaceutical composition.

3. The solid dosage form of claim 1, wherein the total L-HPC mass plus the total croscarmellose sodium (Ac-Di-Sol) mass plus the total PVPP mass is at least 50% of the total mass of the pharmaceutical composition.

4. The solid dosage form of any one of claims 1 to 3, wherein the L-HPC is L-HPC of grade LH-B 1 .

5. The solid dosage form of any one of claims 1 to 4, wherein the croscarmellose sodium (Ac-Di-Sol) is Ac-Di-Sol of grade SD-711.

6. The solid dosage form of any one of claims 1 to 5, wherein the total L-HPC mass is at least 27% and no more than 37% of the total mass of the pharmaceutical composition ; the total croscarmellose sodium (Ac-Di-Sol) mass is at least 1% and no more than

11 % of the total mass of the pharmaceutical composition; and the total PVPP mass is at least 10% and no more than 20% of the total mass of the pharmaceutical composition.

7. Tire solid dosage form of any one of claims 1 to 6, wherein the total L-HPC mass is at least 31% and no more than 33% of the total mass of the pharmaceutical composition; the total croscarmellose sodium (Ac-Di-Sol) mass is at least 5% and no more than 7% of the total mass of the pharmaceutical composition; and the total PVPP mass is at least 14% and no more than 16% of the total mass of the pharmaceutical composition.

8. The solid dosage form of any one of claims 1 to 7, wherein the total L-HPC mass is about 32% of the total mass of the pharmaceutical composition; the total croscarmellose sodium (Ac-Di-Sol) mass is about 6% of the total mass of the pharmaceutical composition; and the total PVPP mass is about 15% of the total mass of the pharmaceutical composition.

9. A solid dosage form of a pharmaceutical composition comprising a pharmaceutical agent and one or more disintegrating agents, wherein the total mass of the one or more disintegrating agents is at least 40% of the total mass of the pharmaceutical composition and wherein the pharmaceutical agent comprises Prevote Ha histicola bacteria.

10. The solid dosage form of claim 9, wherein the one or more disintegrating agents comprises L-HPC.

11. The solid dosage form of claim 10, wherein the L-HPC is L-HPC of grade LH-B1.

12. The solid dosage form of claim 10 or 11, wherein the total L-HPC mass is at least 22% and no more than 42% of the total mass of the pharmaceutical composition.

13. The solid dosage form of any one of claims 9 to 12, wherein the one or mon disintegrating agents comprises croscarmeilose sodium (Ac-Di-Sol).

14. Tire solid dosage form of claim 13, wherein the croscarmeilose sodium (Ac-Di-Sol) is

Ac-Di-Sol of grade SD-711.

15. The solid dosage form of claim 13 or 14, wherein the total croscarmeilose sodium (Ac-Di-Sol) mass is at least 1% and no more than 16% of the total mass of the pharmaceutical composite on .

16. The solid dosage form of any one of claims 9 to 15, wherein the one or more disintegrating agents comprises PVPP.

17. The solid dosage form of claim 16, wherein the total PVPP mass is at least 5% and no more than 25% of the total mass of the pharmaceutical composition.

18. The solid dosage form of any one of claims 1 to 17, wherein the total phannaceutical agent mass is at least 20% and no more than 25% of the total mass of the pharmaceutical composition.

19. Idle solid dosage form of any one of claims 1 to 18, wherein the total pharmaceutical agent mass is about 23% of the total mass of the pharmaceutical composition.

20. The solid dosage form of any one of claims 1 to 19, further comprising mannitol having a total mannitol mass that is at least 18% and no more than 25% of the total mass of the pharmaceutical composition.

21 . The solid dosage form of any one of claims 1 to 20, further comprising magnesium stearate having a total magnesium stearate mass that is at least 0.01% and no more than 10% of the total mass of the pharmaceutical composition.

22. Die solid dosage form of any one of claims 1 to 21, further comprising colloidal silicon dioxide (Aerosil) having a total Aerosil mass that is at least 0.01% and no more than 10% of the total mass of the pharmaceutical composition.

23. A solid dosage form of a pharmaceutical composition comprising about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histicola bacteria; about 21.5% mannitol; about 32% L-HPC; about 6% croscarmellose sodium; about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silica.

24. The solid dosage form of any one of claims 1 to 23, wherein the bacteria are lyophilized bacteria.

25. The solid dosage form of any one of claims 1 to 24, wherein the Prevote Ila histicola is Prevotella histicola Strain B (NRRL accession number B 50329).

26. The solid dosage form of any one of claims 1 to 25, wherein the bacterial are live, attenuated, or dead.

27. The solid dosage form of any one of claims 1 to 26, wherein the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of Prevotella histicola bacteria is about 2.4 x 10” to about 4.0 x 10¹¹, cells, wherein the dose is per tablet or per total number of minitablets in a capsule.

28. The solid dosage form of any one of claims 1 to 27, wherein the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of Prevotella histicola bacteria is about 2.8 x 10ⁿto about 3.6 x 10¹¹, cells, wherein the dose is per tablet or per total number of minitablets in a capsule.

29. The solid dosage form of any one of claims 1 to 28, wherein the pharmaceutical agent comprises Prevotella histicola bacteria and the dose of Prevotella histicola bacteria is about 3.2 x 10¹¹ cells, wherein the dose is per tablet or per total number of minitablets in a capsule.

30. The solid dosage form of any one of claims 1 to 29, wherein the solid dosage form is a tablet.

31. The solid dosage form of claim 30, wherein tablet is a 5mm, 5.5mm, 6mm, 6.5mm, 7mm, 7.5mm, 8mm, 8.5mm, 9mm, 9.5mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, or 18mm tablet.

32. The solid dosage form of any one of claims 1 to 29, wherein the solid dosage form is a minitablet.

33. The solid dosage form of claim 32, wherein the minitablet is a 1mm minitablet, 1 .5 mm minitablet, 2mm minitablet, 3mm minitablet, or 4mm minitablet.

34. The solid dosage form of claim 32 or 33, wherein a plurality of minitablets are contained in a capsule.

35. The solid dosage form of any one of claims 1 to 34, further comprising an enteric coating.

36. The solid dosage form of claim 35, wherein the enteric coating is a single enteric coating or more than one enteric coating.

37. The solid dosage form of claim 35 or 36, wherein the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not identical .

38. The solid dosage form of claim any one of claims 35 to 37, wherein the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1 : 1).

39. The solid dosage form of any one of claims 35 to 38, wherein the enteric coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (esters of aleurtic acid), a plastic, a plant fiber, zein, Aqua-Zein (an aqueous zein formulation containing no alcohol), amylose starch, a starch derivative, a dextrin, a methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), a methyl methacrylate- methacrylic add copolymer, or sodium alginate.

40. The solid dosage form of any one of claims 35 to 38, wherein the enteric coating comprises an anionic polymeric material.

41 . The solid dosage form of any one of claims 1 to 40, wherein the solid dosage form maintains its stability for about 3-24 months.

42. The solid dosage form of any one of claims 1 to 41, wherein the solid dosage form maintains its stability under long-term storage conditions.

43. The solid dosage form of claim 42, wherein the solid dosage form maintains its stability at about 2-8 °C.

44. The solid dosage form of any one of claims 1 to 43, wherein the solid dosage form maintains its stability under accelerated storage conditions.

45. The solid dosage form of claim 44, wherein the solid dosage form maintains its stability at about 25 °C / 60% Relative Humidity (RH).

46. The solid dosage form of any one of claims 1 to 45, wherein the stability of the solid dosage form is determined by total cell count (TCC),

47. The solid dosage form of any one of claim 1 to 46, wherein the water content of the solid dosage form is between about 3% and 6%.

48. The solid dosage form of any one of claims 1 to 47, wherein the solid dosage form maintains its water content tor about 3-24 months.

49. The solid dosage form of any one of claims 1 to 48, wherein the solid dosage form maintains its water content under long-term storage conditions.

50. The solid dosage form of claim 49, wherein the solid dosage form maintains i ts water content at about 2-8 C.

51 . The solid dosage form of any one of claims 1 to 50, wherein the solid dosage form maintains its water content under accelerated storage conditions.

52. The solid dosage form of claim 51, wherein the solid dosage form maintains i ts water content at about 25 °C / 60% Relative Humidity (RH).

53. A method of preventing or treating a disease of a subject, the method comprising administering to tire subject a solid dosage form of any one of claims 1 to 52.

54. Use of a solid dosage form of any one of claims 1 to 52 for the treatment or prevention of a disease of a subject,

55. Use of a solid dosage form of any one of claims 1 to 52 for the preparation of a medicament for treating or preventing a disease in a subject.

56. A solid dosage form of any one of claims 1 to 52 for use in the treatment or prevention of a disease of a subject.

57. A method of preparing a solid dosage form of a pharmaceutical composition, the method comprising:

(a) combining into a pharmaceutical composition:

(i) a pharmaceutical agent having a total pharmaceutical agent mass that is at least 20% and no more than 25% of the total mass of the pharmaceutical composition, wherein the pharmaceutical agent comprises Prevotella histicola bacteria;

(ii) low-substituted hydroxypropyl cellulose (L-HPC) having a total L-HPC mass that is at least 22% and no more than 42% of the total mass of the pharmaceutical composition;

(lii) croscarmellose sodium (Ac-Di-Sol) having a total croscarmellose sodium (Ac-Di-Sol) mass that is at least 0,01% and no more than 16% of the total mass of the pharmaceutical composition; and

(iv) crospovidone (PVPP) having a total PVPP mass that is at least 5% and no more than 25% of the total mass of the pharmaceutical composition; and

(b) compressing the pharmaceutical composition into a solid dosage form.

58. The method of claim 57, further comprising the step of enterically coating the solid dosage form to obtain an enterically coated solid dosage form.

59. The method of claim 57 or 58, wherein the solid dosage form is a tablet.

60. The method of claim 57 or 58, w herein the solid dosage form is a minitablet.