TW202227111A - Solid dosage forms with improved disintegration profiles - Google Patents

Abstract

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

Description

Solid dosage form with improved disintegration profile

The formulation of a drug product's solid dosage form can have a significant impact on the bioavailability of its active pharmaceutical ingredient. To improve bioavailability, disintegrating agents can be included in the solid dosage form. However, there are many potential disintegrants to choose from, each with its own characteristics. Since solid formulation disintegration processes are complex and poorly understood, the effectiveness of any particular disintegrating agent in promoting the disintegration of a particular solid dosage form formulation is unpredictable. As a result, even with the addition of disintegrating agents, the disintegration rate of many solid dosage forms of pharmaceutical products remains slow, adversely affecting the bioavailability of the active ingredient.

The present disclosure is based on the discovery of certain improved solid dosage forms that facilitate oral delivery of Prevotella histicola bacteria. For example, in certain embodiments, the solid dosage forms disclosed herein include certain combinations and/or amounts of disintegrants that result in a disintegration time of the composition that is comparable to that of conventional solid dosage forms (eg, solids comprising conventional amounts of disintegrants). dosage form) is reduced (eg, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold). In certain embodiments, the solid dosage forms provided herein result in increased therapeutic efficacy and/or physiological effects as compared to pharmaceutical products having conventional solid dosage forms.

In certain aspects, provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, the solid dosage form comprises a medicament, wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium). In some embodiments, solid dosage forms maintain their stability, eg, for three, six, ten, long-term (2°C-8°C) and/or accelerated (25°C/60% RH) storage conditions Two, eighteen and/or twenty-four months, eg, as determined by total cell count (TCC), eg, by Quantom Tx and described herein. For example, as described herein, for solid dosage forms in which stability is maintained, where the TCC range is set to 50% to 150% of the target amount, eg, at a given time point (eg, over a long period of time (2°C-8°C) and/or accelerated (25°C/60% RH) storage conditions at time points such as three, six, twelve, eighteen and/or twenty-four months), and the solid dosage form is contained within the set TCC range the TCC. For example, for a target amount of 3.2 x 10 ¹¹ TCC, an acceptable TCC range is set from 1.6 x 10 ¹¹ to 4.8 x 10 ¹¹ , and stability is maintained, wherein the solid dosage form contains TCC within the set TCC range. For example, as described herein, three-month stability is maintained under long-term (2°C-8°C) and/or accelerated (25°C/60% RH) storage conditions (e.g., by determined within the TCC range of 50% to 150%). For example, as described herein, twelve-month stability is maintained under long-term (2°C-8°C) and/or accelerated (25°C/60% RH) storage conditions (e.g., by determined within the 50% to 150% TCC range).

In certain aspects, provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, the solid dosage form comprises a medicament, wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium). In some embodiments, the solid dosage form has a water content of between about 3% and about 6% (eg, about 4.5% to about 5.5%, eg, about 5%), eg, as by European Pharmacopoeia method 2.5.32 The Karl-Fischer method provided in and described herein. In some embodiments, solid dosage forms maintain their water content under long-term (2°C-8°C) and/or accelerated (25°C/60% RH) storage conditions, e.g. Twelve, eighteen and/or twenty-four months. In some embodiments, solid dosage forms maintain their water content, for example, three months, under long-term (2°C-8°C) and/or accelerated (25°C/60% RH) storage conditions. In some embodiments, solid dosage forms maintain their water content, eg, twelve months, under long-term (2°C-8°C) and/or accelerated (25°C/60% RH) storage conditions.

In certain aspects, provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, the solid dosage form comprises a medicament (wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium)) and one or more disintegrants (eg, one, two or three disintegrants) powder). In certain embodiments, the solid dosage form comprises a medicament (wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium)) and three disintegrating powders. In certain embodiments, the total mass of the pharmaceutical agent is at least 20% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament does not exceed 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the one or more disintegrating powders 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 powders does not exceed 70%, 65%, 60% or 55% of the total mass of the pharmaceutical composition. In some embodiments, the one or more disintegrating agents include low-substituted hydroxypropyl cellulose (L-HPC, eg, LH-B1), croscarmellose sodium (Ac-Di-Sol, eg, Ac-Di) -Sol SD-711), and/or crospovidone (PVPP, eg Kollidon, eg Kollidon CL-F).

In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is grade LH-B1. In certain embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC is about 29% to about 35% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of L-HPC (LH-B1) is about 32% of the total mass of the pharmaceutical composition.

In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, Ac-Di-Sol). In some embodiments, the croscarmellose sodium (eg, Ac-Di-Sol) is an SD-711 grade of Ac-Di-Sol. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4% of the total mass of the pharmaceutical composition %, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) is about 3% to about 9% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) (eg, Ac-Di-Sol SD-711) is about 6% of the total mass of the pharmaceutical composition.

In certain embodiments, the solid dosage forms provided herein comprise PVPP (crospovidone, eg, Collidan, eg, Collidan CL-F). In certain embodiments, the total mass of PVPP is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP is about 12% to about 18% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of PVPP is about 15% of the total mass of the pharmaceutical composition.

In some embodiments, the solid dosage forms provided herein comprise: (i) a pharmaceutical agent having a total mass of the pharmaceutical composition that is at least 20% and no more than 25% of the total mass of the pharmaceutical composition, (ii) L -HPC (eg, L-HPC of LH-B1 grade) having a total mass of L-HPC of at least 22% of the total mass of the pharmaceutical composition (eg, 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 not more than 42% of the total mass of the pharmaceutical composition (for example, not more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%); (iii) Croscarmellose sodium (e.g., Ac-Di- Sol) (eg, Ac-Di-Sol, grade SD-711) having a total mass of croscarmellose sodium (eg, Ac-Di-Sol) that is at least 0.01% of the total mass of the pharmaceutical composition (eg, , at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%) and not more than 16% of the total mass of the pharmaceutical composition (eg, not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%); and (iv) PVPP having a total PVPP mass of at least 5% of the total pharmaceutical composition mass (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 not more than 25% of the total mass of the pharmaceutical composition (e.g., not more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In certain embodiments, the total mass of L-HPC plus the total mass of croscarmellose sodium (eg, Ac-Di-Sol) plus the total mass of PVPP is at least 35%, 40% of the total mass of the pharmaceutical composition %, 45% or 50%. In some embodiments, the solid dosage form comprises: the total mass of L-HPC is about 32% of the total mass of the pharmaceutical composition; the total mass of croscarmellose sodium (eg Ac-Di-Sol) is the total mass of the pharmaceutical composition about 6% of the total mass of the PVPP; and about 15% of the total mass of the pharmaceutical composition.

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 does not exceed 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% of the total mass of the pharmaceutical composition %, 23.5%, 24%, 24.5%, or 25%. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 18% to about 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 22% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 21.5% of the total mass of the pharmaceutical composition.

In certain embodiments, the solid dosage forms provided herein comprise magnesium stearate. In certain embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is from about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

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 mass of colloidal silica is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica is from about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of colloidal silica (eg, Aerosil 200) is about 1% of the total mass of the pharmaceutical composition.

In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histolytica bacteria (eg, bacteria and/or powders comprising bacteria); about 22% mannitol (eg, mannitol SD200); about 32% L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone ( eg PVPP); about 1% magnesium stearate; and about 1% colloidal silica (eg Aerosil 200).

In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histolytica bacteria (eg, bacteria and/or powders 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% stearic acid Magnesium; and about 1% colloidal silica (eg Aerosil 200P).

In certain embodiments, solid dosage forms of the medicaments described herein include tablets and microtablets. In some embodiments, the solid dosage form is enteric-coated (eg, includes an enteric coating; eg, is enteric-coated). Tablets or minitablets are coated with one or two enteric coatings (eg, inner and outer enteric coatings). Enteric-coated minitablets (with one enteric coating or with two enteric coatings (eg, inner and outer)) can be encapsulated in capsules; eg, capsules are not enteric-coated Clothes.

In some embodiments, the solid dosage form includes a tablet. In some embodiments, the tablet (eg, enteric-coated tablet) is 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm , 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablets. In some embodiments, the tablet (eg, an enteric-coated tablet) is a 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablet. In some embodiments, the tablet (eg, an enteric-coated tablet) is a 17 mm tablet.

In some embodiments, solid dosage forms include minitablets. In some embodiments, the minitablets (eg, enteric-coated minitablets) are 1 mm minitablets, 1.5 mm minitablets, 2 mm minitablets, 3 mm minitablets, or 4 mm minitablets tablet. In some embodiments, a plurality of enteric-coated minitablets are contained in a capsule (eg, a size 0 capsule may contain from about 31 to about 35 (eg, 33) minitablets, wherein the minitablets are 3 in size mm). In some embodiments, the capsule is a size 00, 0, 1, 2, 3, 4 or 5 capsule. In some embodiments, the capsules comprise HPMC (hydroxypropyl methylcellulose) or gelatin.

In some embodiments, the enteric coating comprises a layer of enteric coating.

In some embodiments, the enteric coating includes an inner enteric coating and an outer enteric coating. In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not the same (eg, the inner and outer enteric coatings do not contain the same components in the same amount).

In some embodiments, the enteric coating (eg, a layer of enteric coating or an inner enteric coating and/or an outer enteric coating) comprises a polymethacrylate-based copolymer.

In some embodiments, the enteric coating (eg, a layer of enteric coating or an inner enteric coating and/or an outer enteric coating) comprises methacrylate ethyl acrylate (MAE) copolymer (1 : 1).

In some embodiments, the layer of enteric coating comprises methacrylate ethyl acrylate (MAE) copolymer (1 : 1) (eg, Kollicoat MAE 100P).

In some embodiments, the layer of enteric coating comprises Eudragit copolymers such as Eudragit L (eg Eudragit L 100-55; Eudragit L 30 D-55), Eudragit S , Eudragit RL, Eudragit RS, Eudragit E, or Eudragit FS (eg Eudragit FS 30 D).

In some embodiments, the enteric coating (eg, a layer of enteric coating or an inner enteric coating and/or an outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT) ), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acid, wax, shellac (ester of eleuic acid), plastic , Vegetable Fiber, Zein, Aqua-Zein (Alcohol-Free Aqueous Zein Formulation), Amylose, Starch Derivatives, Dextrin, Methyl Acrylate-Methacrylic Acid Copolymer, Acetate Succinic Acid Cellulose, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

In some embodiments, the enteric coating (eg, a layer of enteric coating or an inner enteric coating and/or an outer enteric coating) comprises an anionic polymeric material.

In some embodiments, the solid dosage form includes a subcoat, eg, in addition to the enteric coating, eg, the subcoat is below the enteric coating (eg, between the solid dosage form and the enteric coating). In some embodiments, the subcoat comprises Opadry QX, such as Opadry QX Blue.

The medicament may be a powder containing Prevotella histolytica bacteria and/or components thereof, and may contain additional agents such as cryoprotectants. For example, in some embodiments, the pharmaceutical agent is a lyophilized powder of Prevotella histolytica bacteria, the lyophilized powder optionally containing additional agents, such as cryoprotectants.

In some embodiments, such as when the solid dosage form is administered orally, the agent has one or more beneficial immune effects parenterally.

In some embodiments, eg, when the solid dosage form is administered orally, the agent modulates parenteral immunity in a subject.

In some embodiments, eg, when the solid dosage form is administered orally, the agent causes a systemic effect (eg, a parenteral effect).

In some embodiments, eg, when the solid dosage form is administered orally, the agent acts on immune cells and/or epithelial cells in the small intestine (eg, causes systemic effects (eg, parenteral effects)).

In some embodiments, the medicament comprises an isolated Prevotella histolytica bacterium (eg, from one or more bacterial strains (eg, a bacterium of interest) (eg, a therapeutically effective amount thereof)). For example, wherein the pharmaceutical agent is at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% present in an isolated Prevotella infestans bacterium (eg, a bacterium of interest).

In some embodiments, the medicament comprises live bacteria.

In some embodiments, the agent comprises killed bacteria.

In some embodiments, the agent comprises non-replicating bacteria.

In some embodiments, the agent comprises bacteria that have been gamma-irradiated (eg, at 17.5 or 25 kGy).

In some embodiments, the agent comprises bacteria from a bacterial strain.

In some embodiments, the bacteria are lyophilized (eg, the lyophilized product further comprises a pharmaceutically acceptable excipient, such as a cryoprotectant) (eg, in powder form).

In some embodiments, the Prevotella histolytica bacterium is from a bacterium comprising at least 90% (or at least 97%) of the genome, 16S and and/or strains with CRISPR sequence identity. In some embodiments, the Prevotella bacterium is from a species comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Prevotella strain B 50329 (NRRL Accession No. B 50329). strains. In some embodiments, the Prevotella bacterium is from Prevotella strain B 50329 (NRRL accession number B 50329).

In some embodiments, the agent comprises Prevotella histolytica bacteria and the dose of bacteria is about 2.4 x 10 ¹¹ to about 4.0 x 10 ¹¹ cells (eg, wherein the number of cells is determined by total cell count determined by a Coulter counter) ), where the dose is the dose per tablet or the dose of all minitablets in the capsule.

In some embodiments, the agent comprises Prevotella histolytica bacteria and the dose of bacteria is from about 2.8 x 10 ¹¹ to about 3.6 x 10 ¹¹ cells (eg, wherein the number of cells is determined by total cell count determined by a Coulter counter) ), where the dose is the dose per tablet or the dose of all minitablets in the capsule.

In some embodiments, the agent comprises Prevotella histolytica bacteria and the dose of bacteria is about 2.4 x 10 ¹¹ , about 2.8 x 10 ¹¹ , about 3.2 x 10 ¹¹ , about 3.6 x 10 ¹¹ , or about 4.0 x 10 ¹¹ cells, where the dose is the dose per tablet or the dose of all minitablets in the capsule.

In some embodiments, the medicament comprises Prevotella histolytica bacteria and the dose of bacteria is about 3.2 x ¹⁰¹¹ cells, wherein the dose is the dose per tablet or the dose of all minitablets in a capsule.

In some aspects, the present disclosure provides a method of treating a subject (eg, a human) (eg, a subject in need of treatment), the method comprising administering to the subject a solid dosage form provided herein.

In some aspects, the present disclosure provides use of a solid dosage form provided herein in the manufacture of a medicament for the treatment of a subject (eg, a human) (eg, a subject in need of treatment).

In some embodiments, the solid dosage form is administered orally (eg, for oral administration).

In some embodiments, the solid dosage form is administered to a subject in a fed or fasted state. In some embodiments, the solid dosage form is administered to a subject on an empty stomach (eg, one hour before or two hours after eating). In some embodiments, the solid dosage form is administered to the subject one hour before eating. In some embodiments, the solid dosage form is administered to the subject two hours after eating.

In some embodiments, the solid dosage form is administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 1, 2, 3, 4, or 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 2, 4, 6, 8, or 10 solid dosage forms (eg, tablets) are administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) 1 or 2 times per day. In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day.

In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 1011 cells. In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms (eg, each solid dosage form) comprise about 3.2 x 10 ¹¹ Bacterial dose of cells. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells.

In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) daily, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells.

In some embodiments, the solid dosage form provides release of an agent in the small intestine, eg, in the upper small intestine of an agent contained in the solid dosage form.

In some embodiments, a solid dosage form delivers an agent to the small intestine, where the agent can act on immune cells and/or epithelial cells in the small intestine (eg, in the upper part of the small intestine) to cause an effect throughout the body (eg, a systemic effect).

In some embodiments, eg, when administered orally, the agent provides one or more beneficial immune effects parenterally.

In some embodiments, eg, when administered orally, the agent modulates parenteral immunity in the subject.

In some embodiments, eg, when administered orally, the agent causes a systemic effect (eg, a parenteral effect).

In some embodiments, eg, when administered orally, the agent acts on immune cells and/or epithelial cells in the small intestine (eg, in the upper part of the small intestine), eg, causes systemic effects (eg, parenteral effects).

In some embodiments, the solid dosage form is administered orally and has one or more beneficial immune effects parenterally (eg, interactions between the agent and cells in the small intestine modulate the systemic immune response).

In some embodiments, the solid dosage form is administered orally and modulates immune effects parenterally (eg, interactions between the agent and cells in the small intestine (eg, in the upper small intestine) modulate the systemic immune response).

In some embodiments, the solid dosage form is administered orally and activates innate antigen-presenting cells (eg, in the small intestine, eg, in the upper small intestine).

In some embodiments, the subject is in need of treatment (and/or prevention) of an autoimmune disease.

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 Th1, Th2, or Th17 inflammatory disease. In some embodiments, the inflammatory disease is a Th1 inflammatory disease. In some embodiments, the inflammatory disease is a Th2 inflammatory disease. In some embodiments, the inflammatory disease is a Th17 inflammatory disease.

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

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

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

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

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

In some embodiments, the subject is in need of reduced expression of inflammatory cytokines (eg, reduced expression levels of IL-8, IL-6, IL-1β, and/or TNFα).

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

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

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

In some embodiments, the viral infection is a SARS-CoV-2 infection.

In some embodiments, the solid dosage form is administered in combination with a therapeutic agent (eg, an additional therapeutic agent).

In certain aspects, provided herein is a method of preparing a solid dosage form of a pharmaceutical composition, the method comprising combining a pharmaceutical agent (wherein the pharmaceutical agent comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium)) and one or Multiple (eg, one, two, or three) disintegrants are combined into a pharmaceutical composition. In certain embodiments, the total mass of the pharmaceutical agent is at least 20% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament does not exceed 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the one or more disintegrating powders 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 powders does not exceed 70%, 65%, 60% or 55% of the total mass of the pharmaceutical composition.

In some embodiments, the one or more disintegrating agents include low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (Ac-Di-Sol), and/or crospovidone ( PVPP). In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is grade LH-B1. In certain embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, Ac-Di-Sol). In some embodiments, the croscarmellose sodium (eg, Ac-Di-Sol) is an SD-711 grade of Ac-Di-Sol. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4% of the total mass of the pharmaceutical composition %, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%. In certain embodiments, the solid dosage forms provided herein comprise PVPP. In certain embodiments, the total mass of PVPP is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%.

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 does not exceed 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% of the total mass of the pharmaceutical composition %, 23.5%, 24%, 24.5%, or 25%. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 18% to about 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 22% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 21.5% of the total mass of the pharmaceutical composition.

In certain embodiments, the method further comprises combining magnesium stearate. In certain embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is from about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

In certain embodiments, the method further includes the combination comprising colloidal silica. In some embodiments, the colloidal silica is Aerosil 200. In certain embodiments, the total mass of colloidal silica is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica is from about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of colloidal silica (eg, Aerosil 200) is about 1% of the total mass of the pharmaceutical composition.

In certain embodiments, the method further comprises combining about 23% of a medicament, wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium); about 22% mannitol (eg, mannitol SD200 ); about 32% L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone (such as PVPP); about 1% magnesium stearate; and about 1% colloidal silica (eg Aerosil 200).

In certain embodiments, the method further comprises combining about 23% of an medicament, wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium); about 21.5% mannitol; about 32% L -HPC (eg L-HPC LH-B1); about 6% croscarmellose sodium (eg Ac-Di-Sol SD-711); about 15% crospovidone; about 1.5% magnesium stearate ; and about 1% colloidal silica (eg Aerosil 200P).

In certain embodiments, the method further comprises compressing the pharmaceutical composition to form a tablet or minitablet. In some embodiments, the method further comprises enteric coating the tablet or minitablet, thereby producing an enteric coated tablet. In certain embodiments, the method further comprises loading the minitablets into capsules.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of US Provisional Application Serial No. 63/081,108, filed September 21, 2020, and US Provisional Application Serial No. 63/161,528, filed March 16, 2021, the entire contents of each of which are hereby incorporated by reference This article.

The present disclosure provides solid dosage forms comprising Prevotella histolytica (eg, Prevotella histolytica powder) that maintain their stability, eg, over long periods of time (2°C-8°C) and/or Three, six, twelve, eighteen and/or twenty-four months under accelerated (25°C/60% RH) storage conditions. Stability can be determined by total cell count (TCC), eg, by Quantom Tx and described herein.

The present disclosure provides solid dosage forms comprising Prevotella histolytica (eg, Prevotella histiflora powder) having a water content of between about 3% and about 6% (eg, about 4.5% to about 5.5%, For example, about 5%), eg, as determined by the Karl-Fischer method for water content analysis provided in European Pharmacopoeia Method 2.5.32 and as described herein. In some embodiments, solid dosage forms maintain their water content under long-term (2°C-8°C) and/or accelerated (25°C/60% RH) storage conditions, e.g. Twelve, eighteen and/or twenty-four months.

The present disclosure is based, in part, on the discovery that an amount of one or more disintegrants (eg, one, two, or three disintegrants) can improve the disintegration time of solid dosage forms comprising Prevotella infestans powder. For example, for a solid dosage form containing a given amount (eg, dose) of an active ingredient (eg, Prevotella histolytica powder), the blending can be adjusted based on the amount of active ingredient contained in a given formulation (eg, batch) of the medicament The amount of medicament that contains the active ingredient in a solid dosage form. The amount of diluent (eg mannitol) is then adjusted accordingly. For example, if the amount of medicament is increased, the amount of diluent is decreased; and vice versa. As described herein, the amounts of medicament and diluent can be adjusted, but the amount of one or more disintegrants (eg, one, two, or three disintegrants) remains constant, eg, for a given batch of solid dosage form formulations between times. Similarly, the amounts of magnesium stearate and colloidal silica can also be kept constant, eg, from batch to batch for a given solid dosage form formulation.

As an example, in the working examples provided herein, two tablet solid dosage forms were prepared using a medicament containing Prevotella histolytica powder. In both formulations, the three disintegrating agents totaled 53% (w:w) of the tablet, specifically: 32% low-substituted hydroxypropylcellulose; 15% crospovidone; and 6% croscarmellose Sodium cellulose. In addition, magnesium stearate and colloidal silica in both formulations were 1.5% and 1%, respectively. In one formulation, however, 25% of the potion was used. In another formulation, 23% of the drug was used. To adjust for different doses, the amount of mannitol was different: 19.5% mannitol when using 25% dose; 21.5% mannitol when using 23% dose. definition

"Adjuvant" or "adjuvant therapy" broadly refers to an agent that affects an immunological or physiological response in a subject (eg, a human). For example, adjuvants aid in the uptake of antigens from antigen-presenting cells, activate macrophages and lymphocytes, and support the production of cytokines. By altering the immune response, adjuvants may allow the use of smaller doses of the immunointeracting agent to increase the efficacy or safety of a particular dose of the immunointeracting agent. For example, adjuvants can prevent T cell depletion and thereby increase the efficacy or safety of a particular immune interacting agent.

"Administration" broadly refers to the route by which a composition (eg, a pharmaceutical composition, such as a solid dosage form of a medicament described herein) is administered 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. The pharmaceutical compositions described herein can be administered in any form by any effective route including, but not limited to, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (eg, using any a standard patch), intradermal, ocular, nasal (intra), topical, parenteral (eg, aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, vaginal, intraarterial and intrathecal), transmucosal (e.g. sublingual, translingual, (trans)buccal, (trans)urethral, vaginal (e.g. transvaginal and perivaginal), intravesical, intrapulmonary, intraduodenal, intragastric and intrabronchial In preferred embodiments, the pharmaceutical compositions described herein are administered orally, rectally, topically, intravesically, by injection into or adjacent to draining lymph nodes, intravenously Intradermal, by inhalation or aerosol or subcutaneously. In another preferred embodiment, the pharmaceutical composition described herein is administered orally or intravenously. In another embodiment, the pharmaceutical composition described herein Oral administration.

"Carbohydrate" refers to a sugar or sugar polymer. The terms "sugar", "polysaccharide", "carbohydrate" and "oligosaccharide" are used interchangeably. Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually one hydroxyl group on each carbon atom of the molecule. Carbohydrates generally have the molecular formula CnH2nOn. Carbohydrates can be monosaccharides, disaccharides, trisaccharides, oligosaccharides or polysaccharides. The most basic carbohydrates are monosaccharides such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose and fructose. Disaccharides are two joined monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose. Typically, oligosaccharides contain 3 and 6 monosaccharide units (eg, raffinose, stachyose), and polysaccharides contain 6 or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified sugar units such as 2'-deoxyribose, in which the hydroxyl group is removed, 2'-fluororibose, in which the hydroxyl group is replaced by fluorine; or N-acetylglucosamine, which is the nitrogenous form of glucose ( such as 2'-fluororibose, deoxyribose and hexose). Carbohydrates can exist in many different forms, such as conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.

"Cell enhancement" broadly refers to the influx of cells or expansion of cells in an environment that were substantially absent from the environment prior to administration of the composition and not present in the composition itself. Cells that enhance the environment include immune cells, stromal cells, bacterial and fungal cells.

"Clade" refers to an OTU or member of a phylogenetic tree that is downstream of a statistically significant node in the phylogenetic tree. A clade contains a set of terminal leaves in a phylogenetic tree that line different monophyletic evolutionary units and share sequence similarity to some extent.

"Combination" of bacteria from two or more strains includes physical coexistence of bacteria (in the same material or product or in a physically connected product), and temporal co-administration of bacteria from two or more strains or colocalization.

The terms "reduce" or "deplete" mean a change such that the difference after treatment compared to the pre-treatment state (as the case may be) is 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 not detectable. Properties that can be reduced include numbers of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; levels of interleukins; or another physical parameter such as ear thickness (eg, in DTH animals). model) or tumor size).

"Dysbacteriosis" refers to the state of the microbiota or microbiome of the gut or other body area, including, for example, mucosal or skin surfaces (or any other microbiome niche), in which the host gut microbiome ecology The normal diversity and/or function of the network "microbiome" is disrupted. Dysbiosis can lead to disease states, or it can be unhealthy only under certain conditions or only long-term. Dysbiosis can be due to a variety of factors, including environmental factors, infectious agents, host genotype, host diet, and/or stress. Dysbiosis may result in: changes in the prevalence (e.g., increase or decrease) of one or more bacterial types (e.g., anaerobes), species, and/or strains, and changes in the diversity of host microbiome population composition (e.g., , increase or decrease); changes (e.g., increase or decrease) in one or more symbiotic populations that result in a reduction or loss of one or more beneficial effects; overgrowth of one or more pathogen (e.g., pathogenic bacteria) populations; and/or the presence, and/or overgrowth of commensal organisms that cause disease only in certain circumstances.

The term "ecological consortium" refers to a group of bacteria that exchange metabolites and positively co-regulate each other, in contrast to two bacteria that induce host synergy to improve efficacy through activation of complementary host pathways.

As used herein, an "engineered bacterium" is any bacterium and the progeny of any such bacterium that has been genetically altered from its natural state by human activity. Engineered bacteria include, for example, products of targeted genetic modification, products of random mutagenesis screening, and products of directed evolution.

The term "gene" is used broadly to refer to any nucleic acid involved in biological function. The term "gene" applies to a specific genomic sequence as well as to the cDNA or mRNA encoded by the genomic sequence.

"Identity" between nucleic acid sequences of two nucleic acid molecules can be determined using known computer algorithms (such as the "FASTA" program) using, for example, Pearson et al. (1988) Proc. Natl. Acad. Sci. USA [National Academy of Sciences] Proceedings] 85: 2444 are determined as percent identity (other packages include the GCG package (Devereux, J. et al., Nucleic Acids Research 12(1):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F. et al., J Molec Biol 215: 403 (1990); Guide to Huge Computers, edited by Mrtin J. Bishop, Academic Press , San Diego [San Diego], 1994 and Carillo et al. (1988) SIAM J Applied Math 48: 1073). For example, identity can be determined using the BLAST function of the National Center for Biotechnology Information database. Other commercially or publicly available packages include the DNAStar "MegAlign" program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG) "Gap" program (Madison, Wis.).

As used herein, the term "immune disorder" refers to any disease, disorder, or symptom of disease caused by the activity of the immune system, including autoimmune diseases, inflammatory diseases, and allergies. Immune disorders include, but are not limited to, autoimmune diseases (eg, psoriasis, atopic dermatitis, lupus, scleroderma, hemolytic anemia, vasculitis, type 1 diabetes, Grave's disease, rheumatoid arthritis, multiple sclerosis, Goodpasture's syndrome, pernicious anemia and/or myopathy), inflammatory disorders (eg, acne vulgaris, asthma, celiac disease, chronic prostatitis, renal glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and/or interstitial cystitis), and/or allergies (eg, food allergies, drug allergies and/or environmental allergies).

"Immunotherapy" is a treatment that uses a subject's immune system to treat a disease (eg, immune disease, inflammatory disease, metabolic disease) and includes, for example, interferons, cell therapy, CAR-T cells, and dendritic cells therapy.

The term "increase" means a change such that the difference after treatment compared to the state before treatment is (as the case may be) at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% higher %, 90%, 2 times, 4 times, 10 times, 100 times, 10^3 times, 10^4 times, 10^5 times, 10^6 times and/or 10^7 times. Properties that can be increased include numbers of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; levels of interleukins; or another physical parameter such as ear thickness (eg, in DTH animals). model) or tumor size).

"Innate immune agonists" or "immune adjuvants" specifically target innate immune receptors (including Toll-like receptors (TLRs), NOD receptors, RLRs, C-type lectin receptors, STING-cGAS pathway group Inflammasome complexes) small molecules, proteins or other agents. For example, LPS is a bacterial-derived or synthetic TLR-4 agonist and aluminum can be used as an immunostimulatory adjuvant. Immune adjuvants are broader adjuvants or adjuvant therapies of a particular class. 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) (the Rp, Sp isomer of the phosphorodithioate analog of 2'3'-cGAMP). Examples of TLR agonists include, but are not limited to, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, and TLRI1. Examples of NOD agonists include, but are not limited to, N-Acetyl muramyl-L-propylamido-D-isoglutamic acid (muramic dipeptide (MDP)), gamma-D-glutamine Acyl-meso-diaminopimelic acid (iE-DAP) and desmuramylpeptide (DMP).

An "internally transcribed spacer" or "ITS" is a stretch of non-functional RNA located between structural ribosomal RNAs (rRNAs) on common precursor transcripts commonly used to recognize eukaryotic species (particularly fungi). The fungal rRNA that forms the nucleus of the ribosome is transcribed as a signal gene and consists of the 8S, 5.8S and 28S regions and ITS4 and 5 between the 8S and 5.8S and 5.8S and 28S regions, respectively. As previously described, these two intercistronic segments between the 18S and 5.8S regions and between the 5.8S and 28S regions are removed by splicing and contain significant differences between species for barcoding purposes Variation (Schoch et al., Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi. PNAS 109: 6241-6246. 2012) . 18S rDNA is traditionally used for phylogenetic reconstruction, however ITS can perform this function as it is usually highly conserved but contains hypervariable regions with sufficient nucleotide diversity to distinguish most fungal species Genus and species.

The term "isolated" or "enriched" includes at least some components of a microorganism (eg, bacteria) or other entity or substance that has (1) been associated with when it was originally produced (whether in nature or in an experimental setting) isolated, and/or (2) artificially produced, prepared, purified, and/or manufactured. In some embodiments, the isolated microorganism is greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97% , about 98%, about 99% or greater than about 99% pure. As used herein, a substance is "pure" when it is substantially free of other components. The terms "purify, purifying, and purified" refer to at least some that have been associated with it at the time of its initial production or production (eg, whether in nature or in an experimental setting) or at any time after its initial production Microorganisms or other materials from which components are separated. A microorganism or population of microorganisms may be considered purified if at the time of production or after production, such as isolated from a material or environment containing a microorganism or population of microorganisms, and a purified microorganism or population of microorganisms may contain up to about 10%, about 20%, About 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more than about 90% of other material and still considered "isolated." In some embodiments, the purified microorganism or microbiota system is greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, About 97%, about 98%, about 99% or greater than about 99% pure. In the case of a microbial composition provided herein, one or more microbial types present in the composition can be purified independently of one or more other microorganisms that are produced and/or present in the material or environment containing the microbial type . Its microbial composition is usually purified from residual habitat products.

As used herein, "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).

The term "LPS mutant or lipopolysaccharide mutant" refers broadly to selected bacteria that include loss of LPS. LPS loss may be due to mutation or disruption of genes involved in lipid A biosynthesis such as lpxA , lpxC and lpxD . Bacteria containing LPS mutants may be resistant to aminoglycosides and polymyxins (polymyxin B and colistin).

"Metabolite" as used herein refers to any cellular or microbial metabolic reaction that is used as a substrate in any cellular or microbial metabolic reaction or produced as a product compound, constituent, molecule, ion, cofactor, catalyst or nutrient from any cellular or microbial metabolic reaction and all molecular compounds, constituents, molecules, ions, cofactors, catalysts or nutrients.

"Microorganism" means an organism characterized as an archaea, parasite, bacteria, fungi, microscopic algae, protozoa, and developmental stages or life cycle stages associated with such organisms (e.g., plants, spores (including sporulation, dormancy, and germination), Latent, biofilm) any natural or engineered organism. Examples of gut microbes include: Actinomyces graevenitzii , Actinomyces odontolyticus , Akkermansia muciniphila , Bacteroides caccae , Bacteroides fragilis ), Bacteroides putredinis , Bacteroides thetaiotaomicron , Bacteroides vultagus , Bifidobacterium adolescentis , Bifidobacterium bifidum , Bifidobacterium Bilophila wadsworthia , Blautia , Butyrivibrio , Campylobacter gracilis , Clostridia cluster III , Clostridia cluster IV ( Clostridia cluster IV ), Clostridia cluster IX ( Acidaminococcaceae group ), Clostridia cluster XI , Clostridia cluster XIII (Peptostreptococcus group) Peptostreptococcus group ), Clostridia cluster XIV , Clostridia cluster XV , Collinsella aerofaciens , Coprococcus , Corynebacterium sunsvallense ), Desulfomonas pigra , Dorea formicigenerans , Dorea longicatena , Escherichia coli , Eubacterium hadrum , Eubacterium rectum ( Eubacterium rectale), Faecalibacteria prausnitzii , Gemella , Lactococcus , Lanchnospira , Mollicutes cluster XVI , Mollicutes Mollicutes cluster XVIII , Prevotella, Rothia mucilaginosa , Ruminococcus callidus, Ruminococcus gnavus , Ruminococcus torques and Streptococcus .

"Microbiome" broadly refers to the microorganisms that inhabit on or in a body part of a subject or patient. The microorganisms in the microbiome can include bacteria, viruses, eukaryotic microorganisms and/or viruses. Individual microorganisms in the microbiome can be metabolically active, dormant, latent, or exist as spores, can exist in planktonic form or in biofilms, or can exist in the microbiome in a sustainable or transient manner. The microbiome can be a symbiotic or healthy state microbiome or a disease state microbiome. The microbiome may be native to the subject or patient, or components of the microbiome may be modified, introduced, or depleted due to changes in health status or treatment conditions (eg, antibiotic treatment, exposure to different microorganisms) . In some aspects, the microbiome is present on a mucosal surface. In some aspects, the microbiome is the gut microbiome.

The "microbiome profile" or "microbiome signature" of a tissue or sample refers to an at least partial characterization of the bacterial composition of the microbiome. In some embodiments, the microbiota 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 the microbiota.

"Modified" in reference to a bacterium broadly refers to a bacterium that has been altered from the wild-type form. Bacterial modifications can arise from engineered bacteria. Examples of bacterial modifications include genetic modifications, gene expression modifications, phenotypic modifications, formulation modifications, chemical modifications, and dosages or concentrations. Examples of improved properties are described throughout the specification and include, for example, attenuation, auxotrophy, homing, or antigenicity. Phenotypic modification can include, by way of example, growing the bacterium in a medium that modifies the phenotype of the bacterium such that it increases or decreases virulence.

"Operational taxonomic units" and "OTUs" refer to terminal leaves in a phylogenetic tree and are defined by nucleic acid sequences (eg, entire genomes or specific gene sequences and all sequences that share sequence identity at the species level with this nucleic acid sequence). In some embodiments, the specific gene sequence may be a 16S sequence or a portion of a 16S sequence. In other embodiments, the entire genomes of the two entities are sequenced and compared. In another embodiment, selected regions can be compared genetically (eg, multi-locus sequence tags (MLSTs), specific genes or gene sets). For 16S, OTUs that share an average nucleotide identity of ≥ 97% throughout the 16S or some of the 16S variable regions can be considered the same OTU. See, eg, Claesson MJ, Wang Q, O'Sullivan O, Greene-Diniz R, Cole JR, Ross RP, and O'Toole PW. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions [Comparison of two next-generation sequencing techniques for dissecting the composition of highly complex microbiota using tandem variable 16S rRNA gene regions]. Nucleic Acids Res 38: e200. Konstantinidis KT, Ramette A and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci [Royal Society of London Series B: Philosophy of Biological Sciences] 361: 1929-1940. OTUs that share ≥ 95% mean nucleotide identity for complete genomes, MLSTs, specific genes (except 16S), or gene sets are considered identical OTUs. See, for example, 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 [Royal Society of London Series B: Philosophy of Biological Sciences] 361: 1929 -1940. OTUs are generally defined by comparing sequences between organisms. In general, sequences with no more than 95% sequence identity are not considered to form part of the same OTU. OTUs can also be characterized by any combination of nucleotide markers or genes, particularly highly conserved genes (eg, "housekeeping" genes), or combinations thereof. Provided herein are operational taxonomic units (OTUs) that can be assigned, for example, genera, species, and phylogenetic clades.

As used herein, a gene is "overexpressed" in a bacterium if, under at least some conditions, it is expressed at a higher level in the engineered bacterium than in a wild-type bacterium of the same species under the same conditions. Similarly, a gene is "underrepresented" in bacteria if it is expressed at a lower level in the engineered bacteria under at least some conditions than in wild-type bacteria of the same species under the same conditions.

The terms "polynucleotide" and "nucleic acid" are used interchangeably. They refer to polymeric forms of nucleotides of any length (deoxyribonucleotides or ribonucleotides) or their analogs. A polynucleotide can have any three-dimensional structure and can perform any function. Non-limiting examples of polynucleotides are as follows: coding or non-coding regions of genes or gene fragments, multiple loci (locus) defined from linkage analysis, exons, introns, messengers RNA (mRNA), microRNA (miRNA), silent RNA (siRNA), transfer RNA, ribosomal RNA, ribozyme, cDNA, recombinant polynucleotide, branched polynucleotide, plastid, vector, isolated of any sequence DNA, isolated RNA of any sequence, nucleic acid probes and primers. Polynucleotides can include modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. Polynucleotides can be further modified, eg, by conjugation to labeling components. In all nucleic acid sequences provided herein, U nucleotides are interchangeable with T nucleotides.

As used herein, the term "preventing" a disease or disorder in a subject refers to administering an agent to a subject for treatment, eg, administering one or more agents (eg, agents) such that the onset of at least one symptom of the disease or disorder is prevented by delay or prevent.

As used herein, a substance is "pure" when it is substantially free of other components.

"Residual habitat product" refers to material derived from the microbiota habitat in or on a subject. For example, fermentation cultures of microorganisms may contain contaminants such as other strains or forms of microorganisms (eg, bacteria, viruses, mycoplasmas, and/or fungi). For example, microorganisms live in the feces of the gastrointestinal tract, on the skin itself, in saliva, in the mucus of the respiratory tract, or in secretions of the urogenital tract (ie, biological matter associated with the microbial community). Substantially free of residual habitat products means that the microbial composition no longer contains biological matter associated with the microbial environment on or in culture or in a human or animal subject and is 100% free , 99% free, 98% free, 97% free, 96% free, or 95% free of any contaminating biological material associated with the microbial community. Residual habitat products may include abiotic material (including undigested food) or it may include unwanted microorganisms. Substantially free of residual habitat products can also mean that the microbial composition contains no detectable cells from culture contaminants or humans or animals and means that only microbial cell lines are detectable. In one embodiment, substantially free of residual habitat products may also mean that the microbial composition is free of detectable viral (including bacteria, viruses (eg, bacteriophages)), fungi, mycoplasma contaminants. In another embodiment, this means less than 1 x ^10-2 %, 1 x ^10-3 %, 1 x 10-4%, 1 x 10-5%, 1 x 10-5%, 1 x ^10-4 %, 1 x ^10-5 %, 1 x 10 ^-6 %, 1 x 10 ^-7 %, 1 x 10 ^-8 % live cell line human or animal. There are a number of ways to achieve this purity, none of which is limiting. Thus, contaminants can be isolated by performing multiple streaking steps on a single colony on solid medium until replicates (such as, but not limited to, two) from a series of single colonies have shown only single colony morphology. components are reduced. Alternatively, reduction of contaminants can be accomplished by multiple rounds of serial dilutions to a single desired cell (eg, ^10-8 or ^10-9 dilutions), such as by multiple 10-fold serial dilutions. This was further confirmed by showing that multiple isolated colonies had similar cell shapes and Gram staining behavior. Other methods used to demonstrate sufficient purity include genetic analysis (e.g., PCR, DNA sequencing), serological and antigenic analysis, enzymatic and metabolic analysis, and methods using instrumentation such as those using reagents that distinguish the desired components from contaminants. Flow Cytometry.

A "strain" refers to a member of a bacterial species that has a genetic signature such that it is distinguishable from closely related members of the same bacterial species. A gene characteristic may be the absence of all or a portion of at least one gene, the absence of all or a portion of at least one regulatory region (e.g., promoter, terminator, riboswitch, ribosome binding site), the absence ("elimination") of at least one One native plastid, at least one recombinant gene is present, at least one mutated gene is present, at least one foreign gene (gene derived from another species) is present, at least one mutant regulatory region (e.g. promoter, terminator, riboswitch, ribose) is present body binding site), the presence of at least one non-native plastid, the presence of at least one antibiotic resistance cassette, or a combination thereof. Gene signatures between different strains can be identified by PCR amplification followed by DNA sequencing of one or more genomic regions of interest or the whole genome, if desired. If a strain (compared to another strain of the same species) has acquired or lost antibiotic resistance or acquired or lost biosynthetic capacity (eg, an auxotrophic strain), antibiotics or nutrients can be used by selection or counter-selection, respectively / metabolites to distinguish strains.

The term "subject" or "patient" refers to any mammal. A subject or patient described as "in need" refers to a person in need of treatment (or prevention) of a disease. Mammals (ie, mammals) include humans, laboratory animals (eg, primates, rats, mice), livestock (eg, cattle, sheep, goats, pigs), and household pets (eg, dogs, cats, rodents) ). The subject can be a human. The subject can be a non-human mammal including, but not limited to, a dog, cat, cow, horse, pig, donkey, goat, camel, mouse, rat, guinea pig, sheep, llama, monkey, gorilla or chimpanzee . The subject may be healthy, or may be suffering from a disease or disorder at any stage of development.

As used herein, a "systemic effect" in a subject treated with an agent comprising a bacterium of the invention (eg, an agent comprising the bacteria) refers to a physiological effect that occurs at one or more sites outside the gastrointestinal tract. One or more systemic effects may result from immunomodulation (eg, by increasing and/or decreasing one or more immune cell types or subtypes and/or one or more cytokines). Such one or more systemic effects may be the result of modulation of immune cells or other cells (eg, epithelial cells) in the gastrointestinal tract by the bacteria of the invention, which then directly or indirectly lead to one or more biochemical pathways outside the gastrointestinal tract altered activity (activation and/or inactivation). Systemic effects can include treating or preventing a disease or disorder in a subject.

As used herein, the term "treating" a disease in a subject or "treating" a subject with or suspected of having a disease refers to administering a medical treatment (eg, administration of one or more agents) to the subject, thereby reducing at least a A symptom of a disease or preventing its worsening. Thus, in one embodiment, "treating" especially refers to delaying progression, promoting remission, inducing remission, increasing remission, accelerating recovery, increasing efficacy, or reducing resistance to replacement therapy, or a combination thereof.

As used herein, a value is "greater than" another value if it is higher by any amount (eg, 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 (eg, 1, 2, 4, 6, 8, 9, 9.2, 9.4, 9.6, 9.8, 9.9 , 9.99, 9.999 each not exceeding 10). Conversely, as used herein, when the test value is rounded to the anchor value, the test value "is" the anchor value (e.g., if "the mass of the ingredient is 10% of the total mass" (in which case the anchor value 10%), then the test values 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, and 10.4 will also satisfy the feature that the "component mass is 10% of the total mass". bacteria

The medicament of the pharmaceutical composition disclosed herein comprises Prevotella histolyticus bacteria. For example, a medicament of the pharmaceutical composition disclosed herein may comprise a powder containing Prevotella histolyticus bacteria.

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

The growth stage affects the quantity or nature of the Prevotella habitatii bacteria. For example, bacteria can be isolated from the culture, eg, at the beginning of the logarithmic growth phase, in the middle of the logarithmic growth phase, and/or once the steady growth phase is reached.

In some embodiments, the medicament comprises, for example, a Prevotella histolytica bacterium from a strain having at least 80%, 85%, 85% nucleotide sequence with Prevotella strain B 50329 (NRRL Accession No. %, 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. In some embodiments, the medicament comprises a Prevotella bacterium from Prevotella strain B 50329 (NRRL accession number B 50329). In some embodiments, the medicament comprises a strain of Prevotella bacteria. solid dosage form composition

In certain embodiments, provided herein is a solid dosage form (eg, a pharmaceutical product having a solid dosage form) comprising a medicament comprising a Prevotella histolyticus bacterium. In some embodiments, the medicament may optionally contain one or more additional components, such as cryoprotectants. The pharmaceutical agent can be lyophilized (eg, to produce a powder). The medicament may be combined with one or more excipients (eg, pharmaceutically acceptable excipients) in the solid dosage form.

In certain aspects, provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, the solid dosage form comprises a medicament (wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium)) and one or more disintegrants (eg, one, two or three disintegrants) powder). In certain embodiments, the solid dosage form comprises a medicament (wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium)) and three disintegrating powders. In certain embodiments, the total mass of the pharmaceutical agent is at least 20% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament does not exceed 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the one or more disintegrating powders 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 powders does not exceed 70%, 65%, 60% or 55% of the total mass of the pharmaceutical composition. In some embodiments, the one or more disintegrating agents include low-substituted hydroxypropyl cellulose (L-HPC, eg, LH-B1), croscarmellose sodium (Ac-Di-Sol, eg, Ac-Di) -Sol SD-711), and/or crospovidone (PVPP, eg Kollidon, eg Kollidon CL-F).

In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is grade LH-B1. In certain embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC is about 29% to about 35% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of L-HPC (LH-B1) is about 32% of the total mass of the pharmaceutical composition.

In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, Ac-Di-Sol). In some embodiments, the croscarmellose sodium (eg, Ac-Di-Sol) is an SD-711 grade of Ac-Di-Sol. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4% of the total mass of the pharmaceutical composition %, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6% of the total mass of the pharmaceutical composition %, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%. In certain embodiments, the total mass of Ac-Di-Sol is about 3% to about 9% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of croscarmellose sodium (eg, Ac-Di-Sol) (eg, Ac-Di-Sol SD-711) is about 6% of the total mass of the pharmaceutical composition.

In certain embodiments, the solid dosage forms provided herein comprise PVPP (crospovidone, eg, Collidan, eg, Collidan CL-F). In certain embodiments, the total mass of PVPP is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP is about 12% to about 18% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of PVPP is about 15% of the total mass of the pharmaceutical composition.

In some embodiments, the solid dosage forms provided herein comprise: (i) a pharmaceutical agent having a total mass of the pharmaceutical composition that is at least 20% and no more than 25% of the total mass of the pharmaceutical composition, (ii) L -HPC (eg, L-HPC of LH-B1 grade) having a total mass of L-HPC of at least 22% of the total mass of the pharmaceutical composition (eg, 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 not more than 42% of the total mass of the pharmaceutical composition (for example, not more than 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%); (iii) Croscarmellose sodium (e.g., Ac-Di- Sol) (eg, Ac-Di-Sol, grade SD-711) having a total mass of croscarmellose sodium (eg, Ac-Di-Sol) that is at least 0.01% of the total mass of the pharmaceutical composition (eg, , at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%) and not more than 16% of the total mass of the pharmaceutical composition (eg, not more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or 16%); and (iv) PVPP having a total PVPP mass of at least 5% of the total pharmaceutical composition mass (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 not more than 25% of the total mass of the pharmaceutical composition (e.g., not more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In certain embodiments, the total mass of L-HPC plus the total mass of croscarmellose sodium (eg, Ac-Di-Sol) plus the total mass of PVPP is at least 35%, 40% of the total mass of the pharmaceutical composition %, 45% or 50%. In some embodiments, the solid dosage form comprises: the total mass of L-HPC is about 32% of the total mass of the pharmaceutical composition; the total mass of croscarmellose sodium (eg Ac-Di-Sol) is the total mass of the pharmaceutical composition about 6% of the total mass of the PVPP; and about 15% of the total mass of the pharmaceutical composition.

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 does not exceed 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% of the total mass of the pharmaceutical composition %, 23.5%, 24%, 24.5%, or 25%. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 18% to about 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 22% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 21.5% of the total mass of the pharmaceutical composition.

In certain embodiments, the solid dosage forms provided herein comprise magnesium stearate. In certain embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is from about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

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 mass of colloidal silica is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica is from about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of colloidal silica (eg, Aerosil 200) is about 1% of the total mass of the pharmaceutical composition.

In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histolytica bacteria (eg, bacteria and/or powders comprising bacteria); about 22% mannitol (eg, mannitol SD200); about 32% L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone ( eg PVPP); about 1% magnesium stearate; and about 1% colloidal silica (eg Aerosil 200).

In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent, wherein the pharmaceutical agent comprises Prevotella histolytica bacteria (eg, bacteria and/or powders 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% stearic acid Magnesium; and about 1% colloidal silica (eg Aerosil 200P).

Accordingly, in certain embodiments, provided herein are solid dosage forms comprising a pharmaceutical agent comprising a Prevotella histolytica bacterium. Bacteria can be live bacteria (eg, powder or biomass thereof); non-live (dead) bacteria (eg, powder or biomass thereof); non-replicating bacteria (eg, powder or biomass thereof); gamma irradiated bacteria (eg, powder or biomass thereof); and/or lyophilized bacteria (eg, powder or biomass thereof).

In some embodiments, the medicament comprises lyophilized Prevotella histolyticus bacteria.

In some embodiments, a total cell count (TCC) can be used to quantify the amount of Prevotella histolyticus bacteria present in a sample. In some embodiments, to quantify the number of Prevotella histolytica bacteria present in a sample, electron microscopy (eg, EM of ultrathin cryosections) can be used to visualize the bacteria and count their relative numbers.

In certain aspects, provided herein are solid dosage forms comprising pharmaceutical agents comprising Prevotella histolytica bacteria, useful for the treatment and/or prevention of diseases (eg, autoimmune diseases, inflammatory diseases, metabolic diseases or dysbiosis); or the treatment and/or prevention of bacterial septic shock, cytokine storm, and/or viral infections (e.g., coronavirus infection, influenza infection, and/or respiratory syncytial virus infection); or reduction of inflammatory cell-mediated expression (eg, reducing expression levels of IL-8, IL-6, IL-1β, and/or TNFα), and methods of making and/or identifying such bacteria, and using the agents alone or in combination with other therapeutic agents and Methods of solid dosage forms thereof (eg, for the treatment of autoimmune, inflammatory or metabolic diseases, dysbacteriosis, bacterial septic shock, interleukin storm and/or viral infection, or to reduce inflammatory cells interferon performance). In some embodiments, the medicament comprises Prevotella histolytica bacteria (eg, whole bacteria) (eg, live bacteria, dead (eg, killed) bacteria, non-replicating bacteria, gamma irradiated bacteria; reduced poisonous bacteria).

In certain aspects, medicaments for administration to a subject (eg, a human subject) are provided. In some embodiments, the pharmaceutical agent is combined with additional active and/or inactive materials to produce a final product, which may be in a single dosage unit or in multiple dosage forms. In some embodiments, the agent is combined with an adjuvant, such as an immune adjuvant (eg, a STING agonist, TLR agonist, or NOD agonist).

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

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 the group consisting of lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), Pearl acid (17 : 0), heptadecenoic acid (17 : 1), stearic acid (18 : 0), oleic acid (18 : 1), linoleic acid (18 : 2), linolenic acid (18 : 0) 3), stearidonic acid (18 : 4), arachidonic acid (20 : 0), eicosenoic acid (20 : 1), eicosadienoic acid (20 : 2), eicosatetra enoic acid (20 : 4), eicosapentaenoic acid (20 : 5) (EPA), behenic acid (22 : 0), docosaenoic acid (22 : 1), behenic acid Pentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA) and tetracosanoic acid (24:0).

In some embodiments, the solid dosage form comprises at least one mineral or mineral source. Examples of minerals include, but are not limited to, chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the foregoing minerals include soluble mineral salts, sparingly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals and reduced minerals. ) and their combinations.

In some embodiments, the solid dosage form comprises at least one vitamin. At least one vitamin can be a fat-soluble or water-soluble vitamin. Suitable vitamins include, but are not limited to, vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, Pantothenic acid and biotin. Suitable forms of any of the foregoing are vitamin salts, vitamin derivatives, compounds having the same or similar activity as vitamins, and vitamin metabolites.

In some embodiments, solid dosage forms contain excipients. Non-limiting examples of suitable excipients include buffers, preservatives, stabilizers, binders, compacting agents, lubricants, dispersion enhancers, disintegrating agents, flavoring agents, sweetening agents, and coloring agents.

Suitable excipients that can be included in the solid dosage form can be one or more pharmaceutically acceptable excipients known in the art. See, eg, Rowe, Sheskey, and Quinn, eds., Handbook of Pharmaceutical Excipients , Sixth Edition 2009; Pharmaceutical Press and American Pharmacists Association. solid dosage form

The solid dosage forms described herein can be, for example, tablets or minitablets. Additionally, multiple microtablets can be in (eg, encapsulated) in a capsule.

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

In some embodiments, solid dosage forms include minitablets. Microtablets can range in size from 1 mm to 4 mm. For example, microtablets can be 1 mm microtablets, 1.5 mm microtablets, 2 mm microtablets, 3 mm microtablets, or 4 mm microtablets. As known in the art, size refers to the diameter of the microtablets. As used herein, the size of the minitablet refers to the size of the minitablet prior to application of the enteric coating.

Microtablets can be in capsules. The capsule may be a size 00, 0, 1, 2, 3, 4 or 5 capsule. Capsules containing minitablets may contain HPMC (hydroxypropyl methylcellulose) or gelatin. Microtablets can be placed in capsules: the number of microtablets in a capsule will depend on the size of the capsule and the size of the microtablets. For example, a size 0 capsule can hold 31-35 (average 33) 3 mm microtablets. coating

The solid dosage forms (eg, tablets or minitablets) described herein can be enteric coated, eg, with one enteric coating or two enteric coatings (eg, an inner enteric coating and an outer enteric coating). The inner and outer enteric coatings are not the same (eg, the inner and outer enteric coatings do not contain the same components in the same amount). Enteric coatings allow release of the agent, eg, in the small intestine (eg, the upper part of the upper small intestine, eg, the duodenum and/or jejunum).

The release of an agent in the small intestine (eg, in the upper part of the small intestine, such as the duodenum or jejunum) allows the agent to target and affect cells (eg, epithelial cells and/or immune cells) localized at these specific locations, for example, in Causes local effects in the small intestine and/or causes systemic effects (eg, parenteral effects).

EUDRAGIT is a brand name for a wide variety of polymethacrylate based copolymers. It includes anionic, cationic and neutral copolymers based on methacrylic acid and methacrylic acid/acrylates or their derivatives.

Examples of other materials that can be used for enteric coatings (eg, one layer of enteric coating or inner and/or outer enteric coatings) include cellulose acetate phthalate (CAP), cellulose acetate trimellitate ( CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (ester of eleuic acid), Plastic, vegetable fiber, zein, AQUA-ZEIN® (alcohol-free aqueous zein formulation), amylose, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, acetic acid Cellulose succinate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, and/or sodium alginate.

The enteric coating (eg, a layer of enteric coating or an inner enteric coating and/or an outer enteric coating) may comprise methacrylate ethyl acrylate (MAE) copolymer (1 : 1).

This layer of enteric coating may comprise methacrylate ethyl acrylate (MAE) copolymer (1 : 1) (eg Kollicoat MAE 100P).

The layer of enteric coating may comprise Eudragit copolymers such as Eudragit L (eg Eudragit L 100-55; Eudragit L 30 D-55), Eudragit S, Eudragit RL, Eudragit Eudragit RS, Eudragit E, or Eudragit FS (eg Eudragit FS 30 D).

Other examples of materials that can be used in enteric coatings (eg, a layer of enteric coating or an inner enteric coating and/or an 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;

See also, eg, US 9,233,074, which provides pH-dependent enteric polymers, including methacrylic acid copolymers, poly(vinyl acetate phthalate), succinic acid, that can be used with the solid dosage forms provided herein. Hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate; suitable methacrylic acid copolymers include: poly(methacrylic acid, methyl methacrylate) 1 : 1, e.g., sold under the trade name Eudragit L100; poly(methacrylic acid, ethyl acrylate) 1 : 1, e.g., sold under the trade name Eudragit L100-55; partially neutralized poly(methacrylic acid, ethyl acrylate) 1 : 1, eg, sold under the tradename Kollicoat MAE-100P; and poly(methacrylic acid, methyl methacrylate) 1 :2, eg, sold under the tradename Eudragit S100.

In certain aspects, the solid dosage forms (eg, tablets or minitablets) described herein further comprise a subcoating. In some embodiments, the solid dosage form includes a subcoat, eg, in addition to the enteric coating, eg, the subcoat is below the enteric coating (eg, between the solid dosage form and the enteric coating). In some embodiments, the subcoat comprises Opadry QX, such as Opadry QX Blue. dose

A dose of an agent (eg, for a human subject) is a dose per tablet or in total minitablets (eg, all minitablets in a capsule).

In embodiments where the dosage is determined by total cell count (TCC), the total cell count may be determined by a Coulter counter.

In some embodiments, the agent comprises Prevotella histolytica bacteria and the dose of bacteria is about 2.4 x 10 ¹¹ to about 4.0 x 10 ¹¹ cells (eg, wherein the number of cells is determined by total cell count determined by a Coulter counter) ), where the dose is the dose per tablet or the dose of all minitablets in the capsule. In some embodiments, the agent comprises Prevotella histolytica bacteria and the dose of bacteria is from about 2.8 x 10 ¹¹ to about 3.6 x 10 ¹¹ cells (eg, wherein the number of cells is determined by total cell count determined by a Coulter counter) ), where the dose is the dose per tablet or the dose of all minitablets in the capsule. In some embodiments, the medicament comprises Prevotella histolytica bacteria and the dose of bacteria is about 3.2 x 10 ¹¹ cells (eg, wherein the number of cells is determined by total cell count determined by a Coulter counter), wherein the dose is per The dose of a tablet or the dose of all minitablets in a capsule.

In some embodiments, the agent comprises Prevotella histolytica bacteria and the dose of bacteria is about 2.4 x 10 ¹¹ , about 2.8 x 10 ¹¹ , about 3.2 x 10 ¹¹ , about 3.6 x 10 ¹¹ , or about 4.0 x 10 ¹¹ cells, where the dose is the dose per tablet or the dose of all minitablets in the capsule. In some embodiments, the medicament comprises Prevotella histolytica bacteria and the dose of bacteria is about 3.2 x ¹⁰¹¹ cells, wherein the dose is the dose per tablet or the dose of all minitablets in a capsule.

In some aspects, the present disclosure provides a method of treating a subject (eg, a human) (eg, a subject in need of treatment), the method comprising administering to the subject a solid dosage form provided herein.

In some aspects, the present disclosure provides use of a solid dosage form provided herein in the manufacture of a medicament for the treatment of a subject (eg, a human) (eg, a subject in need of treatment).

In some embodiments, the solid dosage form is administered orally (eg, for oral administration).

In some embodiments, the solid dosage form is administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 1, 2, 3, 4, or 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 2, 4, 6, 8, or 10 solid dosage forms (eg, tablets) are administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) 1 or 2 times per day. In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day.

In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells.

In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) daily, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 10 ¹¹ cells (eg, resulting in a total of about 3.2 x 10 ¹¹ cells were administered). In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells (eg, resulting in a bacterial dose in 2 tablets) A total of approximately 6.4 x 10 ¹¹ cells were administered in the case of a single dose). In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells (eg, resulting in a bacterial dose in 3 tablets) A total of approximately 9.6 x 10 ¹¹ cells were administered in the case of a single dose). In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells (eg, resulting in a bacterial dose in 4 tablets) A total of approximately 12.8 x 10 ¹¹ cells were administered in the case of a single dose). In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 10 ¹¹ cells (eg, resulting in a bacterial dose in 5 tablets) A total of approximately 16 x 10 ¹¹ cells were administered in the case of a single dose).

Human doses can be appropriately calculated based on allometric scaling of doses administered to model organisms (eg, mice).

In some embodiments, the solid dosage form is administered orally. In some embodiments, the subject is administered once a day. In some embodiments, the solid dosage form is administered in 2 or more doses (eg, 3 or more, 4 or more, or 5 or more doses). In some embodiments, the two or more doses are administered to the subject at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours apart , 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 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.

In some embodiments, the solid dosage form is administered once a day 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 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.

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.

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.

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.

In some embodiments, one or two solid dosage forms (eg, tablets) may be administered once or twice a day.

In some embodiments, one or two solid dosage forms can be administered per day.

In some embodiments, 3, 4 or 5 solid dosage forms may be administered once or twice daily.

In some embodiments, 3, 4 or 5 solid dosage forms can be administered per day.

In some embodiments, 4 solid dosage forms may be administered once or twice daily.

In some embodiments, 4 solid dosage forms can be administered per day.

The medicament comprises the Prevotella histolytica bacterium or a powder comprising the Prevotella histolytica bacterium, and may also contain one or more additional components, such as a cryoprotectant. Instructions

Solid dosage forms with the disclosed combinations and/or amounts of disintegrants provide a reduction in disintegration time (eg, 2-fold, 4-fold, 6-fold, 8-fold), which can further result in Increased therapeutic efficacy and/or physiological effect compared to the same solid dosage form.

For example, the solid dosage forms described herein allow for oral administration of the agents contained therein.

The solid dosage forms described herein can be used to treat and/or prevent inflammation, autoimmunity, metabolic disorders or dysbiosis.

The solid dosage forms described herein can be used to treat and/or prevent bacterial septic shock, interleukin storms, and/or viral infections (eg, coronavirus infections, influenza infections, and/or respiratory syncytial virus infections).

The solid dosage forms described herein can be used to reduce the expression of inflammatory cytokines (eg, reduce the expression levels of IL-8, IL-6, IL-1β and/or TNFα).

Described herein are methods of using a solid dosage form (eg, for oral administration) (eg, for pharmaceutical use) comprising an agent (eg, a therapeutically effective amount thereof), wherein the agent comprises a Prevotella histolytica bacterium, and wherein the solid dosage form Also contains disclosed components.

For example, the methods and administered solid dosage forms described herein allow for oral administration of the agents contained therein. Solid dosage forms can be administered to subjects in a fed or fasted state. Solid dosage forms can be administered, for example, on an empty stomach (eg, one hour before or two hours after eating). Solid dosage forms can be administered one hour before eating. Solid dosage forms can be administered two hours after eating.

Provided herein are solid dosage forms for the treatment and/or prevention of inflammation, autoimmunity, metabolic disorders or dysbiosis.

Provided herein are solid dosage forms for the treatment and/or prevention of bacterial septic shock, cytokine storm, and/or viral infections (eg, coronavirus infections, influenza infections, and/or respiratory syncytial virus infections).

Provided herein are solid dosage forms for reducing the expression of inflammatory cytokines (eg, reducing the expression levels of IL-8, IL-6, IL-1β, and/or TNFα).

Provided herein is the use of a solid dosage form in the manufacture of a medicament for the treatment and/or prevention of inflammation, autoimmunity, metabolic disorders or dysbiosis.

Provided herein are solid dosage forms in the manufacture of a medicament for the treatment and/or prophylaxis of bacterial septic shock, cytokine storm, and/or viral infections (eg, coronavirus infections, influenza infections, and/or respiratory syncytial virus infections). use.

Provided herein is the use of a solid dosage form in the manufacture of a medicament for reducing the expression of inflammatory interleukins (eg, reducing the level of expression of IL-8, IL-6, IL-1β and/or TNFα). Methods of preparing solid dosage forms

In certain aspects, provided herein is a method of preparing a solid dosage form of a pharmaceutical composition, the method comprising combining a pharmaceutical agent (wherein the pharmaceutical agent comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium)) and one or Multiple (eg, one, two, or three) disintegrants are combined into a pharmaceutical composition. In certain embodiments, the total mass of the pharmaceutical agent is at least 20% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament does not exceed 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the one or more disintegrating powders 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 powders does not exceed 70%, 65%, 60% or 55% of the total mass of the pharmaceutical composition.

In some embodiments, the one or more disintegrating agents include low-substituted hydroxypropyl cellulose (L-HPC), croscarmellose sodium (Ac-Di-Sol), and/or crospovidone ( PVPP). In certain embodiments, the solid dosage forms provided herein comprise L-HPC. In some embodiments, the L-HPC is grade LH-B1. In certain embodiments, the total mass of L-HPC is at least 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC does not exceed 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the total mass of L-HPC is about 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%. In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (Ac-Di-Sol). In some embodiments, the croscarmellose sodium (Ac-Di-Sol) is an SD-711 grade of Ac-Di-Sol. In certain embodiments, the total mass of croscarmellose sodium (Ac-Di-Sol) is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the total mass of croscarmellose sodium (Ac-Di-Sol) does not exceed 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the total mass of croscarmellose sodium (Ac-Di-Sol) is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or 16%. In certain embodiments, the solid dosage forms provided herein comprise PVPP. In certain embodiments, the total mass of PVPP is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In certain embodiments, the total mass of PVPP is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%.

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 does not exceed 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% of the total mass of the pharmaceutical composition %, 23.5%, 24%, 24.5%, or 25%. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 18% to about 25% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 22% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of mannitol (eg, mannitol SD200) is about 21.5% of the total mass of the pharmaceutical composition.

In certain embodiments, the method further comprises combining magnesium stearate. In certain embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is from about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

In certain embodiments, the method further includes the combination comprising colloidal silica. In some embodiments, the colloidal silica is Aerosil 200. In certain embodiments, the total mass of colloidal silica is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silica is from about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of colloidal silica (eg, Aerosil 200) is about 1% of the total mass of the pharmaceutical composition.

In certain embodiments, the method further comprises combining about 23% of a medicament, wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium); about 22% mannitol (eg, mannitol SD200 ); about 32% L-HPC (such as L-HPC LH-B1); about 6% croscarmellose sodium (such as Ac-Di-Sol SD-711); about 15% crospovidone (such as PVPP); about 1% magnesium stearate; and about 1% colloidal silica (eg Aerosil 200).

In certain embodiments, the method further comprises combining about 23% of an medicament, wherein the medicament comprises a Prevotella histolytica bacterium (eg, a bacterium and/or a powder comprising the bacterium); about 21.5% mannitol; about 32% L -HPC (eg L-HPC LH-B1); about 6% croscarmellose sodium (eg Ac-Di-Sol SD-711); about 15% crospovidone; about 1.5% magnesium stearate ; and about 1% colloidal silica (eg Aerosil 200P).

In certain embodiments, the method further comprises compressing the pharmaceutical composition to form a tablet or minitablet. In some embodiments, the method further comprises enteric coating the tablet or minitablet, thereby producing an enteric coated tablet. In certain embodiments, the method further comprises loading the minitablets into capsules. Other aspects of solid dosage forms

For example, a solid dosage form comprising an agent (eg, a therapeutically effective amount thereof) as described herein (wherein the agent comprises Prevotella histolytica bacteria, and wherein the solid dosage form further comprises the described components) can be administered to a subject such as a human A therapeutically effective amount of the agent is provided.

For example, a solid dosage form comprising an agent (eg, a therapeutically effective amount thereof) as described herein (wherein the agent comprises Prevotella histolytica bacteria, and wherein the solid dosage form further comprises the described components) can be administered to a subject such as a human The therapeutically effective component (eg, present in the medicament) is provided in a non-natural amount.

For example, a solid dosage form comprising an agent (eg, a therapeutically effective amount thereof) as described herein (wherein the agent comprises Prevotella histolytica bacteria, and wherein the solid dosage form further comprises the described components) can be administered to a subject such as a human A therapeutically effective component (eg, present in a medicament) is provided in an unnatural amount.

For example, a solid dosage form as described herein comprising an medicament (eg, a therapeutically effective amount thereof), wherein the medicament comprises Prevotella histolytica bacteria, and wherein the solid dosage form further comprises the described components, can be administered to a subject such as a human To bring about one or more changes, such as the treatment or prevention of a disease or health disorder.

For example, a solid dosage form comprising an agent (eg, a therapeutically effective amount thereof) as described herein, wherein the agent comprises Prevotella histolytica bacteria, and wherein the solid dosage form further comprises the described components, has potentially significant utility, such as Affect a subject (eg, a human), such as to treat or prevent a disease or health disorder. Additional therapeutic agents

In certain aspects, the methods provided herein comprise administering to a subject a solid dosage form described herein, alone or in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunosuppressive agent, an anti-inflammatory agent, and/or a steroid.

In some embodiments, prior to administration of the additional therapeutic agent (eg, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 prior to , 18, 19, 20, 21, 22, 23 or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer the solid dosage form to the subject. In some embodiments, after administration of the additional therapeutic agent (eg, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 after , 18, 19, 20, 21, 22, 23 or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer the solid dosage form to the subject. In some embodiments, the solid dosage form and the additional therapeutic agent are administered to the subject at or near the same time (eg, within one hour of each other).

In some embodiments, the solid dosage form is administered to the subject prior to (eg, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 prior to , 17, 18, 19, 20, 21, 22, 23 or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer antibiotics to the subject. In some embodiments, after administration of the solid dosage form to the subject (eg, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 prior to , 17, 18, 19, 20, 21, 22, 23, or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer antibiotics to the subject. In some embodiments, the solid dosage form and the antibiotic are administered to the subject at or near the same time (eg, within one hour of each other).

In some embodiments, the additional therapeutic agent is an antibiotic. For example, if the presence of disease-associated bacteria and/or disease-associated microbiome signatures is detected, antibiotics can be administered, eg, to eliminate disease-associated bacteria from the subject. "Antibiotic" in the broadest sense refers to a compound capable of inhibiting or preventing bacterial infection. Antibiotics can be used in many ways (including according to their use for a particular infection, their mechanism of action, their bioavailability, or their range of target microorganisms (e.g. gram-negative versus gram-positive, aerobic versus anaerobic, etc.) ) and can 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 . [Mayo Hospital Journal] 86(2): 156-167). In certain embodiments, antibiotics can be used to selectively target bacteria in specific niches. In some embodiments, disease-associated microorganisms (including disease-associated bacteria in that niche) can be targeted using antibiotics known to treat a particular infection that includes a disease niche. In other embodiments, the antibiotic is administered after the solid dosage form. In some embodiments, the antibiotic is administered prior to the solid dosage form.

In some aspects, antibiotics can be selected based on bactericidal or bacteriostatic properties. Bactericidal antibiotics include mechanisms of action that damage cell walls (eg, beta-lactam), cell membranes (eg, daptomycin), or bacterial DNA (eg, fluoroquinolones). Bacterial inhibitors inhibit bacterial replication and include sulfonamides, tetracyclines and macrolides and work by inhibiting protein synthesis. Additionally, while some drugs may be bactericidal in some organisms and bacteriostatic in others, knowledge of the target organism allows those skilled in the art to select antibiotics with appropriate properties. In certain therapeutic conditions, bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics. Thus, in certain embodiments, bactericidal and bacteriostatic antibiotics are not combined.

Antibiotics include, but are not limited to, aminoglycosides, ansamycin, carbacephem, carbapenem, cephalosporin, glycopeptides, lincosamide, lipids Peptides, macrolides, monobactam, nitrofurans, oxazolidinones, penicillin, polypeptide antibiotics, quinolone, fluoroquinolinone, sulfonamides, tetracyclines and anti-mycobacterial compounds and combinations thereof.

Aminoglycosides include but are not limited to Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin ( Tobramycin), Paromomycin and Spectinomycin. Aminoglycosides are effective against, for example, Gram-negative bacteria (such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa , and Francisella tularensis ) and against certain Aerobic bacteria, but less effective against obligate/facultative anaerobes. It is believed that aminoglycosides bind to bacterial 30S or 50S ribosomal subunits, thereby inhibiting bacterial protein synthesis.

Ansamycins include, but are not limited to, Geldanamycin, Herbimycin, Rifamycin, and Streptovaricin. It is believed that geldanamycin and herbomycin inhibit or alter the function of heat shock protein 90.

Carbocephems include, but are not limited to, Loracarbef. Carbocephem is believed to inhibit bacterial cell wall synthesis.

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

Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin, Cefalotin, Cefalotin, Cefalexin, Cefaclor, Cefalox Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone ( Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil and Ceftobiprole. Selected cephalosporins are effective against, for example, gram-negative and gram-positive bacteria (including Pseudomonas ), some cephalosporins are effective against methicillin-resistant gold Staphylococcus aureus (MRSA). It is believed that cephalosporins inhibit bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

Glycopeptides include, but are not limited to, Teicoplanin, Vancomycin, and Telavancin. Glycopeptides are effective against, for example, aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile . It is believed that glycopeptides inhibit bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

Lincosamides include, but are not limited to, Clindamycin and Lincomycin. Lincosamide is effective against, for example, anaerobic bacteria as well as Staphylococcus and Streptococcus. It is believed that lincosamide binds to the bacterial 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

Lipopeptides include, but are not limited to, daptomycin. Lipopeptides are effective against, for example, Gram-positive bacteria. It is believed that lipopeptides bind to bacterial membranes and cause rapid depolarization.

Macrolides include but are not limited to Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin ), Telithromycin and Spiramycin. Macrolides are effective against, for example, Streptococcus and Mycoplasma. It is believed that macrolides bind to bacteria or the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

Monoamcin includes, but is not limited to, Aztreonam. Monoamcin is effective against eg Gram-negative bacteria. It is believed that monoamcin inhibits bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

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

Oxazolidinones include, but are not limited to, Linezolid, Posizolid, Radezolid, and Torezolid. It is believed that oxazolidinones are inhibitors of protein synthesis.

Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin (Flucloxacillin), Mezlocillin (Mezlocillin), Methicillin, Nafcillin (Nafcillin), Oxacillin (Oxacillin), Penicillin G, Penicillin V, Piperacillin (Piperacillin), Temocillin (Temocillin) and Ticarcillin. Penicillin is effective against eg Gram-positive bacteria, facultative anaerobes (eg Streptococcus, Borrelia and Treponema). It is believed that penicillin inhibits bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

Penicillin combinations include, but are not limited to, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and ticicillin/clavulanate.

Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and Polymyxin B and E. Polypeptide antibiotics are effective against eg Gram-negative bacteria. It is believed that certain polypeptide antibiotics inhibit the synthesis of prenyl pyrophosphates involved in the peptidoglycan layer of the bacterial cell wall, while other polypeptide antibiotics destabilize the bacterial outer membrane by displacing bacterial relative ions.

Quinolinones and fluoroquinolinones include but are not limited to Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Gpafloxacin ( Grepafloxacin), Sparfloxacin (Sparfloxacin) and temafloxacin (Temafloxacin). Quinolinones/fluoroquinolinones are effective against, for example, Streptococcus and Neisseria . It is believed that quinolinones/fluoroquinolinones inhibit bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.

Sulfonamides include, but are not limited to, Mafenide, Sulfacetamide, Sulfadiazine, Silver Sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxine Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (compound sulfamethoxazole) (Co-trimoxazole) and Sulfonamidochrysoidine. Sulfonamides are believed to inhibit folate synthesis by competitively inhibiting dihydropteroate synthase, thereby inhibiting nucleic acid synthesis.

Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, and tetracycline. Tetracyclines are effective against eg Gram-negative bacteria. It is believed that tetracycline binds to the bacterial 30S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

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

Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin , platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin )/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin ) Pl, clarithromycin, erythromycin, furazolidone, fusidic acid, fusidic sodium, gramicidin, imipenem, indolicidin, josamycin , magainan II, metronidazole, nitroimidazole, mikamycin, mutacin B-Ny266, mutacin B-JHl 140, mutans J-T8, nisin, nisin A, novobiocin, oleandomycin, ostreogrycin, piperacillin/tazobactam, pristinamycin, ramoplanin, bullfrog skin antibacterial peptide (ranalexin), reuterin, rifaximin, rosamicin, rosamid rosaramicin, spectinomycin, spiramycin, staphylomycin, streptogramin, streptavidin A, synergistin, taurolidine , teicoplanin, telithromycin, teicacillin/clavulanic acid, triacetyloleandomycin, tylosin, tyrocidin, short Bacteriocin (tyrothricin), vancomycin, vemamycin (vemamycin) and virginiamycin (virginiamycin).

In some embodiments, the additional therapeutic agent is an immunosuppressant, DMARD, analgesic, steroid, non-steroidal anti-inflammatory drug (NSAID), or interferon antagonist, and combinations thereof. Representative agents include, but are not limited to, cyclosporine, retinoids, corticosteroids, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumelecoxib (lumiracoxib), ibuprofen (ibuprophen), cholin magnesium salicylate, fenoprofen, salsalate, difunisal, Tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac ), ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetamide acetominophen, celecoxib, diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, dross droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, tolfenamic, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprophen, non- Firocoxib, methotrexate (MTX), antimalarial drugs (eg, hydroxychloroquine and chloroquine), sulfasalazine, leflunomide ), azathioprine, cyclosporin, gold salt, minocycline, cyclophosphamide, D-penicillamine, rice Nocycline (minoc ycline), auranofin, tacrolimus, myocrisin, chlorambucil, TNF alpha antagonists (eg, TNF alpha antagonist or TNF alpha) alpha-receptor antagonists), for example, adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®; TA-650), pegylated certolizumab (Cimzia®; CDP870), golimumab (Simpom®; CNTO 148), anakinra (Kineret®), rituximab (Rituxan®; MabThera®), abatacept (Orencia®) , tocilizumab (RoActemra/Actemra®), integrin antagonists (TYSABRI® (natalizumab)), IL-1 antagonists (ACZ885 (Ilaris)), anakinra (Kineret®)) , CD4 antagonists, IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, BLyS antagonists (e.g., Acecept, Benlysta®/LymphoStat-B® (belimhozumab)), p38 inhibitors, CD20 antagonists (Ocrelizumab, ofatumumab (Arzerra®)), interferon gamma antagonists (Fontolizumab), prednisolone ), Prednisone, Dexamethasone, Cortisol, Cortisone, Hydrocortisone, Methylprednisolone, Betamethasone betamethasone, triamcinolone, beclometasome, fludrocortisone, deoxycorticosterone, aldosterone, doxycycline, vancomycin (vancomycin), pioglitazone, SBI-087, SCIO-469, Cura-100, Oncoxin + Viusid, TwHF, Methoxsalen, Vitamin D-ergocalciferol, Rice Milnacipran, Paclitaxel, rosig tazone , Tacrolimus (Prograf®), RADOOl, rapamune, rapamycin, fostamatinib, Fentanyl, XOMA 052, FOSS Fostamatinib disodium, rosightazone, Curcumin (Longvida™), Rosuvastatin, Maraviroc, ramipril , Milnacipran, Cobiprostone, Somatropin, tgAAC94 gene therapy vehicle, MK0359, GW856553, esomeprazole, everolimus, Trastuzumab, JAK1 and JAK2 inhibitors, pan-JAK inhibitors, e.g., tetracycline 6 (P6), 325, PF-956980, denosumab, IL-6 antagonists , CD20 antagonists, CTLA4 antagonists, IL-8 antagonists, IL-21 antagonists, IL-22 antagonists, integrin antagonists (Tysarbri® (natalizumab)), VGEF antagonists, CXCL antagonists , MMP antagonists, defensin antagonists, IL-1 antagonists (including IL-1 beta antagonists), and IL-23 antagonists (eg, receptor traps, antagonistic antibodies, etc.).

In some embodiments, the additional therapy may comprise a JAK inhibitor, eg, baricitinib, rusotinib, tofacitinib, and/or palitinib.

In some embodiments, the additional therapeutic agent is an immunosuppressive agent. Examples of immunosuppressants include, but are not limited to, corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporine A , mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, sodium cromoglycate, anti-leukotrienes, anti-cholesterol for rhinitis Alkaloids, TLR antagonists, inflammasome inhibitors, anticholinergic decongestants, mast cell stabilizers, monoclonal anti-IgE antibodies, vaccines (eg, for vaccinations in which the amount of allergen is gradually increased) vaccines), cytokine inhibitors (such as anti-IL-6 antibodies), TNF inhibitors (such as infliximab, adalimumab, peg-certolizumab, golimumab, or Nasip) and combinations thereof.

In some embodiments, the additional therapeutic agent is an RNA molecule, eg, double-stranded RNA.

In some embodiments, the additional therapeutic agent is an antisense oligonucleotide. administer

In certain aspects, provided herein are methods of delivering the solid dosage forms described herein to a subject. In some embodiments of the methods provided herein, the solid dosage form is administered in combination with an additional therapeutic agent. In some embodiments, the solid dosage form comprises an agent co-formulated with an additional therapeutic agent. In some embodiments, the solid dosage form is co-administered with an additional therapeutic agent. In some embodiments, prior to administration of the solid dosage form (eg, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes before about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days prior), the subject is administered an additional therapeutic agent. In some embodiments, after administration of the solid dosage form (eg, after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes, then about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days thereafter), the subject is administered an additional therapeutic agent. In some embodiments, the same delivery mode is used to deliver the solid dosage form and the additional therapeutic agent. In some embodiments, the solid dosage form and the additional therapeutic agent are administered using different delivery modes. For example, in some embodiments, the solid dosage form is administered orally, while the additional therapeutic agent is administered via injection (eg, intravenously and/or intramuscularly).

Dosage regimens can be any of a variety of methods and amounts and can be determined by known clinical factors by one skilled in the art. As is known in the medical art, the dosage for any patient may depend on a number of factors, including the subject species, size, body surface area, age, sex, immune activity and general health, the particular microorganism to be administered, duration and administration Route, disease type and stage, and other compounds (eg, drugs administered at or near the same time). In addition to the factors described above, these levels can be affected by microbial infectivity and microbial properties, as can be determined by one skilled in the art. In the methods of the present invention, a suitable minimum dosage level of the microorganism may be a level sufficient to allow the microorganism to survive, grow and replicate. The dosage of the agents described herein (eg, in solid dosage form) can be appropriately set or adjusted depending on the dosage form, route of administration, degree or stage of the target disease, and the like. For example, a typical effective dosage range for an agent may range from 0.01 mg/kg body weight/day to 1000 mg/kg body weight/day, 0.1 mg/kg body weight/day to 1000 mg/kg body weight/day, 0.5 mg/kg body weight/day to 0.5 mg/kg body weight/day 500 mg/kg body weight/day, 1 mg/kg body weight/day to 100 mg/kg body weight/day or 5 mg/kg body weight/day to 50 mg/kg body weight/day. Effective doses can be 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500 or 1000 mg/kg body weight/ days or more, but the dose is not limited to this.

In some embodiments, the dose administered to the subject is sufficient to prevent a disease (eg, an autoimmune, inflammatory, or metabolic disease), delay its onset, or slow or halt its progression, or alleviate one or more of the disease symptom. Those skilled in the art will recognize that the dosage will depend on a variety of factors, including the strength of the particular pharmaceutical agent (eg, agent) employed and the age, species, condition, and weight of the subject. Dosage size is also determined based on the route, timing and frequency of administration, and the presence, nature and extent of any adverse side effects that may accompany administration of a particular agent, and the desired physiological effect.

Appropriate dosages and dosage regimens can be determined by conventional range detection techniques known to those skilled in the art. Generally, treatment is initiated with smaller doses that do not exceed the optimal dose of the compound. Then, increase the dose in small increments until the optimum effect under the circumstances is achieved. Effective doses and treatment regimens can be determined in a routine and routine manner, eg, by starting with a low dose and then increasing the dose in laboratory animals, while monitoring the effect, and also systematically changing the dose regimen. Animal studies are typically used to determine the maximum tolerated dose ("MTD") per kilogram of weight of a biologically active agent. Those skilled in the art often extrapolate doses in other species, including humans, to achieve efficacy while avoiding toxicity.

In light of the above, in therapeutic applications, the dosage of the medicament used in the present invention will vary depending on, inter alia, the active agent, age, body weight and the clinical condition of the recipient patient, among other factors affecting the chosen dosage, and The experience and judgment of the clinician or practitioner administering the therapy. As another example, the dose should be sufficient to result in slowing the progression of the disease the subject is treating, preferably ameliorating one or more symptoms of the disease the subject is treating.

The divided administration can include any number of two or more administrations, including two, three, four, five or six administrations. Those skilled in the art can readily determine the number of administrations to perform or the desirability of performing one or more additional administrations based on methods known in the art for monitoring treatment methods and other monitoring methods provided herein. Accordingly, the methods provided herein include methods of providing one or more administrations of a solid dosage form to a subject, wherein the number of administrations can be determined by monitoring the subject, and based on the results of the monitoring, it is determined whether it is necessary to provide one or more additional administrations apply. Whether or not to provide one or more additional administrations can be determined based on the results of various monitoring.

The time period between administrations can be any of the various time periods. The time period between administrations can vary depending on any of a variety of factors, including monitoring steps (as described with respect to the number of administrations), the time period during which the subject develops an immune response. In one example, the time period can vary depending on the time period in which the subject has developed an immune response; for example, the time period can be greater than the time period in which the subject has developed an immune response, eg, greater than about a week, greater than about 10 days, greater than about two weeks or greater than about one month; in another example, the period of time may be no greater than the period over which the subject builds an immune response, such as no greater than about one week, no greater than about ten days, no greater than about two weeks, or no greater than about one month .

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

An effective dose of an additional therapeutic agent described herein is that amount of the additional therapeutic agent that is effective for a particular subject, composition, and mode of administration to achieve the desired therapeutic agent response with minimal toxicity to the subject. Effective dosage levels can be identified using the methods described herein and will depend on a variety of pharmacokinetic factors, including the activity of the particular composition or agent administered, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment , other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and similar factors well known in the medical art. In general, an effective dose of an additional therapeutic agent will be the amount of the additional therapeutic agent that is the lowest dose effective to produce a therapeutic effect. Generally such an effective dose will depend on such factors as described above.

Toxicity of an additional therapeutic agent is the degree of adverse effects experienced by a subject during and after treatment. Adverse events associated with additional treatment toxicity may include, but are not limited to, abdominal pain, acid dyspepsia, acid reflux, anaphylaxis, alopecia, anaphylaxis, anemia, anxiety, loss of appetite, arthralgia, weakness, ataxia, Azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, increased blood pressure, dyspnea, bronchitis, congestion, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, Hemorrhagic cystitis, arrhythmia, heart valve disease, cardiomyopathy, coronary artery disease, cataract, central nervous system toxicity, cognitive impairment, confusion, conjunctivitis, constipation, cough, spasm, cystitis, deep vein thrombosis, dehydration, depression, Diarrhea, dizziness, dry mouth, dry skin, indigestion, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue, loss of fertility, fever, flatulence, flushing, gastric reflux, stomach Esophageal reflux disease, genital pain, neutropenia, gynecomastia, glaucoma, hair loss, hand-foot syndrome, headache, hearing loss, heart failure, palpitations, heartburn, hematoma, hemorrhagic cystitis , hepatotoxicity, hyperamylase, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hyperlipidemia, hypermagnesemia, hypernatremia, hyperphosphatemia, Pigmentation, hypertriglyceridemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia , hypophosphatemia, impotence, infection, injection site reactions, insomnia, iron deficiency, pruritus, arthralgia, renal failure, leukopenia, liver dysfunction, amnesia, amenorrhea, aphtha, mucositis, myalgia, myalgia , myelosuppression, myocarditis, neutropenic fever, nausea, nephrotoxicity, neutropenia, nosebleeds, numbness, ototoxicity, pain, palmar-plantar erythrodysesthesia, various cytopenias Symptoms, pericarditis, peripheral neuropathy, pharyngitis, photophobia, photosensitivity, pneumonia, pneumonitis, proteinuria, pulmonary embolism, pulmonary fibrosis, pulmonary toxicity, rash, rapid heartbeat, rectal bleeding, restlessness , rhinitis, epilepsy, shortness of breath, sinusitis, thrombocytopenia, tinnitus, urinary tract infection, vaginal bleeding, vaginal dryness, vertigo, water retention, weakness, weight loss, weight gain, and dry mouth ( xerostomia). In general, toxicity is acceptable if the benefit to the subject achieved via the therapy outweighs the adverse events experienced by the subject as a result of the therapy. immune disorder

In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of diseases or disorders associated with pathological immune responses (eg, autoimmune diseases, allergic reactions, and/or inflammatory diseases). In some embodiments, the disease or disorder is inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis).

In some embodiments, the disease or disorder is psoriasis.

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

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

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" includes any subject suffering from a disease or disorder associated with a pathological immune response (eg, inflammatory bowel disease), and those with an increased risk of acquiring such a disease or disorder possibility of any subject.

The solid dosage forms described herein can be used, for example, to prevent or treat (partially or completely reduce the adverse effects of) autoimmune diseases such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, Moore-Weir syndrome disease, rheumatoid arthritis, multiple sclerosis, or Hashimoto's disease; allergic diseases, such as food allergies, hay fever, or asthma; infectious diseases, such as Clostridium difficile infection; inflammatory diseases, such as TNF-mediated A pharmaceutical composition for an inflammatory disease of the gastrointestinal tract (eg, gastrointestinal inflammatory disease, such as pouchitis; cardiovascular inflammatory disease, such as atherosclerosis; or inflammatory lung disease, such as chronic obstructive pulmonary disease); Use as a pharmaceutical composition for inhibiting rejection in organ transplantation or other conditions in which tissue rejection may occur; as a supplement, food or drink for improving immune function; or as an agent for inhibiting the proliferation or function of immune cells .

In some embodiments, the methods and solid dosage forms provided herein are suitable for treating inflammation. In certain embodiments, inflammation of any tissue and organ of the body, including musculoskeletal inflammation, vascular inflammation, neuroinflammation, digestive system inflammation, eye inflammation, reproductive system inflammation, and other inflammations, as discussed below.

Immune disorders of the musculoskeletal system include, but are not limited to, those that affect skeletal joints (including those of the hands, wrists, elbows, shoulders, jaw, spine, neck, hips, knees, ankles, and feet), and A disorder of the tissues that connect muscles to bones, such as tendons. Examples of such immune disorders that can be treated with the methods and compositions described herein include, but are not limited to, arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic Infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibromyalgia (fibromyalgia), epicondylitis, myocarditis inflammation and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis cystic fibrosis).

Ocular immune disorders are immune disorders that affect any structure of the eye, including the eyelids. Examples of ocular immune disorders treatable by the methods and compositions described herein include, but are not limited to, blepharitis, ptosis, conjunctivitis, lacrimal gland inflammation, keratitis, keratoconjunctivitis sicca (dry eye), sclera inflammation, trichiasis and uveitis.

Examples of neuroimmunological disorders that can 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 Sexual sclerosis, myelitis and schizophrenia. Examples of inflammations of the vasculature or lymphatic system that can be treated with the methods and compositions described herein include, but are not limited to, joint sclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

Examples of immune disorders of the digestive system that can be treated with the methods and solid dosage forms described herein include, but are not limited to, cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease, ileitis, and proctitis. Inflammatory bowel disease includes, for example, certain art-recognized forms of a group of related disorders. Several major forms of inflammatory bowel disease are known, the most common of which are Crohn's disease (regional bowel disease, eg, inactive and active forms) and ulcerative colitis (eg, inactive and active forms). active form). In addition, inflammatory bowel disease encompasses irritable bowel syndrome, microscopic colitis, lymphocytic-plasmacytic enteritis, celiac 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, Behçet's disease, sarcoidosis, scleroderma, and IBD-related dysplasia , Masses or lesions associated with dysplasia and primary sclerosing cholangitis.

Examples of immune disorders of the reproductive system that can be treated with the methods and solid dosage forms described herein include, but are not limited to, cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, Tubal-ovarian abscess, urethritis, vaginitis, vulvitis and vulvodynia.

The methods and solid dosage forms described herein can be used to treat autoimmune diseases with an inflammatory component. Such conditions include, but are not limited to, systemic acute disseminated alopecia, Behcet's disease, Chagas' disease, chronic fatigue syndrome, autonomic disorders, encephalomyelitis, ankylosing spondylitis, regeneration Obstructive anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes, giant cell arteritis, Goodpas Hill syndrome, Graves Thomas disease, Guillain-Barré 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, Alder's thyroiditis, pemphigus, nodular Polyarteritis, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm Fever autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, localized scleroderma, psoriasis, sarcoidosis, scleroderma, ulcerative colitis and vitiligo.

The methods and solid dosage forms described herein can be used to treat T cell mediated hypersensitivity diseases with an inflammatory component. Such conditions include, but are not limited to, contact hypersensitivity, contact dermatitis (including due to poison ivy), urticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis, house dust mite allergy) and Gluten-sensitive enteropathy (celiac disease).

Other immune disorders treatable by the methods and solid dosage forms of the invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibromytitis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis , mastitis, myocarditis, nephritis, otitis, pancreatitis, mumps, pericarditis, peritonoitis, pharyngitis, pleurisy, localized pneumonia, prostatistis, pyelonephritis and stomatitis, Transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (eg, islet cells), bone marrow, cornea, small intestine, skin allografts, skin allografts and heart valve xenografts, serum sickness and grafts anti-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sexary's syndrome, congenital adrenal hyperplasia, nonsuppurative thyroiditis, hypercalcemia-related cancer, Herpes, bullous dermatitis, erythema multiforme severe, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity Reaction, allergic conjunctivitis, keratitis, ophthalmic herpes zoster, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated pulmonary tuberculosis chemotherapy, adult idiopathic Thrombocytopenic purpura, adult secondary thrombocytopenia, acquired (autoimmune) hemolytic anemia, adult leukemia and lymphoma, childhood acute leukemia, localized enteritis, autoimmune vasculitis, multiple sclerosis , chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis. Preferred treatments include the following treatments: transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic obstructive pulmonary disease and Inflammation accompanying infectious conditions (eg, sepsis). metabolic disorders

In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of metabolic diseases or disorders, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, Nonalcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, ketoacidosis, hypoglycemia, thrombotic disease, dyslipidemia, nonalcoholic Fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or related conditions. In some embodiments, the associated disease is cardiovascular disease, atherosclerosis, renal disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, or edema. In some embodiments, the methods and pharmaceutical compositions described herein relate to the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

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" includes any subject with a metabolic disease or disorder, as well as any subject with an increased likelihood of acquiring such a disease or disorder.

The solid dosage forms described herein can be used, for example, to prevent or treat (partially or completely reduce the adverse effects of) metabolic diseases such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia Blood sugar, hyperinsulinemia, fatty liver, nonalcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, ketoacidosis, hypoglycemia, Thrombotic disease, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or related conditions. In some embodiments, the associated disease is cardiovascular disease, atherosclerosis, renal disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, or edema. Other diseases and disorders

In some embodiments, the methods and solid dosage forms described herein relate to the treatment of liver disease. This disease includes (but is not limited to) Alagille Syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, benign liver tumors, bile duct atresia, cirrhosis, galactosemia , Gilbert's syndrome, hemochromatosis, hepatitis A, hepatitis B, hepatitis C, hepatic encephalopathy, intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D ), hepatic cyst, liver cancer, neonatal jaundice, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Reye syndrome, type I glycogen storage disease and Wilson Disease.

The methods and solid dosage forms described herein can be used to treat neurodegenerative and neurological diseases. In certain embodiments, the neurodegenerative and/or neurological disease is Parkinson's disease, Alzheimer's disease, Prion's disease, Huntington's disease, motor neuron disease (MND), spinocerebellar ataxia, spinal cord Muscular dystrophy, dystonia, idiopathic intracranial hypertension, epilepsy, neurological disorders, central nervous system disorders, movement disorders, multiple sclerosis, encephalopathy, peripheral neuropathy, or postoperative cognitive impairment. Dysbiosis

In recent years, it has become increasingly clear that the gut microbiome (also known as the "gut microbiota") can be influenced by the activity and (local and/or distal) effects of microorganisms on the host's immune and other cells. Significant effects on individual health (Walker, WA, Dysbiosis [dysbiosis]. The Microbiota in Gastrointestinal Pathophysiology [microbes in gastrointestinal pathophysiology]. Chapter 25. 2017; Weiss and Thierry, Mechanisms and consequences of intestinal dysbiosis [ Mechanisms and consequences of gut 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)).

A healthy host gut microbiome homeostasis is sometimes referred to as "ecological balance" or "normal microbiome", while deleterious changes in the composition and/or diversity of the host microbiome may lead to an unhealthy imbalance of the microbiome, or "microbiome". Dysbiosis and its discontents” (Hooks and O'Malley. Dysbiosis and its discontents . American Society for Microbiology. 2017 Oct. Vol 8. Issue 5. mBio 8:e01492 -17. https://doi.org/10.1128/mBio.01492-17). Dysbiosis and associated local or distant host inflammatory or immune effects may occur when microbiome homeostasis is lost or diminished, resulting in: increased susceptibility to pathogens; altered host bacterial metabolic activity; induction of host pro-inflammatory activity and/or decrease host anti-inflammatory activity. Such effects are caused in part by host immune cells (eg, T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (IECs), macrophages, and phagocytes) and interleukins, as well as by such cells. mediated by interactions with other substances released by other host cells.

Dysbiosis may occur within the gastrointestinal tract ("gastrointestinal dysbiosis" or "gut dysbiosis"), or it may occur outside the lumen of the gastrointestinal tract ("distal dysbiosis"). Gastrointestinal dysbiosis is often associated with decreased intestinal epithelial barrier integrity, decreased 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 TEER Measurement Techniques]. J. Lab. Autom [Journal of Laboratory Automation]. 20: 107-126 (2015). Dysbiosis of the gastrointestinal tract can have physiological and immune effects both in and out of the gastrointestinal tract.

The presence of dysbiosis has been associated with a variety of diseases and conditions, including: infections, cancer, autoimmune disorders (eg, systemic lupus erythematosus (SLE)) or inflammatory disorders (eg, functional gastrointestinal disorders such as inflammatory bowel disease) (IBD), ulcerative colitis, and Crohn's disease), neuroinflammatory diseases (eg, multiple sclerosis), transplantation disorders (eg, graft-versus-host disease), fatty liver disease, type 1 diabetes, rheumatoid Arthritis, Sjögren's syndrome, celiac disease, cystic fibrosis, chronic obstructive pulmonary disease (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 [Dysbiosis of gut microbes in disease]. Microb. Ecol. Health Dis [Microbial Ecology and Health Diseases]. (2015); 26: 10: 3402/mehd.v26.2619; Levy et al, Dysbiosis and the Immune System [dysbiosis and the immune system], Nature Reviews Immunology 17: 219 (April 2017).

Exemplary pharmaceutical compositions (eg, solid dosage forms) disclosed herein can treat dysbiosis and its effects by modifying the immune activity present at the site of the dysbiosis. As described herein, such compositions can reduce inflammation in a subject by acting on host immune cells (resulting in, for example, increased secretion of anti-inflammatory interleukins and/or decreased secretion of pro-inflammatory cytokines) Or modify dysbiosis by changes in metabolite production.

Exemplary pharmaceutical compositions (eg, solid dosage forms) disclosed herein that can be used to treat disorders associated with dysbiosis include one or more types of immunomodulatory bacteria (eg, anti-inflammatory bacteria) derived from such bacteria. Such compositions are capable of affecting the immune function of the recipient host in the gastrointestinal tract, and/or producing systemic effects at distal sites outside the gastrointestinal tract of the subject.

Exemplary pharmaceutical compositions (eg, solid dosage forms) disclosed herein that can be used to treat disorders associated with dysbiosis comprise a population of immunomodulatory bacteria (eg, anti-inflammatory bacteria) of a single bacterial species (eg, single strain). Such compositions are capable of affecting the immune function of the recipient host in the gastrointestinal tract, and/or producing systemic effects at distal sites outside the gastrointestinal tract of the subject.

In one embodiment, a pharmaceutical composition (eg, a solid dosage form) comprising an isolated Prevotella histolytica bacterium is administered in an amount effective to treat dysbiosis and one or more effects thereof in a mammalian recipient (eg, orally) to the recipient. The dysbiosis can be a gastrointestinal dysbiosis or a distal dysbiosis.

In another embodiment, the pharmaceutical compositions (eg, solid dosage forms) of the invention can treat dysbiosis of the gastrointestinal tract and one or more of its effects on host immune cells, resulting in increased secretion of anti-inflammatory cytokines and/or The secretion of pro-inflammatory cytokines is reduced, thereby reducing inflammation in the test recipient.

In another embodiment, a pharmaceutical composition (eg, a solid dosage form) can treat gastrointestinal dysbiosis and one or more effects thereof by modulating the recipient's immune response through cellular and interferon modulation to Reduces intestinal permeability by increasing the integrity of the intestinal epithelial barrier.

In another embodiment, a pharmaceutical composition (eg, a solid dosage form) can treat distal dysbiosis and one or more effects thereof by modulating the recipient immune response at the site of dysbiosis by modulating host immune cells .

Other exemplary pharmaceutical compositions (e.g., solid dosage forms) that can be used to treat disorders associated with dysbiosis include one or more types of bacteria capable of altering host immune cell subsets in a recipient (e.g. subsets of T cells, immune lymphoid cells, dendritic cells, NK cells, and other immune cells) relative proportions or their functions.

Other exemplary pharmaceutical compositions that can be used to treat disorders associated with dysbiosis include populations of immunomodulatory bacteria of a single bacterial species (e.g., a single strain) capable of altering immune cell subsets (e.g., a single strain) in a recipient. T cell subsets, immune lymphoid cells, NK cells, and other immune cells) relative proportions or their functions.

In one embodiment, the present invention provides a method of treating gastrointestinal dysbiosis and one or more effects thereof by orally administering to a subject in need thereof a pharmaceutical composition that alters the presence of bacterial Microbiome populations at sites of dysbiosis. The pharmaceutical composition may comprise one or more types of immunomodulatory bacteria or a population of immunomodulatory bacteria of a single bacterial species (eg, a single strain).

In one embodiment, the present invention provides a method of treating distal dysbiosis and one or more effects thereof by orally administering to a subject in need thereof a pharmaceutical composition and/or solid dosage form, the pharmaceutical composition Substances (eg, solid dosage forms) alter the parent's immune response in a subject. The pharmaceutical composition may comprise one or more types of immunomodulatory bacteria or a population of immunomodulatory bacteria of a single bacterial species (eg, a single strain).

In an exemplary embodiment, a pharmaceutical composition useful in the treatment of a dysbiosis-related disorder stimulates the secretion of one or more anti-inflammatory interleukins by host immune cells. Anti-inflammatory interkines include, but are not limited to, IL-10, IL-13, IL-9, IL-4, IL-5, TGF[beta], and combinations thereof. In other exemplary embodiments, pharmaceutical compositions useful in the treatment of disorders associated with dysbiosis reduce (eg, inhibit) secretion of one or more pro-inflammatory interleukins by host immune cells. Pro-inflammatory interferons include, but are not limited to, IFNγ, IL-12p70, IL-1α, IL-6, IL-8, MCP1, MIP1α, MIP1β, TNFα, and combinations thereof. Other exemplary interleukins are known in the art and described herein.

In another aspect, the present invention provides a method of treating or preventing a dysbiosis-related disorder in a subject in need thereof, the method comprising administering to the subject (eg, orally administering) a probiotic food or medical food form A therapeutic composition comprising bacteria in an amount sufficient to alter the microbiome at the site of dysbiosis, thereby treating a dysbiosis-related disorder.

In another embodiment, the therapeutic composition of the present invention in the form of a probiotic food or medical food can be used to prevent or delay the onset of dysbiosis in a subject at risk of developing a dysbiosis. Infect

Inflammation can be a protective response to noxious stimuli such as invading pathogens, damaged cells, toxic compounds, or cancer cells. However, an excessive inflammatory response to this stimulus can lead to severe adverse effects, including tissue damage and even death. For example, the production of proinflammatory interleukins such as interleukin 8 (IL-8), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNFα) to Responding to many viral infections is one of the leading causes of adverse infection-related symptoms, including death in some cases. For example, the release of inflammatory cytokines is associated with a variety of viral infections, including infections with coronaviruses (eg, SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), influenza virus, and respiratory syncytial virus) of disease severity. For example, patients with severe COVID-19 often exhibit elevated levels of inflammatory interleukins in the lungs, which contribute to the lung damage experienced by patients with COVID-19.

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.

In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of viral infections, such as respiratory viral infections, such as coronavirus infections (eg, MERS (Middle East Respiratory Syndrome), Severe Acute Respiratory Syndrome (SARS) infections, such as SARS-CoV-2 infection), influenza infection and/or respiratory syncytial virus infection. In some embodiments, the methods and solid dosage forms described herein provided herein are used to treat coronavirus infections (eg, MERS infections, severe acute respiratory syndrome (SARS) infections, eg, SARS-CoV-2 infections). In some embodiments, provided herein are methods and solid dosage forms for the treatment of COVID-19.

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

In some embodiments, the subject is administered an additional therapy. In some embodiments, the additional therapy comprises an antiviral drug. In some embodiments, the additional therapy comprises antiviral drugs such as ribavirin, neuraminidase inhibitors, protease inhibitors, recombinant interferons, antibodies, oseltamivir, zanamivir, peramivir vir or balosavir marbolate. In some embodiments, the additional therapy comprises hydroxychloroquine and/or chloroquine. In some embodiments, the additional therapy comprises remdesivir. In some embodiments, the additional therapy comprises plasma from a subject who has recovered from infection with the same virus that infected the subject (eg, 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 an NSAID or an anti-inflammatory steroid. In some embodiments, the additional therapy includes dexamethasone.

In some embodiments, the additional therapy includes an antibody specific for IL-6 and/or the IL-6 receptor. In some embodiments, the additional therapy includes tocilizumab (Actemra®). In some embodiments, the additional therapy includes sarelumab (Kevzara®).

In some embodiments, the additional therapy may comprise antiviral therapy. For example, antiviral therapy may comprise nucleotide analogs such as remdesivir, galidevir or clavudine; viral RNA polymerase inhibitors such as favipiravir or galidevir; protease inhibitors, such as ritonavir, darunavir or danoprevir; viral membrane fusion inhibitors such as ulfinovir; and/or anti-SARS-CoV-2 plasma.

In some embodiments, the additional therapy can include anti-inflammatory therapy. For example, the anti-inflammatory therapy can include corticosteroids; sirolimus; anakinra; filamod; or antibodies. In some embodiments, the antibody may include a GMSF inhibitor, such as remzizumab or gensulkumab; an anti-IL1 beta inhibitor, such as canakinumab; an IL-6 inhibitor, such as tocilizumab or Sertuximab; IL-6R inhibitors, such as sarelumab; and/or CCR5 antagonists, such as leronlimab.

In some embodiments, the additional therapy may comprise a JAK inhibitor, eg, baricitinib, rusotinib, tofacitinib, and/or palitinib.

In some embodiments, the additional therapy may comprise a TLR7 agonist, such as imiquimod or reisquimod.

In some embodiments, the additional therapy may comprise 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 adipose-derived mesenchymal stem cells, such as AstroStem.

In some embodiments, the additional therapy may comprise an ACE receptor inhibitor.

In some embodiments, the additional therapy may comprise modulators of the sigma1 and/or sigma2 receptors. EXAMPLES Example 1: Powder Preparation Sample Protocol

After reaching the desired level of bacterial culture growth, centrifuge the culture, discard the supernatant, and allow the pellet to be as dry as possible. Resuspend the pellet in the desired cryoprotectant solution to make a formulated cell paste. Cryoprotectants may include, for example, maltodextrin, sodium ascorbate, sodium glutamate, and/or calcium chloride. The formulated cell paste is loaded onto stainless steel trays and then loaded into a freeze dryer, eg, running in automatic mode with defined cycle parameters. The freeze-dried product is fed into a mill and the resulting powder is collected.

The powder is stored eg in a desiccator (eg in a vacuum sealed bag) at 2-8 degrees Celsius (eg at 4 degrees Celsius). Example 2: Gamma-Irradiation: Sample Protocol:

The powder can be gamma irradiated at ambient temperature with 17.5 kGy radiation units. Frozen biomass can be gamma irradiated at 25 kGy radiation units in the presence of dry ice. Example 3: Preparation of tablets containing Prevotella histolyticus

The following formulations in Table 1 were prepared. [ Table 1 ] : Composition of Prevotella spp. tablet Material Active dose ( % w/w ) Prevotella histolytica strain B (NRRL accession number B 50329) powder 23.0 Mannitol 200 SD 21.5 L-HPC (LH-B1) 32.0 Crospovidone (Colidan CL-F) 15.0 Croscarmellose sodium (Ac-Di-Sol SD-711) 6.0 Colloidal silica (Aerosil 200) 1.0 Magnesium stearate 1.5 total 100.0

The tablets were prepared as 17.4 mm x 7.1 mm tablets. The tablet is enteric coated. The tablet contains 3.2 x 10 ¹¹ TCC of Prevotella histolytica strain B (NRRL accession number B 50329).

The above-mentioned Prevotella histolytica strain has been deposited as Prevotella histolytica strain B (NRRL accession number B 50329). Example 4: Preparation of Solid Dosage Forms Containing Prevotella Histolytica

Tablets according to the formulation in Table 2 were prepared. Compression was performed and the manufactured batches were first subcoated with Opadry QX Blue and then topcoated with Kollicoat MAE100P for enteric release. [ Table 2 ] : Prevotella habitatii tablet composition , 3.2 x ¹⁰ 11 cells / tablet Material Active dose ( % w/w ) Prevotella histolytica strain B ( NRRL accession number B 50329 ) powder 25.0 Mannitol 200 SD 19.5 L-HPC (LH-B1) 32.0 Crospovidone (Colidan CL-F) 15.0 Croscarmellose sodium (Ac-Di-Sol SD-711) 6.0 Colloidal silica (Aerosil 200) 1.0 Magnesium stearate 1.5 total 100.0

The above-mentioned Prevotella histolytica strain has been deposited as Prevotella histolytica strain B (NRRL accession number B 50329).

The dosage compositions of Table 2 are provided in 17.4 mm x 7.1 mm tablets. [ Table 3 ] : Subcoating composition Material ( % w/w ) Opadry QX Blue 15.00 WFI 85.00 total 100.00 [ Table 4 ] : Top coat composition Material ( % w/w ) Kollicoat MAE 100P 15.00 TEC 2.25 talc 3.00 water 79.75 total 100

The target weight per tablet is 650 mg (dose strength is 162.5 mg). Example 5: Preparation of tablets containing Prevotella histolyticus

Tablets of the formulations in Table 5 were prepared. [ Table 5 ] : Composition of Prevotella histolytica coated tablets, 3.2 x 10 ¹¹ cells / tablet the name of one or more ingredients % w/w Chip Prevotella histolytica strain B ( NRRL accession number B 50329 ) powder ^24.6a Mannitol ^19.9a Hydroxypropyl Cellulose, Low Substitution (L-HPC) 32.0 Croscarmellose sodium 6.0 Crospovidone 15.0 Colloidal silica 1.0 Magnesium stearate 1.5 total die weight Coating (subcoating) polyvinyl alcohol 6.0 Titanium dioxide 3.8 Macrogol/Polyethylene glycol 3.0 talc 2.2 Water for Injection 85.0 Coating (Enteric Coated) Poly(methacrylic acid-co-ethyl acrylate) 1 : 1 15.0 Triethyl citrate 2.3 talc 3.0 Water for Injection 79.7 ^aAdjust the amount based on the potency of the drug substance to ensure the target strength.

The total coated tablet weight is 777 mg. Example 6: Tablet Total Cell Count

I.: Determine the total cell count (TCC) for tablets prepared according to the formulation in Example 5.

Total cell count (TCC) was measured by fluorescence microscopy with Quantom Tx. The acceptable range was set at 1.6 x 10 ¹¹ -4.8 x 10 ¹¹ total cells/tablet.

A total cell count (TCC) method using fluorescence microscopy by Quantom Tx™ was developed and used in conjunction with the coulter counter method for drug product release and stability studies. It counts fluorescently stained microbial cells by fluorescent imaging and analysis to produce accurate and objective bacterial cell counts.

Samples were diluted in pH 6.8 buffer in the presence of glass beads and vortexed. Prepare additional dilutions as needed and place the samples into the cell counting chamber and count under the microscope. Results are reported as TCC/tablet.

The following formula (Quantom Tx formula) was used to calculate TCC/tablet: [(Q × 2 × D)/QCF] × W in: Q = average number of cells in 10 images. QCF (Quantom Tx™ Correction Factor) = 0.00000864, D is the dilution factor of the sample, i.e. 1E-4 dilution = 1/0.0001 W is the weight of the single-coated tablet.

Results: The TCC for the tablet thus calculated was 2.8 x 10 ¹¹ cells/tablet.

II.: Determine the total cell count (TCC) for tablets prepared according to the formulation in Example 4.

Total cell count (TCC) was measured by fluorescence microscopy with Quantom Tx. The acceptable range was set at 1.6 x 10 ¹¹ -4.8 x 10 ¹¹ total cells/tablet.

A total cell count (TCC) method using fluorescence microscopy by Quantom Tx™ was developed and used in conjunction with the coulter counter method for drug product release and stability studies. It counts fluorescently stained microbial cells by fluorescent imaging and analysis to produce accurate and objective bacterial cell counts.

Samples were diluted in pH 6.8 buffer in the presence of glass beads and vortexed. Prepare additional dilutions as needed and place the samples into the cell counting chamber and count under the microscope. Results are reported as TCC/tablet.

The following formula is used to calculate TCC/tablet: [(Q × 2 × D)/QCF] × W in: Q = average number of cells in 10 images. QCF (Quantom Tx™ Correction Factor) = 0.00000864, D is the dilution factor of the sample, i.e. 1E-4 dilution = 1/0.0001 W is the weight of the single-coated tablet.

Results: The TCC of the tablet thus calculated was 3.76 x 10 ¹¹ cells/tablet. Example 7: Water content

I.: Evaluation of the water content of the tablets prepared according to the formulation in Example 5.

The water content (%) was determined by Karl-Fischer (European Pharmacopoeia 2.5.32).

The Karl-Fischer method for water content analysis followed European Pharmacopoeia method 2.5.32 and confirmed its applicability.

Results: The water content calculated by this method was 4.9%.

II.: Evaluation of the water content of the tablets prepared according to the formulation in Example 4.

The water content (%) was determined by Karl-Fischer (European Pharmacopoeia 2.5.32).

The Karl-Fischer method for water content analysis followed European Pharmacopoeia method 2.5.32 and confirmed its applicability.

Results: The water content calculated by this method was 4.8%. Example 8: Stability Data

Tablets prepared according to the formulation in Example 4 were evaluated for stability.

Stability data to date for Prevotella spp. medicinal products stored under long-term (up to 3 months) and accelerated storage (up to 3 months) conditions.

Tablet Content and Potency: Total Cells/Tablet:

To date, total cells/tablets of viability batches tested for up to 3 months have shown comparable total cell counts: in long-term (2°C-8°C) and accelerated (25°C/60% RH ( relative humidity)) under storage conditions. TCC is determined by Quantom Tx. There is no clear trend in data for immediate and accelerated temperature conditions up to 3 months. The data is shown in Figure 1.

Total cells/tablets of viability batches tested for up to 12 months show expiry under long-term (2°C-8°C) and accelerated (25°C/60%RH (relative humidity)) storage conditions A comparable total cell count was obtained. TCC is determined by Quantom Tx. There is no clear trend in data for immediate and accelerated temperature conditions up to 12 months. The data is shown in Figure 3.

Water content:

Water content is within stability specifications for up to 3 months under long-term (2°C-8°C) and accelerated (25°C/60% RH) storage conditions. The results are shown in Figure 2. There is no clear trend for each of the immediate and accelerated data up to 3 months.

The water content was measured using the Karl Fisher method (Karl Fisher titration). Data are within stability specifications for up to 12 months under long-term (2°C-8°C and accelerated (25°C/60% RH) storage conditions. Results are shown in Figure 4. Each immediate and accelerated data for up to 12 months without a clear trend. incorporated by reference

All publications, patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In case of conflict, this application, including any definitions herein, will control. Equivalent form

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 covered by the following claims.

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[ Figure 1 ] is a graph showing the total cell/tablet stability profile under long-term (2°C-8°C) and accelerated (25°C/60% RH) storage conditions over 3 months. The lower traces (diamonds) in the graph provide values for accelerated (25°C/60% RH) storage conditions. The upper traces (circles) in the figure provide values under long-term (2°C-8°C) storage conditions. Total cell count (TCC) was determined by Quantom Tx.

[ Figure 2 ] is a graph showing the water content stability profile under long-term (2°C-8°C) and accelerated (25°C/60% RH) storage conditions over 3 months. The lower traces (diamonds) in the graph provide values for accelerated (25°C/60% RH) storage conditions. The upper traces (circles) in the figure provide values under long-term (2-8°C) storage conditions. The water content was determined by the Karl Fisher method.

[ Figure 3 ] is a graph showing the total cell/tablet stability profile under long-term (2°C-8°C) and accelerated (25°C/60% RH) storage conditions over 12 months. Total cell count (TCC) was determined by Quantom Tx.

[ Figure 4 ] is a graph showing the water content stability profile under long-term (2°C-8°C) and accelerated (25°C/60% RH) storage conditions over 12 months. The water content was determined by the Karl Fisher method.

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Claims (60)

A solid dosage form of a pharmaceutical composition comprising: A medicament, the total mass of the medicament is at least 20% of the total mass of the pharmaceutical composition and not more than 25% of the total mass of the pharmaceutical composition, wherein the medicament contains Prevotella habitatii bacteria; Low-substituted hydroxypropyl cellulose (L-HPC), the total mass of L-HPC is at least 22% of the total mass of the pharmaceutical composition and not more than 42% of the total mass of the pharmaceutical composition; Croscarmellose sodium (Ac-Di-Sol), the total mass of Ac-Di-Sol is at least 0.01% of the total mass of the pharmaceutical composition and not more than 16% of the total mass of the pharmaceutical composition; as well as Crospovidone (PVPP), the total mass of PVPP is at least 5% of the total mass of the pharmaceutical composition and not more than 25% of the total mass of the pharmaceutical composition. The solid dosage form of claim 1, wherein the total mass of the L-HPC plus the total mass of the croscarmellose sodium (Ac-Di-Sol) plus the total mass of the PVPP is the total mass of the pharmaceutical composition of at least 40%. The solid dosage form of claim 1, wherein the total mass of the L-HPC plus the total mass of the croscarmellose sodium (Ac-Di-Sol) plus the total mass of the PVPP is the total mass of the pharmaceutical composition of at least 50%. The solid dosage form of any one of claims 1 to 3, wherein the L-HPC is LH-B1 grade L-HPC. The solid dosage form according to any one of claims 1 to 4, wherein the croscarmellose sodium (Ac-Di-Sol) is Ac-Di-Sol of SD-711 grade. The solid dosage form of any one of claims 1 to 5, wherein The total mass of the L-HPC is at least 27% of the total mass of the pharmaceutical composition and does not exceed 37% of the total mass of the pharmaceutical composition; The total mass of croscarmellose sodium (Ac-Di-Sol) is at least 1% and not more than 11% of the total mass of the pharmaceutical composition; and The total mass of the PVPP is at least 10% of the total mass of the pharmaceutical composition and not more than 20% of the total mass of the pharmaceutical composition. The solid dosage form of any one of claims 1 to 6, wherein The total mass of the L-HPC is at least 31% of the total mass of the pharmaceutical composition and does not exceed 33% of the total mass of the pharmaceutical composition; The total mass of croscarmellose sodium (Ac-Di-Sol) is at least 5% of the total mass of the pharmaceutical composition and not more than 7% of the total mass of the pharmaceutical composition; and The total mass of the PVPP is at least 14% of the total mass of the pharmaceutical composition and not more than 16% of the total mass of the pharmaceutical composition. The solid dosage form of any one of claims 1 to 7, wherein The total mass of the L-HPC is about 32% of the total mass of the pharmaceutical composition; The total mass of the croscarmellose sodium (Ac-Di-Sol) is about 6% of the total mass of the pharmaceutical composition; and The total mass of the PVPP is about 15% of the total mass of the pharmaceutical composition. A solid dosage form of a pharmaceutical composition, the solid dosage form comprising a medicament 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 medicament comprises Lavotella bacteria. The solid dosage form of claim 9, wherein the one or more disintegrants comprise L-HPC. The solid dosage form of claim 10, wherein the L-HPC is LH-B1 grade L-HPC. The solid dosage form of claim 10 or 11, wherein the total mass of the L-HPC is at least 22% of the total mass of the pharmaceutical composition and not more than 42% of the total mass of the pharmaceutical composition. The solid dosage form of any one of claims 9 to 12, wherein the one or more disintegrating agents comprise croscarmellose sodium (Ac-Di-Sol). The solid dosage form of claim 13, wherein the croscarmellose sodium (Ac-Di-Sol) is Ac-Di-Sol of SD-711 grade. The solid dosage form of claim 13 or 14, wherein the total mass of the croscarmellose sodium (Ac-Di-Sol) is at least 1% of the total mass of the pharmaceutical composition and does not exceed the total mass of the pharmaceutical composition 16% of the mass. The solid dosage form of any one of claims 9 to 15, wherein the one or more disintegrants comprise PVPP. The solid dosage form of claim 16, wherein the total mass of PVPP is at least 5% of the total mass of the pharmaceutical composition and not more than 25% of the total mass of the pharmaceutical composition. The solid dosage form according to any one of claims 1 to 17, wherein the total mass of the medicament is at least 20% of the total mass of the pharmaceutical composition and does not exceed 25% of the total mass of the pharmaceutical composition. The solid dosage form of any one of claims 1 to 18, wherein the total mass of the medicament is about 23% of the total mass of the pharmaceutical composition. The solid dosage form according to any one of claims 1 to 19, further comprising mannitol, the total mass of mannitol having a total mass of at least 18% of the total mass of the pharmaceutical composition and no more than the total mass of the pharmaceutical composition 25% of the mass. The solid dosage form according to any one of claims 1 to 20, further comprising magnesium stearate, the total mass of magnesium stearate having a total mass of at least 0.01% of the total mass of the pharmaceutical composition and not exceeding the 10% of the total mass of the pharmaceutical composition. The solid dosage form according to any one of claims 1 to 21, further comprising colloidal silicon dioxide (Aerosil), the total mass of Aerosil having a total mass of at least 0.01% of the total mass of the pharmaceutical composition and not exceeding the 10% of the total mass of the pharmaceutical composition. A solid dosage form of a pharmaceutical composition comprising about 23% medicament, wherein the medicament comprises Prevotella histolytica bacteria; about 21.5% mannitol; about 32% L-HPC; about 6% cross-linked carboxymethyl Sodium cellulose; about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silica. The solid dosage form of any one of claims 1 to 23, wherein the bacteria are lyophilized bacteria. The solid dosage form of any one of claims 1 to 24, wherein the Prevotella histolytica is Prevotella histolytica strain B (NRRL accession number B 50329). The solid dosage form of any one of claims 1 to 25, wherein the bacteria are live, attenuated or dead. The solid dosage form of any one of claims 1 to 26, wherein the medicament comprises Prevotella histolytica bacteria, and the dosage of the Prevotella histolytica bacteria is from about 2.4 x 10 ¹¹ to about 4.0 x 10 ¹¹ cells, where the dose is the dose per tablet or the dose of all minitablets in the capsule. The solid dosage form of any one of claims 1 to 27, wherein the medicament comprises Prevotella histolytica bacteria, and the dosage of the Prevotella histolytica bacteria is from about 2.8 x 10 ¹¹ to about 3.6 x 10 ¹¹ cells, where the dose is the dose per tablet or the dose of all minitablets in the capsule. The solid dosage form of any one of claims 1 to 28, wherein the medicament comprises Prevotella histolytica bacteria and the dose of Prevotella histolytica bacteria is about 3.2 x 10 ¹¹ cells, wherein the dose is The dose per tablet or the dose of all minitablets in the capsule. The solid dosage form of any one of claims 1 to 29, wherein the solid dosage form is a tablet. The solid dosage form of claim 30, wherein the tablet is 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm or 18 mm tablets. The solid dosage form of any one of claims 1 to 29, wherein the solid dosage form is a minitablet. The solid dosage form of claim 32, wherein the minitablets are 1 mm minitablets, 1.5 mm minitablets, 2 mm minitablets, 3 mm minitablets, or 4 mm minitablets. The solid dosage form of claim 32 or 33, wherein the plurality of microtablets are contained in a capsule. The solid dosage form of any one of claims 1 to 34, further comprising an enteric coating. The solid dosage form of claim 35, wherein the enteric coating is a single enteric coating or more than one enteric coating. 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 the same. The solid dosage form of any one of claims 35 to 37, wherein the enteric coating comprises methacrylate ethyl acrylate (MAE) copolymer (1 : 1). 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) dicarboxylate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (ester of eleuic acid), plastics, vegetable fibers, zein , Aqua-Zein (alcohol-free aqueous zein formulation), amylose, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methyl Cellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, or sodium alginate. The solid dosage form of any one of claims 35 to 38, wherein the enteric coating comprises an anionic polymeric material. 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. 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. The solid dosage form of claim 42, wherein the solid dosage form maintains its stability at about 2°C-8°C. The solid dosage form of any one of claims 1 to 43, wherein the solid dosage form maintains its stability under accelerated storage conditions. The solid dosage form of claim 44, wherein the solid dosage form maintains stability at about 25°C/60% relative humidity (RH). 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). The solid dosage form of any one of claims 1 to 46, wherein the solid dosage form has a water content between about 3% and 6%. The solid dosage form of any one of claims 1 to 47, wherein the solid dosage form maintains its water content for about 3-24 months. 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. The solid dosage form of claim 49, wherein the solid dosage form maintains its water content at about 2°C-8°C. 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. The solid dosage form of claim 51, wherein the solid dosage form maintains its water content at about 25°C/60% relative humidity (RH). A method of preventing or treating a disease in a subject, the method comprising administering to the subject the solid dosage form of any one of claims 1-52. Use of a solid dosage form as claimed in any one of claims 1 to 52 for the treatment or prevention of a disease in a subject. Use of the solid dosage form of any one of claims 1 to 52 for the manufacture of a medicament for the treatment or prevention of a disease in a subject. The solid dosage form of any one of claims 1 to 52, for use in the treatment or prevention of a disease in a subject. A method for preparing a solid dosage form of a pharmaceutical composition, the method comprising: (a) Combining the following into a pharmaceutical composition: (i) a medicament having a total mass of at least 20% of the total mass of the pharmaceutical composition and no more than 25% of the total mass of the pharmaceutical composition, wherein the medicament comprises Prevotella histolytica bacteria; (ii) low-substituted hydroxypropyl cellulose (L-HPC), which has a total mass of L-HPC that is at least 22% and not more than 42% of the total mass of the pharmaceutical composition; (iii) Croscarmellose sodium (Ac-Di-Sol), which has a total mass of croscarmellose sodium (Ac-Di-Sol) that is at least 0.01% of the total mass of the pharmaceutical composition and does not exceed 16% of the total mass of the pharmaceutical composition; and (iv) crospovidone (PVPP) having a total PVPP mass of at least 5% and not more than 25% of the total mass of the pharmaceutical composition; and (b) compressing the pharmaceutical composition into a solid dosage form. The method of claim 57, further comprising the step of enteric coating the solid dosage form to obtain an enteric coated solid dosage form. The method of claim 57 or 58, wherein the solid dosage form is a tablet. The method of claim 57 or 58, wherein the solid dosage form is a microtablet.

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