TW202140049A - Compositions and methods for treating hepatitis b (hbv) and hepatitis d (hdv) - Google Patents

Abstract

The present disclosure is in the field of pharmaceutical compositions suitable for the treatment of HBV or HDV in mammals. The disclosure provides novel compositions comprising non-pathogenic fecal microbes for treating HBV or HDV and related diseases. The disclosure also provides methods for treating a subject with the compositions disclosed herein.

Description

Composition and method for treating hepatitis B (HBV) and hepatitis D (HDV)

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Hepatitis B is a severe liver infection caused by viral infection of hepatitis B virus (HBV). Hepatitis B infection can cause acute and chronic diseases. Acute illness lasts less than six months. Chronic diseases can last for more than 6 months and increase the risk of liver failure, liver cancer, NASH or cirrhosis. Hepatitis B is spread through blood and other body fluids. Hepatitis B is most commonly transmitted from mother to child during childbirth and childbirth.

Hepatitis B is a serious health problem worldwide. In 2015, more than 250 million people lived with chronic hepatitis B infection and the infection caused approximately 890,000 deaths. Most deaths from hepatitis B are caused by liver cirrhosis and hepatocellular carcinoma. The Western Pacific region and Africa have the highest prevalence of hepatitis B. HBV virus can survive in vitro for at least 7 days. HBV has an incubation period of 30 to 180 days and can be detected within 30 to 60 days.

Compared with adults, HBV infection is more serious in infants and children. Infections in adults cause chronic hepatitis in less than 5% of cases. About 20 to 30% of adults who have been infected with HBV for a long time may develop cirrhosis and/or liver disease. However, 80 to 90% of babies infected with HBV during the first year of life develop chronic infections and 30 to 50% of children infected before the age of 6 develop chronic infections.

Mammals have diverse microbial species in their gastrointestinal (GI) tract. The interactions between these microorganisms and between the microorganisms and the host, such as the host's immune system, shape the microbial phase. A healthy microbial phase provides the host with multiple benefits, including immune stimulation against the colonization of a broad spectrum of pathogens, the biosynthesis and absorption of basic nutrients, and the maintenance of healthy digestive epithelium and appropriately controlled systemic immunity. Unbalanced microbial phase (also known as dysbiosis or disrupted symbiosis) may lose its function and cause increased susceptibility to pathogens, altered metabolic profile, or may cause local or systemic inflammation or autologous Induction of immune-promoting inflammatory signals. In addition, such damaged microbial phases may be infected with one or more pathogens, which can cause pain, diarrhea, flatulence and constipation, and other symptoms. Therefore, the intestinal microbiota plays a significant role in the pathogenesis of many diseases of the digestive tract such as pathogenic infections.

Implanting or administering human colonic microbes into the intestines of diseased patients is called Fecal Microbiota Transplantation (FMT), which is also often referred to as fecal bacteriotherapy (fecal bacteriotherapy). It is believed that FMT replenishes the digestive tract by controlling a series of different microorganisms of key pathogens and creating an ecological environment that is not conducive to the proliferation and survival of these key pathogens. FMT represents a treatment regimen that allows rapid restoration of the normal combined and functional digestive tract microflora.

FMT has been used to treat Clostridium difficile infection (CDI). It is also proposed to use FMT to treat other gastrointestinal infections such as E. coli and Vancomycin resistant Enterococci (VRE). It requires the human microbial phase in the form of homogenized stool or cultured stool components (such as Clostridia) via colonoscopy, enema, or via nasojejunal tube in order to implant in the colon and thereby excrete or eradicate For example, the pathogenic bacteria of C. difficile (C. difficile).

In one aspect, the present invention provides a method for treating HBV or HDV in an individual in need, the method comprising administering to the individual a pharmaceutically active dose of a therapeutic composition, the therapeutic composition comprising uncultured feces Bacterial preparations.

In another aspect, the present invention provides a method for treating HBV or HDV in an individual in need, the method comprising administering to the individual a pharmaceutically active dose of a therapeutic composition, the therapeutic composition comprising a bacterial mixture.

In another aspect, the present invention provides a method for treating HBV or HDV in an individual in need, the method comprising administering to the individual a pharmaceutically active dose of a therapeutic composition, the therapeutic composition comprising a live non-pathogenic Sexual fecal bacteria or non-cellular fecal filter.

In one aspect, the present invention provides a method for treating at least one symptom of HBV or HDV in an individual in need, the method comprising administering to the individual a pharmaceutical composition, the pharmaceutical composition comprising: (i) a source A bacterial population in the feces of a human donor, where the bacterial population has not been cultured; and (ii) bacterial isolates.

In one aspect, the present invention provides a method for treating at least one symptom of HBV or HDV in an individual in need, the method comprising administering to the individual a pharmaceutical composition comprising a human donor The bacterial colony of the feces, where the bacterial colony has not been cultured.

In one aspect, the present invention provides a method comprising: extracting a bacterial colony from the feces of a healthy human donor; and mixing the bacterial colony and the bacterial isolate; wherein the bacterial colony is not cultured.

In one aspect, the present invention provides a method for treating at least one symptom of HBV or HDV in an individual in need, the method comprising administering to the individual (i) a pharmaceutical composition comprising a human donor The bacterial population of the feces, and (ii) at least one, at least two, or all three types of non-pathogenic microorganisms selected from the group consisting of: bacterial isolates, fungal isolates and archaea isolates.

In one aspect, the present invention provides a method comprising: extracting a bacterial population from the feces of a healthy human donor; and mixing the bacterial population with (i) non-pathogenic bacterial isolates and (ii) at least one, at least Two or all three types of non-pathogenic microorganisms selected from the group consisting of: bacterial isolates, fungal isolates, and archaea isolates.

In one aspect, the present invention provides a method for treating the signs or symptoms of HBV or HDV in an individual in need, which comprises: administering a pharmaceutical composition to the individual in need, wherein the pharmaceutical composition comprises The abundance of at least one component in the fecal microbial phase of the donor is from a microbial population selected from the human fecal donor, wherein the microbial population is uncultured and contains at least one, at least two, or all three selected from the group consisting of Types of non-pathogenic microorganisms: bacterial isolates, fungal isolates and archaea isolates.

In another aspect, the present invention provides a method for treating at least one symptom of HBV or HDV in an individual in need and suffering from HBV or HDV, the method comprising administering to the individual a pharmaceutical composition, the pharmaceutical combination The thing contains a bacterial population or community derived from the feces of a human donor, wherein the bacterial population or community has not been cultured.

In another aspect, the present invention provides a method for treating at least one symptom of HBV or HDV in an individual in need and suffering from HBV or HDV, the method comprising administering to the individual a pharmaceutical composition, the pharmaceutical combination The material contains bacterial populations or communities derived from the feces of human donors.

In another aspect, the present invention provides a method for treating HBV/D hepatitis virus (HBV/HDV) co-infection in an individual in need, the method comprising administering to the individual a pharmaceutical composition, the pharmaceutical combination The material contains bacterial populations or communities derived from the feces of human donors.

In another aspect, the present invention provides a method for treating at least one symptom of HBV/HDV co-infection in an individual in need, the method comprising administering a pharmaceutical composition to the individual, the pharmaceutical composition comprising The bacterial colony or community in the feces of human donors.

Cross reference of related applications

This application claims the priority of U.S. Provisional Application No. 62/959,512 filed on January 10, 2020 and U.S. Provisional Application No. 63/070,072 filed on August 25, 2020, which are incorporated by reference in their entirety. Into this article.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those who are familiar with the present invention.

All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference, and the degree of citation is the same as that of individual publications, patents, or patent applications. The way of citation is incorporated into the general.

Unless the context clearly dictates otherwise, as used herein and in the scope of the appended application, the singular forms "a/an" and "the" include plural indicators. For example, "an element" means at least one element and may include more than one element.

As used herein, the term "substantially" when used to modify quality generally allows a certain degree of change without quality loss. For example, in some aspects, the degree of such change may be less than 0.1%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8 %, about 0.9%, about 1%, between 1%-2%, between 2%-3%, between 3%-4%, between 4%-5% or greater than 5% or 10%.

As used in this article, whenever "as appropriate" is mentioned, the following two situations are covered. First, explicitly exclude the optional components or steps according to the situation; and second, explicitly include the optional components or steps according to the situation.

When a range of values is provided, it should be understood that each intermediate value between the upper limit and the lower limit of the range and any other stated value or intermediate values within the stated range are encompassed by the present invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed by the present invention, subject to any specific exclusive limitations within the stated range. When the stated range includes one or both of the limits, a range excluding either or both of these included limits is also included in the present invention.

For the avoidance of any doubt, when used in this article, such terms as "about", "at least", "at least about", "at most", "less than", "greater than", "within" or similar terms or phrases When a term or phrase is followed by a percentage of a list of numbers, such terms or phrases are considered to modify the percentage of each number in the series or list, regardless of whether adverbs, prepositions or other modifying phrases appear before each member in this way.

As used herein, the term "relative abundance" refers to a specific kind of organisms (for example, bacterial strains, species or genus) relative to all organisms in a community with similar properties (for example, uncultured fecal bacterial preparations) Or bacterial mixture). Relative abundance is calculated by dividing the number of creatures of a particular type by the total number of all creatures of similar nature in a community. In one aspect, by qPCR, the relative abundance is measured by comparing the PCR product generated with the 16S primer targeting the relevant specific bacterial strain with the PCR product generated with the universal primer targeting the entire 16S sequence. See, for example, Chu, N. et al., "Profiling living bacteria informs preparation of fecal microbiota transplantations." PLoS One 12(1): 1-16 (2017). In another aspect, based on Qualcomm as described in Gevers et al., "The treatment-naïve microbiomes in new-onset Crohn's disease." Cell Host & Microbe , 15(3):382-92(2014) The relative abundance is measured by the number of sequence reads detected by sequencing. In one aspect, the high-throughput sequencing system is based on 16S rRNA gene sequencing. In another aspect, the high-throughput sequencing system is based on whole-genome short-gun metagenomic sequencing. Unless otherwise specified, the relative abundance of bacteria mentioned herein is based on the 16S rRNA targeting the V4 variable region as described in Gevers et al., Cell Host & Microbe, 15(3):382-92 (2014) The high-throughput sequencing to measure. In another aspect, as shown in Chu et al., PLoS One 12(1): 1-16 (2017), propidium monoazide (PMA) is used to distinguish live fecal microorganisms from dead fecal microorganisms.

The term "treating" as used herein refers to (i) completely or partially inhibiting a disease, disorder, or condition, such as curbing its development; (ii) completely or partially alleviating a disease, disorder, or condition, such as causing The symptoms and/or symptoms disappear; or (iii) completely or partially prevent the disease, disease, or disease from being likely to be susceptible to the disease, disease, and/or disease, but has not yet been diagnosed as having the disease, disease, or disease Appear in the patients. Similarly, "treatment" refers to therapeutic treatment and preventive or preventive measures. In the case of HBV or HDV, "treat/treating" covers alleviation, amelioration of one or more symptoms related to HBV or HDV, delaying its onset, inhibiting its progression, or reducing its severity. In the case of HBV, "treatment" also covers the reduction of HBsAg levels.

As used herein, "individual" refers to humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs, turkeys, chickens) And any individual animal of domestic pets (for example, dogs, cats, rodents, etc.). The preferred individual is a human individual. The human individual can be a child, adult, or elderly individual. A human individual can also be a pregnant individual. In some aspects, the terms "patient" and "individual" are used interchangeably. The individual may be healthy or may suffer from one or more of the symptoms of HBV or HDV.

As used herein, "HBV individual" or "HBV patient" refers to an individual or patient suffering from acute HBV or chronic HBV. Any aspect referred to herein or described about "HBV" is applicable to acute or chronic HBV. Any aspect referred to in this article or described about "HBV" also applies to HBV/HDV co-infection.

As used herein, HBV "indicator" and "symptom severity" refer to pathological conditions in an individual, which can be detected to predict the risk of HBV in an individual or to confirm the existence and/or degree of HBV infection. Detection can be performed by blood tests or imaging techniques. In addition, indicators can refer to markers used to diagnose liver injury and the severity of injury (such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamine aminotransferase ( GGT) or fat accumulation in the liver). In addition, one or more systems or scales selected from the group consisting of: changes in the Chronic Liver Disease Questionnaire (CLDQ), blood tests, imaging tests, and liver function tests can be used to assess liver damage. In blood tests, a complete blood count is used to check for red blood cells, white blood cells, and platelets. The blood test can also be used to check the blood content of sodium, potassium and ammonia. Excessive levels of these substances are a sign of impaired liver function. Liver function tests check for elevated enzyme levels. An increase in enzymes indicates pressure on the liver or liver damage.

As used herein, "microbial phase" and "biota" refer to microbial communities that live in or on an individual's body sustainably and temporarily, including eukaryotes, archaea, bacteria, and viruses ( Including bacterial viruses (i.e., bacteriophages)). "Fecal microbial phase" or "fecal microbial phase preparation" refers to the microbial community present in or prepared from the feces of an individual. Generally, the pharmaceutical composition described herein is prepared by incorporating the fecal microbial phase into the composition without culturing the fecal microbial phase after purifying the fecal microbial phase from the feces. As used herein, "uncultivated fecal bacterial preparation" refers to multiple live bacterial strains that have been collected, extracted, or purified from one or more stool samples, wherein the strains are not cultured (for example, in a culture medium).

In some aspects, the uncultured fecal bacteria preparation contains non-selected fecal bacteria. As used herein, "non-selected fecal bacteria" refers to a population or community of live fecal bacterial strains extracted from one or more stool samples (for example, present in the fecal microbial phase), wherein the extracted population or community is not Experience environmental conditions that deliberately select specific bacterial types, states, or classification categories (for example, by deliberately removing certain bacterial strains, treating populations or communities with reagents such as ethanol or chloroform, or culturing). Such non-selected fecal bacteria may include bacterial strains whose content is proportional to the corresponding bacterial strains in the fecal or intestinal microbial phase of a normal healthy human. Steps for non-selectively extracting populations or communities of fecal bacteria from a stool sample may include, for example, homogenization and filtration of the stool sample to separate fecal bacterial strains from non-cellular fecal material such as fibers and coarse granular materials and, for example, eukaryotic hosts Cells and viruses. In this context, generally, non-selected fecal bacterial preparations can be prepared under aerobic or anaerobic conditions or a combination thereof. In some aspects, the non-selected fecal bacterial preparation contains all or substantially all of the bacteria in the fecal microbial phase of the fecal sample. In some aspects, the non-selected fecal bacterial preparation contains all or substantially all of the strains in the fecal microbial phase of the fecal sample. In some aspects, the non-selected fecal bacterial preparation contains all or substantially all species in the fecal microbial phase of the fecal sample. In some aspects, the non-selected fecal bacterial preparation contains all or substantially all of the fecal microbial phase of the fecal sample. In some aspects, the non-selected fecal bacterial preparation contains all or substantially all of the fecal microbial phase of the fecal sample. Therefore, such non-selective fecal microbial phases can be substantially similar to the microbial composition and bacterial population or community structure found in such fecal samples.

In one aspect, the uncultured fecal bacterial preparation and/or uncultured bacterial population or community contains at least 2, 5, 10, 20, 30, 40, 50, 100, 200, 300, 400, 500 or 600 kinds of bacterial substances or strains. In another aspect, the uncultured fecal bacterial preparation and/or uncultured bacterial population or community includes 2 to 5, 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 100, 100 to 200, 200 to 300, 300 to 400, 400 to 500 or 500 to 600 bacterial substances or strains.

In one aspect, the uncultured fecal bacteria and/or non-selected fecal bacteria preparations do not contain antibacterial colony antibiotics.

In another aspect, the manufacture of uncultured fecal bacterial preparations may involve the selection of specific bacterial types, states, or classification categories (for example, by deliberately removing certain bacterial strains and/or using selective methods such as ethanol or chloroform). Reagent treatment population) steps. In certain aspects, such uncultured fecal bacterial preparations can be combined with one or more bacterial isolates to form a bacterial mixture for incorporation into pharmaceutical compositions. For example, feces or fecal bacteria extracted from the feces can be incubated with a selective agent such as ethanol for a period of time, the ethanol is removed after the incubation, and the cultivated bacteria are mixed with one or more bacterial isolates to produce bacteria mixture. In one aspect, the viable bacteria remaining in the formulation after incubation with the selective agent essentially comprise or consist of spores.

In this context, uncultured fecal bacterial preparations are distinguished from single, purified bacterial strains such as bacterial isolates. As used herein, "bacterial isolate" refers to an isolated population of substantially genetically identical bacterial cells produced by proliferating through two divisions from a single precursor bacterial cell (for example, by culturing bacteria). Generally, bacterial isolates are originally separated into single cells or genetically pure cell populations on solid media or through serial dilutions in liquid cultures, such as single colonies, and then preserved (for example, as frozen stock solutions) ) To provide a consistent and stable source of isolates. After separation, in some aspects, the bacterial isolate can grow as a pure cell culture; in other aspects, multiple bacterial isolates can be grown in the same container as a mixed culture at the same time. In the context of bacteria, the term "substantially genetically identical" refers to the extremely high (for example, >99.9%) genetic identity shared by different cells in the uncontaminated pure bacterial isolate composition due to their proliferation from a common predecessor , But explains the tiny genetic differences between cells caused by the accumulation of relatively rare mutations. Generally, bacterial isolates are synonymous with pure bacterial cell cultures. Generally, in this context, bacterial isolates consist of non-pathogenic bacteria. In one aspect, the bacterial isolate may be a probiotic or a component of a probiotic.

As used herein, the term "bacterial mixture", sometimes referred to as "bacterial consortium" or "synthetic bacterial mixture", refers to an engineered symbiotic species containing multiple bacterial isolates as defined Modified bacterial mixture. The term "the defined symbiotic species of a plurality of bacterial isolates" means that the bacterial mixture contains two or more bacterial isolates, and the consistency of each bacterial isolate in the mixture is known, and therefore the mixture is mixed Liquids can be produced consistently (for example, by combining isolated bacterial strains) to have stable composition and characteristics in independent batches. As used herein, the "identity" of a bacterial isolate may refer to any characteristic that uniquely identifies the isolate as being different from one or more other bacterial isolates or isolates of bacterial strains. Examples of identifying characteristics of bacterial isolates include nucleotide sequences such as 16S rRNA sequences, sequences of one or more coding or non-coding regions of nucleic acids and complete genome sequences, gene expression levels, physiological or metabolic properties, or such as staining Anatomical characteristics of patterns or cell wall features.

As used herein, "bacterial mixture" refers to an engineered composition containing live bacterial cells, which in some aspects may include one or more non-pathogenic bacterial isolates and/or uncultured bacterial cells preparation. In some aspects, the bacterial mixture includes one or more non-pathogenic bacterial isolates. In some aspects, the bacterial mixture comprises an uncultured fecal bacterial preparation. In some aspects, the bacterial mixture includes one or more non-pathogenic bacterial isolates and uncultured fecal bacterial preparations.

As used herein, "fungal isolate" refers to a population of isolated, substantially genetically identical fungal cells produced by proliferating through two divisions from a single precursor fungal cell (for example, by culturing the fungus). Generally, fungal isolates are originally separated into single cells or genetically pure cell populations on solid medium or through serial dilution in liquid cultures, for example, as single colonies, and then stored (for example, as a frozen stock solution) ) To provide a consistent and stable source of isolates. After separation, in some aspects, the fungal isolate can grow as a pure cell culture; in other aspects, multiple fungal isolates can grow in the same container as a mixed culture at the same time. In the case of fungi, the term "substantially genetically identical" refers to the extremely high (eg, >99.9%) genetic identity shared by different cells in the uncontaminated pure fungal isolate composition due to their proliferation from a common predecessor , But explains the tiny genetic differences between cells caused by the accumulation of relatively rare mutations. Generally, fungal isolates are synonymous with pure fungal cell cultures. Generally, in this context, fungal isolates consist of non-pathogenic fungi. In one aspect, the fungal isolate may be a probiotic or a component of a probiotic.

Any aspect referred to herein or described in relation to bacterial isolates may equally apply to fungal isolates. For example, all the disclosures and descriptions of the mixture of uncultured fecal bacteria preparations containing enriched, supplemented, or "admixed" one or more bacterial isolates in this article are equally applicable to include enriched, supplemented or "admixed" Addition of a mixture of uncultured fecal bacteria preparations of one or more fungal isolates. In addition, for example, all the disclosures and descriptions of the mixture of uncultured fecal bacteria preparations containing enriched, supplemented, or "admixed" one or more bacterial isolates in this article are equally applicable to include enriched, supplemented Or "admix" a mixture of uncultured fecal bacterial preparations of one or more bacterial isolates and one or more fungal isolates.

As used herein, an "archaeal isolate" refers to an isolated, substantially genetically identical archaeal produced by proliferating through two divisions from a single precursor archaeal cell (for example, by culturing archaea). Bacterial cell population. Generally, archaeal isolates are originally isolated into single cells or genetically pure cell populations on solid media or via serial dilution in liquid cultures, for example as single colonies, and then preserved (for example, in the form of frozen stock solutions). Preservation) to provide a consistent and stable source of isolates. After isolation, in some aspects, the archaeal isolates can grow as pure cell cultures; in other aspects, multiple archaeal isolates can grow in the same container as a mixed culture at the same time. In the context of archaea, the term "substantially genetically identical" refers to the extremely high (eg, >99.9%) genes shared by different cells in the uncontaminated pure archaeal isolate composition due to their proliferation from a common predecessor Consistency, but explains the tiny genetic differences between cells due to the accumulation of relatively rare mutations. Generally, archaeal isolates are synonymous with pure archaeal cell cultures. Generally, in this context, the archaea isolates consist of non-pathogenic archaea. In one aspect, the archaeal isolate may be a probiotic or a component of a probiotic.

Any aspect referred to herein or described with respect to bacterial isolates may equally apply to archaeal isolates. For example, all the disclosures and descriptions of the mixture of uncultured fecal bacteria preparations containing enriched, supplemented, or "admixed" one or more bacterial isolates in this article are equally applicable to include enriched, supplemented or "admixed" "Admixed" is a mixture of uncultured fecal bacteria preparations of one or more archaeal isolates (and/or one or more fungal isolates). In addition, for example, all the disclosures and descriptions of the mixture of uncultured fecal bacteria preparations containing enriched, supplemented, or "admixed" one or more bacterial isolates in this article are equally applicable to include enriched, supplemented Or "admix" a mixture of uncultured fecal bacterial preparations of one or more bacterial isolates and one or more archaeal isolates. Similarly, all the disclosures and descriptions of the mixture of uncultured fecal bacteria preparations containing enriched, supplemented or "admixed" one or more bacterial isolates in this article are equally applicable to include enriched, supplemented or "admixed" Add "a mixture of one or more bacterial isolates, one or more archaea isolates, and one or more uncultured fecal bacterial preparations of archaeal isolates."

As used herein, "therapeutically effective amount", "effective amount" or "pharmaceutically active dose" refers to the amount of the composition that effectively treats the mentioned disease, disorder, condition, or symptom.

As used herein, "isolated" or "purified" means that at least some of its related components have been (1) separated from when it was first produced (whether it was originally produced in nature or in an experimental environment), And/or (2) Bacteria or other entities or substances manually produced, prepared, purified and/or manufactured by humans. The isolated or purified bacteria can be at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% of other components that are originally related to it. % Or more separation.

As used herein, the term "non-pathogenic" with respect to bacteria or any other organism or entity includes any such organism or entity that cannot cause or affect the disease, disorder, or condition of the host organism containing the organism or entity.

As used herein, "spores" or "spores" populations include those that are generally active, more resistant to environmental influences such as heat and fungicides than the asexual form of the same bacteria, and are generally able to germinate and grow Bacteria (or other single-celled organisms). "Spore formers" or "spore-forming" bacteria are bacteria that contain genes and other required abilities for producing spores under suitable environmental conditions.

As used herein, "colony forming unit" (CFU) refers to the estimated number of viable microbial cells in a given sample. The CFU value can be evaluated by counting the number of colonies on the agar plate as is the standard method used to determine the number of viable bacterial cells in the sample.

As used herein, "living" means having the ability to proliferate. The viability of the bacterial population can be monitored as a function of the integrity of the cell membrane. Cells with defective membranes are considered dead or dying, while cells with intact membranes are considered alive. For example, SYTO 9 and propidium iodide are used to stain and distinguish live bacteria from dead bacteria. See, for example, Stocks, Cytometry A. 2004.10;61(2):189-95. Cell viability can also be evaluated by, for example, molecular viability analysis based on PCR methods, which can distinguish nucleic acids related to living cells from nucleic acids related to inactivated cells. See Cangelosi and Mescheke, Appl Environ Microbiol. 2014 October; 80(19): 5884-5891.

解釋存在於既定群落中之物種之豐度及均勻度之多樣性指數，其中H為向農多樣性指數，R為群落中之物種之總數目，且p_i 為由第i物種組成之R之比例。較高值指示多樣且均等分佈之群落，且值0指示僅一個物種存在於既定群落中。關於其他論述，參見Shannon及Weaver, (1949)The mathematical theory of communication . The University of Illinois Press, Urbana. 117pp。As used in this article, "Shannon Diversity Index (Shannon Diversity Index)" refers to the use of

Explain the diversity index of the abundance and evenness of the species that exist in a given community, where H is the index of diversification to agriculture, R is the total number of species in the community, and p _{i is the} number of R consisting of the i-th species Proportion. A higher value indicates a diverse and evenly distributed community, and a value of 0 indicates that only one species exists in a given community. For other discussions, see Shannon and Weaver, (1949) The mathematical theory of communication . The University of Illinois Press, Urbana. 117pp.

As used herein, "antibiotic" refers to substances used to treat and/or prevent bacterial infections by killing bacteria, inhibiting bacterial growth, or reducing bacterial viability.

As used herein, "adverse event (AE)" refers to any dose that causes symptoms or symptoms related to surgery or microbiology. As used herein, "serious adverse event (SAE)" refers to any medical occurrence (medical occurrence) at any dose that causes death or life-threatening. As used herein, "life-threatening" refers to an event in which the patient is at risk of death at the time of the event. Adverse events are classified according to the scale used by those who are generally familiar with this technology (for example, the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)).

This document describes a pharmaceutical composition comprising bacteria and a method of using the pharmaceutical composition to treat HBV or HDV. Although early detection and intervention are encouraged to maximize benefits and reduce the severity of symptoms, individuals of any age can benefit from interventions and therapies that can reduce symptoms. Individuals suitable for the methods described herein include (but are not limited to) humans who have been diagnosed with or suspected of having HBV or HDV. In some cases, individuals suitable for the methods provided herein are deemed to have an increased risk of developing HBV or HDV (e.g., moderate or high risk). Without being bound by theory, in some cases, the risk of HBV or HDV increases with the following: unprotected sex with multiple partners, needle sharing with IV drug users, contact with chronic HBV or HDV infected patients, Infants delivered by infected mothers and travel to areas with high HBV or HDV infection rates (such as Asia, Pacific Islands, Africa and Eastern Europe). In some cases, the individual is diagnosed with acute HBV or HDV or chronic HBV or HDV. In some cases, the individual suffers from symptoms selected from the group consisting of abdominal pain, red urine, fever, joint pain, loss of appetite, nausea and vomiting, weakness and fatigue, or jaundice. In some cases, the individual has detectable levels of serum HBsAg. In some cases, the individual is negative for HBeAg and has detectable levels of serum HBsAg. In some cases, individuals have persistently low levels of HBV DNA in the liver and no detectable HBsAg. See Song, J. et al., Ann Transl Med. 4(18): 338 (2016). In another case, the HBV of an individual is detected by measuring the viral load of HBV (such as Q-PCR). Previous reports on HBV treatment can be found in Ren et al., Hepatology 65(5): 1765-1768 (2017) and Xie et al., Gut 67(Supplement 2): A110 (2018). Another report on HBV treatment can be found in Chauhan et al. Fecal Microbiota Transplantation in Hepatitis B e Antigen-Positive Chronic Hepatitis B Patients: A Pilot Study [Published online, April 11, 2020]. Dig Dis Sci. 2020 .

Also disclosed herein are compositions and methods for treating HDV infection in individuals in need. People who have been infected with HDV for a long time usually develop liver cirrhosis and hepatocellular carcinoma. HDV, an RNA pseudovirus, relies on its helper virus HBV to produce chronic infections. Chronic infection always occurs in the form of HDV/HBV co-infection, because HDV requires HBV surface protein (HBsAg) to assemble and secrete functional progeny virus particles. The various aspects of HBV treatment or prevention disclosed in this article are also applicable to HDV/HBV co-infection.

In an aspect of the invention, the pharmaceutical composition comprises a bacterial mixture comprising an uncultured fecal bacterial preparation such as non-selected fecal bacteria. In one aspect, the bacterial mixture includes a single bacterial isolate or multiple bacterial isolates (e.g., in the form of a bacterial mixture). In one aspect, the pharmaceutical composition comprises a bacterial mixture comprising (i) an uncultured fecal bacterial preparation; and (ii) at least one bacterial isolate. Such bacterial mixtures can be referred to as uncultured fecal bacterial preparations enriched, supplemented or "admixed" with one or more bacterial isolates. By enriching or adding one or more non-pathogenic bacterial isolates to uncultured fecal bacterial preparations derived from fecal samples from healthy donors (for example, fecal microbial phase), one or more specific bacterial strains can be produced (That is, the amount of one or more bacterial isolates incorporated) is a composition that can be considered and precisely controlled. Without being bound by theory, for example, at least one bacterial isolate incorporated into an uncultured fecal bacterial preparation is for the treatment of an individual (for example, suffering from or susceptible to one or more symptoms of HBV or HDV) This situation is advantageous when it is important or relevant, but not sufficient on its own to produce an enhanced or optimal therapeutic response in an individual. Probiotics can be relied upon in their role in relation to the administration of a single bacterial isolate or a few bacterial isolates. Unlike probiotics, the administration of one or more bacterial isolates and uncultured fecal bacterial preparations (that is, derived from healthy donors) to individuals with HBV or HDV can provide individuals with the advantages and advantages of the bacterial isolates administered. A combination of multi-factor benefits conferred by other fecal bacterial strains present in uncultivated microbial preparations. These other fecal bacterial strains can be combined to, for example, provide a desired environment or interaction (e.g., via one or more release factors) so that the bacterial isolate can induce an optimal response in the individual, or can directly induce the response in the individual , The response is combined and/or synergistically working with the response induced by the bacterial isolate used to treat the individual. Therefore, in certain aspects, a pharmaceutical composition comprising a mixture of one or more bacterial isolates and an uncultured fecal bacterial preparation may be more effective in treating an individual (for example, suffering from Or susceptible to one or more symptoms of HBV or HDV).

Enriching, supplementing, or adding one or more microbial isolates to uncultured fecal bacterial preparations (to produce the ``admixed'' version of uncultivated fecal bacterial preparations) and those that do not have enriched, supplemented or admixed Microbial isolates have many advantages over uncultured fecal bacteria preparations. For example, first, without being bound by theory, one or more bacterial isolates added to an uncultured fecal bacterial preparation may be a bacterial strain in the feces derived from the donor used to make the uncultivated fecal bacterial preparation The medium is not presented or only exists in low relative abundance. Therefore, the addition of one or more bacterial isolates to uncultured fecal bacterial preparations can increase one or more corresponding bacterial strains in the digestive tract of patients administered the bacterial mixture (ie, derived from one or more incorporated The relative abundance of bacterial isolates), thereby increasing the possibility of transplantation of the required bacterial strains into the digestive tract of the patient. For example, relatively low-abundance bacterial strains in uncultured fecal bacterial preparations can reside in the intestinal mucosal layer or small intestine of the donor and are therefore usually not present in high levels in the production of uncultured feces. Bacterial preparation in the feces of the donor. Second, without being bound by theory, the incorporation of uncultured fecal bacteria preparations can also reduce donor feces (for example, between feces collected from the same donor at different times or between feces of different donors) The heterogeneity of bacterial strain composition. For example, certain bacterial strains are present or abundant in the feces of some donors, but are absent or less abundant in the feces of other donors. Such problems can be solved by supplementing donor-derived uncultured fecal bacteria preparations with one or more microbial isolates exhibiting variable contents in the donor. Third, without being bound by theory, the added type can also promote or enhance the redundancy of important strains or functional objects. The presence of the strain in the donor-derived fecal extract drug product does not guarantee that the strain will be transplanted when administered to the patient. The effect of transplantation can be determined by various factors such as the ecology of the patient's digestive tract microbial phase, the abundance of strains in the medicine, and the inheritance of microbial strains. If the microbial species is related to the desired function in the patient's digestive tract, the possibility of introducing the species/function into the patient's digestive tract during treatment can be increased by co-administering multiple different strains of the species in the drug. Therefore, if the desired species is represented by a specific strain in the fecal microbial component of the drug, the introduction of a different strain of the species in the incorporated component can increase the possibility of transplanting one of the strains to impart the desired function .

Enriching, supplementing, or adding one or more microbial isolates to uncultured fecal bacterial preparations (for example, using donor-derived fecal extracts as the "backbone" to produce the blended form) and in the absence of uncultured In the case of fecal bacterial preparations, the use of the same one or more microbial isolates (for example, a single bacterial isolate or a symbiotic species of bacterial isolates) also has many advantages. First of all, without being bound by theory, the blended type makes it possible to reduce the complexity (that is, the number of isolates) of the isolate symbiotic species administered to treat the patient without compromising the quality of the product. Improve manufacturing schedule and reduce costs. Second, without being bound by theory, the incorporated composition can potentially improve the transplantation of one or more bacterial strains in the digestive tract of the recipient. Third, without being bound by theory, if the basic mechanism of action for the prevention or treatment of diseases by digestive tract bacteria is unknown, including the overall microbial community from a healthy donor in the composition can ensure that the basic microbes of the prevention or treatment mechanism are Present.

In one aspect, the pharmaceutical composition comprises an uncultured fecal bacterial preparation that is effective in treating individuals suffering from or susceptible to one or more symptoms of HBV or HDV. In another aspect, a pharmaceutical composition comprising a mixture of one or more bacterial isolates and an uncultured fecal bacterial preparation can treat an individual more effectively than a composition comprising a separate uncultured fecal bacterial preparation (e.g., Suffering from or susceptible to one or more symptoms of HBV or HDV). For example, without being bound by theory, the bacterial isolate added to an uncultured fecal bacterial preparation may have an activity that is lacking in an uncultured fecal bacterial preparation (that is, effective treatment or prevention of HBV or HDV). One or more symptoms), for example, because the uncultured fecal bacteria preparation lacks bacterial strains of the same classification as the bacterial isolate (or lacks bacteria with a genetic identity percentage higher than the threshold level with the bacterial isolate Strains), or because the abundance of bacterial strains genetically corresponding to bacterial isolates (for example, in the same classification category as bacterial isolates) is lower than the threshold level in uncultured fecal bacterial preparations.

In one aspect, the pharmaceutical composition includes a bacterial isolate and an uncultivated fecal bacterial preparation lacking bacterial strains of the same classification as the bacterial isolate (for example, prepared from the fecal microbial phase of a healthy human donor). For example, the bacterial isolate may belong to a phylum, class, order, family, genus, or species that is not present in the uncultured fecal bacterial preparation. In another aspect, the pharmaceutical composition comprises a bacterial isolate and an uncultured fecal bacterial preparation lacking a bacterial strain with 100% genetic identity to the bacterial isolate (e.g., by comparing the 16S rRNA of the bacterial isolate The sequence is determined by the genetic identity between the 16S rRNA sequence of the bacterial strain of the uncultured fecal bacterial preparation or the whole genome sequence). In another aspect, the pharmaceutical composition comprises a bacterial isolate and the lack of a bacterial isolate has greater than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%. %, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% genetic identity Uncultured fecal bacterial preparations of bacterial strains (e.g., by comparing the 16S rRNA sequence of bacterial isolates with the 16S rRNA sequences of bacterial strains of uncultured fecal bacterial preparations or between the entire genome sequence Measured by consistency).

In another aspect, the pharmaceutical composition includes bacterial isolates and includes the same classification category as the bacterial isolates, but the abundance or relative abundance below the threshold level of one or more bacterial strains. Cultured fecal bacteria preparation (for example, prepared from the fecal microbial phase of a healthy human donor). For example, an uncultured fecal bacterial preparation may include one of the same phyla, class, order, family, genus, or species as the bacterial isolate, but at an abundance or relative abundance below the threshold level Or multiple bacterial strains. In various aspects, one or more bacterial strains of uncultured fecal bacterial preparations of the same classification as the bacterial isolates can be lower than 10 ¹ , 10 ² , 10 ³ , 10 ⁴ , 10 ⁵ , 10 ⁶ , 10 ^The threshold abundance of 7, 10 ⁸ , 10 ⁹ or 10 ¹⁰ CFU/unit weight (for example, gram) of uncultured fecal bacteria preparation. In various aspects, one or more bacterial strains of uncultured fecal bacterial preparations of the same classification as bacterial isolates can be lower than 0.1%, 0.2%, 0.3%, 0.4% of uncultured fecal bacterial preparations , 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14 %, 15%, 16%, 18%, 20%, 22%, 24%, 25%, 26%, 28%, 30%, 35%, 40% or 50% threshold relative abundance.

In one aspect, the pharmaceutical composition includes a bacterial mixture comprising a bacterial isolate and an uncultured fecal bacterial preparation, so that the relative abundance of living cells of the bacterial isolate in the bacterial mixture is less than that of an uncultured fecal bacterial preparation The relative abundance of live cells (that is, where the bacterial mixture contains only one bacterial isolate, less than 50% of the live cells of the bacterial mixture are cells of the bacterial isolate). In one aspect, the relative abundance of living cells of the bacterial mixture in the bacterial mixture containing the bacterial mixture and the uncultured fecal bacterial preparation is less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, Less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%.

In one aspect, the pharmaceutical composition includes a bacterial mixture comprising a bacterial mixture and an uncultured fecal bacterial preparation, so that the relative abundance of viable cells in the uncultivated fecal bacterial preparation in the bacterial mixture is less than that of the bacterial isolate The relative abundance of live cells (that is, where the bacterial mixture contains only one bacterial isolate, less than 50% of the live cells of the bacterial mixture are cells of an uncultured fecal bacterial preparation). In another aspect, the relative abundance of viable cells of the uncultured fecal bacterial preparation in the bacterial mixture containing the uncultured fecal bacterial preparation and the bacterial mixture is less than 50%, less than 45%, less than 40%, and less than 35 %, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1%.

In one aspect, the pharmaceutical composition includes a bacterial mixture comprising a bacterial isolate and an uncultured fecal bacterial preparation, so that the relative abundance of viable cells of the uncultured fecal bacterial preparation is approximately equal to the living cells of the bacterial isolate The relative abundance (that is, where the bacterial mixture contains only one bacterial mixture, about 50% of the living cells of the bacterial mixture are cells of bacterial isolates, and about 50% of the living cells of the bacterial mixture are uncultured fecal bacteria The cells of the preparation).

In one aspect, the pharmaceutical composition includes a bacterial mixture comprising a bacterial isolate and an uncultured fecal bacterial preparation, so that the relative abundance of living cells in the bacterial isolate is greater than any bacteria in the uncultured fecal bacterial preparation The relative abundance of living cells of strains, any bacterial species, any bacterial genus, any bacterial family, any bacterial order, any bacterial class, or any bacterial phylum.

In one aspect, the pharmaceutical composition includes a bacterial mixture comprising at least one non-pathogenic bacterial isolate and/or sterilized pathogenic bacterial isolate. Bacterial isolates can be isolated from any non-living source (e.g., soil) or live source (e.g., animal), which includes mammals such as sheep, pigs, cattle, primates, or humans. If the animal is separated, the bacterial isolate can be derived from or isolated from any part of the animal such as organs, body fluids or secretions, including intestines, oral cavity, emulsion, saliva or feces. In another aspect, the bacterial isolate is derived from humans. In another aspect, the bacterial isolate is derived from the human fecal microbial phase or intestinal microbial phase. In one aspect, the pharmaceutical composition administered herein contains fecal bacteria. In another aspect, the pharmaceutical composition administered herein includes one or more bacterial isolates extracted, separated, and/or cultured from a stool sample of a healthy human donor.

In some aspects, the bacterial isolates incorporated into the pharmaceutical compositions described herein comprise viable asexual cells. In some aspects, the bacterial isolate contains spore-forming bacteria. In some aspects, the bacterial isolate includes bacteria in the form of spores, such as live spores. In some aspects, the bacterial isolate includes bacteria in the form of viable asexual cells and spores. In some aspects, the bacterial isolate is substantially free of viable asexual cells. In some aspects, the whole bacterial mixture contains substantially no viable asexual cells. In some aspects, the bacterial isolate is substantially free of spores. In some aspects, the overall bacterial mixture is substantially free of spores.

In one aspect, the pharmaceutical composition may include a bacterial isolate (for example, combined with an uncultured fecal bacterial preparation or admixed to an uncultured fecal bacterial preparation), the bacterial isolate including, for example, Lactobacillus ), Bifidus (Bifidobacterium), Streptococcus (Streptococcus), Clostridium (Clostridium), Collins bacteria (Collinsella), Dole coli (Dorea), rumen cocci (Ruminococcus), fecal cocci (Coprococcus), Prairie Wo bacteria (Prevotella), Fanyong Shi cocci (Veillonella), Bacteroides (Bacteroides), Bacillus (Baccillus) or a combination of species. In another aspect, the pharmaceutical composition may include cocci families comprise Fanyong Shi (Veillonellaceae), Firmicutes (Firmicutes), γ- Proteobacteria (the Gammaproteobacteria), Bacteroides door (Bacteroidetes) or a combination of species The bacterial isolates. In another aspect, the pharmaceutical composition may include a bacterial isolate containing bacterial spores. In one aspect, the fecal bacteria spores are Clostridium spores, Bacillus spores, or a combination thereof.

In one aspect, the pharmaceutical composition may include a bacterial isolate containing, for example, a species from the genus Bifidobacterium (for example, as part of a synthetic bacterial mixture or in combination with an uncultured fecal bacterial preparation (or admixed to an uncultured fecal bacterial preparation). Cultured fecal bacteria preparation)). In one aspect, the pharmaceutical composition may include bacterial isolates including, for example, species from the genus Lactobacillus (for example, as part of a synthetic bacterial mixture or in combination with an uncultured fecal bacterial preparation (or admixed to uncultured fecal bacteria). Cultured fecal bacteria preparation)). In another aspect, the pharmaceutical composition may include, for example, bacterial isolates (such as Lachnospiraceae ), Ruminococcaceae , and Clostridiales Incertae Sedis XIV (Clostridiales Incertae Sedis XIV) , As part of a synthetic bacterial mixture or combined with uncultured fecal bacteria preparations (or blended into uncultivated fecal bacteria preparations)). In one aspect, the pharmaceutical composition does not include bacterial isolates (for example, combined with an uncultured fecal bacterial preparation or admixed to an uncultured fecal bacterial preparation) Bifidobacterium longum (Bifidobacterium longum). In one aspect, the pharmaceutical composition does not include a bacterial isolate (e.g., formulation composition of fecal bacterial culture without or spiked with fecal bacteria to the culture medium without formulation) enterococci (Enterococcus). In one aspect, the pharmaceutical composition does not include bacterial isolates (for example, combined with an uncultured fecal bacterial preparation or admixed to an uncultured fecal bacterial preparation) Enterobacteriaceae . In another aspect, the pharmaceutical composition does not include bacterial isolates (for example, combined with an uncultured fecal bacterial preparation or admixed to an uncultured fecal bacterial preparation) Bacteroidaceae .

In one aspect, the bacterial isolate incorporated into the pharmaceutical composition described herein is a probiotic or a component of a probiotic. In one aspect, the various bacterial isolates incorporated into the pharmaceutical compositions described herein are probiotics or ingredients in probiotics. In one aspect, the one or more bacterial isolates are in the form of probiotics when incorporated into the pharmaceutical composition.

In an aspect of the present invention, the pharmaceutical composition may include a bacterial mixture containing a plurality of bacterial isolates (for example, in the form of a bacterial mixture). In aspects of the present invention, the bacterial mixture may comprise at least two bacterial isolates, at least three bacterial isolates, at least four bacterial isolates, at least five bacterial isolates, at least six bacterial isolates, and at least seven bacterial isolates. Isolates, at least eight bacterial isolates, at least nine bacterial isolates, at least ten bacterial isolates or a larger number of bacterial isolates, such as fifteen, twenty, twenty-five, thirty or More kinds of bacterial isolates.

In various aspects, the pharmaceutical composition includes one or more bacterial isolates that can be transplanted into the GI tract of the individual after the composition is administered to the individual. As used herein, "engrafting/engraftment" refers to the stable presence of cells of bacterial strains or bacterial isolates in the intestinal tract of an individual over time (for example, when administered by, for example, oral or rectal administration as described herein The composition is used to introduce bacterial strains or isolates into the intestinal tract of the individual). Generally, the transplantation of bacterial isolates introduced into the intestine of an individual (for example, by oral and/or rectal administration) is by comparing the bacteria in the fecal sample of the individual before and after the administration of the bacterial isolate to the individual The abundance of the isolate is measured longitudinally or over time. In one aspect, the bacterial isolate introduced into the intestine of the individual does not exist prior to administration. In another aspect, the bacterial isolate introduced into the intestine of the individual was present in the intestine before administration, but increased in abundance after administration. In some aspects, the transplantation system recognizes that at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days after the bacterial strain is administered to the individual. Days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, At least 7 weeks, at least 8 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, or more than 6 months after administration to the intestine of the individual The abundance of bacterial strains increases to determine.

In an aspect of the invention, the transplantation of the bacterial isolate in the intestine of the individual occurs when the individual is administered a dose of the bacterial isolate equal to or higher than the threshold. In aspects of the invention, the transplantation of the bacterial isolate in the intestine of the individual does not occur or occurs relatively inefficiently (e.g., in a patient) when the bacterial isolate is administered to the individual at a lower than a threshold dose. For example, a bacterial isolate of the subject to the stent in the intestine can be administered to an individual (e.g., the pharmaceutical compositions described herein are administered orally or rectally) the dose is at least ¹⁰⁶ cells, at least 10 Occurs with a bacterial isolate of ⁷ cells, at least 10 ⁸ cells, at least 10 ⁹ cells, at least 10 ¹⁰ cells, at least 10 ¹¹ cells, or at least 10 ^{12 cells.}

In an aspect of the present invention, the transplantation of the bacterial isolate in the intestine of the individual occurs when the individual is administered the bacterial isolate at or below the threshold dose. In one aspect, the transplantation of the bacterial isolate in the intestine of the individual does not occur or occurs relatively inefficiently (e.g., in a patient) when the bacterial isolate is administered to the individual at a higher than a threshold dose. By way of example, to the intestinal bacteria isolated was the subject of the graft may be administered to an individual (e.g., the pharmaceutical compositions described herein are administered orally or rectally) the dose is not more than 10 ⁸ cells, not Occurs when there are bacterial isolates with more than 10 ⁹ cells, no more than 10 ¹⁰ cells, no more than 10 ¹¹ cells, or no more than 10 ^{12 cells.}

In one aspect, the dosage of one or more bacterial isolates for patients in need may be determined based on the transplantation threshold of the bacterial isolates.

In one aspect, the bacterial isolate in the pharmaceutical composition administered to the individual is transplanted into the duodenum of the individual. In one aspect, the bacterial isolate in the pharmaceutical composition administered to the individual is transplanted into the jejunum of the individual. In one aspect, the bacterial isolate in the pharmaceutical composition administered to the individual is transplanted into the ileum of the individual. In one aspect, the bacterial isolate in the pharmaceutical composition administered to the individual is transplanted into the colon of the individual.

In some aspects, the bacterial isolate is a non-pathogenic bacterial strain. In one aspect, the non-pathogenic bacterial strain contains a gene body that lacks genes or manifestations of virulence and/or toxicity. For example, in some aspects, a bacterial mixture containing one or more bacterial isolates is substantially free of organisms or entities capable of causing diseases or disorders in the individual to which the bacterial mixture is administered (e.g., substantially free of organisms or entities). Contains pathogenic bacteria).

In one aspect, bacterial isolates can be obtained from laboratory stock solutions or bacterial cell banks of bacterial strains originally obtained from stool samples from healthy human donors. For example, a fecal microbial phase (e.g., purified from a fecal sample using the methods described herein) can be used as the source of bacterial isolates incorporated into the pharmaceutical compositions described herein. In some aspects, all or part of the fecal microbial phase of the stool sample is cultured on a solid culture substrate and one or more bacterial isolates are identified as a single colony. In other aspects, all or part of the fecal microbial phase may be inoculated into a liquid culture to produce a mixed bacterial culture, and then the mixed bacterial culture may be serially diluted to produce a single cell culture containing bacterial isolates . In one aspect, the identified bacterial isolate can then be cultured (e.g., in a solid or liquid medium) and expanded using known techniques. Methods for isolating, purifying and/or culturing bacterial strains are described in Sadowsky et al., WO 2012/122478 and Borody et al., WO 2012/016287, each of which is incorporated herein by reference.

In one aspect, the pharmaceutical composition comprises an uncultured fecal bacterial preparation including, for example, non-selected fecal bacteria and/or feces or parts thereof (e.g., from a healthy human donor) substantially intact fecal microorganisms Phase of the bacterial mixture. As used herein, the term "substantially complete fecal microbial phase" refers to the unretained living bacterial cells containing all or substantially all of the bacterial taxa present in the living bacterial cells in the feces from which the fecal microbial phase is extracted. Cultured fecal bacteria preparation. In one aspect, the relative abundance of viable bacterial cells from at least two of the taxa in the substantially complete fecal microbial phase and the relative abundance of living cells from the taxa in the feces used to extract the fecal microbial phase The abundance is proportional. In one aspect, the bacterial mixture further includes one or more bacterial isolates. In one aspect, the bacterial mixture does not contain bacterial isolates.

In one aspect, the pharmaceutical composition comprises a mixture comprising, for example, an uncultured fecal bacterial preparation of non-selected fecal bacteria and/or feces or parts thereof (e.g., from a healthy human donor) substantially intact Fecal microbial phase and non-pathogenic fungal isolates. In another aspect, the relative abundance of living cells in the fungal isolate in the mixture is at least 5, 10, 20, 30, 40, or 50%. In another aspect, the present invention provides a pharmaceutical composition comprising a mixture comprising: (i) an uncultured fecal bacterial preparation derived from the feces of a human donor; and (ii) a non-pathogenic fungus Separation. In one aspect, the relative abundance of live cells in the fungal isolate in the mixture is greater than the relative abundance of live cells in any bacterial strain in the uncultured fecal bacterial preparation. In another aspect, the fungal isolate is a component of the species, and the fungal isolate is the only component of the species in the mixture. In another aspect, the uncultured fecal microorganism preparation does not include fungal strains that meet the following conditions: 16S rRNA sequences that have greater than 99% identity with the 16S rRNA sequence of the fungal isolate. In another aspect, the fungal isolate is transplanted into the ileum of an HBV or HDV subject to which the composition is administered.

In one aspect, the uncultivated fecal bacterial preparation contains a complete or substantially complete fecal microbial phase from a fecal sample of the donor. In one aspect, the uncultured fecal bacterial preparation contains a non-selective fecal microbial phase. In another aspect, the uncultivated fecal bacterial preparation comprises a population or community of isolated or purified live non-pathogenic fecal bacteria. In another aspect, the uncultured fecal bacterial preparation comprises a non-selective and substantially complete fecal microbial phase preparation from a single donor. In another aspect, the pharmaceutical composition used herein comprises a mixture of a live non-pathogenic bacterial isolate and a live non-pathogenic, purified or extracted uncultured fecal bacterial preparation.

In one aspect, the preparation of the uncultured fecal bacteria preparation involves treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonic treatment. In another aspect, the preparation of the uncultured fecal bacteria preparation does not involve treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonic treatment. In one aspect, the preparation of the uncultured fecal bacterial preparation involves a separation step selected from the group consisting of density gradient, filtration (e.g., sieve, nylon mesh), and chromatography. In another aspect, the preparation of the uncultured fecal bacteria preparation does not involve separation steps selected from the group consisting of density gradient, filtration (for example, sieve, nylon mesh), and chromatography. In another aspect, the uncultured fecal bacterial preparation contains a complete or substantially complete fecal microbial phase from a stool sample of the individual. In another aspect, the pharmaceutical composition administered herein comprises a fecal microbial phase that is substantially free of donor eukaryotic cells.

In one aspect, the pharmaceutical composition provided or administered herein comprises an uncultured fecal bacterial preparation with a agricultural diversity index greater than or equal to 0.3, greater than or equal to 0.4, greater than or equal to 0.5, greater than or equal to 0.6 , Greater than or equal to 0.7, greater than or equal to 0.8, greater than or equal to 0.9, greater than or equal to 1.0, greater than or equal to 1.1, greater than or equal to 1.2, greater than or equal to 1.3, greater than or equal to 1.4, greater than or equal to 1.5, greater than or equal to 1.6 , Greater than or equal to 1.7, greater than or equal to 1.8, greater than or equal to 1.9, greater than or equal to 2.0, greater than or equal to 2.1, greater than or equal to 2.2, greater than or equal to 2.3, greater than or equal to 2.4, greater than or equal to 2.5, greater than or equal to 3.0 , Greater than or equal to 3.1, greater than or equal to 3.2, greater than or equal to 3.3, greater than or equal to 3.4, greater than or equal to 3.5, greater than or equal to 3.6, greater than or equal to 3.7, greater than or equal to 3.8, greater than or equal to 3.9, greater than or equal to 4.0 , Greater than or equal to 4.1, greater than or equal to 4.2, greater than or equal to 4.3, greater than or equal to 4.4, greater than or equal to 4.5, or greater than or equal to 5.0. In another aspect, the pharmaceutical composition comprises a fecal microbial phase, and the agricultural diversity index of the fecal microbial phase is between 0.1 and 3.0, between 0.1 and 2.5, between 0.1 and 2.4, between 0.1 and 2.3 Between, between 0.1 and 2.2, between 0.1 and 2.1, between 0.1 and 2.0, between 0.4 and 2.5, between 0.4 and 3.0, between 0.5 and 5.0, between 0.7 and 5.0 Between 0.9 and 5.0, between 1.1 and 5.0, between 1.3 and 5.0, between 1.5 and 5.0, between 1.7 and 5.0, between 1.9 and 5.0, between 2.1 and 5.0 , Between 2.3 and 5.0, between 2.5 and 5.0, between 2.7 and 5.0, between 2.9 and 5.0, between 3.1 and 5.0, between 3.3 and 5.0, between 3.5 and 5.0, Between 3.7 and 5.0, between 31.9 and 5.0, or between 4.1 and 5.0. In one aspect, the Xiangnong Diversity Index is calculated at the gate level. In another aspect, the Xiangnong Diversity Index is calculated under the departmental standard. In one aspect, the Xiangnong Diversity Index is calculated under the genus level. In another aspect, the agricultural diversity index is calculated at the species level. In another aspect, the pharmaceutical composition includes a biota agent in a proportional content similar to that of normal healthy human fecal biota.

In another aspect, the pharmaceutical composition contains fecal bacteria from at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 different families. In another aspect, the pharmaceutical composition comprises fecal bacteria from at least 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 different families. In another aspect, the pharmaceutical composition comprises fecal bacteria from at least 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 different families. In another aspect, the pharmaceutical composition comprises fecal bacteria from at least 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 different families. In another aspect, the pharmaceutical composition comprises fecal bacteria from at least 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 different families. In another aspect, the pharmaceutical composition comprises between 1 and 10, between 10 and 20, between 20 and 30, between 30 and 40, between 40 Fecal bacteria of different families between 1 and 50. In one aspect, the pharmaceutical composition provided or administered herein includes an uncultured fecal bacterial preparation, and the fecal bacterial preparation contains no more than 0.05% by weight, 0.1% by weight, or 0.2% by weight based on the weight of the biological material. %, 0.3% by weight, 0.4% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6wt%, 7wt%, 8wt%, 9wt% or 10wt% of non-living substances. In another aspect, the pharmaceutical composition provided or administered herein contains an uncultivated fecal microbial phase, and the uncultivated fecal microbial phase contains no more than 20% by weight, 25% by weight based on the weight of the biological material. Weight%, 30% by weight, 35% by weight, 40% by weight, 45% by weight, 50% by weight, 55% by weight, 60% by weight, 65% by weight, 70% by weight, 75% by weight, 80% by weight, 85% by weight , 90% by weight or 95% by weight of non-living substances. In another aspect, the pharmaceutical composition provided herein or administered with it comprises, consists of, or consists essentially of: a sieve, exclusion, or particle filter with a size of 2.0 mm, 1.0 mm, 0.5 mm , 0.33 mm, 0.25 mm, 0.212 mm, 0.180 mm, 0.150 mm, 0.125 mm, 0.106 mm, 0.090 mm, 0.075 mm, 0.063 mm, 0.053 mm, 0.045 mm, 0.038 mm, 0.032 mm, 0.025 mm, 0.020 mm, 0.01 The non-living matter particles and/or biological matter particles of the fecal sample of the sieve, pipe column or similar filter device of mm or 0.002 mm. "Non-living substances" do not include excipients added to the treated fecal material, such as pharmaceutical inactive substances, such as cryoprotectants. "Biological material" refers to the living material in the fecal material and includes microorganisms, including prokaryotic cells such as bacteria and archaea (for example, living prokaryotic cells and spores that can form spores to become living prokaryotic cells), such as Eukaryotic cells and viruses of protozoa and fungi. In one aspect, "biological material" refers to living substances such as microorganisms, eukaryotic cells, and viruses that exist in the colon of normal healthy humans. In one aspect, the pharmaceutical composition provided or administered herein comprises a human fecal extract, wherein the composition is substantially odorless. In one aspect, the pharmaceutical composition provided or administered herein comprises a fecal material or a fecal biota preparation in a lyophilized, crude, semi-purified, or purified formulation.

In one aspect, the uncultured fecal bacterial preparation included in the pharmaceutical composition comprises, for example, highly refined or purified fecal biota that is substantially free of non-biological fecal material. In one aspect, the uncultured fecal microbial phase (including the uncultured fecal bacterial preparation) collected from the donor may be further processed, for example, to undergo microfiltration before, after, or before and after screening. In another aspect, the highly purified fecal microbial phase product is ultrafiltered to remove macromolecules, but retain the therapeutic microflora, such as bacteria.

In another aspect, the uncultured fecal bacterial preparation in the pharmaceutical composition used herein comprises or consists essentially of: substantially isolated or purified fecal biota or complete (or substantially complete) ), which is (or contains) at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7 %, 99.8% or 99.9% are separated or pure or have no more than about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more An isolate of a fecal biota material; or as described in Sadowsky et al., WO 2012/122478 A1 or as described in Borody et al., WO 2012/016287 A2, which is substantially separated, purified or substantially separated On the complete microbial phase.

In one aspect, the uncultivated fecal bacterial preparation included in the pharmaceutical composition comprises a substantially complete or non-selected fecal microbial phase of the donor. In another aspect, the fecal microbial phase in the pharmaceutical composition does not include antibiotic resistant populations. In another aspect, the pharmaceutical composition contains an uncultured fecal microbial phase and is mostly free of foreign materials (for example, including non-cellular materials such as residual fiber, DNA, RNA, virus coating materials, and non-biological materials). Non-living substances; and living substances such as eukaryotic cells from fecal material donors).

In one aspect, the uncultured fecal bacterial preparation included in the pharmaceutical composition is derived from a stool sample for disease screening from a human donor. In one aspect, the stool sample does not include antibiotic resistant populations. For example, the composition may comprise a live biota agent that may be in proportionate content, similar to a normal healthy human fecal biota that does not include antibiotic-resistant populations.

In one aspect, the uncultured fecal bacteria preparation described and used herein includes one or more, two or more, three or more, four or more selected from the group consisting of One or five or more live fecal microorganisms: Acidaminococcus , Akkermansia , Alistipes , Anaerotruncus , Bacteroides, Bifidobacterium, Blautia , Butyrivibrio , Clostridium spores, Collins, Coccus, Corynebacterium , Dallella, Enterococcus , Escherichia ), Eubacterium (Eubacterium), fecal coli (Faecalibacterium), Haemophilus (Haemophilus), Haldeman coli (Holdemania), lactic acid bacteria, Moraxella (Moraxella), Vice Bacteroides (Parabacteroides), Prairie Vortex , Propionibacterium , Raoultella, Roseburia, Rumenococcus , Staphylococcus , Streptococcus, Subdoligranulum and Vanyoung Coccus. In one aspect, the fecal microbial phase preparation comprises one or more, two or more, three or more, four or more, or five or more live feces selected from the group consisting of: Microorganisms: Bacteroides fragilis ssp. vulgatus , Collinsella aerofaciens , Bacteroides fragilis ssp. thetaiotaomicron , Peptostreptococcus productus II , Parabacteroides distasonis , Faecalibacterium prausnitzii , Coprococcus eutactus , Peptostreptococcus productus I, Ruminococcus bromii , Double Bifidobacterium adolescentis , Gemmiger formicilis , Bifidobacterium longum , Eubacterium siraeum , Ruminococcus torques , Eubacterium rectale , Eubacterium eligens , Bacteroides eggerthii , Clostridium leptum , Bacteroides fragilis ssp. A, Eubacterium biforme , infant Bifidobacterium infantis , Eubacterium rectum, Coprococcus comes , Pseudoflavonifractor capillosus , Ruminococcus albus , Dorea formicigenerans , Hodgkin Eubacterium hallii (Eubacterium hallii), Eubacterium ventriosum I (Eubacterium ventriosum I), Fusobacterium russi , Ruminococcus obeum , Eubacterium rectum, Clostridium ramosum , Lactobacillus leichmannii , Ruminococcus callidus ), Butyrivibrio crossotus , Acidaminococcus fermentans , Eubacterium ventriosum , Bacteroides fragilis ssp. fragilis , S. dexterous (Coprococcus catus), Hastelloy anaerobic corynebacteria (Aerostipes hadrus), a cylindrical Eubacterium (Eubacterium cylindroides), Eubacterium rumination (Eubacterium ruminantium), Staphylococcus epidermidis (Staphylococcus epidermidis), Eubacterium mucus (Eubacterium limosum), Tissierella praeacuta , Fusobacterium mortiferum I, Fusobacterium naviforme , Clostridium innocuum , Clostridium acnes, Propionibacterium acnes ( Propionibacterium acnes , Ruminococcus flavefaciens , Bacteroides fragilis ssp. ovatus , Fusobacterium nucleatum , Fusobacterium mortiferum , Escherichia coli ( Escherichia coli , Gemella morbillorum , Finegoldia magnus , Streptococcus intermedius , Ruminococcus lactaris , Eubacterium tenue ), Eubacterium ramulus , Bacteroides clostridiiformis ssp. clostridliformis , Bacteroides coagulans , Prevotella oralis , Rumen Prevo Bacteria ( Prevotella ruminicola ), Odoribacter splanchnicus and Desuifomonas pigra .

In one aspect, the fecal microbial phase preparation described and used herein does not have or substantially does not contain one or more, two or more, three or more, or four selected from the group consisting of: Or more or five or more live fecal microorganisms: Amino acid cocci, Akkermansia, other-like bacilli, anaerobic bacilli, Bacteroides, Bifidobacteria, Blautella, Vibrio butyricum Bacteria, Clostridium sporosphaeroides, Collins bacteria, Faecococcus, Corynebacterium, Dallella, Enterococcus, Escherichia, Eubacterium, Faebacterium, Haemophilus, Holdmania, Lactobacillus, Mora Bacteria, Parabacteroides, Prevotella, Propionibacterium, Raoultella, Rosella, Rumenococcus, Staphylococcus, Streptococcus, Rare Micrococcus, and Fanyon cocci. In one aspect, the fecal microbial phase preparation has no or substantially no one or more, two or more, three or more, four or more or five selected from the group consisting of Or more kinds of live fecal microorganisms: Bacteroides fragilis subsp. common, Collins aerogenes, Bacteroides fragilis subsp. polymorphous, Peptostreptococcus extensii II, Parabacteroides diundi, Faeculus praecox, Coccus regular, Strains Peptostreptococcus I, Rumencoccus brucellus, Bifidobacterium adolescentis, Bacillus formic acid, Bifidobacterium longum, Eubacterium inert, Rumencoccus twisted strand, Eubacterium rectum, Eubacterium fusiformis, Bacteroides escherichia, Clostridium vulgaris Bacteria, Bacteroides fragilis subspecies A, Eubacterium biformis, Bifidobacterium infantis, Eubacterium rectum, Accompany faecalis, Pseudoflavonoids pluvialis, Rumencoccus albicans, Dallella long-chain, Eubacterium hosei, Convex Eubacterium I, Clostridium lavendere, Rumenococcus ovale, Eubacterium rectum, Clostridium polymycosporum, Lactobacillus Leichmannii, Clever Rumenococcus, Vibrio spike butyricum, Acidococcus spiculata, Eubacterium bulgingis, Bacteroides fragilis subsp. fragilis, Faecoccus dexterous, Anaerobic Corynebacterium harveyi, Eubacterium cylindrica, Eubacterium ruminant, Staphylococcus epidermidis, Eubacterium mucin, Typhimurium extreme, Clostridium dysentum Bacteria I, Clostridium naviculare, Clostridium innocuous, Clostridium polycladi, Propionibacterium acnes, Rumenococcus chrysogenum, Bacteroides fragilis subsp. ovale, Clostridium nucleus, Clostridium nucleatum, Clostridium dead, Escherichia coli , Geminicoccus measles, Fingoldiella, Streptococcus intermedius, Rumencoccus yoghurt, Eubacterium gracilis, Mycobacterium mycobacterium, Bacteroides fusiformis subsp. fusiformis, Bacteroides coagulans, Oral Prevotella, rumen roosting Prevotella, Odreella viscera and Desulfovibrio inert.

In one aspect, the uncultured fecal bacteria preparation for incorporation into the pharmaceutical composition comprises one or more, two or more, three or more, or four or more selected from the group consisting of: More non-pathogenic spores of Clostridium species: Clostridium absonum , Clostridium argentinense , Clostridium baratii , Clostridium botulinum , Clostridium cadaveris , Clostridium carnis , Clostridium celatum , Clostridium chauvoei , Clostridium clostridioforme , spatulate Clostridium (Clostridium cochlearium), Juezha Clostridium (Clostridium fallax), Virginia fee of Clostridium (Clostridium felsineum), Ge apos Clostridium (Clostridium ghonii), ethylene glycol Clostridium (Clostridium glycolicum , Clostridium haemolyticum , Clostridium hastiforme , Clostridium histolyticum , Clostridium indolis , Clostridium irregulare ), Clostridium limosum , Clostridium malenominatum , Clostridium novyi , Clostridium oroticum , Clostridium paraputrificum ), Clostridium perfringens , Clostridium piliforme , Clostridium putrefaciens , Clostridium putrificum , Sardinia spore Clostridium sardiniense , Clostridium sartagoforme , Clostridium scindens , Clostridium septicum , Clostridium sordellii, Clostridium cuneiformis Clostridium sphenoides , Clostridium spiroforme , Clostridium sporogenes , Clostridium subterminale , Clostridium symbiosum , Clostridium tertium ), Clostridium tetani , Clostridium welchii and Clostridium villosum . In one aspect, the pharmaceutical composition comprises one or more, two or more, three or more, or four or more non-pathogenic Bacteroides species selected from the group consisting of: Bacteroides faecalis ( Bacteroides coprocola ), Bacteroides plebeius , Bacteroides massiliensis , Bacteroides vulgatus , Bacteroides helcogenes , Bacteroides pyogenes , Bacteroides cryptica ( Bacteroides tectus , Bacteroides uniformis , Bacteroides stercoris , Bacteroides eggerthii , Bacteroides finegoldii , Bacteroides thetaiotaomicron , Oval Bacteroides (Bacteroides ovatus), acid generator Bacteroides (Bacteroides acidifaciens), fecal Bacteroides (Bacteroides caccae), Nuti Bacteroides (Bacteroides nordii), Sally's Wells Bacteroides (Bacteroides salyersiae), Bacteroides fragilis (Bacteroides fragilis , Bacteroides intestinalis , Bacteroides coprosuis , Bacteroides distasonis , Bacteroides goldsteinii , Bacteroides merdae , Forsyth Bacteroides forsythus , Bacteroides splanchnicus , Bacteroides capillosus , Bacteroides cellulosolvens and Bacteroides ureolyticus .

In one aspect, the pharmaceutical composition comprises live non-pathogenic Clostridium spp Non-pathogenic microorganisms. In another aspect, the pharmaceutical composition comprises a plurality of live non-pathogenic species from one or more genera selected from the group consisting of Clostridium spores, Collins bacteria, Coccus faecalis, Dallella, Eubacteria, and Rumenococcus microorganism.

In one aspect, the pharmaceutical composition includes two or more genera selected from the group consisting of Collins, Faecococcus, Dallella, Eubacterium, and Rumenococcus. In another aspect, the pharmaceutical composition comprises two or more genera selected from the group consisting of faecalis, Dallella, Eubacterium, and Rumenococcus. In another aspect, the pharmaceutical composition comprises one or more, two or more, three or more, four or more, or five or more selected from the group consisting of Species: Faecoccus dexteroides , Faecoccus accompaniment, Dallella long-chain, Eubacterium fusiformis, Eubacterium hadrum (Eubacterium hadrum), Eubacterium hosei, Eubacterium rectum, and Gastrococcus twisted strand.

In one aspect, the uncultured fecal bacteria preparation described herein comprises living cells from the 100% viable bacterial taxa present in the feces from which the fecal bacteria are derived. In one aspect, the uncultivated fecal bacterial preparation described herein comprises living cells from at least 99% of the viable bacterial taxa present in the feces from which the fecal bacteria are derived. In one aspect, the uncultured fecal bacteria preparations described herein comprise viable cells from at least 98% of the viable bacterial taxa present in the feces from which the fecal bacteria are derived. In one aspect, the uncultured fecal bacteria preparation described herein comprises living cells from at least 97% of the taxa of live bacteria present in the feces from which the fecal bacteria are derived. In one aspect, the uncultured fecal bacteria preparation described herein contains living cells from 96% of the viable bacterial taxa present in the feces from which the fecal bacteria are derived. In one aspect, the uncultured fecal bacteria preparation described herein contains at least 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 85%, 84%, 83%, 82%, 81%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% Living cells of the taxa of living bacteria.

In one aspect, the pharmaceutical composition disclosed herein includes a sterile fecal filter or a non-cellular fecal filter. In one aspect, the sterile fecal filter is derived from donor feces. In another aspect, the sterile fecal filter is derived from cultured microorganisms. In another aspect, the sterile fecal filter contains non-cellular, non-particulate fecal components. In one aspect, a sterile fecal filter is manufactured as described in WO2014/078911 published on May 30, 2014. In another aspect, as described in Ott et al., Gastroenterology 152:799-911 (2017), a sterile fecal filter is produced.

In one aspect, the fecal filtrate contains secreted, excreted, or other liquid components or microbial phases, such as biologically active molecules (BAM), which can be antibiotics or anti-inflammatory agents, and are preserved, retained, or preserved in biota extracts. recovery.

In one aspect, an exemplary pharmaceutical composition comprising a fecal filter includes a starting material from a donor from an established donor pool, wherein this donor contributes feces, the feces are homogenized and centrifuged, and then used, for example, with a metal sieve It is filtered by a very high level filtration through a sub or Millipore filter or equivalent method to finally allow retention of only bacteria-derived cells, for example, which are usually less than about 5 microns in diameter. After the initial centrifugation, the solid material can be separated from the liquid, and then, for example, using Millipore filtration and optionally also including the use of nanomembrane filtration to filter the solids in gradually decreasing size filters and tangential filters. Filtration can also be performed as described in WO 2012/122478, but in contrast, using a sieve of less than 0.0120 mm to about 0.0110 mm is performed by sieving, which ultimately results in the presence of only bacterial cells.

In some aspects, the separated supernatant during centrifugation can be gradually filtered in, for example, a Millipore filtration or equivalent system filtration to produce a liquid that is finely filtered through an approximately 0.22 micron filter. This removes all particulate matter including all living matter including bacteria and viruses. Subsequently, the product is sterile, but the goal is to remove the bacteria, but retain its secretions, especially including the following antimicrobial bacteriocins, bacterial-derived cytokines-like products and all accompanying biologically active molecules (BAM): Su Yunjin Thuricin (which is secreted by bacilli in the feces of the donor), bacteriocins (including colicin, troudulixine or putaindicine or microcin) Or subtilisin A), lantibiotics (including nisin, subtilin, epidermin, mutacin, mersacidin, akaga (Actagardine), cinnamycin (cinnamycin), nisin and other anti-microbial or anti-inflammatory compounds.

In one aspect, the pharmaceutical composition comprises a reconstituted fecal biota consisting essentially of a combination of a purified fecal microbial phase (including an uncultured fecal bacterial preparation) and a non-cellular fecal filter. In another aspect, the pharmaceutical composition comprises a purified fecal microbial phase (comprising an uncultured fecal bacterial preparation) supplemented with one or more non-cellular, non-granular fecal components. In one aspect, the pharmaceutical composition includes one or more non-cellular, non-granular stool components. In one aspect, the one or more non-cellular, non-granular fecal components comprise synthetic molecules, biologically active molecules produced by fecal microorganisms, or both. In another aspect, one or more non-cellular non-granular fecal components include biologically active proteins or peptides, micronutrients, fats, sugars, small carbohydrates, trace elements, mineral salts, ash, mucus, amino acids, Nutrients, vitamins, minerals or any combination thereof. In one aspect, the one or more non-cellular non-granular fecal components comprise one or more biologically active molecules selected from the group consisting of bacteriocins, lantibiotics, and nisin. In another aspect, the one or more non-cellular non-particulate fecal components include one or more selected from the group consisting of colistin, tedulin, pratadisine, microcin and subtilisin A Bacteriocins. In one aspect, the one or more non-cellular non-granular fecal components are selected from the group consisting of thuringicin, nisin, subtilisin, fibrin, mutanin, medicidin, acagardine and cinnamon One or more of the group consisting of lantibiotics. In another aspect, the one or more non-cellular non-particulate fecal components comprise anti-spore compounds, anti-microbial compounds, anti-inflammatory compounds, or any combination thereof. In another aspect, the one or more non-cellular non-particulate fecal components comprise interleukin, cytokine, leukotriene, eicosanoid, or any combination thereof.

In another aspect, the pharmaceutical composition includes uncultured fecal bacterial preparations that partially or completely represent the human GI microbial phase and the biota (microbial phase) separated, processed, filtered, concentrated, and Reconstituted and/or artificial liquid components (for example, fecal filtration), the liquid components in particular contain, among other components, secretory products of bacteria such as the following: bacteriocins (protein toxins produced by bacteria, including colicins, Tedurisine or Protadesine or microcin or subtilisin A), lantibiotic (a peptide antibiotic that contains the characteristic polycyclic thioether amino acid lanthionine or methyllanthionine) And unsaturated amino acids dehydroallanine and 2-aminoisobutyric acid; which include thuringicin (which is secreted by the bacillus in the donor feces), nisin, subtilisin, fibrin, and mutated chain , Medicidin, acagardine, cinnamycin), nisin (pore-forming peptide toxin family) and other anti-microbial or anti-inflammatory compounds and/or produced by bacteria or other microorganisms in the microbial phase and/or in Other biologically active molecules (BAM) found in the "liquid components" of the microbial phase.

In one aspect, a pharmaceutical composition containing an uncultured fecal bacterial preparation is used in parallel with a pharmaceutical composition based on a non-cell filter of feces. In another aspect, the patient is treated with a first pharmaceutical composition based on a fecal non-cell filter, followed by administration of a second pharmaceutical composition comprising an uncultured fecal bacterial preparation, or vice versa. In another aspect, the treatment method includes three steps: first, pretreatment with antibiotics for non-selective removal of one or more infectious pathogens; second, used to further inhibit the selected one or more infections Treatment steps for sexual pathogens based on fecal non-cell filters; and thirdly, treatment with pharmaceutical compositions containing uncultured fecal bacteria preparations for the reconstruction of functional intestinal microflora.

In one aspect, the administration of a composition comprising a bacterial mixture containing an uncultured fecal bacterial preparation to an individual (e.g., HBV or HDV patient) is based on the use of bacterial cells from the bacterial mixture administered to the individual’s intestines The endogenous bacterial cells of the biological cluster are replaced to achieve the cure, alleviation of symptoms, or the percentage of alleviation of symptoms. The change in the biota can be as "almost complete" as possible. Generally, changes in the intestinal biota include the introduction of an array of biotas derived from the feces of healthy human donors into the gastrointestinal system of the individual, which can substantially or completely replace patients in need of such treatments (for example, HBV or HDV patients) The pathogenic intestinal flora.

The pharmaceutical composition described herein may include microorganisms, such as bacteria, derived from a stool sample of a donor (eg, a healthy human donor). In one aspect, the composition incorporates an uncultured fecal bacterial preparation derived from all or part of the fecal microbial phase of a stool sample from a healthy human donor. For example, the composition may incorporate a substantially complete fecal microbial phase of a stool sample from a healthy human donor. In one aspect, the composition incorporates a bacterial isolate of the fecal microbial phase, wherein the bacterial isolate has been purified and/or cultured from all or part of the fecal microbial phase of a stool sample from a healthy human donor. Therefore, the collection, extraction and/or purification of the fecal microbial phase from the fecal sample can be performed to prepare a composition containing at least one of an uncultured fecal bacterial preparation or bacterial isolate.

In one aspect, an exemplary fecal microorganism used to prepare the composition described herein (e.g., a bacterial mixture containing one or more of an uncultured fecal bacterial preparation and at least one bacterial isolate) The phase contains starting material from a human donor. In another aspect, the exemplary faecal microbial phase includes material from one or more healthy human donors. In another aspect, the exemplary faecal microbial phase contains starting material from a known, established donor pool. In another aspect, the donor is an adult male. In another aspect, the donor is an adult female. In another aspect, the donor is a young male. In another aspect, the donor is a young female. In another aspect, the donor is a female infant. In another aspect, the donor is a male child. In another aspect, the donor is healthy. In one aspect, the human donor is a child less than about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In another aspect, the human donor is an elderly individual. In another aspect, the human donor is an individual who is greater than about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old. In another aspect, the donor is between 1 and 5 years old, between 2 and 10 years old, between 3 and 18 years old, between 21 and 50 years old, between 21 and 40 years old. Between the ages of, between 21 and 30, between 50 and 90, between 60 and 90, between 70 and 90, between 60 and 80, or between Between 65 and 75 years old. In one aspect, the donor is a young, elderly individual (65-74 years old). In one aspect, the donor is a moderately elderly individual (75-84 years old). In one aspect, the donor is an elderly individual (>85 years old). In another aspect, the donor is a human being in a healthy general neurological state that has been carefully screened.

In one aspect, the fecal donor is pre-screened for its fecal microbial community profile. In another aspect, the fecal donor is selected for the presence of one or more classes, families, genera, or species of fecal bacteria in the feces of the donor. In another aspect, the fecal donor is selected for one or more classes, families, genera, species, or strains of fecal bacteria that are present in the feces of the donor at a content above the threshold abundance. In one aspect, it can be based on one or more bacterial genera selected from the group consisting of Lactobacillus, Bifidobacterium, Streptococcus, Prevotella, Desulfovibrio and combinations thereof. Existence or critical abundance in the selection of fecal donors. In one aspect, it can be based on one or more bacteria selected from the group consisting of Clostridium spores, Bacteroides, Eggerthella, Bifidobacterium, Prevotella, Desulfovibrio, and combinations thereof The fecal donor is selected based on the presence or threshold abundance in the feces of the donor. In one aspect, it can be based on one or more bacterial taxa selected from the group consisting of Prevotella, Faecococcus, Prevotaceae, Fanyon Coccus, and combinations thereof in the feces of the donor. Existence or threshold abundance to select fecal donors. In one aspect, the fecal donor may be selected based on the presence or threshold abundance of one or more bacterial genera selected from the group consisting of Lactobacillus, Bifidobacterium, Streptococcus, and combinations thereof.

In one aspect, a stool sample can be selected as an uncultured sample for incorporation into a pharmaceutical composition based on the presence or threshold abundance of one or more classes, families, genera, species, or strains of bacteria in the stool sample The source of fecal bacteria preparations. In one aspect, the stool sample may be selected based on the presence or threshold abundance of members of the bacterial genus selected from the group consisting of Lactobacillus, Bifidobacterium, Streptococcus, and combinations thereof.

An uncultured fecal bacterial preparation extracted from the feces of a donor selected based on the presence or abundance of one or more bacterial genera, species, or strains can be directly incorporated into the pharmaceutical composition described herein without adding to the preparation Any bacterial isolate is added, or alternatively, a bacterial isolate of the same genus, species, or strain as the genus, species, or strain on which the selection is based may be added.

In one aspect, compared with the relative fecal abundance of bacterial genera, species or strains in the absence of probiotics and/or probiotics ingestion, the fecal donor promotes bacterial genera, species or strains through ingestion. The probiotics and/or probiotics that the strains proliferate in the donor’s digestive tract have a higher relative fecal abundance of bacterial genus, species or strains.

In another aspect, the donor receives or ingests certain probiotics such as fructo-oligosaccharides, inulin, barley probiotics or another dietary fiber before fecal feeding. In another aspect, the donor receives or ingests the growth stimulant for the selected fecal bacteria before performing the fecal supply. In another aspect, before performing fecal supply, the donor receives or ingests one or more of apple pectin, N-acetylglucosamine, cysteine, glutathione, riboflavin, and flavin .

In one aspect, a carefully screened donor undergoes a comprehensive medical history and physical examination. If the donor is at risk of infection, it is excluded. Other exclusion criteria include the following: 1. Known viral infections caused by hepatitis B, hepatitis C or HIV. 2. Known exposure to HIV or viral hepatitis at any time. 3. High-risk behaviors, including sexual behavior due to drugs or money, sexual behavior between men and men, more than one sexual partner in the previous 12 months, any past use of intravenous drugs or intranasal cocaine, and a history of claustrophobia. 4. Tattoos or body piercings within 12 months. 5. The risk of diarrhea for travelers to travel to the United States is higher than that for travel to the United States. 6. Current infectious diseases that can be broadcast, such as upper respiratory tract viral infections. 7. History of irritable bowel syndrome. Specific symptoms can include frequent abdominal cramps, excessive gas, bloating, enlarged abdomen, urgency, diarrhea, and constipation. 8. History of inflammatory bowel disease such as Crohn's disease, ulcerative colitis, and microscopic colitis. 9. Chronic diarrhea. 10. Chronic constipation or use of laxatives. 11. History of gastrointestinal malignancies or known colonic polyps. 12. A history of any abdominal surgery such as gastric bypass, bowel resection, appendectomy, cholecystectomy, etc. 13. Use probiotics or any other non-prescription additives used by potential donors for the purpose of regulating digestion. Yogurt and kefir products that are only allowed to be taken as food and not as nutritional supplements. 14. Antibiotics used for any indication within the first 6 months. 15. Any prescription immunosuppressive or anti-neoplastic drugs. 16. An established or newly emerging metabolic syndrome. The criteria used for definitions in this article are stricter than any established criteria. Metabolic syndrome includes a history of hypertension, diabetes, or glucose intolerance. 17. Known systemic autoimmunity such as connective tissue disease and multiple sclerosis. 18. Known atopic diseases including asthma or eczema. 19. Chronic pain syndrome including muscle fiber pain and chronic fatigue syndrome. 20. Continuous (even intermittent) use of any prescription drugs including inhalants or topical creams and ointments. 21. Including autism, Parkinson's disease (Parkinson's disease) neurological, neurodevelopmental and neurodegenerative disorders. 22. Comprehensive. Body mass index> 26 kg/m ² , central obesity defined by waist-to-hip ratio> 0.85 (male) and> 0.80 (female). 23. Blood pressure> 135 mmHg systolic blood pressure and> 85 mmHg diastolic blood pressure. 24. Skin-rash, tattoo or body piercing or jaundice that occurred within one year. 25. Enlarged lymph nodes. 26. Wheezing during auscultation. 27. Skin erythema due to hepatomegaly or liver disease. 28. Joint swelling or tenderness. Muscle weakness. 29. Abnormal nerve examination. 30. Toxin B of Clostridium difficile feces by PCR test positive. 31. For the positive stool culture of any of the conventional pathogens including Salmonella, Shigella, Yersinia, Campylobacter, and Escherichia coli 0157:H7. 32. Examination of abnormal eggs and parasites. 33. Positive antigens of Giardia, Cryptosporidium or Helicobacter pylori. 34. Positive screening for any viral diseases including HIV 1 and 2, A viral hepatitis IgM, hepatitis surface antigen and nuclear Ab. 35. Abnormal RPR (syphilis screening). 36. Tests for any abnormal liver function including alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase. 37. High serum triglycerides >150 mg/Dl. 38. HDL cholesterol <40 mg/dL (male) and <50 mg/dL (female). 39. High sensitivity CRP>2.4 mg/L. 40. High fasting plasma glucose (>100 mg/dL)

In one aspect, methods for collecting and processing stool samples to produce uncultured fecal bacterial preparations and/or one or more bacterial isolates are provided herein. The method can include first collecting a stool sample from one or more healthy (e.g., screened) donors. In one aspect, fresh feces are transported via a fecal collection device, which may provide or contain a suitable container that is oxygen-free (or substantially oxygen-free). In one aspect, the container can be made free of oxygen by, for example, incorporating a built-in or clip-on oxygen scavenging mechanism (such as oxygen scavenging pellets, as described in, for example, US Patent No. 7,541,091) into the container . In another aspect, the container itself is made of oxygen scavenging material such as oxygen scavenging iron (such as described by O2BLOCKTM) or equivalent. The container uses purified and improved layered clay as the oxygen scavenging iron performance Enhanced carrier; active iron is directly dispersed in the polymer. In one aspect, the oxygen scavenging polymer is used to manufacture the container itself or to coat the container, or as a pellet to be added; for example, as described in U.S. Patent Application Publication 20110045222 (herein incorporated by reference in its entirety) Description, the case describes polymer blends with the following: one or more unsaturated olefin homopolymers or copolymers; one or more polyamide homopolymers or copolymers; one or more polyethylene terephthalate Ester homopolymers or copolymers; these polymer blends exhibit oxygen scavenging activity. In one aspect, the oxygen scavenging polymer is used to manufacture the container itself or to coat the container, or as a pellet to be added; for example, as described in U.S. Patent Application Publication 20110008554 (herein incorporated by reference in its entirety) Description: This case describes a composition comprising polyester, copolyester ether and an oxidation catalyst, wherein the copolyester ether contains a polyether segment containing poly(tetramethylene-co-alkylene ether). In one aspect, the oxygen scavenging polymer is used to manufacture the container itself or to coat the container, or as pellets to be added; for example, as described in U.S. Patent Application Publication No. 201000255231 (herein incorporated by reference in its entirety) Description: The case describes dispersed iron/salt particles in a polymer matrix and an oxygen scavenging membrane with oxygen scavenging particles.

Alternatively, in addition to or instead of the oxygen scavenging mechanism, the air in the container can be replaced (completely or substantially) with nitrogen and/or one or more other inert non-reactive gases. In one aspect, the container partially, substantially or completely simulates (establishes) an anaerobic environment.

In one aspect, the stool (e.g., a stool sample) is kept in a container that does not leak and emit no smell, but maintains an anaerobic environment that is aesthetically acceptable. In one aspect, the container is sterile before containing the fecal biota.

In one aspect, the stool samples provided herein are maintained at room temperature during most or all of their transportation and/or storage at, for example, a "fecal storage". For example, once it is delivered to the "feces processing warehouse", it is stored at an ambient temperature such as room temperature. In one aspect, a stabilizer such as glycerol is added to the collected and/or stored material.

In one aspect, as described above, the stool is tested for various pathogens. In one aspect, once the infectious agent is eliminated, the stool sample is homogenized and filtered to remove large material particles. In one aspect, the stool is subdivided into required volumes, for example, the required volumes may be between 5 cubic centimeters and 3 liters or more. For example, in one aspect, the container contains 50 grams (g) of feces, and the feces can be kept in a suitable oxygen resistant plastic such as metalized polyethylene terephthalate polyester film or metalized MYLARTM.

In one aspect, the stool undergoes homogenization by, for example, mixing, agitating, stirring, or shaking. In some aspects, the stool sample is diluted with a homogenization buffer before homogenization. The homogenization buffer may, for example, contain a cryoprotectant (for example, trehalose), an antioxidant or reducing agent (for example, cysteine), and a buffer (for example, 0.25X PBS at pH 7.4).

In one aspect, in order to separate the non-bacterial components from the fecal microorganisms, the feces can be homogenized from the coarse particulate matter and filtered. In one aspect, the fibers/non-biological materials are then separated from the bacteria under the microscope. Several methods can be used, including, for example, repeated filtration with filter sizes, such as gradually reducing to the size of typical bacteria.

In one aspect, different filters or techniques such as those used by Williams in WO 2011/033310A1 (herein incorporated by reference in its entirety) are used to isolate bacterial species. Coarse filtration technology.

In one aspect, the filtration procedure for filtering intact feces is suitably used to achieve the highest concentration of almost 100% bacteria. In one aspect, the filtration procedure is a two-step procedure that appropriately uses a glass fiber depth filter for initial clarification. In one aspect, the stool is filtered under positive pressure. In one aspect, this should be done using a combination or sandwich configuration with 30 micron PVDF filters. In one aspect, this interlayer procedure should filter the product under positive pressure. Subsequently, in one aspect, membrane concentration can be used as another step to reduce the volume of the filtrate. In one aspect, this can be done before freeze drying or spray drying under nitrogen blanketing.

Alternative membranes that can be used for filtration include (but are not limited to) nylon filters, nitrocellulose filters, PES filters, polytetrafluoroethylene (PTFE) filters, TEFLON™ filters, mixed cellulose Ester filter, polycarbonate filter, polypropylene filter, polyvinyl chloride (PVC) filter or quartz filter. Various combinations of these filters can be used to achieve high purity bacteria while removing solids and liquids. Pharmaceutical composition, formulation and administration

A pharmaceutical composition comprising a bacterial mixture in various formulations described herein, the bacterial mixture comprising an uncultured fecal bacterial preparation and/or one or more bacterial isolates. Any of the pharmaceutical compositions described herein can be in the form of tablets, pills, pellets, capsules, liquid-containing capsules, multi-particulate capsules, powders, solutions, emulsions, drops, suppositories, emulsions, aerosols, sprays, suspensions Liquid, delayed-release formulations, sustained-release formulations, controlled-release formulations or any other forms suitable for use.

The formulation containing the pharmaceutical composition may suitably be presented in unit dosage form. For example, the dosage form can be prepared by a method that includes the step of associating the therapeutic agent with a carrier that constitutes one or more accessory ingredients. For example, the formulation is achieved by uniformly and intimately associating the therapeutic agent with a liquid carrier, a finely powdered solid carrier, or both, and then shaping the product into the dosage form of the desired formulation as needed (e.g. , Wet or dry granulation, powder blending, etc., followed by pressing) to prepare.

In another aspect, a pharmaceutical composition and a pharmaceutically acceptable carrier can be provided. As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant or a pharmaceutical composition mixed with live bacteria to allow the formation of, for example, a dosage form that can be administered to a patient Other materials. The pharmaceutically acceptable carrier may be a diluent, adjuvant, excipient, or acid-resistant encapsulated ingredient in liquid (for example, physiological saline), gel or solid form. Suitable diluents and excipients include pharmaceutical grade physiological saline, dextrose, glycerin, mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like, and combinations thereof. In another aspect, the pharmaceutical composition may contain auxiliary substances such as wetting or emulsifying agents, stabilizers or pH buffering agents. In one aspect, the pharmaceutical composition contains about 1%-5%, 5%-10%, 10%-15%, 15-20%, 20%-25%, 25-30%, 30-35%, 40-45%, 50%-55%, 1%-95%, 2%-95%, 5%-95%, 10%-95%, 15%-95%, 20%-95%, 25%- 95%, 30%-95%, 35%-95%, 40%-95%, 45%-95%, 50%-95%, 55%-95%, 60%-95%, 65%-95% , 70%-95%, 45%-95%, 80%-95% or 85%-95% active ingredients. In one aspect, the pharmaceutical composition contains about 2%-70%, 5%-60%, 10%-50%, 15%-40%, 20%-30%, 25%-60%, 30%- 60% or 35%-60% active ingredients.

In one aspect, the pharmaceutical composition may be incorporated into a lozenge, bolus liquid, bolus, capsule, premix, or patch. The formulation of these active ingredients into such dosage forms can be achieved by methods well known in the pharmaceutical formulation technology. See, for example, U.S. Patent No. 4,394,377. Filling gelatin capsules with any desired form of the active ingredient is easy to produce capsules. If necessary, for the convenience of filling the capsules, these materials can be diluted with inert powdered diluents such as sugar, starch, powdered milk, purified crystalline cellulose or the like to increase the volume.

In one aspect, in order to prepare a solid composition such as a lozenge, the active ingredient is combined with, for example, conventional lozenge ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate). , Dicalcium phosphate or gel) or other pharmaceutical diluents such as water to form a solid pre-formulated composition containing a homogeneous mixture of the composition described herein. When it is mentioned that these pre-formulated compositions are homogeneous compositions, it means that the active ingredients can be uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms, such as lozenges, pills, and capsule. Then, this solid pre-formulated composition is subdivided into a desired amount of active ingredients (for example, at least about 10 ⁵ , 10 ⁶ , 10 ⁷ , 10 ⁸ , 10 ⁹ , 10 ¹⁰ , 10 ¹¹ , 10 ¹² or 10 ¹³ CFU) is a unit dosage form of the type described above. The pharmaceutical compositions described herein can be flavored.

In one aspect, a pharmaceutical composition comprising the bacterial mixture described herein (and optionally one or more other therapeutic agents) is formulated into a composition suitable for the mode of administration described herein.

In various aspects, the pharmaceutical composition is administered orally, intravenously, intraperitoneally, and parenterally. For example, the route of administration includes, but is not limited to, oral, intraperitoneal, intravenous, intramuscular, or transrectal. In various aspects, the administration of the pharmaceutical composition is carried out via oral, nasogastric, antegrade gastrointestinal, retrograde gastrointestinal, endoscopic or enemic.

In one aspect, the pharmaceutical composition described herein may be formulated as a composition suitable for oral administration. The composition for oral delivery may, for example, be in the form of lozenges, lozenges, aqueous or oily suspensions, granules, powders, sprays, emulsions, capsules, syrups or elixirs. Compositions for oral administration may contain one or more agents, such as sweeteners, such as fructose, aspartame or saccharin; flavoring agents such as peppermint, wintergreen oil; or cherry; coloring agents; and Preservatives to provide medicinal palatable preparations. In addition, in the case of a lozenge or pill form, the composition may be coated to delay disintegration, so as to provide continuous delivery of the bacterial mixture over an extended period of time. The selectively permeable membrane surrounding the osmotically active agent is also suitable for oral administration of the composition. In these latter platforms, the fluid from the environment surrounding the capsule is absorbed by the driving compound, causing it to expand to displace the drug or drug composition through the orifice. Compared to the incorporation profile of immediate-release formulations, these delivery platforms can provide a substantially zero-level delivery profile. Time delay materials such as glyceryl monostearate or glyceryl stearate may also be suitable. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, ethacrylic acid and its derivative polymers, and magnesium carbonate. In one aspect, the excipient is pharmaceutical grade. In addition to the active compound, the suspension may also contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, Scutellaria, etc. and their mixtures.

In various aspects, the pharmaceutical composition is formulated into solid dosage forms such as tablets, dispersible powders, granules or capsules. In one aspect, the pharmaceutical composition is formulated as a capsule. In another aspect, the pharmaceutical composition is formulated as a lozenge. In another aspect, the pharmaceutical composition is formulated as a soft gel capsule. In another aspect, the pharmaceutical composition is formulated as a gelatin capsule.

In one aspect, the pharmaceutical composition is in the following form: an enema composition that can be reconstituted with a suitable diluent; an enteric-coated capsule; an enteric-coated microcapsule; an acid-resistant tablet; an acid-resistant capsule ; Acid-resistant microcapsules; powders for rehabilitation with appropriate diluents for nasal and enteral infusion or colonoscopy; powders for rehabilitation with appropriate diluents, flavors and gastric acid inhibitors for oral ingestion; with food or drink Powders for reconstitution; or foods or food supplements, powders, jellies or liquids containing enteric coating and/or acid-resistant microcapsules containing the composition.

In one aspect, the pharmaceutical composition described herein is formulated in the form of microcapsules. Microencapsulation is to coat liquid or solid with a protective wall material that inhibits volatilization and prevents chemical deterioration. The solid or liquid contained in the wall material is called the core, and the completely microencapsulated particles are called microcapsules. The wall materials that can be used herein include gum arabic, carboxymethyl cellulose, alginate, gelatin, whey protein, sodium casein and soy protein.

In one aspect, (a) an uncultured fecal bacterial preparation and (b) a mixture of one or more bacterial isolates are jointly encapsulated in the same microcapsule pool and administered to the individual. In another aspect, the uncultured fecal bacterial preparation and one or more bacterial isolates are microencapsulated separately and separated (e.g., sequentially) or together (e.g., having different encapsulated contents when mixed After the microcapsule) is administered to the individual. In another aspect, according to the desired ratio or ratio of each of the bacterial isolates, the bacteria from each of the different bacterial isolates are separately microencapsulated and then the resulting microcapsules are mixed together for administration to the individual (With or without separate microcapsules containing uncultured fecal bacteria preparations).

Microencapsulation can be performed with microencapsulation devices including microfluidic droplet generation or encapsulation devices. Exemplary microencapsulation devices are described in, for example, US Patent No. 7,482,152, which is incorporated herein by reference in its entirety. The microcapsules may contain one or more stabilizers or gelling agents that can be used to stabilize the microcapsules or emulsions. The stabilizer or gelling agent may include, but is not limited to, alginate (and algin or alginic acid) and agar. Alginates can include (but are not limited to) various forms of inorganic salts such as sodium alginate, potassium alginate, calcium alginate and combinations thereof. Alginate can be derived from, for example, seaweed (e.g., Macrocystis pyrifera, Ascophyllum nodosum, Laminaria spp.) or bacteria (e.g., Pseudomonas spp.) , Azotobacter spp. (Azotobacter spp.)) source. Cross-linking agents or solutions such as calcium chloride can be used to stabilize or gel the microcapsules. In one aspect, alginate-based microcapsules are manufactured according to US20160317583 and used. In one aspect, the concentration of the alginate polymer is about 2.5% (w/v), where the microcapsules include an additional continuous outer surface coating of poly-L-lysine. In another aspect, the microcapsules contain divalent cations from the group of calcium or barium or a mixture of calcium and barium to crosslink the alginate polymer into microcapsules.

The microcapsules can be characterized by size (for example, diameter). The size of the microcapsules can be about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mm. The size of the microcapsules can be less than or equal to about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mm. The size of the microcapsules can be greater than or equal to about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mm. The size of the microcapsules can be from about 0.05 to about 1 mm. The size distribution in the population of microcapsules can be uniform or substantially uniform. For example, the microcapsule population can be characterized by less than or equal to about 20, 19, 18, 17, 16, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4.9 , 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4 , 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.14, 1.13, 1.12, 1.11, 1.10, 1.09, 1.08, 1.07, 1.06 , 1.05, 1.04, 1.03, 1.02, 1.01 or 1.00 dispersion or polydispersity index (PDI).

In various aspects, the formulation may additionally include pharmaceutically acceptable carriers or excipients. Those familiar with the art will recognize that the formulation can be in any suitable form suitable for the desired use and route of administration.

In some dosage forms, the pharmaceutical composition described herein is mixed with: at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate, dicalcium phosphate, etc.; and/or a) Fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, silicic acid, microcrystalline cellulose and baking sugar, etc.; b) Binders, such as carboxymethyl cellulose, alginate, gelatin , Polyvinylpyrrolidone, sucrose, gum arabic, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose (HPC) and hydroxymethyl cellulose, etc.; c) humectants, such as glycerin Etc.; d) Disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, such as cross-linked povidone (cross-linked polyvinylpyrrolidone), cross-linked Cross-linked polymers of croscarmellose sodium/cross-linked sodium carboxymethylcellulose, sodium starch glycolate, etc.; e) Solution retarders, such as paraffin wax, etc.; f) Absorption accelerators, such as quaternary ammonium compounds Etc.; g) wetting agents, such as cetyl alcohol and glycerol monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, Solid polyethylene glycol, sodium lauryl sulfate, glyceryl behenate, etc.; and mixtures of such excipients. Those skilled in the art will recognize that in oral dosage forms, specific excipients can have two or more functions. In the case of oral dosage forms such as capsules or lozenges, the dosage forms may also contain buffering agents.

In one aspect, a pharmaceutical composition comprising a mixture of bacteria is combined with the following: one or more pharmaceutically acceptable cryoprotectants, freeze-dried protectants, binders, disintegrants, excipients, fillers, and /Or preservatives, acid inhibitors, antacids, H2 antagonists and proton pump inhibitors or combinations thereof.

In one aspect, a pharmaceutical composition containing a mixture of bacteria and other adjuvants such as antacids for reducing the inactivation of bacteria in the stomach (such as Mylanta, Mucaine, Stomach) Gel (Gastrogel)) combination. In another aspect, H2 antagonists or proton pump inhibitors can also be used to inhibit acid secretion in the stomach in a pharmacological manner. An exemplary H2 antagonist is ranitidine. An exemplary proton pump inhibitor is omeprazole. In one aspect, the acid inhibitor is administered before or with the pharmaceutical composition.

In one aspect, the pharmaceutical composition administered herein further comprises an acid inhibitor, an antacid, an H2 antagonist, a proton pump inhibitor, or a combination thereof. In one aspect, the pharmaceutical composition administered herein is substantially free of non-biological substances. In another aspect, the pharmaceutical composition administered herein is substantially free of non-cellular substances selected from the group consisting of residual fiber, DNA, virus coating substances, and non-viable substances. In another aspect, the administered pharmaceutical composition does not contain acid inhibitors, antacids, H2 antagonists, proton pump inhibitors, or a combination thereof. In another aspect, the pharmaceutical composition administered does not contain an acid inhibitor. In another aspect, the administered pharmaceutical composition does not contain an antacid. In another aspect, the administered pharmaceutical composition does not contain an H2 antagonist. In another aspect, the administered pharmaceutical composition does not contain a proton pump inhibitor. In another aspect, the administered pharmaceutical composition does not contain metoclopramide.

In one aspect, for example, when the bacterial mixture includes freeze-dried bacterial cells/spores or includes dry binders, fillers, and dispersants, it is dry. Alternatively, for example, when the contained bacterial mixture contains non-drying binders, fillers, and dispersants, it may be aqueous.

In one aspect, the bacterial mixture described herein may undergo lyophilization. As used herein, "freeze drying" or "freeze drying" refers to the process of drying the material by first freezing the material and then promoting the sublimation of ice within it in a vacuum environment.

In one aspect, the bacterial mixture includes a lyophilized formulation that further includes a reducing agent and/or an antioxidant. In some aspects, the reducing agent includes cysteine selected from the group consisting of D-cysteine and L-cysteine. In another aspect, the concentration of cysteine is at least about 0.025%. In one aspect, the concentration of cysteine is about 0.025%. In another aspect, the concentration of cysteine is 0.025%. In another aspect, another reducing agent other than cysteine is used instead of cysteine or used in combination with cysteine. In one aspect, the other reducing agent is selected from the group consisting of ascorbic acid, sodium ascorbate, thioglycolic acid, sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, glutathione Peptides, methionine, thioglycerol and alpha tocopherol.

In one aspect, the concentration of cysteine is at least about 0.005%, at least about 0.01%, at least about 0.015%, at least about 0.02%, at least about 0.025%, at least about 0.03%, at least about 0.035%, at least about 0.04%, at least about 0.045%, at least about 0.05%, at least about 0.055%, at least about 0.06%, at least about 0.065%, at least about 0.07%, at least about 0.075%, at least about 0.08%, at least about 0.085%, at least about 0.09%, at least about 0.095%, at least about 0.1%, at least about 0.12%, at least about 0.14%, at least about 0.16%, at least about 0.18%, at least about 0.2%, at least about 0.25%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, at least about 1%, at least about 2%, at least about 4%, at least about 6%, at least about 8%, at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 22%, at least about 24%, or at least about 26%.

In one aspect, the bacterial mixture includes a cryoprotectant or a mixture of cryoprotectants. As used herein, "cryoprotectant" refers to a substance added to a formulation to protect the active ingredient during freezing. For example, the cryoprotectant may comprise, consist essentially of, or consist of polyethylene glycol, skim milk, erythritol, arabitol, sorbitol, glucose, fructose, propylamine Acid, glycine, proline, sucrose, lactose, ribose, trehalose, dimethylsulfene (DMSO) or equivalent, glycerin, polyethylene glycol (PEG) or equivalent or amino acid (such as , Alanine, Glycine, Proline). In one aspect of the present invention, the cryoprotectant may be selected from the group comprising: 5% sucrose; 10% sucrose; 10% skimmed milk; 10% trehalose and 2.5% sucrose; 5% trehalose and 2.5% sucrose ; 5% mannitol; 5% mannitol and 0.1% polysorbate 80; 10% mannitol; 10% mannitol and 0.1% polysorbate 80; 5% trehalose; 5% Trehalose and 0.1% polysorbate 80; 10% trehalose; and 10% trehalose and 0.1% polysorbate 80.

In one aspect, the bacterial mixture contains a lyoprotectant. As used herein, "lyoprotectant" refers to a substance added to a formulation to protect the active ingredient during the freeze-drying (also known as freeze-drying) stage. In one aspect, the same substance or the same combination of substances is used as the cryoprotectant and lyoprotectant. Exemplary lyoprotectants include sugars, such as sucrose or trehalose; amino acids, such as monosodium glutamate or histidine; methylamine, such as betaine; hydrotropic salts, such as magnesium sulfate; polyols, such as Triols or higher sugar alcohols, such as glycerol, erythritol, glycerol, arabitol, xylitol, sorbitol, and mannitol; propylene glycol; polyethylene glycol; Pluronic; and Its combination. In one aspect, the lyoprotectant is a non-reducing sugar such as trehalose or sucrose. In one aspect, the cryoprotectant or lyoprotectant basically consists of or consists of one or more of the substances mentioned in this paragraph and the previous paragraph.

In one aspect, the cryoprotectant or lyoprotectant includes intracellular reagents such as DMSO, glycerol, or PEG, which penetrates the inside of the cell and prevents the formation of ice crystals that may cause membrane rupture. In one aspect, the cryoprotectant or lyoprotectant includes extracellular reagents such as sucrose, trehalose, or dextrose, which do not penetrate into the cell membrane, but are used to improve the permeability that occurs during freezing. balance.

In one aspect, the present invention provides a pharmaceutical composition comprising a lyophilized fecal microbial preparation, the lyophilized fecal microbial preparation comprising a lyophilized formulation containing at least about 12.5% trehalose.

In one aspect, the lyophilized formulation includes trehalose. In one aspect, the lyophilized formulation contains 2% to 30%, 3% to 25%, 4% to 20%, 5% to 15%, 6% to 10%, 2% to 30%, 2 % To 25%, 2% to 20%, 2% to 15%, or 2% to 10% trehalose. In one aspect, the lyophilized formulation contains at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 15% trehalose. In one aspect, the lyophilized formulation contains at most 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or 15% trehalose. In another aspect, the lyophilized formulation contains about 5% trehalose. In another aspect, the lyophilized formulation includes trehalose and sucrose. In another aspect, the lyophilized formulation contains between about 8% and 12% trehalose and between about 1.5% and 3.5% sucrose and between about 0.5% and 1.5% NaCl .

In one aspect, the lyophilized formulation comprises at least about 5%, at least about 7.5%, at least about 10%, at least about 12.5%, at least about 13%, at least about 13.5%, at least about 14%, at least about 14.5% , At least about 15%, at least about 15.5%, at least about 16%, at least about 16.5%, at least about 17%, at least about 17.5%, at least about 18%, at least about 18.5%, at least about 19%, at least about 19.5% , At least about 20%, at least about 22.5%, at least about 25%, at least about 27.5%, at least about 30%, at least about 32.5%, at least about 35%, at least about 37.5%, at least about 40%, at least about 42.5% , At least about 45%, at least about 47.5%, at least about 50%, at least about 52.5%, at least about 55%, at least about 57.5%, or at least about 60% trehalose.

In one aspect, after storage at ambient temperature or lower for at least 12 weeks, the pharmaceutical composition provided herein effectively treats individuals with HBV or HDV. In one aspect, the pharmaceutical composition remains effective after storage at ambient temperature or lower for at least 4, 8, 10, 16, 20, 24, 30, 40, 50, 60, 70, 80, or 100 weeks.

In one aspect, the pharmaceutical composition described herein can be lyophilized or freeze-dried and stored at ambient temperature (e.g., room temperature), at a freezing temperature, or between about 2°C and 8°C. In one aspect, freeze-drying allows most cells to remain viable and produces a product in a powdered form that can be gently crushed into a powder. Subsequently, the powder or the freeze-dried or freeze-dried composition can be encapsulated into a carrier such as a lozenge, gelling agent, pill, or capsule (such as an enteric-coated capsule), or placed in an oil Fill the capsule for ingestion. Alternatively, the freeze-dried or freeze-dried product or powder can be placed in, for example, a fluid, such as a sterile fluid (such as physiological saline), a buffer, or a medium (such as fluid-glucose-cellobiose agar) at ambient temperature before being delivered to the individual. (RGCA) media).

In one aspect, for freeze-drying, the bacteria are kept in a liquid, which prevents the cells from bursting during thawing. This liquid may include various stabilizers such as glycerol and appropriate buffers and/or ethylene glycol. In one aspect, the cryoprotection process uses one or more stabilizers with final concentrations between about 10% and 80%, 20% and 70%, 30% and 60%, or 40% and 50%, depending on the situation. Depending on the use of one or more stabilizers; in one aspect, this action helps stabilize the protein by preventing the formation of ice crystals that otherwise destroy the protein structure.

In one aspect, stabilizers that help reduce the destruction of live bacteria include skim milk, erythritol, arabitol, sorbitol, glucose, fructose, and other polyols. Polymers such as polydextrose and polyethylene glycol can also be used to stabilize bacterial cells.

In one aspect, the manufacturing of the pharmaceutical composition may include the following steps: (1) coating the exterior of the dissociated capsule (that is, including a separate capsule body and capsule cap) with an external enteric coating, (2) using a bacterial mixture (For example, containing one or more bacterial isolates and/or uncultured fecal bacterial preparations) filling the capsule body, and (3) closing the capsule cap above the capsule body, thereby encapsulating the bacterial mixture in the coated enteric package Yizhi's capsule.

Optionally, the manufacturing of the pharmaceutical composition may include the following steps: (1) coating the outer portion of the dissociated capsule (that is, including a separate capsule body and capsule cap) with an external enteric coating, (2) coating with an internal coating Cover the inside of the dissociated capsule, (3) fill the capsule body with a bacterial mixture (for example, containing one or more bacterial isolates and/or uncultured fecal bacteria preparation), and (4) close the capsule cap on the capsule body, In this way, the bacterial mixture is encapsulated in a double-coated capsule.

Alternatively, the manufacturing of the pharmaceutical composition may include the following steps: (1) coating the inside of the dissociated capsule (that is, including an independent capsule body and capsule cap) with an internal coating, (2) coating the capsule with an external enteric coating The outside of the dissociated capsule, (3) filling the capsule body with a bacterial mixture (for example, containing one or more bacterial isolates and/or uncultured fecal bacteria preparation), and (4) closing the capsule cap above the capsule body, thereby The bacterial mixture is encapsulated in double-coated capsules.

In one aspect, one or more other therapeutic agents may be included in the pharmaceutical composition and encapsulated.

In one aspect, the body and cap of the gelatin capsule (for example, size number 00) are separated. The external enteric coating suspension is prepared by dispersing one or more enteric coating polymers and other components in a solution. For example, a fluidized bed Wurster tube coater, a fluidized bed coater, or an equivalent device is used to coat the external enteric coating suspension to the outside of the separated capsule body and cap. The capsule is fluidized in the product tank, and the external enteric coating suspension is sprayed to produce the external coating, reaching a target of between about 2 mg/cm ² and 6 mg/cm ² , such as 3 mg/cm ² . After completing this step, for example, between about 8 hours and 24 hours, the capsules are set to dry. After drying, the exemplary capsules were weighed to calculate the weight gain relative to the external enteric coating. The irregularity of the capsule can be checked.

In one aspect, dissolve EUDRAGIT® S100 (poly(methacrylic acid, methyl methacrylate)), starch, triethyl citrate and PlasACRYL® T20 in a solution of water, ethanol and n-butanol, and mix And then fill it into a suitable spray device. Then, spray the solution on the outer surface of the capsule body and the capsule cap to achieve the target weight increase. The capsule body and the capsule cap are allowed to dry for about 8 hours to about 24 hours or more, such as one week, one month or more, and then further processing, such as filling with a bacterial mixture.

In one aspect, in addition to providing the composition in the capsule body, it may also be necessary to provide a certain amount of bacterial mixture to the capsule cap. In this aspect, the capsule should contain more composition and/or the closed capsule should contain less air.

In one aspect, the inner surface of the capsule contains an internal coating, such as an internal coating that is insoluble in water.

Any of the above-described compositions and materials (e.g., bacterial mixture, internal coating, capsule, and external coating) can be combined into the pharmaceutical compositions described herein. Those skilled in the art should know how to choose the inner coating, capsule and outer coating according to their current needs. The selection can be based, for example, on the incorporation of one or more specific bacterial isolates into the composition and/or the individual The location to be delivered (for example, in the colon or small intestine including the ileum, jejunum, or duodenum), and where one or more bacterial isolates should be delivered.

Other relevant teachings are disclosed in WO 2007122374, which is incorporated herein by reference in its entirety.

In one aspect, during the manufacture of the pharmaceutical composition, pharmaceutically acceptable cryoprotectants, freeze-dried protectants, binders, disintegrants, fillers, preservatives, acid inhibitors, and antacids can be used , H2 antagonists and proton pump inhibitors, or combinations thereof, are mixed into a pharmaceutical composition (for example, containing a bacterial mixture) to promote the desired properties.

In one aspect, the pharmaceutical composition includes a surfactant. Suitable surfactants include (but are not limited to) any pharmaceutically acceptable non-toxic surfactants. The types of surfactants suitable for use include (but are not limited to) polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid monoesters and diester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil conversion Esterification products, polyglycerated fatty acids, propylene glycol fatty acid esters, propylene glycol ester-glyceride mixtures, monoglycerides and diglycerides, sterols and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, poly Ethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, ionic surfactants and the like mixture. In some aspects, the composition may include one or more surfactants, including (but not limited to) sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate Sorbitol ester 80 and triethyl citrate.

In one aspect, the pharmaceutical composition includes a pharmaceutically acceptable plasticizer to obtain desired mechanical properties such as flexibility and hardness. Such plasticizers include (but are not limited to) triacetin, citrate, triethyl citrate, phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, poly Sorbitol esters or other plasticizers.

In another aspect, the pharmaceutical composition includes one or more coating solvents. For example, some of the more common solvents that can be used for coating of delayed-release coating compositions include isopropanol, acetone, methylene chloride and the like.

In another aspect, the pharmaceutical composition includes one or more alkaline materials. Alkaline materials suitable for use in the composition include, but are not limited to, sodium, potassium, calcium, magnesium and aluminum salts of acids such as phosphoric acid, carbonic acid, citric acid, and other aluminum/magnesium compounds. In addition, the alkaline material may be selected from antacid materials such as aluminum hydroxide, calcium hydroxide, magnesium hydroxide, and magnesium oxide.

In addition to an inert diluent, the composition for oral administration may also include adjuvants such as sweeteners, flavoring agents, and aromatics.

In various aspects, the pharmaceutical composition is formulated for systemic or local delivery. In one aspect, administration is systemic administration. In another aspect, local administration may be required to the area in need of treatment.

Various methods can be used to formulate the pharmaceutical compositions described herein (eg, including a bacterial mixture) and/or deliver to relevant locations. For example, the pharmaceutical composition can be formulated for delivery to the GI tract. The GI tract includes organs of the digestive system such as the oral cavity, esophagus, stomach, small intestine, duodenum, jejunum, ileum, large intestine, and rectum and includes all of its subparts (for example, the small intestine may include the duodenum, jejunum, and ileum; the large intestine may include the transverse colon, descending Colon, ascending colon, sigmoid colon and cecum). For example, the composition can be formulated for the delivery of one or more active agents to the stomach, small intestine, large intestine, and rectum, or any sub-parts thereof (e.g., duodenum, jejunum and ileum, transverse colon, descending colon, ascending colon, sigmoid colon And cecum) one or more of them. In some aspects, the compositions described herein can be formulated for delivery to the upper or lower GI tract. In one aspect, the composition may be administered to the individual by, for example, directly or indirectly contacting the mucosal tissue of the GI tract with the composition.

In various aspects, the pharmaceutical composition is administered via, for example, oral delivery, nasogastric tube, intestinal cannula (for example, intestinal tube or feeding tube such as jejunal tube or gastro-jejunal tube, etc.), direct infusion (for example, duodenal tube) Infusion), endoscopy, colonoscopy, or enema to reach the GI tract.

In one aspect, the method comprises administering the pharmaceutical composition orally, by enema, or via rectal suppository. In one aspect, the pharmaceutical composition administered herein is formulated as an enteric coated (and/or acid-resistant) capsule or microcapsule, or is formulated as one of the following parts or administered together with: food , Food additives, dairy-based products, soy-based products or their derivatives, jellies, gelatin-based chews (for example, jelly), flavored liquids, ice cubes, ice cream or yogurt. In another aspect, the pharmaceutical composition administered herein is formulated as an acid-resistant enteric coated capsule. The pharmaceutical composition may be provided in powder form for sale in combination with food or drink. The food or drink may be a dairy-based product or a soy-based product. In another aspect, the food or food supplement contains an enteric coating containing the pharmaceutical composition and/or acid-resistant microcapsules.

In one aspect, the pharmaceutical composition comprises a liquid culture. In another aspect, the pharmaceutical composition is homogenized, lyophilized, pulverized, and is in powder form. Then, it can be infused as an enema and dissolved in, for example, normal saline. Alternatively, the powder can be encapsulated into an enteric coating and/or acid-resistant delayed-release capsule for oral administration. In one aspect, the powder may be double-encapsulated in acid-resistant/delayed-release capsules for oral administration. These capsules may be in the form of enteric coating and/or acid-resistant delayed-release microcapsules. The powder can be provided in a palatable form for reconstitution for drinking or reconstitution as a food additive. In another aspect, the food is yogurt. In one aspect, the powder can be reconstituted for infusion via nasal-duodenal infusion.

In another aspect, the pharmaceutical composition administered herein is in liquid, frozen, freeze-dried, spray-dried, foam dehydrated, freeze-dried or powder form. In another aspect, the pharmaceutical composition administered herein is formulated as a delayed or gradual enteric release form. In another aspect, the pharmaceutical composition administered herein includes excipients, physiological saline, buffer, buffer, or fluid-glucose-cellobiose agar (RGCA) medium. In another aspect, the pharmaceutical composition administered herein includes a cryoprotectant. In one aspect, the cryoprotectant includes polyethylene glycol, skimmed milk, erythritol, arabitol, sorbitol, glucose, fructose, alanine, glycine, proline, sucrose, lactose, Ribose, trehalose, dimethylsulfoxide (DMSO), glycerin, or a combination thereof.

In various aspects, provided herein is a modified release formulation comprising a bacterial mixture (for example, a combination comprising one or more bacterial isolates and an uncultured fecal bacterial preparation), wherein the formulation combines a large number of bacterial mixtures (and depending on Other therapeutic agents selected by the situation) are released into one or more areas of the GI tract. For example, the formulation can release at least about 60% of bacterial isolates behind the stomach and reach one or more areas of the GI tract.

In various aspects, the modified release formulation can release at least 60% of the bacterial mixture (and optionally other therapeutic agents) into one or more areas of the intestine after the stomach. For example, the modified release formulation releases at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81% , At least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% bacterial mixture (and other therapeutic agents as appropriate).

In various aspects, the modified release formulation can release at least 60% of the bacterial mixture (and other therapeutic agents as appropriate) in the small intestine. For example, the modified release formulation releases at least 60%, at least 61%, at least 62%, at least 63%, at least one or more of the duodenum, jejunum, ileum, and ileocecal junction. 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76% , At least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% bacterial mixture (and depending on Other therapeutic agents selected by the situation).

In various aspects, the modified release formulation can release at least 60% of the bacterial mixture in the large intestine (and optionally other therapeutic agents). For example, the modified release formulation releases at least 60%, at least 61%, at least one or more of the cecum, ascending part, transverse part, descending part or sigmoid part of the colon, and rectum in the large intestine 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74% , At least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% Or 100% bacterial isolates (and/or other therapeutic agents).

In some aspects, the pharmaceutical composition is formulated for release in the stomach. In other aspects, the pharmaceutical composition is formulated so as not to substantially release the bacterial mixture in the stomach.

In some aspects, the modified release formulation releases a mixture of bacteria (and other therapeutic agents as appropriate) at a specific pH. For example, in some aspects, the modified release formulation is substantially stable in an acidic environment and substantially unstable in an almost neutral to alkaline environment (e.g., rapidly dissolves or is physically unstable). In some aspects, stability indicates substantially no release, while instability indicates substantially release. For example, in some aspects, the modified release formulation is about 7.0 or less, or about 6.5 or less, or about 6.0 or less, or about 5.5 or less, or about 5.0 or less, Or about 4.5 or less, or about 4.0 or less, or about 3.5 or less, or about 3.0 or less, or about 2.5 or less, or about 2.0 or less, or about 1.5 or less, or It is substantially stable at a pH of about 1.0 or less. In some aspects, the formulations of the present invention are stable in the lower pH region and therefore are not substantially released in, for example, the stomach. In some aspects, the modified release formulation is substantially stable at pH values of about 1 to about 4 or lower and substantially unstable at greater pH values. In these aspects, the modified release formulation is not substantially released in the stomach. In these aspects, the modified release formulation is in the small intestine (for example, one or more of the duodenum, jejunum, and ileum) and/or the large intestine (for example, one of the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon) Or more) in the actual release. In some aspects, the modified release formulations are substantially stable at pH values of about 4 to about 5 or lower, and necessarily substantially unstable at greater pH values, and therefore in the stomach and/or small intestine (For example, one or more of the duodenum, jejunum, and ileum) is not substantially released. In these aspects, the modified release formulation is substantially released in the large intestine (for example, one or more of the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon). In various aspects, taking into account the individual's state, for example, whether in an empty stomach or a postprandial state, it is known in this technology to adjust the pH value described herein.

In some aspects, the modified release formulation is substantially stable in gastric juice and substantially unstable in intestinal juice, and correspondingly in the small intestine (eg, one or more of the duodenum, jejunum, and ileum) and/or large intestine (For example, one or more of the cecum, ascending colon, transverse colon, descending colon, and sigmoid colon).

In some aspects, the modified release formulation is stable in gastric juice or stable in an acidic environment. These modified release formulations have a pH value of about 4 to about 5 or less in gastric juice or a pH value of about 4 to about 5 or less in about 15 or about 30 or about 45 or about 60 or about 90 minutes Simulates the release of about 30% by weight or less of the pharmaceutical composition (for example, containing a bacterial mixture) in the modified release formulation in the gastric juice. The modified release formulation can release about 15 or about 30 or about 45 or about 60 or about 90 minutes in gastric juice with a pH of 4-5 or less or simulated gastric juice with a pH of 4-5 or less. 0% by weight to about 30% by weight, about 0% by weight to about 25% by weight, about 0% by weight to about 20% by weight, about 0% by weight to about 15% by weight, about 0% by weight to about 10% by weight, about 5% by weight to about 30% by weight, about 5% by weight to about 25% by weight, about 5% by weight to about 20% by weight, about 5% by weight to about 15% by weight, about 5% by weight to about 10% by weight in the improvement The composition in a release formulation. The modified release formulations can release about 1%, about 1%, about 1%, about 1%, about 1%, about 1%, about 1%, about 15%, about 15%, about 15%, about 30%, about 30%, about 45, about 60%, or about 90 minutes, in gastric juice with a pH of 5 or less or simulated gastric juice with a pH of 5 or less. 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% by weight of the total composition in the modified release formulation.

In some aspects, the modified release formulation is unstable in intestinal juice. These modified release formulations release about 70% by weight or more of the bacterial mixture in the modified release formulation and/ Or other therapeutic agents. In some aspects, modified release formulations are unstable in almost neutral to alkaline environments. These modified release formulations are in intestinal juice with a pH of about 4-5 or greater or simulated intestinal juice with a pH of about 4-5 or greater within about 15 or about 30 or about 45 or about 60 or about 90 minutes The medium releases about 70% by weight or more of the bacterial mixture and/or other therapeutic agents in the modified release formulation. Modified release formulations that are unstable in almost neutral or alkaline environments can take about 5 minutes to about 90 minutes, or about 10 minutes to about 90 minutes, or about 15 minutes to about 90 minutes, or about 20 minutes to about About 90 minutes, or about 25 minutes to about 90 minutes, or about 30 minutes to about 90 minutes, or about 5 minutes to about 60 minutes, or about 10 minutes to about 60 minutes, or about 15 minutes to about 60 minutes, or For about 20 minutes to about 60 minutes, or about 25 minutes to about 90 minutes, or about 30 minutes to about 60 minutes in a fluid with a pH value greater than about 5 (for example, a pH value of about 5 to about 14, about 6 to about 14 , About 7 to about 14, about 8 to about 14, about 9 to about 14, about 10 to about 14, or about 11 to about 14) released 70% by weight or more in the modified release formulation Pharmaceutical composition (for example, containing a mixture of microorganisms).

Examples of simulated gastric juice and simulated intestinal juice include (but are not limited to) the simulated gastric juice and simulated intestinal juice disclosed on page 2858 of Test Solutions in 2005 Pharmacopeia 23NF/28USP and/or other simulated gastric juice and simulated intestinal juice known to those familiar with the technology , Such as simulated gastric juice and/or intestinal juice prepared without enzymes.

In various aspects, the modified release formulation can be substantially stable in the chyme. For example, in some aspects, the bacterial activity in the bacterial mixture within about 10, or 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2, or 1 hour from the administration Or the loss of vitality is less than about 50%, or about 40%, or about 30%, or about 20%, or about 10%.

In various aspects, modified release formulations can be designed for immediate release (eg, upon ingestion). In various aspects, the modified release formulation may have a sustained release profile, that is, the slow release of one or more active ingredients in the body (eg, GI tract) over an extended period of time. In various aspects, modified-release formulations may have a delayed release profile, that is, one or more active ingredients are not released immediately upon ingestion; conversely, the release of one or more active ingredients is delayed until the composition is lower in the GI tract ; For example, in the small intestine (for example, one or more of duodenum, jejunum, ileum) or large intestine (for example, one or more of the cecum, ascending part, transverse part, descending part or sigmoid part of the cecum, colon, and rectum) Released. For example, the composition may be enteric coated to delay the release of one or more active ingredients until it reaches the small or large intestine.

In various aspects, modified-release formulations can utilize one or more modified-release coatings such as delayed-release coatings to provide a mixture of bacteria reaching the GI tract and optionally other therapeutic agents that are effective, delayed but substantial. Sexual delivery.

In one aspect, the delayed release coating includes an enteric agent that is substantially stable in an acidic environment and substantially unstable in an almost neutral to alkaline environment. In one aspect, the delayed release coating contains an enteric agent that is substantially stable in gastric juice. The enteric agent may be selected from, for example, the following solutions or dispersions: methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate , Carboxymethyl ethyl cellulose and EUDRAGIT® polymers (poly(methacrylic acid, methyl methacrylate)), hydroxypropyl methyl cellulose acetate succinate, cellulose acetate trimellitate, insect Gum or other suitable enteric coating polymers. EUDRAGIT® type polymers include, for example, UDRAGIT® FS 30D, L 30 D-55, L 100-55, L 100, L 12,5, L 12,5 P, RL 30 D, RL PO, RL 100, RL 12, 5. RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5 and S 12,5 P. Similar polymers include Kollicoat® MAE 30 DP and Kollicoat® MAE 100 P. In some aspects, use EUDRAGIT® FS 30D, L 30 D-55, L 100-55, L 100, L 12,5, L 12,5 P RL 30 D, RL PO, RL 100, RL 12,5 , RS 30 D, RS PO, RS 100, RS 12,5, NE 30 D, NE 40 D, NM 30 D, S 100, S 12,5 S 12,5 P, Kollicoat® MAE 30 DP and Kollicoat® MAE One or more of 100 P. In various aspects, the enteric agent may be a combination of the aforementioned solutions or dispersions.

In some aspects, one or more coating system additives are used together with enteric agents. For example, one or more PlasACRYLTM additives can be used as anti-sticking agent coating additives. Illustrative PlasACRYLTM additives include (but are not limited to) PlasACRYLTM HTP20 and PlasACRYLTM T20.

In another aspect, the delayed release coating can degrade over time when in an aqueous solution regardless of the pH value of the solution and/or the presence of enzymes. Such coatings may contain polymers that are insoluble in water. Therefore, its solubility in aqueous solution does not depend on the pH value. The term "pH-independent" as used herein means that the water permeability of the polymer and its ability to release pharmaceutical ingredients do not change with the pH value and/or only slightly depend on the pH value. Such coatings can be used to prepare, for example, sustained-release formulations. Independent of the pH of the solution, suitable water-insoluble polymers include pharmaceutically acceptable non-toxic polymers that are substantially insoluble in an aqueous medium such as water. Suitable polymers include, but are not limited to, cellulose ethers, cellulose esters, or cellulose ether-esters, that is, some of the hydroxyl groups on the cellulose backbone are substituted with alkyl groups and some are modified with alkyl acyl groups. Cellulose derivatives. Examples include ethyl cellulose, acetyl cellulose, nitrocellulose and the like. Other examples of insoluble polymers include (but are not limited to) lacquers and acrylate and/or methacrylate polymers, polymers or copolymers of acrylate or methacrylate with low quaternary ammonium content, or mixtures thereof And its analogues. Other examples of insoluble polymers include EUDRAGIT RS®, EUDRAGIT RL® and EUDRAGIT NE®. The insoluble polymer may include polyvinyl ester, polyvinyl acetal, polyacrylate, butadiene styrene copolymer, and the like. In one aspect, colonic delivery is achieved by using slowly eroding wax embolization (eg, various PEGs, including, for example, PEG6000).

In another aspect, the delayed-release coating can be degraded by microbial enzymes present in the biota of the digestive tract. In one aspect, the delayed release coating can be degraded by bacteria present in the small intestine. In another aspect, the delayed release coating can be degraded by bacteria present in the large intestine.

In various aspects, modified release formulations can be designed for release in the colon. Various colon-specific delivery methods are available. For example, a modified release formulation can be formulated using a colon-specific drug delivery system (CODES) as described in, for example, Li et al., AAPS PharmSciTech (2002), 3(4): 1-9, the entire document The content is incorporated into this article by reference. Drug release in such systems is triggered by colonic microflora coupled with pH-sensitive polymer coatings. For example, the formulation can be designed as a core lozenge with a three-layer polymer. The first coating is an acid-soluble polymer (for example, EUDRAGIT E), the outer coating is enteric-coated, and a barrier layer of hydroxypropyl methylcellulose is interposed therebetween. In another aspect, colonic delivery can be achieved by formulating a pharmaceutical composition (for example, containing a mixture of microorganisms) with specific polymers such as gum degraded in the colon. Pectin can be further gelatinized or cross-linked with cations such as zinc cations. In one aspect, the formulation is in the form of ionically cross-linked pectin beads further coated with a polymer (for example, EUDRAGIT polymer). Other colon-specific formulations include, but are not limited to, controlled pressure drug delivery systems (made from, for example, ethyl cellulose) and controlled osmotic pressure drug delivery systems (ie, ORDS-CT).

As described herein, formulations for colon-specific delivery of bacterial mixtures (and optionally other therapeutic agents) can be evaluated using, for example, an in vitro dissolution test. For example, parallel dissolution studies can be performed in different buffers to characterize the properties of the formulation at different pH levels. Alternatively, an in vitro enzyme test can be performed. For example, the formulation can be grown in a fermentation tank containing a suitable culture medium for bacteria, and the amount of drug released at different time intervals can be measured. It is also possible to conduct drug release studies in a buffer medium containing enzymes or rat, guinea pig or rabbit cecal contents, and determine the amount of drug released within a specific time. In another aspect, in vivo assessment can be performed using animal models such as dogs, guinea pigs, rats, and pigs. In addition, the clinical evaluation of colon-specific drug delivery formulations can be calculated by considering the relative ratio of RCE (relative colonic tissue exposure to the drug) and RSC (relative amount of the drug in the blood, that is, the relative systemic exposure to the drug) Drug Delivery Index (DDI) to evaluate. The higher the drug DDI, the better the colonic drug delivery. Colonic drug absorption can be monitored by colonoscopy and intubation.

In various aspects, the formulation of the present invention provides a substantially uniform delivery of the bacterial mixture (and optionally other therapeutic agents) in the release area of the GI tract. In one aspect, the formulation of the present invention minimizes the flaky or uneven release of the bacterial mixture.

In various aspects, the formulations of the present invention provide multiple doses of one or more bacterial mixtures to be released along the GI tract. For example, the composition and/or formulation can release multiple doses of the same bacterial mixture at different locations along the intestine, at different times and/or at different pH values. Alternatively, the composition and/or formulation may release a dose of different bacterial mixtures at different locations along the intestine, at different times, and/or at different pH values. In one aspect, the pharmaceutical composition comprises a first bacterial mixture containing one or more bacterial isolates released at a first location in the intestine and a first bacterial mixture containing uncultured fecal bacteria released at a second location in the intestine The second bacterial mixture of the formulation. In one aspect, the first bacterial mixture is released in the ileum and the second bacterial mixture is released in the colon.

The overall release profile of such formulations can be adjusted using, for example, multiple particle types or multiple layers. For example, in one aspect, the first bacterial mixture (or the first dose of bacterial mixture) may be formulated for release in, for example, the small intestine (eg, one or more of the duodenum, jejunum, and ileum, The second bacterial mixture (or the second dose of bacterial mixture) is formulated for use in, for example, the large intestine (for example, one or more of the cecum, the ascending part, the transverse part, the descending part or the sigmoid part of the colon, and the rectum) In another example, the first bacterial mixture (or the first dose of bacterial mixture) may be formulated for release in, for example, the small intestine (eg, one or more of the duodenum, jejunum, and ileum), The second bacterial mixture (or the second dose of bacterial mixture) is formulated for delayed release in another part of the small intestine (for example, one or more of the duodenum, jejunum, and ileum). In another aspect The first bacterial mixture (or the first dose of bacterial mixture) can be formulated for use in, for example, one or more of the large intestine (for example, the cecum, ascending part, transverse part, descending part or sigmoid part of the colon, and rectum ), and the second bacterial mixture (or the second dose of bacterial mixture) is formulated for use in another part of the large intestine (for example, the cecum, the ascending part, the transverse part, the descending part or the sigmoid part of the large intestine, and the rectum One or more of them). In various aspects, the composition and/or formulation can release at least one dose, at least at different locations, at different times and/or at different pH values along the intestine Two doses, at least three doses, at least four doses, or at least five doses of a bacterial mixture. Similarly, in various aspects, the composition and/or formulation can be placed at different locations along the intestine at different times And/or release at least one bacterial mixture, at least two bacterial mixtures, at least three bacterial mixtures, at least four bacterial mixtures, or at least five bacterial mixtures at different pH values.

In another aspect, the delayed or gradual enteric release formulations include the use of double-layer tablets or capsules containing polyoxyalkylene, polyvinylpyrrolidone, lubricants or mixtures thereof The first layer and the second permeable pushing layer containing polyethylene oxide, carboxymethyl cellulose or both. In one aspect, the delayed or gradual enteric release formulation includes the use of a delayed release matrix material selected from the group consisting of acrylic polymer, cellulose, wax, fatty acid, shellac, zein, hydrogenated vegetable oil, Hydrogenated castor oil, polyvinylpyrrolidone, vinyl acetate copolymer, vinyl alcohol copolymer, polyethylene oxide, acrylic acid and methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate polymerization Compounds, cyanoethyl methacrylate polymer, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkyl amide methacrylate copolymer, poly(methyl methacrylate) Ester), poly(methacrylic anhydride), methyl methacrylate polymer, polymethacrylate, poly(methyl methacrylate) copolymer, polypropylene amide, aminoalkyl methacrylate copolymer , Glycidyl methacrylate copolymer, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl fiber Vegetarian, croscarmellose sodium, cross-linked hydroxypropyl cellulose, natural wax, synthetic wax, fatty alcohol, fatty acid, fatty acid ester, fatty acid glyceride, hydrogenated fat, hydrocarbon wax, stearic acid, stearin Alcohol, beeswax, sugar wax, castor wax, carnauba wax, polylactic acid, polyglycolic acid, lactic acid and glycolic acid copolymer, carboxymethyl starch, potassium methacrylate/divinylbenzene copolymer, cross-linked polyvinylpyrrole Pyridone, polyvinyl alcohol, polyvinyl alcohol copolymer, polyethylene glycol, non-crosslinked polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate copolymer, or any combination thereof. In one aspect, delayed or gradual enteric release formulations include the use of microenvironmental pH adjusting agents.

It should be understood that the pharmaceutical composition described herein may contain a variety of different bacterial mixtures, for example, to achieve a different delivery location profile for each bacterial mixture. In one aspect, the pharmaceutical composition includes at least two bacterial mixtures such that the first bacterial mixture includes one or more bacterial isolates and the second bacterial mixture includes an uncultured fecal bacterial preparation. In one aspect, the second bacterial mixture further includes one or more bacterial isolates that are different from the bacterial isolates in the first bacterial mixture. Alternatively, the second bacterial mixture may consist essentially of an uncultured fecal bacterial preparation. In another aspect, the first bacterial mixture contains only one bacterial isolate. The pharmaceutical composition may contain any number of bacterial mixtures, such as one, two, three, four, five, six, seven, eight, nine, ten, or more than ten species each containing different bacterial isolates, Different combinations of bacterial isolates, uncultured fecal bacterial preparations or uncultured fecal bacterial preparations and bacterial mixtures of different combinations of one or more bacterial isolates.

In one aspect, the pharmaceutical composition may be a large-dose liquid medicine. In one aspect, the large-dose liquid medicine is prepared by selecting the pharmaceutical composition in the form of a suspension of physiological saline. The water-soluble form of one ingredient can be combined with the water-insoluble form of another ingredient by preparing a suspension of one ingredient and an aqueous solution of the other ingredient. The water-insoluble form of any active ingredient can be prepared as a suspension or in some physiologically acceptable solvent such as polyethylene glycol. The suspension of any active ingredient in water-insoluble form can be in oils such as peanut oil, corn oil, sesame oil or the like, in glycols such as propylene glycol or polyethylene glycol, or in water, depending on the solubility of the specific active ingredient preparation. A suitable physiologically acceptable adjuvant may be required in order to keep the active ingredient in suspension. The adjuvant may include and be selected from among the following: thickeners such as carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, and alginate. Surfactants are generally used to suspend active ingredients, specifically fat-soluble propionate enhanced compounds. Alkylphenol polyoxyethylene adducts, naphthalene sulfonates, alkylbenzene sulfonates and polyoxyethylene sorbitan esters are most suitable for making suspensions in liquid non-solvents. In addition, in individual cases, many substances that affect the hydrophilicity, density and surface tension of the liquid can assist in the manufacture of suspensions. For example, polysiloxane antifoams, glycols, sorbitol, and sugars can be suitable suspending agents.

In one aspect, the pharmaceutical composition can be administered by a patch.

In some aspects, the bacterial isolates described herein are in the form of viable asexual cells. In some aspects, the bacterial isolates described herein are in the form of spores. In some aspects, the bacterial isolates described herein are lyophilized. As a non-limiting example, lyophilization can be performed by methods known in the art, including the method described in US Patent No. 7,799,328, the content of which is incorporated herein by reference in its entirety. In some aspects, the freeze-dried bacterial mixture described herein is placed in a soft gel or capsule coated with an enteric coating.

In various aspects, the formulation may be in the form described in one or more of the following: U.S. Patent Nos. 8,535,713 and 8,9117,77, and U.S. Patent Publication Nos. 20120141585, 2012.41531, No. 2006/001896, No. 2007/0292523, No. 2008/0020018, No. 2008/0113031, No. 2010/0203120, No. 2010/0255087, No. 2010/0297221, No. 2011/0052645, No. 2013 No. /0243873, No. 2013/0330411, No. 2014/0017313 and No. 2014/0234418, the contents of these cases are incorporated herein by reference in their entirety.

In various aspects, the formulation may be in the form described in International Patent Publication No. WO 2008/135090, the content of which is incorporated herein by reference in its entirety.

In various aspects, the formulation may take the form described in one or more of the following: U.S. Patent No. 4,196,564; No. 4,196,565; No. 4,247,006; No. 4,250,997; No. 4,268,265; No. 5,317,849; No. 6,572,892; No. 7,712,634; No. 8,074,835; No. 8,398,912; No. 8,440,224; No. 8,557,294; No. 8,646,591; No. 8,739,812; No. 8,810,259; No. 8,852,631; and No. 8,911,788 and U.S. Patent Publication No. No. 2014/0302132; No. 2014/0227357; No. 20140088202; No. 20130287842; No. 2013/0295188; No. 2013/0307962; and No. 20130184290, the contents of these cases are incorporated herein by reference in their entirety . Dosing and dosage

It should be understood that the dosage of the pharmaceutical composition or the bacterial cells therein (for example, a bacterial mixture containing one or more bacterial isolates and/or uncultured fecal bacterial preparations) should be based on, for example, the specific dosage form, the mode of administration to the individual, and the combination The consistency of the bacterial isolates (if present) in the composition, the number of bacterial isolates (if present) in the composition, and the presence or absence of uncultured fecal bacterial preparations in the composition. These factors and variables (for example, individual body weight, gender and diet, administration time, route of administration, excretion rate, individual condition, drug combination, genetic predisposition and reaction sensitivity) that can adjust the bacterial activity in the bacterial mixture can be familiar with this The skilled person considers to produce an effective dose or dosage regimen to treat or prevent at least one symptom of HBV or HDV in a patient. Administration can be performed continuously within the maximum tolerated dose or in one or more discrete doses. The optimal dosing rate for a given set of conditions can be determined by those skilled in the art using conventional dose dosing tests.

In various aspects, the dosage of the pharmaceutical composition or the bacterial cells therein (for example, a bacterial mixture containing one or more bacterial isolates and/or uncultured fecal bacterial preparations) can effectively regulate the patient’s microorganisms to promote Ecological balance in order to treat or prevent one or more symptoms of HBV or HDV.

In one aspect, the pharmaceutical activity or therapeutically effective dose of the bacterial isolate administered to an individual (that is, in single or multiple administrations) to treat at least one symptom of HBV or HDV comprises at least 10 ⁵ , at least 10 ⁶ , at least 10 ⁷ , at least 10 ⁸ , at least 10 ⁹ , at least 10 ¹⁰ , at least 10 ¹¹ , at least 10 ¹² , at least 10 ¹³ , at least 10 ¹⁴ or at least 10 ¹⁵ CFU bacterial isolates. In another aspect, the pharmaceutical activity or therapeutically effective dose of the bacterial isolate administered to an individual (ie, in single or multiple administrations) to treat at least one symptom of HBV or HDV contains at most 10 ⁵ , at most A bacterial isolate of 10 ⁶ , at most 10 ⁷ , at most 10 ⁸ , at most 10 ⁹ , at most 10 ¹⁰ , at most 10 ¹¹ , at most 10 ¹² , at most 10 ¹³ , at most 10 ¹⁴ or at most 10 ^{15 CFU.} In another aspect, the pharmacological activity or therapeutically effective dose of the bacterial isolate administered to an individual (that is, in single or multiple administrations) to treat at least one symptom of HBV or HDV is selected from the group consisting of Group: 10 ⁸ CFU to 10 ¹⁴ CFU, 10 ⁹ CFU to 10 ¹³ CFU, 10 ¹⁰ CFU to 10 ¹² CFU, 10 ¹⁰ CFU to 10 ¹¹ CFU, 10 ⁹ CFU to 10 ¹⁴ CFU, 10 ⁹ CFU to 10 ¹² CFU, 10 ⁹ CFU to 10 ¹¹ CFU, 10 ⁹ CFU to 10 ¹⁰ CFU, 10 ¹⁰ CFU to 10 ¹⁴ CFU, 10 ¹⁰ CFU to 10 ¹³ CFU, 10 ¹¹ CFU to 10 ¹⁴ CFU, 10 ¹¹ CFU to 10 ¹³ CFU, 10 ¹² CFU to 10 ¹⁴ CFU, and 10 ¹³ CFU to 10 ¹⁴ CFU of bacterial isolates.

In one aspect, the pharmaceutical composition comprises one or more bacterial isolates, wherein each bacterial isolate has a unit weight of about 0.2, 0.4, 0.6, 0.8, or 1.0 g or about 0.2, 0.4, 0.6, 0.8, or 1.0 ml. The unit volume is present in each unit dose in one of the aforementioned medically active or therapeutically effective doses.

In one aspect, the pharmaceutical activity or therapeutically effective dose of the bacterial isolate administered to an individual (that is, in single or multiple administrations) to treat at least one symptom of HBV or HDV comprises at least 10 ⁵ , at least 10 ⁶ , at least 10 ⁷ , at least 10 ⁸ , at least 10 ⁹ , at least 10 ¹⁰ , at least 10 ¹¹ , at least 10 ¹² , at least 10 ¹³ , at least 10 ¹⁴ or at least 10 ¹⁵ cells or spores of bacterial isolates. In another aspect, the pharmaceutical activity or therapeutically effective dose of the bacterial isolate administered to an individual (that is, in single or multiple administrations) to treat at least one symptom of HBV or HDV comprises a total of up to 10 ⁵ , At most 10 ⁶ , at most 10 ⁷ , at most 10 ⁸ , at most 10 ⁹ , at most 10 ¹⁰ , at most 10 ¹¹ , at most 10 ¹² , at most 10 ¹³ , at most 10 ¹⁴ or at most 10 ¹⁵ cells or spores of bacterial isolates. In another aspect, the pharmacological activity or therapeutically effective dose of the bacterial isolate administered to an individual (that is, in single or multiple administrations) to treat at least one symptom of HBV or HDV is selected from the group consisting of Group: 10 ⁸ to 10 ¹⁴ , 10 ⁹ to 10 ¹³ , 10 ¹⁰ to 10 ¹² , 10 ¹⁰ to 10 ¹¹ , 10 ⁹ to 10 ¹⁴ , 10 ⁹ to 10 ¹² , 10 ⁹ to 10 ¹¹ , 10 ⁹ to 10 ¹⁰ , 10 ¹⁰ to 10 ¹⁴ , 10 ¹⁰ to 10 ¹³ , 10 ¹¹ to 10 ¹⁴ , 10 ¹¹ to 10 ¹³ , 10 ¹² to 10 ¹⁴ and 10 ¹³ to 10 ¹⁴ cells or spores of bacterial isolates.

In one aspect, the medicinal activity or therapeutically effective dose cell count of the bacterial isolate is related to living cells. In one aspect, the pharmaceutical composition comprises one or more bacterial isolates, wherein each bacterial isolate has a unit weight of about 0.2, 0.4, 0.6, 0.8, or 1.0 g or about 0.2, 0.4, 0.6, 0.8, or 1.0 ml. The unit volume is present in each dosage unit in one of the aforementioned pharmaceutically active or therapeutically effective doses.

In one aspect, the pharmaceutical composition described herein is in the form of a capsule, and each capsule contains at least 10 ⁵ , at least 10 ⁶ , at least 10 ⁷ , at least 10 ⁸ , at least 10 ⁹ , at least 10 ¹⁰ , at least 10 ¹¹ , At least 10 ¹² , at least 10 ¹³ , at least 10 ¹⁴ or at least 10 ¹⁵ cells or spores of bacterial isolates. In one aspect, the pharmaceutical composition described herein is in the form of a capsule, and each capsule contains 10 ⁸ to 10 ¹⁴ , 10 ⁹ to 10 ¹³ , 10 ¹⁰ to 10 ¹² , 10 ¹⁰ to 10 ¹¹ , 10 ⁹ to 10 ¹⁴ , 10 ⁹ to 10 ¹² , 10 ⁹ to 10 ¹¹ , 10 ⁹ to 10 ¹⁰ , 10 ¹⁰ to 10 ¹⁴ , 10 ¹⁰ to 10 ¹³ , 10 ¹¹ to 10 ¹⁴ , 10 ¹¹ to 10 ¹³ , 10 ¹² to 10 ¹⁴ or 10 ¹³ to 10 ¹⁴ cells or spores of bacterial isolates.

In one aspect, the pharmaceutical activity or therapeutically effective dose of an uncultured fecal bacterial preparation administered to an individual (ie, in single or multiple administrations) to treat at least one symptom of HBV or HDV contains at least 10 ⁵ , at least 10 ⁶ , at least 10 ⁷ , at least 10 ⁸ , at least 10 ⁹ , at least 10 ¹⁰ , at least 10 ¹¹ , at least 10 ¹² , at least 10 ¹³ , at least 10 ¹⁴ or at least 10 ¹⁵ CFU of uncultured fecal bacteria preparation. In another aspect, the pharmaceutical activity or therapeutically effective dose of an uncultured fecal bacterial preparation administered to an individual (ie, in single or multiple administrations) to treat at least one symptom of HBV or HDV contains at most 10 ⁵ , up to 10 ⁶ , up to 10 ⁷ , up to 10 ⁸ , up to 10 ⁹ , up to 10 ¹⁰ , up to 10 ¹¹ , up to 10 ¹² , up to 10 ¹³ , up to 10 ¹⁴ or up to 10 ¹⁵ CFU of uncultured feces Bacterial preparations. In another aspect, the pharmacological activity or therapeutically effective dose of an uncultured fecal bacterial preparation administered to an individual (ie, in single or multiple administrations) to treat at least one symptom of HBV or HDV is selected Free from the following groups: 10 ⁸ CFU to 10 ¹⁴ CFU, 10 ⁹ CFU to 10 ¹³ CFU, 10 ¹⁰ CFU to 10 ¹² CFU, 10 ¹⁰ CFU to 10 ¹¹ CFU, 10 ⁹ CFU To 10 ¹⁴ CFU, 10 ⁹ CFU to 10 ¹² CFU, 10 ⁹ CFU to 10 ¹¹ CFU, 10 ⁹ CFU to 10 ¹⁰ CFU, 10 ¹⁰ CFU to 10 ¹⁴ CFU, 10 ¹⁰ CFU To 10 ¹³ CFU, 10 ¹¹ CFU to 10 ¹⁴ CFU, 10 ¹¹ CFU to 10 ¹³ CFU, 10 ¹² CFU to 10 ¹⁴ CFU, and 10 ¹³ CFU to 10 ¹⁴ CFU of uncultured Fecal bacteria preparations.

In one aspect, the uncultured fecal bacterial preparation has a unit weight of about 0.2, 0.4, 0.6, 0.8 or 1.0 g or a unit volume of about 0.2, 0.4, 0.6, 0.8 or 1.0 ml with the aforementioned medical activity or therapeutic effect. One of the doses is present in each unit dose of the pharmaceutical composition.

In one aspect, the pharmaceutical activity or therapeutically effective dose of an uncultured fecal bacterial preparation administered to an individual (ie, in single or multiple administrations) to treat at least one symptom of HBV or HDV contains at least 10 ⁵ , at least 10 ⁶ , at least 10 ⁷ , at least 10 ⁸ , at least 10 ⁹ , at least 10 ¹⁰ , at least 10 ¹¹ , at least 10 ¹² , at least 10 ¹³ , at least 10 ¹⁴ or at least 10 ¹⁵ uncultured fecal bacterial preparations Cells or spores. In another aspect, the pharmaceutical activity or therapeutically effective dose of an uncultured fecal bacterial preparation administered to an individual (ie, in single or multiple administrations) to treat at least one symptom of HBV or HDV comprises a total of Up to 10 ⁵ , up to 10 ⁶ , up to 10 ⁷ , up to 10 ⁸ , up to 10 ⁹ , up to 10 ¹⁰ , up to 10 ¹¹ , up to 10 ¹² , up to 10 ¹³ , up to 10 ¹⁴ or up to 10 ¹⁵ uncultured fecal bacteria The cells or spores of the preparation. In another aspect, the pharmacological activity or therapeutically effective dose of an uncultured fecal bacterial preparation administered to an individual (ie, in single or multiple administrations) to treat at least one symptom of HBV or HDV is selected Free the following groups: 10 ⁸ to 10 ¹⁴ , 10 ⁹ to 10 ¹³ , 10 ¹⁰ to 10 ¹² , 10 ¹⁰ to 10 ¹¹ , 10 ⁹ to 10 ¹⁴ , 10 ⁹ to 10 ¹² , 10 ⁹ to 10 ¹¹ , 10 ⁹ To 10 ¹⁰ , 10 ¹⁰ to 10 ¹⁴ , 10 ¹⁰ to 10 ¹³ , 10 ¹¹ to 10 ¹⁴ , 10 ¹¹ to 10 ¹³ , 10 ¹² to 10 ¹⁴ and 10 ¹³ to 10 ¹⁴ cells of uncultured fecal bacterial preparation or spore.

In one aspect, the medicinal activity or therapeutically effective dose cell count of an uncultured fecal bacterial preparation is related to living cells. In one aspect, the uncultured fecal bacterial preparation has a unit weight of about 0.2, 0.4, 0.6, 0.8 or 1.0 g or a unit volume of about 0.2, 0.4, 0.6, 0.8 or 1.0 ml with the aforementioned medical activity or therapeutic effect. One of the doses is present in each unit dose of the pharmaceutical composition.

In one aspect, the pharmaceutical composition described herein is in the form of a capsule, and each capsule contains at least 10 ⁵ , at least 10 ⁶ , at least 10 ⁷ , at least 10 ⁸ , at least 10 ⁹ , at least 10 ¹⁰ , at least 10 ¹¹ , At least 10 ¹² , at least 10 ¹³ , at least 10 ¹⁴ or at least 10 ¹⁵ cells or spores of uncultured fecal bacterial preparation. In one aspect, the pharmaceutical composition described herein is in the form of a capsule, and each capsule contains 10 ⁸ to 10 ¹⁴ , 10 ⁹ to 10 ¹³ , 10 ¹⁰ to 10 ¹² , 10 ¹⁰ to 10 ¹¹ , 10 ⁹ to 10 ¹⁴ , 10 ⁹ to 10 ¹² , 10 ⁹ to 10 ¹¹ , 10 ⁹ to 10 ¹⁰ , 10 ¹⁰ to 10 ¹⁴ , 10 ¹⁰ to 10 ¹³ , 10 ¹¹ to 10 ¹⁴ , 10 ¹¹ to 10 ¹³ , 10 ¹² to 10 ¹⁴ or 10 ¹³ to 10 ¹⁴ cells or spores of uncultured fecal bacterial preparations.

A combination of one or more bacterial isolates and an uncultured fecal bacterial preparation can be administered to an individual to treat one or more symptoms of HBV or HDV. In such cases, one or more bacterial isolates and an uncultured fecal bacterial preparation can be administered to the individual together in the same pharmaceutical composition or in separate compositions. In addition, a pharmaceutical composition (eg, comprising one or more bacterial isolates, an uncultured fecal bacterial preparation, or both) can be administered to an individual in a single unit dose or multiple unit doses, for example, as part of a dosage regimen. In one aspect, the dose of the uncultured fecal bacterial preparation administered to the individual (for example, as measured by CFU or cell/spore count) is greater than the dose of the bacterial isolate. Alternatively, the dose of the uncultured fecal bacterial preparation administered to the individual (for example, measured by CFU or cell/spore count) may be less than the dose of the bacterial isolate. In another aspect, the dose of the uncultured fecal bacteria preparation (for example, measured by CFU or cell/spore count) may be approximately the same as the dose of the bacterial isolate. For example, in one aspect, a bacterial isolate with a dose of about 10 ^{10 cells and an uncultured fecal bacterial preparation with a dose of about 10 10} cells can be administered to an individual to treat or prevent HBV or HDV. One or more symptoms.

In one aspect, the number of cells of the bacterial isolate administered to the individual to treat one or more of the symptoms of HBV or HDV is approximately equal to or greater than the total number of cells administered to the individual with the uncultured fecal bacterial preparation. Alternatively, the number of cells of the bacterial isolate administered to the individual to treat one or more symptoms of HBV or HDV may be approximately equal to or less than the total number of cells administered to the individual with an uncultured fecal bacterial preparation.

In one aspect, the pharmaceutical composition includes a bacterial mixture containing multiple bacterial isolates. In another aspect, at least two bacterial isolates are present in about the same amount or dose (eg, about the same number of live cells or spores or about the same CFU). In another aspect, at least three bacterial isolates, at least four bacterial isolates, at least five bacterial isolates, at least six bacterial isolates, at least seven bacterial isolates, at least eight bacterial isolates, at least nine bacterial isolates One bacterial isolate, at least ten bacterial isolates, or more than ten bacterial isolates are present in the pharmaceutical composition in about the same amount or dosage (for example, about the same number of living cells or spores or about the same CFU). In another aspect, all bacterial isolates in the bacterial mixture are present in approximately the same amount.

In one aspect, the pharmaceutical composition includes a bacterial mixture containing multiple bacterial isolates, and at least two of the multiple bacterial isolates are present in different amounts or doses (for example, different numbers of living cells or spores or different CFUs) . In another aspect, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more than ten bacterial isolates are present in different amounts or dosages In a mixture of bacteria.

The pharmaceutical composition may comprise a bacterial mixture comprising a combination of various bacterial isolates and an uncultured fecal bacterial preparation. In one aspect, each bacterial isolate is present in the composition in an amount or dose (for example, measured as the number of viable cells or spores or CFU) that is greater than the amount or dose of the uncultured fecal bacterial preparation. In another aspect, each bacterial isolate is present in the composition in an amount or dose (for example, measured as the number of viable cells or spores or CFU) that is less than the amount or dose of an uncultured fecal bacterial preparation. In another aspect, at least one bacterial isolate is present in the composition in an amount or dose (e.g., measured as the number of viable cells or spores or CFU) greater than the amount or dose of the uncultured fecal bacterial preparation, and At least one bacterial isolate is present in the composition in an amount or dose that is less than the amount or dose of an uncultured fecal bacterial preparation.

In one aspect, the pharmaceutical composition comprises one or more bacterial isolates in an amount or a dose equal to or higher than the minimum amount or dose of bacterial isolates required for the transplantation of bacterial isolates in the intestine of the individual administered to the individual . For example, bacterial isolates were transplanted to a minimum required dose of the individual intestinal bacterial isolates may be of at least ¹⁰⁶ cells, ¹⁰⁷ cells at least 10, at least 10 ⁸ cells, at least ¹⁰⁹ cells, at least 10 ¹⁰ cells, at least 10 ¹¹ cells, or at least 10 ¹² cells. In one aspect, the first bacterial isolate and the second bacterial isolate of the microorganism mixture are transplanted into the individual’s intestine in different minimum doses or amounts, and the first bacterial isolate and the second bacterial isolate in the microorganism mixture The dose or amount of each of them corresponds to the respective minimum dose or amount change required to transplant the respective bacterial isolate.

Individual doses of pharmaceutical compositions (for example, containing a mixture of bacteria) can be administered in unit dosage forms (for example, tablets or capsules) containing, for example, about 0.01 mg to about 5,000 mg, about 0.01 mg to about 4,000 mg, about 0.01 mg to about 3,000 mg, about 0.01 mg to about 2,000 mg, about 0.01 mg to about 1,000 mg, about 0.01 mg to about 950 mg, about 0.01 mg to about 900 mg, about 0.01 mg to about 850 mg, about 0.01 mg To about 800 mg, about 0.01 mg to about 750 mg, about 0.01 mg to about 700 mg, about 0.01 mg to about 650 mg, about 0.01 mg to about 600 mg, about 0.01 mg to about 550 mg, about 0.01 mg to about 500 mg, about 0.01 mg to about 450 mg, about 0.01 mg to about 400 mg, about 0.01 mg to about 350 mg, about 0.01 mg to about 300 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 200 mg , About 0.01 mg to about 150 mg, about 0.01 mg to about 100 mg, about 0.1 mg to about 90 mg, about 0.1 mg to about 80 mg, about 0.1 mg to about 70 mg, about 0.1 mg to about 60 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 40 mg, about 0.1 mg to about 30 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 5 mg, about 0.1 mg To about 3 mg, about 0.1 mg to about 1 mg active ingredient per unit dosage form, or about 5 mg to about 80 mg per unit dosage form. For example, the unit dosage form may include about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, About 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, About 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, or about 5,000 mg of active ingredient (including all values and ranges therebetween).

In one aspect, the pharmaceutical composition (for example, containing a bacterial mixture) is administered in the following amounts: about 0.01 mg to about 100 mg per day, about 0.01 mg to about 5,000 mg per day, about 0.01 mg to about 4,000 mg per day, About 0.01 mg to about 3,000 mg, about 0.01 mg to about 2,000 mg per day, about 0.01 mg to about 1,000 mg per day, about 0.01 mg to about 950 mg per day, about 0.01 mg to about 900 mg per day, about 0.01 mg to about 0.01 mg per day 850 mg, about 0.01 mg to about 800 mg per day, about 0.01 mg to about 750 mg per day, about 0.01 mg to about 700 mg per day, about 0.01 mg to about 650 mg per day, about 0.01 mg to about 600 mg per day, about 0.01 mg to about 550 mg, about 0.01 mg to about 500 mg per day, about 0.01 mg to about 450 mg per day, about 0.01 mg to about 400 mg per day, about 0.01 mg to about 350 mg per day, about 0.01 mg to about 300 mg per day mg, about 0.01 mg to about 250 mg per day, about 0.01 mg to about 200 mg per day, about 0.01 mg to about 150 mg per day, about 0.1 mg to about 100 mg per day, about 0.1 mg to about 95 mg per day, about 0.1 mg per day mg to about 90 mg, about 0.1 mg to about 85 mg per day, about 0.1 mg to about 80 mg per day, about 0.1 mg to about 75 mg per day, about 0.1 mg to about 70 mg per day, about 0.1 mg to about 65 mg per day , About 0.1 mg to about 60 mg per day, about 0.1 mg to about 55 mg per day, about 0.1 mg to about 50 mg per day, about 0.1 mg to about 45 mg per day, about 0.1 mg to about 40 mg per day, about 0.1 mg per day To about 35 mg, about 0.1 mg to about 30 mg per day, about 0.1 mg to about 25 mg per day, about 0.1 mg to about 20 mg per day, about 0.1 mg to about 15 mg per day, about 0.1 mg to about 10 mg per day, About 0.1 mg to about 5 mg per day, about 0.1 mg to about 3 mg per day, about 0.1 mg to about 1 mg per day, or about 5 mg to about 80 mg per day. In each aspect, the bacterial mixture is administered in the following daily doses: about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, About 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, About 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1,000 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, or about 5,000 mg (including all values and ranges therebetween).

In some aspects, the appropriate dosage of the pharmaceutical composition (for example, containing a bacterial mixture) is within the following range: about 0.01 mg/kg to about 100 mg/kg of the body weight, for example, about 0.01 mg/kg, about 0.02 mg/kg. kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, About 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/ kg, 1.9 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg body weight, about 50 mg/kg body weight, about 60 mg/kg body weight, about 70 mg /kg body weight, about 80 mg/kg body weight, about 90 mg/kg body weight, or about 100 mg/kg body weight, (including all values and ranges therebetween). In other aspects, the suitable dosage of the composition is in the range of about 0.01 mg/kg to about 100 mg/kg body weight, in the range of about 0.01 mg/kg to about 90 mg/kg body weight, and in the range of about 0.01 mg/kg body weight. To about 80 mg/kg body weight, about 0.01 mg/kg to about 70 mg/kg body weight, about 0.01 mg/kg to about 60 mg/kg body weight, about 0.01 mg/kg to about In the range of 50 mg/kg body weight, in the range of about 0.01 mg/kg to about 40 mg/kg body weight, in the range of about 0.01 mg/kg to about 30 mg/kg body weight, in the range of about 0.01 mg/kg to about 20 mg /Kg body weight, in the range of about 0.01 mg/kg to about 10 mg/kg body weight, in the range of about 0.01 mg/kg to about 9 mg/kg body weight, in the range of about 0.01 mg/kg to about 8 mg/kg Within the range of body weight, within the range of about 0.01 mg/kg to about 7 mg/kg of body weight, within the range of 0.01 mg/kg to about 6 mg/kg of body weight, and within the range of about 0.05 mg/kg to about 5 mg/kg of body weight , In the range of about 0.05 mg/kg to about 4 mg/kg body weight, in the range of about 0.05 mg/kg to about 3 mg/kg body weight, in the range of about 0.05 mg/kg to about 2 mg/kg body weight, in the range of about 0.05 mg/kg to about 2 mg/kg body weight, It is in the range of about 0.05 mg/kg to about 1.5 mg/kg of body weight or in the range of about 0.05 mg/kg to about 1 mg/kg of body weight.

According to certain aspects, it may be more than once a day, about once a day, about every other day, about every three days, about once a week, about once every two weeks, about once a month, about once every two months, about every The pharmaceutical composition (for example, containing a mixture of bacteria) is administered once every three months, about once every six months, or about once a year.

In one aspect, the pharmaceutical composition may be administered to patients in need at least once a day for at least two consecutive days. In another aspect, the pharmaceutical composition is administered at least once a day for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive days. In another aspect, the pharmaceutical composition is administered at least once a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In another aspect, the pharmaceutical composition is administered at least twice, three times, four times or five times a week for at least continuous 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 Or 12 weeks. In another aspect, the pharmaceutical composition is administered at least once a day for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20 days or weeks. In another aspect, the pharmaceutical composition is administered at least once a day for at most continuous 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks or months. In another aspect, the pharmaceutical composition is administered at least once for at least continuous 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or years, long-term administration to the individual The entire life span or for an indefinite period of time.

In one aspect, the pharmaceutical composition can be administered to patients in need at least twice a day for at least two consecutive days. In one aspect, the pharmaceutical composition is administered at least twice a day for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive days. In another aspect, the pharmaceutical composition is administered at least twice a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In another aspect, the pharmaceutical composition is administered at least twice a day for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days or weeks. In another aspect, the pharmaceutical composition is administered at least twice a day for at most consecutive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks or months. In another aspect, the pharmaceutical composition is administered at least twice for at least consecutive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or years, long-term administration continues The entire life span of the individual or for an indefinite period of time.

In one aspect of the present invention, the pharmaceutical composition can be administered to patients in need at least three times a day for at least two consecutive days. In one aspect, the pharmaceutical composition is administered at least three times a day for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive days. In one aspect, the pharmaceutical composition is administered at least three times a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks. In one aspect, the pharmaceutical composition is administered at least three times a day for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days or weeks. In one aspect, the pharmaceutical composition is administered at least three times a day for at most consecutive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks or months. In one aspect, at least three administrations of the pharmaceutical composition maintain at least consecutive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or years, and long-term administration continues throughout the individual. Life or continuous period of indefinite time.

In one aspect, the pharmaceutical composition can be administered to patients in need at least once or twice a day, maintaining a dosing schedule of at least three consecutive days or weeks. In one aspect, the dose is administered at least once, twice or three times a day for between 1 and 12 weeks, between 2 and 12 weeks, between 3 and 12 weeks, between 4 and 12 weeks, Between 5 and 12 weeks, between 6 and 12 weeks, between 7 and 12 weeks, between 8 and 12 weeks, between 9 and 12 weeks, between 10 and 12 weeks, between 1 Between and 2 weeks, between 2 and 3 weeks, between 3 and 4 weeks, between 4 and 5 weeks, between 5 and 6 weeks, between 6 and 7 weeks, between 7 and 8 The period between weeks, between 8 and 9 weeks, between 9 and 10 weeks, or between 10 and 11 weeks.

In one aspect, the pharmaceutical composition can be administered to patients in need on a schedule of once a week, twice a week, or three times a week. The term "once a week" means that usually only once a week, for example, the dose is administered on the same day in each week. "Twice a week" means that usually only twice a week, for example, the dose is administered on the same two days in each weekly period. "Three times a week" means that usually only three times a week, for example, the dose is administered on the same three days in each weekly period.

In one aspect, the pharmaceutical composition may be administered to a patient in need, wherein the administration includes a first administration schedule followed by a second administration schedule. In one aspect, the first dosing schedule includes a therapeutic or inducing dose. In one aspect, the second dosing schedule includes a maintenance dose. For example, the maintenance dose of medical activity in the second dosing period may be lower than or equal to the inducing dose of medicinal activity in the first dosing period. In other examples, the maintenance dose for the second dosing schedule may be higher than the induction dose for the first dosing schedule.

At least one of the first dosing schedule and the second dosing schedule for administering the pharmaceutical composition may include administering the composition at least once a day for at least one day. In one aspect, at least one of the first dosing schedule or the second dosing schedule includes administering the composition at least once a day, maintaining at least continuous 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 days. In one aspect, at least one of the first dosing schedule or the second dosing schedule includes administering the composition at least once a day, maintaining at least continuous 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks. In one aspect, at least one of the first dosing schedule or the second dosing schedule includes the administration composition, maintained at most consecutive 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20 days or weeks. In one aspect, at least one of the first dosing schedule or the second dosing schedule includes the administration composition, maintained at most continuously 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11 or 12 weeks or months. In one aspect, at least one of the first dosing schedule or the second dosing schedule includes administering the composition to maintain at least continuous 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or years, long-term administration lasts the entire life of the individual or for an indefinite period of time.

In one aspect, at least one of the first dosing schedule or the second dosing schedule used in the method may be once a week, twice a week, or three times a week.

In one aspect, at least one of the first dosing schedule and the second dosing schedule can last for at least about 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, or 96 moon. In one aspect, the second dosing schedule lasts permanently, for the entire lifespan of the individual being treated, or for an indefinite period of time. In one aspect, at least one of the first dosing schedule and the second dosing schedule is a continuous dosing schedule. In one aspect, at least one of the first dosing schedule and the second dosing schedule is an intermittent dosing schedule. In one aspect, at least one of the first dosing schedule and the second dosing schedule includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Or a treatment period of 14 days, followed by an intermittent dosing schedule of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of dormancy. In one aspect, at least one of the first dosing schedule and the second dosing schedule includes a dose administered every other day, every two days, or every 3, 4, 5, 6, 7, or 8 days. In one aspect, the dose is administered for an extended period of time with or without titration (or otherwise changing the dose or administration schedule).

In one aspect, the large interval between the first dosing schedule and the second dosing schedule is at least about 1, 2, 3, 4, 5, 6, or 7 days, or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks, or at least about 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, or 12 months.

In one aspect, the second dosing schedule (eg, maintenance dose) contains about 2, 3, 4, 5, 6, less than the dose used in the first dosing schedule (eg, initial induction dose). 7, 8, 9, 10, 20, 30, 40, 50, 75, 100, 200, 400, 800, 1000, 5000 or more times the dose. In another aspect, the second dosing schedule (for example, the maintenance dosing schedule) has a dosing frequency equal to or lower than the first dosing schedule (for example, the initial treatment dosing schedule). In one aspect, the second dosing schedule (eg, maintenance dosing schedule) has a higher dosing interval than the first dosing schedule (eg, initial treatment dosing schedule).

In one aspect, the first dosing schedule includes administering a single dose of the pharmaceutical composition to the individual. In one aspect, the second dosing schedule includes administering a single dose or multiple doses of the pharmaceutical composition to the individual, wherein the dose of the pharmaceutical composition during the second dosing schedule is less than the first dosing schedule The dosage of the pharmaceutical composition during the period.

In various aspects, the methods described herein are suitable for treating human individuals. In some aspects, humans are child humans. In other aspects, humans are adults. In other aspects, humans are elderly people. In other aspects, humans can be called patients. In some aspects, humans are females. In some aspects, humans are males.

In some aspects, the age of humans is in the following range: about 1 to about 18 months, about 18 to about 36 months, about 1 to about 5 years old, about 5 to about 10 years old, about 10 to about 15 years old Years old, about 15 to about 20 years old, about 20 to about 25 years old, about 25 to about 30 years old, about 30 to about 35 years old, about 35 to about 40 years old, about 40 to about 45 years old, about 45 to about 50 years old , About 50 to about 55 years old, about 55 to about 60 years old, about 60 to about 65 years old, about 65 to about 70 years old, about 70 to about 75 years old, about 75 to about 80 years old, about 80 to about 85 years old, About 85 to about 90 years old, about 90 to about 95 years old, or about 95 to about 100 years old.

In one aspect, the individual being treated is a human patient. In one aspect, the patient is a male patient. In one aspect, the patient is a female patient. In one aspect, the patient is a premature newborn. In one aspect, the patient is a full-term newborn. In one aspect, the patient is a newborn. In one aspect, the patient is a baby. In one aspect, the patient is an infant. In one aspect, the patient is a young child. In one aspect, the patient is a child. In one aspect, the patient is a youth. In one aspect, the patient is a child patient. In one aspect, the patient is an elderly patient. In one aspect, the human patient is a pediatric patient less than about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In another aspect, the human patient is an adult patient. In another aspect, the human patient is an elderly patient. In another aspect, the human patient is a patient who is greater than about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old. In another aspect, the patient is approximately between 1 and 5 years old, between 2 and 10 years old, between 3 and 18 years old, between 21 and 50 years old, between 21 and 40 years old. Between the ages of, between 21 and 30, between 50 and 90, between 60 and 90, between 70 and 90, between 60 and 80, or between Between 65 and 75 years old. In one aspect, the patient is a young elderly patient (65-74 years old). In one aspect, the patient is a moderately elderly patient (75-84 years old). In one aspect, the patient is an elderly patient (>85 years old). Other therapeutic agents and co-formulations

In addition to bacterial mixtures, the pharmaceutical compositions described herein can also include one or more therapeutic agents that can be administered to individuals in need in the methods described herein. The other therapeutic agent can be administered simultaneously or sequentially with the bacterial mixture described herein (for example, comprising one or more bacterial isolates and/or uncultured fecal bacterial preparations). In addition, the compositions and formulations of the present invention may contain other therapeutic agents (for example, via co-formulation). For example, other therapeutic agents, one or more bacterial isolates, and uncultured fecal bacterial preparations can be combined into a single formulation.

In one aspect, the other therapeutic agent and the bacterial mixture are administered to the individual at the same time. The term "simultaneous" as used herein means that the other therapeutic agent and the bacterial mixture are not more than about 60 minutes, such as not more than about 30 minutes, not more than about 20 minutes, not more than about 10 minutes, not more than about 5 minutes Or do not exceed about 1 minute intervals. Administration of other therapeutic agents and bacterial mixtures can be achieved by simultaneously administering a single formulation (for example, a formulation containing other therapeutic agents and bacterial mixtures) or separate formulations (for example, a first formulation including other therapeutic agents and including The second formulation of the bacterial mixture).

If the timing of the administration of other therapeutic agents is such that the pharmacological activities of the other therapeutic agent and the bacterial mixture (for example, containing one or more bacterial isolates and/or uncultured fecal bacterial preparations) overlap in time, the co-administration does not need to be simultaneous Administer other therapeutic agents. For example, other therapeutic agents and bacterial mixtures can be administered sequentially. The term "sequentially" as used herein means that other therapeutic agents and bacterial mixtures are administered at intervals of more than about 60 minutes. For example, the time between the sequential administration of other therapeutic agents and bacterial mixtures can be more than about 60 minutes, more than about 2 hours, more than about 5 hours, more than about 10 hours, more than about 1 day, more than about 2 days, More than about 3 days or more than about 1 week. The optimal administration time depends on metabolism, excretion rate and/or pharmacodynamic activity of other therapeutic agents and bacterial mixtures administered. Either the other therapeutic agent or the bacterial mixture can be administered first.

In another aspect, other therapeutic agents and bacterial mixtures can be administered to the individual at the same time, but the release of other therapeutic agents and bacterial mixtures from their respective dosage forms (or a single unit dosage form if formulated together) in the GI tract can depend on Order occurs.

Co-administration does not require multiple other therapeutic agents to be administered to the individual through the same route of administration as the bacterial mixture. In fact, each of the other therapeutic agents can be administered by any appropriate route such as parenteral or enteral.

In some aspects, the other therapeutic agent is an agent used to treat one or more symptoms of HBV or HDV in an individual. In some aspects, other therapeutic agents are selected from the group consisting of risperidone, fluoxetine, aripiprazole, vitamin D, levocarnitine and its combination.

In some aspects, the other therapeutic agent is an anti-inflammatory agent such as a steroidal anti-inflammatory agent or a non-steroidal anti-inflammatory agent (NSAIDS). Steroids, specifically adrenal corticosteroids and their synthetic analogs are well known in the art. Non-limiting examples of corticosteroids that can be administered to individuals as other therapeutic agents include hydroxyltriamcinolone, alpha-methyl dexamethasone, and beta-methyl dexamethasone. methyl betamethasone), beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol valerate, desonide , Desoximetasone, dexamethasone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluadrenolone (Fluclorolone acetonide), flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluoroacetate Prednidene (fluprednidene/fluprednylidene), flurandrenolone, halcinonide, hydrocortisone acetate, hydrocorticosterone butyrate, methylprednisolone (methylprednisolone), acetone cortisol (Triamcinolone acetonide), corticosterone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide ), methamphetamine, amcinafel, amcinafide, betamethasone and the rest of its esters, chloroprednisone, clocortelone, clescinolone ), dichlorosone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednate ( fluprednisolone, hydrocorticosterone, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate. Usable (NSAIDS) include (but are not limited to) salicylic acid, acetylsalicylic acid, methyl salicylate, ethylene glycol salicylate, salicamide, benzyl-2,5-diethyloxy Benzoic acid, ibuprofen, fulindac, naproxen, ketoprofen, etofenamate, phenylbutazone, indomethacin (Indomethacin) and its combination. Other anti-inflammatory agents are described in, for example, US Patent No. 4,537,776, the entire content of which is incorporated herein by reference in its entirety.

In some aspects, other therapeutic agents that can be incorporated into the pharmaceutical composition are probiotics. Probiotics are those that are administered to an individual to promote the growth, proliferation, or activity of one or more microorganisms (for example, bacteria) in the intestines of the individual (for example, by providing a substrate to be metabolized by one or more microorganisms). Or multiple compounds (for example, containing one or more nutrients). Without wishing to be bound by theory, probiotics can be added to the pharmaceutical composition to supplement the bacteria in the endogenous microbial community of the individual and/or in the pharmaceutical composition itself in a nutritional manner, for example to stimulate one or more The growth or activity of strains of uncultured fecal bacterial preparations and/or one or more bacterial isolates. In addition, one or more probiotics may be added to the composition, for example, after isolation and/or purification of uncultured fecal bacterial preparations or after freezing, freeze drying, spray drying, reconstitution in solution, and the like Before or after the transfer of bacterial cells to a new environment, buffer the "impact" of these cells.

Non-limiting examples of probiotics that can be added to the pharmaceutical composition include amino acids, lactic acid, ammonium nitrate, amylose, barley mulch, biotin, carbonate, cellulose, chitin, choline , Fructooligosaccharides (FOS), fructose, galactooligosaccharides (GOS), glucose, glycerol, heteropolysaccharides, histidine, homopolysaccharides, hydroxylapatite, inulin, isomaltulose, lactose, Lactulose, maltodextrin, maltose, mannose oligosaccharides, nitrogen, oligodextrose, fructooligosaccharides, inulin, oligosaccharides, pectin, phosphate, phosphorus, polydextrose , Polyols, potash, potassium, sodium nitrate, starch, sucrose, sulfur, solar fiber, tagatose, thiamine, trans-galacto-oligosaccharides, trehalose, vitamins, water-soluble carbohydrates, xylo-oligosaccharides ( XOS) and its combination. Illustrative probiotics include complex carbohydrates, amino acids, peptides or other basic nutritional components for the survival of the bacterial composition.

In one aspect, the probiotics are not used for pre-treatment before the individual is treated with the pharmaceutical composition. In another aspect, the pharmaceutical composition does not supplement the probiotics of beneficial bacteria.

In one aspect, for example, a pharmaceutical composition described herein that includes a bacterial mixture may include probiotics (eg, in dry or liquid form).

Alternatively or additionally, a different pharmaceutical composition that does not have a bacterial mixture may include probiotics (for example, in dry or liquid form) to be administered to the individual (for example, suffering from one or more symptoms of HBV or HDV).

The probiotic probiotics can be administered to the individual in the same pharmaceutical composition or in a separate pharmaceutical composition before, at the same time and/or after the pharmaceutical composition comprising the bacterial mixture is administered.

Probiotics can be provided and administered in a single dose or in multiple doses. When provided as a single dose, a single composition may contain only one probiotic supplement or a mixture of probiotic supplements. When provided in multiple doses, each composition administered to the subject may include a single probiotic supplement or a mixture of probiotic supplements, and/or the first composition administered to the subject may contain one or more of the same The second composition has different probiotics and bio-promoting qualities.

As an example, when multiple doses are provided, the first composition containing the probiotic supplement may include the first probiotic supplement such as inulin, and the second composition with or without the first probiotic supplement may Including different probiotics such as if glue. Alternatively, the first composition may include a combination of probiotics such as inulin and pectin and the second composition may include a different combination of probiotics such as inulin and FOS. The first composition may include a combination of probiotics and the second composition may include only one kind of probiotics.

The amount of probiotics included in the composition depends on the specific probiotics, one or more specific bacterial strains targeted by the probiotics, and/or the disease condition of the individual/patient.

In some aspects, other therapeutic agents that can be incorporated into the pharmaceutical composition are antidiarrheal agents. Non-limiting examples of antidiarrheal agents suitable for inclusion in the pharmaceutical compositions described herein include (but are not limited to) DPP-IV inhibitors; such as opium tincture, paregoric and codeine natural Opioids; synthetic opioids such as difenoxin, difenoxin, and loperamide; bismuth hyposalate; lanreotide; vapreotide and octreotide ( octreotide); enteromotor antagonist; COX2 inhibitors like celecoxib (COX2 inhibitors like celecoxib); glutamic acid; thalidomide and such as kaolin, pectin, berberine and Traditional antidiarrheal remedies for muscarinic agents and their combinations.

In some aspects, the other therapeutic agent incorporated into the pharmaceutical composition may be an analgesic agent. Analgesics suitable for use in the compositions and methods described herein include (but are not limited to) morphine, codeine, heroine, methadone and related compounds, thebaine, oripa Oripavine and its derivatives, buprenorphine, piperidine, morphinans, benzomorphin, tetrahydroisoquinoline, thiambutane, benzylamine, tilidine ( tilidine), viminol (viminol), nefopam (nefopam), capsaicin (8-methyl-N-vanillyl-6E-nonenylamide), "synthetic" capsaicin (N-vanillylnonanol) Amine) and related compounds and their combinations.

In some aspects, other therapeutic agents are antiviral agents, which include (but are not limited to) entecavir (Baraclude), tenofovir (Viread) , Lamivudine (Epivir), adefovir (Hepsera) and telbivudine (Tyzeka). In another aspect, the other therapeutic agent is an antiviral agent administered prior to administration of the pharmaceutical composition described herein. In another aspect, the other therapeutic agent is an antiviral agent administered during the administration of the pharmaceutical composition described herein. In another aspect, the other therapeutic agent is an antiviral agent administered after administration of the pharmaceutical composition described herein.

In some aspects, the other therapeutic agent is interferon alpha-2b (intron A). In one aspect, intron A is administered before the pharmaceutical composition described herein. In another aspect, intron A is administered during the administration of the pharmaceutical composition described herein. In one aspect, intron A is administered after administration of the pharmaceutical composition described herein. In another aspect, the pharmaceutical composition described herein is administered before or after the individual receives a liver transplant. In another aspect, the pharmaceutical composition containing the bacterial mixture described herein is used to treat HBV or HDV patients without the use of interferon.

In some aspects, other therapeutic agents include (but are not limited to) the following antibacterial agents: cephalosporin antibiotics (cephalexin, cefuroxime, cefadroxil) , Cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil and ceftobiprole) ; Fluoroquinolone antibiotics (cipro, levofloxacin (Levaquin), floxacin (floxin), tequin, avelox and norflox); tetracycline antibiotics (tetracycline) , Minocycline, oxytetracycline and doxycycline; penicillin antibiotics (amoxicillin, ampicillin, penicillin V, dicloxacillin, dicloxacillin) Benxilin (carbenicillin, vancomycin (vancomycin) and xylene penicillin); monocyclic β-lactam antibiotics (aztreonam); carbapenem antibiotics (ertapenem (ertapenem), doni Doripenem, imipenem/cilastatin and meropenem); and combinations thereof. In some aspects, the antibacterial agent may be penicillin, cephalosporin Any one or a combination of steroid, monocyclic β-lactam (monobactam) and carbapenem antibiotic (carbapenem antibiotic). In one aspect, in the case of antibiotic pre-treatment, use as described herein The pharmaceutical composition containing a bacterial mixture treats HBV or HDV patients. In another aspect, the pharmaceutical composition containing the bacterial mixture described herein is used to treat HBV or HDV patients without interferon pretreatment .

In one aspect, the method further comprises pre-treating the individual with the antibiotic composition before administering the therapeutic bacterial mixture. In one aspect, the antibiotic composition administered herein includes an antibiotic selected from the group consisting of: rifabutin, clarithromycin, clofazimine, vancomycin Chloramphenicol, rifampicin, nitroimidazole, chloramphenicol, and combinations thereof. In another aspect, the antibiotic composition administered herein includes an antibiotic selected from the group consisting of: rifaximin, rifamycin derivatives, rifaximin ), rifabutin, rifapentine, rifalazil, bicyclomycin, aminoglycoside, gentamycin, neomycin ( neomycin, streptomycin, paromomycin, verdamicin, mutamicin, sisomicin, netilmicin, reiter Rice star (retymicin), kanamycin (kanamycin), antreonam (aztreonam), antreonam macrolide, clarithromycin (clarithromycin), dirithromycin (dirithromycin), roxithromycin , Telithromycin, azithromycin, bismuth hyposalicylate, vancomycin, streptomycin, fidaxomicin, amikacin, arbekacin, Neomycin, nettimycin, paromomycin, rhodostreptomycin, tobramycin, apramycin, and combinations thereof. In another aspect, the subject is not pre-treated with the antibiotic composition prior to administration of the bacterial mixture. In another aspect, the pharmaceutical composition is not supplemented with an antibiotic composition. In another aspect, the method further comprises pre-treating the individual with an anti-inflammatory drug before administering the bacterial mixture. In another aspect, the individual is not pretreated with anti-inflammatory drugs prior to administration of the bacteria or mixture. In another aspect, the bacterial mixture is not supplemented with anti-inflammatory agents.

As described herein, the delivery of other therapeutic agents can target various parts of the GI tract.

When newly infected with HBV, most individuals infected with HBV do not experience any symptoms. Mild to severe symptoms usually appear about 1 to 4 months after infection, but they can also be found within a few weeks after infection. Signs and symptoms of HBV include abdominal pain, red urine, fever, joint pain, loss of appetite, nausea and vomiting, weakness and fatigue, jaundice, acute liver disease, chronic liver infection, cirrhosis and liver cancer.

It is difficult to distinguish HBV from other forms of hepatitis caused by other viral agents. HBV infection and treatment efficiency can be detected by measuring the viral load of HBV (for example, via Q-PCR). A blood test can be used to distinguish acute from chronic HBV infection. For example, the detection of HBV infection is carried out by detecting the HBV surface antigen HBsAg. Song, J. et al., Ann Transl Med. 4(18):338 (2016). Acute HBV infection is characterized by the presence of HBsAg and immunoglobulin M (IgM) antibodies against the nuclear antigen HBcAg. During the initial infection phase, the patient was seropositive for hepatitis B e antigen (HBeAg). HBeAg is a sign of a large amount of virus replication and indicates highly infectious blood and body fluids. Chronic infection is characterized by the presence of HBsAg for at least 6 months. The increase in HBsAg may be accompanied or not accompanied by the simultaneous presence of HBeAg. The persistence of HBsAg is the main indicator of the risk of chronic liver disease and hepatocellular carcinoma.

Hepatic steatosis is a common histopathological feature found in 14 to 70% of chronic HBV cases. See Baclig, M. et al., Int J Mol Epidemiol Genet. 9(2): 13-19 (2018). Hepatic steatosis is characterized by the deposition of lipid droplets in liver cells to exceed 5% of the total weight of the liver. Hepatic steatosis is usually classified as 0-3 based on the number of cells with intracellular fat vesicles. For example, grade 0 (normal) has up to 5% of cells affected, grade 1 (mild) has 5 to 33% of cells affected, and grade 2 (moderate) has 34 to 66% of cells affected. Grade 3 (severe) has 67% or more of the cells affected. Reeder, S. and Sirlin, C., Magn Reson Imaging Clin N Am. 18(3): 337-357 (2010).

Chronic HBV infection can be treated with antiviral agents. Antiviral agents slow down the progression of liver cirrhosis and reduce the incidence of liver cancer to improve long-term survival. The drugs used for the treatment of chronic HBV include Tenofovir (Verud), Intifo (Balalud), Lamefu Tablet (Epuvir), Adefovir (Chanshineng) and Telbivudine ( Tizeka). HBV vaccine can also be used. In one aspect of the invention, the individual treated with the pharmaceutical composition described herein has not been treated with an antiviral agent. In one aspect of the invention, an individual treated with the pharmaceutical composition described herein has been treated with an antiviral agent for at least 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60, 72, 78, 84, 90, 96 or 102 months. In one aspect of the invention, individuals treated with the pharmaceutical compositions described herein have been treated with antiviral agents for less than 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60, 72, 78, 84, 90, 96 or 102 months. In another aspect, a system is treated with an antiviral agent before, during, or after the pharmaceutical composition described herein. In another aspect, the pharmaceutical composition containing the bacterial mixture described herein is used to treat HBV or HDV patients without the use of antiviral agents. In one aspect of the invention, the individual treated with the pharmaceutical composition described herein has not been treated with HBV or HDV vaccine. In another aspect, each system is treated with HBV or HDV vaccine before, during or after treatment with the pharmaceutical composition described herein. In another aspect, the individual is also treated with the first, second or third dose of HBV or HDV vaccine before, during or after treatment with the pharmaceutical composition described herein.

The pharmaceutical composition described herein (for example, including one or more bacterial mixtures comprising, for example, one or more bacterial isolates and/or uncultured fecal bacterial preparations) can be administered to individuals in need for treatment or prevention One or more disorders, diseases, or conditions. In one aspect, a pharmaceutical composition is administered to an individual to prevent or treat one or more symptoms of HBV or HDV in the individual. Provided herein is a method for treating or preventing one or more symptoms of HBV or HDV in an individual in need, the method comprising administering to the individual the pharmaceutical composition described herein.

The methods provided herein cause or aim to achieve the detectable improvement of one or more indicators or symptoms of HBV or HDV. The one or more indicators or symptoms include abdominal pain, red urine, fever, joint pain, loss of appetite, nausea, and Vomiting, weakness and fatigue, and jaundice. In another aspect, the methods provided herein cause or aim to achieve detectable improvements in one or more of HBV or HDV, the one or more indicators including the presence of HBsAg and immunoglobulin M against nuclear antigen (IgM) Antibody, HBcAg, HBeAg, HBsAg or a combination thereof.

There are several screening devices known in the art for evaluating HBV or HDV. Evaluation can include liver biopsy, abdominal ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), temporary elastography, and magnetic resonance elastography (MRE). Diagnosis can also be in the form of blood tests. For example, medical professionals can assess a patient's complete blood count or lipid profile. Medical professionals can also perform liver enzyme and liver function tests as well as tests for chronic viral hepatitis.

In one aspect, the application provides a method for treating one or more symptoms of HBV or HDV in an individual in need, the method comprising administering to the individual a pharmaceutical composition in an amount effective to treat HBV or HDV, wherein the The pharmaceutical composition comprises an uncultured fecal bacterial preparation and at least one bacterial isolate, wherein the individual exhibits at least a 10% reduction in the severity of HBV or HDV symptoms after treatment compared to before starting treatment. In another aspect, HBV or HDV treatment causes at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% improvement in one or more HBV or HDV indicators or symptom severity %, as determined by blood tests or imaging procedures. The blood test is selected from the group consisting of: complete blood count, lipid profile, liver enzyme and liver function test, test for chronic viral hepatitis, or a combination thereof. The imaging procedures used to detect the severity of HBV or HDV symptoms are selected from the group consisting of liver biopsy, abdominal ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), temporary elastography and magnetic resonance Elastography (MRE) or a combination thereof.

In one aspect, the application provides a method for treating liver steatosis in an individual in need, the method comprising administering to the individual a certain amount of a pharmaceutical composition as provided herein, wherein the treatment begins Compared to before, individuals exhibited at least a 10% reduction in liver steatosis after treatment. In another aspect, HBV or HDV treatment causes a reduction in liver steatosis by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In another aspect, HBV or HDV treatment causes 5 to 10%, 10 to 20%, 20 to 30%, 30 to 40%, 40 to 50%, 50 to 60%, 60 to 70% reduction in liver steatosis , 70 to 80% or 80 to 90%. In one aspect, the amount of liver steatosis is measured by magnetic resonance imaging (MRI).

In one aspect, the application provides a method for treating liver steatosis in an individual in need, the method comprising administering to the individual a certain amount of a pharmaceutical composition as provided herein, wherein the treatment begins Compared to before, the individual exhibited a reduction in the number of cells affected by intracellular fat vesicles by at least 5% after treatment. In another aspect, HBV or HDV treatment causes a decrease in the number of cells affected by intracellular fat vesicles by at least 10%, 20%, 30%, 40%, 50%, 60% after treatment, compared to before starting treatment. %, 70%, 80% or 90%. In another aspect, HBV or HDV treatment causes a decrease in the number of cells affected by intracellular fat vesicles by 5 to 10%, 10 to 20%, 20 to 30%, 30 to 30% after treatment compared to before starting treatment. 40%, 40 to 50%, 50 to 60%, 60 to 70%, 70 to 80%, or 80 to 90%.

In one aspect, the application provides a method for treating liver steatosis in an individual in need, the method comprising administering to the individual a certain amount of a pharmaceutical composition as provided herein, wherein the treatment begins Compared to before, the individual exhibited at least one degree of reduction in steatosis after treatment. In another aspect, the present application provides a method for treating liver steatosis in an individual in need, the method comprising administering to the individual a certain amount of the pharmaceutical composition as provided herein, wherein the initial Compared to before treatment, the individual showed a reduction in steatosis to a moderate level after treatment. In another aspect, the present application provides a method for treating liver steatosis in an individual in need, the method comprising administering to the individual a certain amount of the pharmaceutical composition as provided herein, wherein the initial Compared with before the treatment, the individual showed a reduction in steatosis to a mild level after the treatment. In another aspect, the present application provides a method for treating liver steatosis in an individual in need, the method comprising administering to the individual a certain amount of the pharmaceutical composition as provided herein, wherein the initial Compared with before the treatment, the individual showed a reduction in steatosis to a normal level after the treatment.

In another aspect, compared with the serum HBsAg content in the individual before the pharmaceutical composition treatment, the HBV or HDV treatment with the pharmaceutical composition described herein causes the serum HBsAg content to decrease by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In another aspect, compared with the serum HBsAg content in the individual before the pharmaceutical composition treatment, the HBV or HDV treatment with the pharmaceutical composition described herein causes the serum HBcAg content to decrease by at least 10%, 20%, 30%. %, 40%, 50%, 60%, 70%, 80% or 90%. In another aspect, compared with the serum HBeAg content in the individual before the pharmaceutical composition treatment, the HBV or HDV treatment with the pharmaceutical composition described herein causes the serum HBsAg content to decrease by at least 10%, 20%, 30%. %, 40%, 50%, 60%, 70%, 80% or 90%.

In one aspect, treatment with the pharmaceutical composition described herein achieves a reduction in one or more HBV or HDV indicators or symptom severity by at least 10 after 2 weeks or more of treatment, compared to before starting treatment. %, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, where HBV or HDV indicators or symptom severity are assessed by a method selected from the group consisting of: liver biopsy , Abdominal ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), temporary elastography, magnetic resonance elastography (MRE) or a combination thereof.

In another aspect, treatment with the pharmaceutical composition described herein achieves a reduction in one or more HBV or HDV indicators or symptom severity after 2 weeks or more of treatment, compared to before starting treatment. % To 20%, 10% to 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90%, 20% to 30%, 20% to 40%, 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50% , 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40 % To 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90%, where HBV or HDV indicators or symptom severity are assessed by a program selected from the following groups : Liver biopsy, abdominal ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), temporary elastography, magnetic resonance elastography (MRE) or a combination thereof.

In another aspect, treatment with the pharmaceutical composition described herein achieves a reduction in serum HBsAg content of 10% to 20%, 10% to 10% after 2 weeks or more of treatment compared to before starting treatment. 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90%, 20% to 30%, 20% to 40% , 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50%, 30% to 60%, 30 % To 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40% to 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90%.

In another aspect, treatment with the pharmaceutical composition described herein achieves a reduction in serum HBcAg content of 10% to 20%, 10% to 10% after 2 weeks or more of treatment compared to before starting treatment. 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90%, 20% to 30%, 20% to 40% , 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50%, 30% to 60%, 30 % To 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40% to 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90%.

In another aspect, treatment with the pharmaceutical composition described herein achieves a reduction in serum HBeAg content of 10% to 20%, 10% to 10% after 2 weeks or more of treatment compared to before starting treatment. 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90%, 20% to 30%, 20% to 40% , 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50%, 30% to 60%, 30 % To 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40% to 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90%.

In another aspect, treatment with the pharmaceutical composition described herein achieves a reduction in serum HBsAg content after 4, 6, 8, 10, or 12 weeks or more of treatment, compared to before the start of treatment. % To 20%, 10% to 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90%, 20% to 30%, 20% to 40%, 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50% , 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40 % To 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90%.

In another aspect, treatment with the pharmaceutical composition described herein achieves a reduction in serum HBcAg content after 4, 6, 8, 10, or 12 weeks or more of treatment compared to before starting treatment. % To 20%, 10% to 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90%, 20% to 30%, 20% to 40%, 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50% , 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40 % To 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90%.

In another aspect, treatment with the pharmaceutical composition described herein achieves a reduction in serum HBeAg content after 4, 6, 8, 10, or 12 weeks or more of treatment compared to before starting treatment. % To 20%, 10% to 30%, 10% to 40%, 10% to 50%, 10% to 60%, 10% to 70%, 10% to 80%, 10% to 90%, 20% to 30%, 20% to 40%, 20% to 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50% , 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40 % To 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90%.

In one aspect, this application provides a method for treating HBV or HDV in an individual in need, the method comprising administering to the individual a certain amount of a pharmaceutical composition as provided herein, wherein the treatment begins Compared to before, individuals exhibited at least a 10% reduction in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) after treatment. In another aspect, HBV or HDV treatment causes at least 10%, 20%, 30%, 40%, 50% reduction in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) %, 60%, 70%, 80% or 90%. In another aspect, HBV or HDV treatment causes a 5 to 10%, 10 to 20%, 20 to 30% reduction in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) , 30 to 40%, 40 to 50%, 50 to 60%, 60 to 70%, 70 to 80%, or 80 to 90%. The normal range of the value of AST is about 5 to 40 units/liter of serum. The normal range of ALT is about 7 to 56 units/liter of serum. However, these equivalent values may vary slightly depending on the technology and solution used.

In one aspect, increased levels of γ-glutaminyl transpeptidase (GGT) can indicate liver damage. The normal content of GGT is about 9 to 48 U/L. In one aspect, this application provides a method for treating HBV or HDV in an individual in need, the method comprising administering to the individual a certain amount of a pharmaceutical composition as provided herein, wherein the treatment begins Compared to before, the individual exhibited at least a 10% reduction in GGT content after treatment. In another aspect, HBV or HDV treatment causes a decrease in GGT content by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In another aspect, HBV or HDV treatment causes a decrease in GGT content by 5 to 10%, 10 to 20%, 20 to 30%, 30 to 40%, 40 to 50%, 50 to 60%, 60 to 70%, 70 to 80% or 80 to 90%.

In one aspect, treatment with the pharmaceutical composition described herein achieves a reduction in HBV or HDV indicators or symptom severity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% and substantially maintain the symptom severity reduction for at least 8, 12, 16, 20, 24, or 28 weeks after the treatment is discontinued. The HBV or HDV indicators or the symptom severity are measured by blood tests, liver biopsy, Abdominal ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), temporary elastography, magnetic resonance elastography (MRE), or a combination of evaluations. In one aspect, treatment achieves a reduction in HBV or HDV indicators or symptom severity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% and is substantial after interruption of treatment The upper maintenance index or symptom severity is reduced for at least 8, 12, 16, 20, 24, or 28 weeks, where the HBV or HDV index or symptom severity is assessed by blood tests or imaging procedures.

In one aspect, the HBV or HDV individual being treated does not show gastrointestinal (GI) symptoms before starting treatment. In one aspect, the treated HBV or HDV individual does not show gastrointestinal (GI) symptoms for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 Weeks, 4 weeks, 1 month, 2 months, 6 months, 1 year or 2 years. In another aspect, the treated HBV or HDV individual exhibits one or more GI symptoms before starting treatment. In one aspect, the treated HBV or HDV individual presents gastrointestinal (GI) symptoms on a continuous or intermittent basis for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 6 months, 1 year or 2 years. In one aspect, the treated individual with HBV or HDV presents symptoms of chronic abnormal bowel function for at least 1 year. Such symptoms of chronic abnormal bowel function may include, for example, constipation and/or diarrhea. In one aspect, the treated HBV or HDV individual exhibits at least 20%, 30%, 40%, 50%, 60%, 70%, 80% reduction in the severity of GI symptoms after treatment, compared to before starting treatment. Or 90%. In one aspect, the severity of GI symptoms is assessed by the Gastrointestinal Symptom Rating Scale (GSRS). In another aspect, compared with before the start of treatment, after treatment for 2 weeks or longer, the severity of GI symptoms in HBV or HDV patients is reduced by 20% to 30%, 20% to 40%, and 20%. To 50%, 20% to 60%, 20% to 70%, 20% to 80%, 20% to 90%, 30% to 40%, 30% to 50%, 30% to 60%, 30% to 70 %, 30% to 80%, 30% to 90%, 40% to 50%, 40% to 60%, 40% to 70%, 40% to 80%, 40% to 90%, 50% to 60%, 50% to 70%, 50% to 80%, or 50% to 90%, where the severity of GI symptoms is assessed by GSRS.

GSRS is a disease-specific instrument that combines 15 items in five symptom clusters depicting reflux, abdominal pain, indigestion, diarrhea, and constipation. See Svedlund et al., Dig. Dis. Sci., 33(2):129-34 (1988). GSRS has a seven-point graded Likert-type scale (seven-point graded Likert-type scale) which is used to improve the sensitivity of the scale, where 0 means no distressing symptoms and 3 means extreme degree of symptoms . In one aspect, the treatment methods provided herein alleviate, relieve or eliminate one or more, two or more, three or more, four or more, five One or more, six or more or seven or more GI symptoms: epigastric pain, colic, dull abdominal pain, ambiguous abdominal pain, heartburn, acid reflux, sucking sensation in the upper abdomen, nausea And vomiting, abdominal ringing, abdominal distension, belching, increased gastrointestinal gas, decreased laxative, increased laxative, loose stools, hard stools, urgent need for defecation, and feeling of incomplete discharge. In another aspect, the treatment methods provided herein alleviate, alleviate or eliminate 2 to 4, 4 to 6, 6 to 8, 8 to 10, 10 to 12, 2 to 3, 2 To 4 types, 2 to 5 types, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 2 to 11, 2 to 12, 3 to 4, 3 To 5 types, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11, 3 to 12, 4 to 5, 4 to 6, 4 To 7, 4 to 8, 4 to 9, 4 to 10, 4 to 11, 4 to 12, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 To 10 types, 5 to 11 types, 5 to 12 types, 6 to 7, 6 to 8, 6 to 9, 6 to 10 types, 6 to 11 types, 6 to 12 types, 7 to 8, 7 Up to 9, 7 to 10, 7 to 11 or 7 to 12 GI symptoms, these GI symptoms are selected from the group consisting of: epigastric pain, colic, dull abdominal pain, ambiguous abdominal pain, heartburn, stomach acid Reflux, sucking sensation in the upper abdomen, nausea and vomiting, abdominal swelling, abdominal distension, belching, increased gastrointestinal gas, decreased laxative, increased laxative, loose stools, hard stools, urgent need for defecation, feeling of incomplete discharge, and weekly Less than 3 complete spontaneous bowel movements.

In one aspect, the abdominal pain of the treated individual is reduced from a more severe degree to a less severe degree, where the degree of pain is selected from the group consisting of: severe or severely harmful pain that has an impact on all social activities, and causes Relieve the long-term and troublesome dull pain and pain that interfere with many social activities, and the occasional dull pain and pain that interfere with some social activities, as well as no pain or temporary pain.

In another aspect, the heartburn of the treated individual is reduced from a more severe degree to a less severe degree, wherein the degree of pain is selected from the group consisting of: only accompanied by temporary relief by antacids Continuous discomfort, frequent long-term discomfort events, demanding relief, occasional short-term discomfort, and no or temporary heartburn.

In another aspect, the acid reflux condition of the treated individual is improved from a more severe degree to a less severe degree, wherein the degree of the disease state is selected from the group consisting of: reflux several times a day, performed by antacids It is only temporary and insignificant relief, reflux once or twice a day, demand relief, occasional distressing reflux, and no reflux or temporary reflux.

In another aspect, the sucking sensation in the upper abdomen of the treated individual is improved from a more severe degree to a less severe degree, wherein the degree of the condition is selected from the group consisting of: continuous discomfort, frequent requests between meals Food or antacids, frequent long-term discomfort events, food and antacids required between meals, occasional short-term discomfort, no food or antacids between meals, and no sucking sensation or temporary sucking sensation. As used herein, the sucking sensation in the upper abdomen is accompanied by the relief of the sucking sensation in the upper abdomen by food or antacids. If food or antacids are not available, the sucking sensation develops into dull pain and pain.

In another aspect, the nausea or vomiting of the treated individual is improved from a more severe degree to a less severe degree, wherein the degree of the disease state is selected from the group consisting of: continuous nausea accompanied by frequent vomiting, without There are frequent and long-term nausea of vomiting, occasional short-term nausea and no nausea.

In another aspect, the symptom of the abdomen of the treated individual is improved from a more severe degree to a less severe degree, wherein the degree of the symptom is selected from the group consisting of: continuous abdomen which seriously interferes with social performance, In the case of impaired social performance, it can be controlled by frequent and long-term events, occasional short-term distressing abdominis, and absence of abdominis or temporary abdominis.

In another aspect, the abdominal distension of the treated individual is improved from a more severe degree to a less severe degree, wherein the degree of the disease is selected from the group consisting of: continuous discomfort that severely interferes with social performance, which can be Adjust the control of clothing frequently and long-term events, occasional short-term discomfort, and no swelling or temporary swelling.

In another aspect, the belching condition of the individual being treated is improved from a more severe degree to a less severe degree, wherein the degree of the symptom is selected from the group consisting of: frequent events that seriously interfere with social performance, interference with some social activities Frequent events, occasional troublesome belching, and no belching or temporary belching.

In another aspect, the gastrointestinal gastrointestinal symptoms of the treated individual is improved from a more severe degree to a less severe degree, wherein the degree of the symptoms is selected from the group consisting of: frequent events that severely interfere with social performance, some interference Frequent and long-term social activities, occasional short-term discomfort, and no gastrointestinal increase.

In another aspect, the decrease in stool frequency of the treated individual is improved from a more severe degree to a less severe degree, where the degree is selected from the group consisting of: every six days or lower frequency, every five days , Every four days, every three days, every two days, every other day and once every day.

In another aspect, the increase in stool frequency of the treated individual is improved from a more severe degree to a less severe degree, where the degree is selected from the group consisting of: a frequency of seven or more times a day, six times a day, Five times a day, four times a day, three times a day, twice a day, and once a day.

In another aspect, the condition of loose stools of the treated individual is improved from a more severe degree to a less severe degree, where the degree is selected from the group consisting of: watery, excessively hydrated, slightly thinner, and normal consistency.

In another aspect, the sclerophyte condition of the individual being treated is improved from a more severe degree to a less severe degree, where the degree is selected from the group consisting of: hard and segmented, hard, hard with occasional diarrhea, Slightly firm and normal consistency. In one aspect, the stool of the treated individual is assessed using Daily Stool Records (DSR). In one aspect, according to DSR, the treated individual presents all Type 1 hard stools, Type 2 hard stools, Type 6 soft stools, Type 7 liquid stools and alleviation of abnormal stools.

In another aspect, the urgency of defecation of the treated individual is improved from a more severe degree to a less severe degree, where the degree is selected from the group consisting of: inability to control defecation, interference with social performance accompanied by sudden need to go to the toilet A sense of urgency for frequent bowel movements, a sense of urgency for occasional bowel movements, and normal bowel control.

In another aspect, the feeling of incomplete excretion of the treated individual is improved from a more severe degree to a less severe degree, where the degree is selected from the group consisting of: extremely difficult defecation accompanied by a feeling of incomplete excretion on a regular basis, accompanied by There is a sense of frequent incomplete discharge, clear difficulty in defecation, slightly difficulty in defecation, occasional feeling of incomplete discharge, and a sense of complete discharge without strain.

In another aspect, the number of fully spontaneous bowel movements (CSBM) per week of the treated individual is increased compared to baseline. In another aspect, the CSBM of the treated individual increases by at least 1, 2, 3, 4, 5, 6, 7 per week after at least 1, 2, 3, 4, 5, 6, 7 or 8 weeks of treatment , 8, 9, or 10 complete spontaneous bowel movements (CSBM). In another aspect, the number of complete spontaneous bowel movements (CSBM) of the individual is 1 or more weeks, 2 or more weeks, 3 or more weeks, 4 or more weeks, 5 weeks or After more weeks, 6 weeks or more weeks, or 7 or more weeks of treatment, increase CSBM at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times a week. In another aspect, the number of CSBMs per week of the treated individual maintains at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, after the completion of the treatment. 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks. In another aspect, the number of CSBMs per week of the treated individual increases by at least 1, 2, 3, 4, 5, 6, 7, 8, at 4, 8, 16, and 32 weeks compared with baseline. 9 or 10 CSBM.

In one aspect, the reduction in severity of symptoms (for example, for HBV or HDV symptoms, GI symptoms, or both) continues uninterrupted during treatment or after completion or interruption of treatment. In one aspect, the reduction in the severity of symptoms (for example, for HBV or HDV symptoms, GI symptoms, or both) is at a specific point in time during or after treatment, such as about 2, 4, 6, 8 after starting treatment , 12, 18, 24, 32, 40, 48 weeks or about 2, 4, 6, 8, 12, 18, 24, 32, 40, 48 weeks after completion or interruption of treatment.

In one aspect, the method further comprises administering antibiotics to the individual before administering the pharmaceutical composition comprising the fecal microbial preparation. In another aspect, the method further comprises subjecting the individual to bowel cleansing.

In another aspect, provided herein is a method for treating HBV or HDV in a human individual. In an exemplary aspect, the method comprises the following steps or consists essentially of the following steps: administering antibiotics to the human individual; subjecting the human individual to intestinal cleansing after the antibiotics are administered; and administering the article to the human individual after intestinal cleansing The pharmaceutical composition described in wherein the HBV or HDV of the human individual is treated.

In an exemplary aspect, treating HBV or HDV includes alleviating or improving one or more of HBV or HDV, two or more, three or more, four or more, five or more, Six or more, seven or more, eight or more symptom characteristics, delaying its onset, inhibiting its development, or reducing its severity. In one aspect, the treatment relieves, ameliorates one or more social and cognitive HBV or HDV-related symptoms, delays its onset, inhibits its development, or reduces its severity. In some aspects, the symptoms are selected from the group consisting of: abdominal pain, red urine, fever, joint pain, loss of appetite, nausea and vomiting, weakness and fatigue, or jaundice. In some aspects, the symptoms are detectable serum HBsAg levels. In some aspects, the symptoms are detectable serum HBsAg levels, with or without detectable HBeAg and has levels. In some aspects, the symptoms are persistently low levels of HBV DNA in the liver and no detectable HBsAg. The methods described herein can cause an improvement in any combination of the aforementioned symptoms.

Individuals who are suitable for treatment according to the methods provided herein may not be accompanied by or report symptoms of gastrointestinal distress before beginning the methods provided herein. In some cases, for example, human subjects suitable for treatment according to the methods provided herein do not show gastrointestinal symptoms before or at the start of treatment. In one aspect, the HBV or HDV individuals treated herein exhibit one or more or two or more GI symptoms selected from the group consisting of: abdominal pain, reflux, dyspepsia, irritable bowel syndrome, chronic persistence Diarrhea, diarrhea, gastrointestinal gas, constipation and alternate constipation/diarrhea.

Regardless of the presence or absence of gastrointestinal distress symptoms, human individuals suitable for the methods provided herein generally have significantly fewer gastrointestinal bacterial species prior to the treatment method compared to humans with general neurological conditions. In some cases, the human individual to be treated by the method exhibits at least about 20%, 30%, 40%, 50%, 60%, 70%, 80% less than the general human neurological state before administration of the pharmaceutical composition Or 90% of the bacterial species in the digestive tract.

In one aspect, the treated individual has reduced adverse events during treatment. In another aspect, the treated individual has no adverse events during the treatment period. In one aspect of the present invention, the adverse event is selected from the group consisting of abdominal cramps, fullness, gastrointestinal gas, abdominal distension, diarrhea, blood in the stool, fever, and combinations thereof. In another aspect, regardless of severity, any clinically significant laboratory abnormality, or any abnormality detected during physical examination, the adverse event is any sign or symptom. In another aspect, the adverse event is due to the pharmaceutically active dose. In another aspect, the adverse event is not due to the pharmaceutically active dose. In another aspect, the adverse event includes a solicited adverse event, an unsolicited adverse event, a serious adverse event, or a combination thereof. In one aspect, serious adverse events require hospitalized patients to be hospitalized or extend existing hospitalizations; cause persistent or significant impairment and/or disability, cause congenital abnormalities and/or birth defects; or are of any importance based on medical and scientific judgments A medical event, which may not be immediately life-threatening or cause death or hospitalization, but may pose a substantial risk to the patient or may require medical intervention to prevent one of the other results listed above.

In one aspect of the present invention, after 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 weeks of treatment, the treated individual has reduced Or there may be no adverse events.

This article also provides methods for reducing the severity of HBV or HDV in patients with HBV or HDV. In an exemplary aspect, the method comprises the following steps or consists essentially of the following steps: orally administer non-absorbable antibiotics to autistic human individuals; subject HBV or HDV patients to bowel cleansing; and administer HBV or HDV patients With a bacterial mixture, the bacterial mixture comprises one or more bacterial isolates from a human donor in a general neurological state and an uncultured fecal bacterial preparation, wherein the HBV or HDV patient presents HBV after the method compared to before starting the method Or a significant reduction in the severity of HDV symptoms, as assessed by blood tests or imaging procedures. In some cases, patients with HBV or HDV exhibit at least a 10% or 20% reduction in the severity of HBV or HDV symptoms compared to the severity assessed before starting the method, as assessed by blood tests or imaging procedures.

In one aspect, the present invention provides a method for treating HBV or HDV in an individual in need, wherein the method comprises orally administering to the individual a pharmaceutically active dose of the pharmaceutical composition described herein, wherein the pharmaceutically active The dose is administered with at least 50 ml of water. In another aspect, the method comprises administering the bacterial mixture not less than 2 hours after eating food or liquid other than water. In another aspect, the method includes consuming food or water no less than one hour after administration of the bacterial mixture. In one aspect, the present invention provides a method of treating HBV or HDV in an individual in need by administering the pharmaceutical composition described herein, wherein the method comprises at least 2 hours after ingestion of any solid or liquid calories. Administer the pharmaceutical composition within hours. In another aspect, the method comprises administering the pharmaceutical composition at least 1 hour before ingestion of any solid or liquid calories.

In one aspect, the present invention provides a method for treating HBV or HDV in an individual in need, the method comprising administering to the individual a pharmaceutical composition in an amount effective to improve the evaluation score by at least 10%. In one aspect, the pharmaceutical composition includes a bacterial mixture comprising an uncultured fecal bacterial preparation (for example, a substantially complete fecal microbial phase) and one or more bacterial isolates. In another aspect, the individual has GI symptoms associated with constipation with less than 3 complete spontaneous bowel movements per week for a period of time. In another aspect, the individual presents an improvement in the HBV or HDV index or symptom severity after treatment compared to before the start of treatment, and wherein the index or symptom severity is determined by a blood test selected from the group consisting of To determine: complete blood count, lipid profile, liver enzyme and liver function tests, tests for acute or chronic viral hepatitis (for example, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBS or HBsAb) and Hepatitis B nuclear antibody (anti-HBc or HBcAb) HBV test set) or a combination thereof. In another aspect, the individual presents an improvement in the index or symptom severity after treatment compared to before starting treatment, and wherein the index or symptom severity is determined by an imaging procedure selected from the group consisting of: Liver biopsy, abdominal ultrasound, computerized tomography (CT), magnetic resonance imaging (MRI), temporary elastography, magnetic resonance elastography (MRE), or a combination thereof. In another aspect, the individual presents an improvement in the severity of symptoms after the treatment compared to before the start of the treatment, and wherein the severity of the symptoms is determined by analyzing the stiffness of the patient's liver. Liver stiffness indicates fibrosis or scarring. Without being bound by theory, the hardness can be measured by temporary elastography or magnetic resonance elastography.

In one aspect, the present invention provides a method of treating HBV or HDV in an individual in need by administering a certain amount of the pharmaceutical composition described herein, wherein the individual in need has an associated weekly dose GI symptoms of constipation after 3 times of completely spontaneous bowel movements. In another aspect, an individual in need has GI symptoms with constipation accompanied by complete spontaneous bowel movements less than 2 times a week. In another aspect, an individual in need has GI symptoms with constipation accompanied by complete spontaneous bowel movements less than 2 times a week. In another aspect, an individual in need has GI symptoms accompanied by constipation with complete spontaneous bowel movements less than once a week. In one aspect, the individual in need has GI symptoms of constipation for a period of time selected from the group consisting of about 1 week, 2 weeks, 3 weeks, and 4 weeks. In another aspect, the individual in need has GI symptoms of constipation for a period of time selected from the group consisting of about 10 days, 20 days, 30 days, and 40 days. In another aspect, individuals in need have GI symptoms of constipation for 10 days and 15 days, 15 days and 20 days, 20 days and 25 days, 25 days and 30 days, 30 days and 35 days, 35 days The period between and 40 days.

In one aspect, the present invention provides a method for treating HBV or HDV in an individual in need by administering the pharmaceutical composition described herein, wherein the individual in need is at least 1, 2, 3, 4, After 5, 6, 7 or 8 weeks of treatment, it has improved GI symptoms of constipation with at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 complete spontaneous bowel movements (CSBM) per week. In another aspect, the individual in need is in 1 or more weeks, 2 or more weeks, 3 or more weeks, 4 or more weeks, 5 or more weeks, 6 weeks or Constipation with improved at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 complete spontaneous bowel movements (CSBM) per week after treatment for more weeks or between 7 or more weeks GI symptoms. In another aspect, the individual in need has GI symptoms of constipation that remain improved for at least 1, 2, 3, 4, 5, 6, 7 or 8 weeks after completing the treatment.

In one aspect, the present invention provides a method of treating HBV or HDV in an individual in need by administering the pharmaceutical composition described herein, wherein the method comprises analyzing the blood of the individual before, during, and after treatment , Overview of metabolites in feces or urine. In another aspect, the method further comprises analyzing the individual's blood, stool, or urine metabolite profile at least twice during the treatment and at least once after the treatment. In another aspect, the method further includes analyzing the individual's blood metabolite profile before starting treatment.

In one aspect of the invention, the age of the individual in need is between 5 and 17 years old. In another aspect, the individual in need is at least 5 years old. In another aspect, the individual in need is less than 17 years old. In one aspect, an individual in need is less than 5 years old. In one aspect, individuals in need are between 1 and 5 years old. In another aspect, the individual in need is less than 1 year old.

In another aspect, the individual in need does not have any serious medical condition that requires drug dosage adjustment, and the serious medical condition is selected from the group consisting of: single gene disease, severe brain malformation, tube feeding, and immediate treatment Severe GI problems (life-threatening), diagnosed celiac disease, eosinophilic gastroenteritis, severe underweight/malnutrition, and recent/scheduled surgery.

In one aspect, the present invention provides a method of screening individuals for compliance by administering a capsule containing a placebo for at least 7 consecutive days. In another aspect, the placebo capsules are administered for at least 14 consecutive days.

In one aspect, after at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks of treatment, the pharmaceutical composition effectively makes HBV Or improve the severity of HDV symptoms by at least 10%. In another aspect, in 1 or more weeks, 2 or more weeks, 3 or more weeks, 4 or more weeks, 5 or more weeks, 6 or more weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more weeks, 14 After weeks or more weeks, 15 weeks or more weeks, or 16 weeks of treatment, the pharmaceutical composition effectively improves the severity of HBV or HDV symptoms by at least 10%. In another aspect, treatment in 1 week and 3 weeks, 3 weeks and 5 weeks, 5 weeks and 7 weeks, 7 weeks and 9 weeks, 9 weeks and 11 weeks, 11 weeks and 13 weeks, 13 weeks and 16 weeks In between, the pharmaceutical composition effectively improves the severity of HBV or HDV symptoms by at least 10%. In another aspect, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 after the treatment has been completed After 20, 21, 22, 23 or 24 weeks, the pharmaceutical composition effectively maintains at least a 10% improvement in the severity of HBV or HDV symptoms. In another aspect, after the treatment has been completed, 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or More weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more Multiple weeks, 14 weeks or more, 15 weeks or more, or 16 weeks or more, 17 weeks or more, 18 weeks or more, 19 weeks or more, 20 weeks or more After many weeks, 21 weeks or more weeks, 22 weeks or more weeks, 23 weeks or more weeks, or 24 weeks or more weeks, the pharmaceutical composition effectively maintains at least a 10% improvement in the severity of HBV or HDV symptoms.

In one aspect, after at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks of treatment, the pharmaceutical composition effectively makes HBV Or improve the severity of HDV index symptoms by at least 15%. In another aspect, in 1 or more weeks, 2 or more weeks, 3 or more weeks, 4 or more weeks, 5 or more weeks, 6 or more weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more weeks, 14 After weeks or more weeks, 15 weeks or more weeks, or 16 weeks of treatment, the pharmaceutical composition effectively improves the HBV or HDV indicators or the severity of symptoms by at least 15%. In another aspect, treatment in 1 week and 3 weeks, 3 weeks and 5 weeks, 5 weeks and 7 weeks, 7 weeks and 9 weeks, 9 weeks and 11 weeks, 11 weeks and 13 weeks, 13 weeks and 16 weeks In between, the pharmaceutical composition effectively improves HBV or HDV indicators or symptom severity by at least 15%. In another aspect, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 after the treatment has been completed After 20, 21, 22, 23 or 24 weeks, the pharmaceutical composition effectively maintains HBV or HDV indicators or improves the severity of symptoms by at least 15%. In another aspect, after the treatment has been completed, 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or More weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more Multiple weeks, 14 weeks or more, 15 weeks or more, or 16 weeks or more, 17 weeks or more, 18 weeks or more, 19 weeks or more, 20 weeks or more After many weeks, 21 weeks or more weeks, 22 weeks or more weeks, 23 weeks or more weeks, or 24 weeks or more weeks, the pharmaceutical composition effectively maintains HBV or HDV indicators or improves the severity of symptoms by at least 15% .

In one aspect, after at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks of treatment, the pharmaceutical composition effectively makes HBV Or improve the severity of HDV index symptoms by at least 20%. In another aspect, in 1 or more weeks, 2 or more weeks, 3 or more weeks, 4 or more weeks, 5 or more weeks, 6 or more weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more weeks, 14 After weeks or more weeks, 15 weeks or more weeks, or 16 weeks of treatment, the pharmaceutical composition effectively improves the HBV or HDV indicators or the severity of symptoms by at least 20%. In another aspect, treatment in 1 week and 3 weeks, 3 weeks and 5 weeks, 5 weeks and 7 weeks, 7 weeks and 9 weeks, 9 weeks and 11 weeks, 11 weeks and 13 weeks, 13 weeks and 16 weeks In between, the pharmaceutical composition effectively improves HBV or HDV indicators or symptom severity by at least 20%. In another aspect, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 after the treatment has been completed After 20, 21, 22, 23 or 24 weeks, the pharmaceutical composition effectively maintains HBV or HDV indicators or improves the severity of symptoms by at least 20%. In another aspect, after the treatment has been completed, 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or More weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more Multiple weeks, 14 weeks or more, 15 weeks or more, or 16 weeks or more, 17 weeks or more, 18 weeks or more, 19 weeks or more, 20 weeks or more After many weeks, 21 weeks or more weeks, 22 weeks or more weeks, 23 weeks or more weeks, or 24 weeks or more weeks, the pharmaceutical composition effectively maintains HBV or HDV indicators or improves the severity of symptoms by at least 20% .

In one aspect, after at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks of treatment, the pharmaceutical composition effectively makes HBV Or improve the severity of HDV index symptoms by at least 30%. In another aspect, in 1 or more weeks, 2 or more weeks, 3 or more weeks, 4 or more weeks, 5 or more weeks, 6 or more weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more weeks, 14 After weeks or more weeks, 15 weeks or more weeks, or 16 weeks of treatment, the pharmaceutical composition effectively improves the HBV or HDV indicators or the severity of symptoms by at least 30%. In another aspect, treatment in 1 week and 3 weeks, 3 weeks and 5 weeks, 5 weeks and 7 weeks, 7 weeks and 9 weeks, 9 weeks and 11 weeks, 11 weeks and 13 weeks, 13 weeks and 16 weeks In between, the pharmaceutical composition effectively improves HBV or HDV indicators or symptom severity by at least 30%. In another aspect, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 after the treatment has been completed After 20, 21, 22, 23 or 24 weeks, the pharmaceutical composition effectively maintains HBV or HDV indicators or improves the severity of symptoms by at least 30%. In another aspect, after the treatment has been completed, 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or More weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more Multiple weeks, 14 weeks or more, 15 weeks or more, or 16 weeks or more, 17 weeks or more, 18 weeks or more, 19 weeks or more, 20 weeks or more After many weeks, 21 weeks or more weeks, 22 weeks or more weeks, 23 weeks or more weeks, or 24 weeks or more weeks, the pharmaceutical composition effectively maintains HBV or HDV indicators or improves the severity of symptoms by at least 30% .

In one aspect, after at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks of treatment, the pharmaceutical composition effectively makes HBV Or improve the severity of HDV index symptoms by at least 40%. In another aspect, in 1 or more weeks, 2 or more weeks, 3 or more weeks, 4 or more weeks, 5 or more weeks, 6 or more weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more weeks, 14 After weeks or more weeks, 15 weeks or more weeks, or 16 weeks of treatment, the pharmaceutical composition effectively improves HBV or HDV indicators or symptom severity by at least 40%. In another aspect, treatment in 1 week and 3 weeks, 3 weeks and 5 weeks, 5 weeks and 7 weeks, 7 weeks and 9 weeks, 9 weeks and 11 weeks, 11 weeks and 13 weeks, 13 weeks and 16 weeks In the meantime, the pharmaceutical composition effectively improves HBV or HDV indicators or symptom severity by at least 40%. In another aspect, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 after the treatment has been completed After 20, 21, 22, 23 or 24 weeks, the pharmaceutical composition effectively maintains HBV or HDV indicators or improves the severity of symptoms by at least 40%. In another aspect, after the treatment has been completed, 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or More weeks, 7 weeks or more weeks, 8 weeks or more weeks, 9 weeks or more weeks, 10 weeks or more weeks, 11 weeks or more weeks, 12 weeks or more weeks, 13 weeks or more Multiple weeks, 14 weeks or more, 15 weeks or more, or 16 weeks or more, 17 weeks or more, 18 weeks or more, 19 weeks or more, 20 weeks or more After many weeks, 21 weeks or more weeks, 22 weeks or more weeks, 23 weeks or more weeks, or 24 weeks or more weeks, the pharmaceutical composition effectively maintains HBV or HDV indicators or improves the severity of symptoms by at least 40% .

In one aspect, the present invention provides a method for treating HBV or HDV in an individual in need, wherein the method comprises administering to the individual a pharmaceutically active or therapeutically effective dose of the pharmaceutical composition described herein. In one aspect, the present invention provides a method for treating HBV or HDV in an individual in need, wherein the method comprises daily administering to the individual a therapeutically effective dose of the pharmaceutical composition described herein. In one aspect, the pharmaceutical composition may be administered to patients in need at least once a day for at least two consecutive days. In one aspect, the pharmaceutical composition is administered at least once a day for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive days. In another aspect, the pharmaceutical composition is administered at least once a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 week. In one aspect, the pharmaceutical composition is administered at least once a day for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days or weeks. In another aspect, the pharmaceutical composition is administered at least once a day for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 Week or month. In another aspect, the pharmaceutical composition is administered at least once for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 months Or annual or long-term administration for the entire life of the individual or for an indefinite period of time.

In one aspect, the pharmaceutical composition is administered to patients in need at least twice a day for at least two consecutive days. In one aspect, the pharmaceutical composition is administered at least twice a day for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive days. In another aspect, the pharmaceutical composition is administered at least twice a day for at least continuous 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks. In one aspect, the pharmaceutical composition is administered at least twice a day for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20 days or weeks. In another aspect, the pharmaceutical composition is administered at least twice a day for at most continuous 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks or months. In another aspect, the pharmaceutical composition is administered at least twice for at least consecutive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months or years, long-term administration continues The entire life span of the individual or for an indefinite period of time.

In one aspect, the pharmaceutical composition can be administered to patients in need at least three times a day for at least two consecutive days. In one aspect, the pharmaceutical composition is administered at least three times a day for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive days. In another aspect, the pharmaceutical composition is administered at least three times a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 week. In one aspect, the pharmaceutical composition is administered at least three times a day for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days or weeks. In another aspect, the pharmaceutical composition is administered at least three times a day for at most consecutive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 Week or month. In another aspect, the pharmaceutical composition is administered at least three times for at least consecutive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or years, long-term administration to the individual The entire life span or for an indefinite period of time.

In one aspect, the present invention provides a method for treating HBV or HDV in an individual in need, wherein the method comprises orally administering to the individual a therapeutically active dose of a pharmaceutical composition comprising a bacterial mixture, wherein the dose is It should be administered at least once or twice a day for at least three consecutive days or weeks. In another aspect, the dosage is administered at least once, twice or three times a day for between 1 week and 16 weeks, between 2 weeks and 16 weeks, between 3 weeks and 16 weeks, and 4 weeks Between and 16 weeks, between 5 and 16 weeks, between 6 and 16 weeks, between 7 and 16 weeks, between 8 and 16 weeks, between 10 and 16 weeks , Between 12 weeks and 16 weeks, between 1 week and 12 weeks, between 2 weeks and 12 weeks, between 3 weeks and 12 weeks, between 4 weeks and 12 weeks, between 5 weeks and Between 12 weeks, between 6 weeks and 12 weeks, between 7 weeks and 12 weeks, between 8 weeks and 12 weeks, between 9 weeks and 12 weeks, between 10 weeks and 12 weeks, Between 1 and 2 weeks, between 2 and 3 weeks, between 3 and 4 weeks, between 4 and 5 weeks, between 5 and 6 weeks, between 6 and 7 The period between weeks, between 7 weeks and 8 weeks, between 8 weeks and 9 weeks, between 9 weeks and 10 weeks, or between 10 weeks and 11 weeks.

In one aspect, the present invention provides a method of treating HBV or HDV in an individual in need by administering the pharmaceutical composition described herein, wherein the method comprises a single administration schedule. In one aspect, the administration schedule includes at least a continuous treatment period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 weeks. In one aspect, the administration schedule includes daily, every other day, every two days, or every 3, 4, 5, 6, 7, or 8 days.

In one aspect, the present invention provides a method of treating HBV or HDV in an individual in need by administering the pharmaceutical composition described herein, wherein the method comprises a first dosing schedule followed by a second Time course of administration. In one aspect, the first dosing schedule includes a therapeutic or inducing dose. In one aspect, the first dosing schedule includes a continuous dosing schedule. In another aspect, the first dosing schedule includes two consecutive days of dosing schedule. In another aspect, the first dosing schedule includes an equivalent dose of the dosing schedule for two consecutive days. In another aspect, the first dosing schedule includes a single daily dose. In another aspect, the first dosing schedule includes three consecutive days of dosing schedule. In another aspect, the first dosing schedule includes four consecutive days of dosing schedule. In another aspect, the first dosing schedule includes five consecutive days of dosing schedule. In another aspect, the first dosing schedule includes six consecutive days of dosing schedule. In another aspect, the first dosing schedule includes seven consecutive days of dosing schedule. In another aspect, the first administration schedule includes at least a continuous administration schedule of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days. In another aspect, the second administration schedule includes a maintenance dose that is less than or equal to the pharmaceutically active dose of the first administration schedule. In another aspect, the second dosing schedule lasts for at least about 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48, 72, or 96 weeks. In another aspect, the second administration schedule includes at least consecutive 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48, 72 or 96 weeks of administration. Time course of medicine. In another aspect, the second administration schedule includes at least consecutive 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48, 72 or 96 weeks of administration. Time course of medicine. In another aspect, the second administration schedule includes at least a continuous administration schedule of 12, 14, 21, 28, 35, 42, 49, 56, 63, 70, or 77 days. In one aspect, the second dosing schedule lasts permanently, for the entire lifespan of the individual being treated, or for an indefinite period of time. In one aspect, the second dosing schedule is a continuous dosing schedule. In another aspect, the second dosing schedule is an intermittent dosing schedule. In one aspect, the second administration schedule is a treatment period comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, followed by at least Intermittent dosing schedule for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of dormancy. In another aspect, the second administration schedule includes administration of the second dose (eg, maintenance dose) every other day, every two days, or every 3, 4, 5, 6, 7, or 8 days. In another aspect, the maintenance dose is administered for an extended period of time with or without titration (or otherwise changing the dose or administration schedule). In one aspect, there is no gap between the first dosing schedule and the second dosing schedule. In another aspect, the interval between the first dosing schedule and the second dosing schedule is at least 1, 2, 3, 4, 5, 6, or 7 days. In one aspect, the interval between the first dosing schedule and the second dosing schedule is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In another aspect, the second dosing schedule includes about 2, 3, 4, 5, 10, 50, 100, 200 less than the dose used in the first dosing schedule (eg, the initial therapeutic dose) , 400 or 500 times the dose (for example, maintenance dose). In another aspect, the second dosing schedule (for example, the maintenance dosing schedule) has a dosing frequency equal to or lower than the first dosing schedule (for example, the initial treatment dosing schedule). In another aspect, the second dosing schedule (for example, the maintenance dosing schedule) has a higher dosing interval than the first dosing schedule (for example, the initial treatment dosing schedule).

In one aspect, the present invention provides a method for treating an individual in need, wherein the method comprises administering to the individual a pharmaceutically active dose of a pharmaceutical composition comprising a bacterial mixture, the bacterial mixture comprising a plurality of carefully screened Uncultured fecal bacteria preparations from healthy donors. In one aspect, the pharmaceutical composition is administered to the individual during the administration period, wherein the first dose comprises at least one pharmaceutical composition comprising a preparation of uncultured fecal bacteria from a single donor, and the second dose of the pharmaceutical composition A preparation of uncultured fecal bacteria containing a single donor different from the first dose of the donor. In another aspect, the first dose includes a pharmaceutical composition that includes an uncultured fecal bacteria preparation from a single donor and the second dose includes an uncultivated fecal bacteria preparation from a donor pool. The first dose and the second dose do not indicate the order of administration to the individual, and in fact uncultured fecal bacterial preparations from independent donors can be used in a non-blended form. In another aspect, uncultured fecal bacterial preparations from multiple carefully screened healthy donors are provided in a blended form.

In one aspect, the pharmaceutical composition used herein comprises a bacterial mixture comprising an uncultured fecal bacterial preparation derived from a donor with pre-selected desired characteristics or receiving some pre-treatment. In one aspect, the donor does not have a current or previous HBV or HDV diagnosis or does not have HBV or HDV symptoms. In another aspect, the donor does not have family members or immediate relatives who have been diagnosed with HBV or HDV or exhibit HBV or HDV symptoms. In another aspect, the donor does not have siblings, parents or children who have been diagnosed with HBV or HDV or exhibit HBV or HDV symptoms. In one aspect, the donor has not previously received any fecal microbial transplantation. In one aspect, a fecal donor used for HBV or HDV treatment was previously supplied with feces to treat GI disorders such as Clostridium difficile infection or inflammatory bowel disease (IBD).

In one aspect, the individual receiving the treatment described herein is a pregnant woman. In another aspect, the pregnant women receiving treatment herein have older children who have been diagnosed with HBV or HDV or present with HBV or HDV syndrome. In another aspect, the fecal donor is pregnant. In another aspect, an uncultured fecal bacterial preparation prepared from feces from a pregnant donor (for example, in combination with one or more bacterial isolates) is administered to the pregnant individual. In another aspect, an uncultured fecal bacterial preparation prepared from feces from a pregnant donor is administered to a pregnant individual who is at risk of having children with HBV or HDV. In another aspect, the individual receiving the treatment described herein is a pregnant individual who is at risk of having children with HBV or HDV.

In one aspect, the individual receiving the treatment described herein is an individual at risk of developing HBV or HDV. In another aspect, the individual receiving the treatment described herein is an individual suffering from HBV or HDV and hypertension. In another aspect, the individual receiving the treatment described herein is an individual suffering from HBV or HDV and heart disease. In another aspect, the individual receiving the treatment described herein is an individual suffering from HBV or HDV and high blood lipid content. In another aspect, the individual receiving the treatment described herein is an individual suffering from HBV or HDV and insulin resistance. In another aspect, the individual receiving the treatment described herein is an individual suffering from HBV or HDV and type 2 diabetes. In another aspect, the individual receiving the treatment described herein is an individual suffering from HBV or HDV and obesity. In another aspect, the individual receiving the treatment described herein is an individual suffering from HBV or HDV and liver cancer.

In one aspect, the present invention provides a method for treating an individual in need, the treatment is performed by administering to the individual a pharmaceutically active dose of a pharmaceutical composition comprising a single donor's uncultured The fecal bacterial preparation and one or more bacterial isolates can be selected according to the situation. In another aspect, a test for determining the efficacy of the pharmaceutical composition of the pharmaceutical active dose is performed after the administration. In another aspect, the individual's test provides results for determining whether the active dose of the pharmaceutical composition should be adjusted. In another aspect, a pharmaceutical composition is administered after the test, the pharmaceutical composition comprising blended, uncultured fecal bacterial preparations from multiple donors and optionally one or more microbial isolates. In one aspect of the present invention, methods for treating individuals in need are provided, the methods comprising: (1) administering to the individual a first pharmaceutically active dose of an uncultured fecal bacterial preparation containing a single donor (And select one or more bacterial isolates as appropriate); (2) if additional doses are needed or if the dose should be adjusted, test the individual to determine the efficacy; (3) the administration contains from multiple sources The second pharmaceutical composition of a blended uncultured fecal bacterial preparation (and one or more bacterial isolates as appropriate); (4) as appropriate, if additional doses are needed or if the dose should be adjusted , Then test the individual to determine efficacy; and (5) administer a blended, uncultured fecal bacterial preparation (and optionally one or more bacterial isolates) from multiple donors as appropriate The third pharmaceutical composition, wherein multiple donors (a) include all the donors of the second pharmaceutical composition and other donors, (b) include fecal bacteria donors not included in the second pharmaceutical composition, (c) It includes some but not all of the fecal bacteria donors included in the second pharmaceutical composition, or includes the fecal bacteria donors that are not included in the second pharmaceutical composition. In another aspect, the first, second, and third pharmaceutical compositions are in a different order (ie, first, third, second; third, second, first; third, first, Second; second, first, third, etc.) vote.

In another aspect, the present invention provides a method for treating an individual in need, the treatment is carried out with a capsule containing a pharmaceutical composition comprising an uncultured fecal bacterial preparation from a single donor . In another aspect, the capsule contains a pharmaceutical composition containing uncultured fecal bacteria preparations from multiple donors. In one aspect, the individual is administered two or more pellets containing a preparation of uncultured fecal bacteria from a single but different donor.

In one aspect, the present invention provides methods for treating individuals in need, the methods comprising administering a pharmaceutical composition similar to or different from the previous administration during the treatment period, the pharmaceutical composition comprising a single donor Cultured fecal bacteria preparation. In another aspect, the treatment period includes administering the first dose of a pharmaceutical composition containing an uncultured fecal bacterial preparation containing a single donor and administering the first dose of a pharmaceutical composition containing uncultured fecal bacteria containing multiple donors. The second dose of the pharmaceutical composition of the bacterial preparation.

In one aspect, an uncultured fecal bacterial preparation and one or more bacterial isolates are administered to an individual in the same pharmaceutical composition according to the methods described herein. In one aspect, an uncultured fecal bacterial preparation and one or more bacterial isolates are administered to an individual in different pharmaceutical compositions according to the methods described herein. In one aspect, multiple bacterial isolates are administered to an individual in the same pharmaceutical composition according to the methods described herein. In one aspect, multiple bacterial isolates are administered to an individual in different pharmaceutical compositions according to the methods described herein. For example, the method may comprise administering to an individual in need an effective amount of a plurality of pharmaceutical compositions as disclosed herein, such as two or more pharmaceutical compositions, three or more pharmaceutical compositions, four One or more pharmaceutical compositions or five or more pharmaceutical compositions. Multiple pharmaceutical compositions can be provided simultaneously or sequentially. Therefore, if an individual is to be treated with, for example, an uncultured fecal bacterial preparation and two bacterial isolates, the first composition may comprise two bacterial isolates and the second composition may comprise an uncultured fecal bacterial preparation. In a different example, if the individual is to be treated with an uncultured fecal bacterial preparation and two bacterial isolates, the first composition may include an uncultured combination (or "admixed" with) the first bacterial isolate The fecal bacteria preparation, and the second composition may include a second bacterial isolate. In a different example, if an individual is to be treated with an uncultured fecal bacterial preparation and three bacterial isolates, the first composition may include the first bacterial isolate, the second composition may include the second bacterial isolate, and the third The composition may include a third bacterial isolate, and the fourth composition may include an uncultured fecal bacterial preparation.

In one aspect, the method for treating one or more symptoms of HBV or HDV in an individual in need comprises administering to the individual: (i) one or more bacterial isolates; (ii) uncultured fecal bacteria Preparation; and (iii) one or more antibiotics. The different components of (i)-(iii) can be administered to the individual in any order. For example, one or more antibiotics can be administered to an individual, followed by a bacterial mixture comprising an uncultured fecal bacterial preparation and one or more bacterial isolates. In another example, one or more antibiotics can be administered to an individual, followed by an uncultured fecal bacterial preparation, followed by one or more bacterial isolates. In another example, one or more antibiotics can be administered to an individual, followed by one or more bacterial isolates, followed by an uncultured fecal bacterial preparation. For each of the above examples, it should also be understood that any given component of the treatment method can be administered multiple times. For example, an individual can be administered antibiotics, followed by an uncultured fecal bacterial preparation, followed by one or more bacterial isolates, followed by a second administration of an uncultivated fecal bacterial preparation.

In one aspect, the method for treating one or more symptoms of HBV or HDV in an individual in need comprises administering to the individual: (i) one or more bacterial isolates; (ii) uncultured fecal bacteria Preparation; and (iii) one or more probiotics. The different components of (i)-(iii) can be administered to the individual in any order. For example, one or more probiotic probiotics can be administered to an individual, followed by a bacterial mixture comprising an uncultured fecal bacterial preparation and one or more bacterial isolates. In another example, one or more probiotics may be administered to an individual, followed by an uncultured fecal bacterial preparation, followed by one or more bacterial isolates. In another example, one or more probiotics may be administered to an individual, followed by one or more bacterial isolates, followed by an uncultured fecal bacterial preparation. In another example, one or more probiotics may be administered to the individual after one or both of one or more bacterial isolates and/or uncultured fecal bacteria preparations are administered. For each of the above examples, it should also be understood that any given component of the treatment method can be administered multiple times. For example, an uncultured fecal bacterial preparation can be administered to the individual, followed by one or more bacterial isolates, followed by a probiotic probiotic, followed by a second administration of an uncultivated fecal bacterial preparation.

In one aspect, the method for treating one or more symptoms of HBV or HDV in an individual in need comprises administering to the individual: (i) one or more bacterial isolates; (ii) uncultured fecal bacteria Preparation; (iii) one or more probiotics; and (iv) one or more antibiotics. The different components of (i)-(iv) can be administered to the individual in any order. For example, one or more antibiotics can be administered to the individual, followed by one or more probiotics, followed by a bacterial mixture comprising an uncultured fecal bacterial preparation and one or more bacterial isolates. In another example, one or more antibiotics can be administered to the individual, followed by one or more probiotics, followed by an uncultured fecal bacterial preparation, followed by one or more bacterial isolates. In another example, one or more antibiotics can be administered to the individual, followed by one or more probiotics, followed by one or more bacterial isolates, and then an uncultured fecal bacterial preparation. In another example, the probiotic probiotic may be administered after one or both of one or more bacterial isolates and/or uncultured fecal bacterial preparations have been administered. For each of the above examples, it should also be understood that any given component of the treatment method can be administered multiple times. For example, antibiotics can be administered to the individual, followed by an uncultured fecal bacterial preparation, followed by one or more bacterial isolates, followed by probiotics, and then a second administration of uncultured fecal bacteria. Fecal bacteria preparations.

In each of the above combination treatments, the duration between different treatments (for example, between the administration of an uncultured fecal bacterial preparation and one or more bacterial isolates) can be at least 1 hour, at least 2 hours , At least 6 hours, at least 12 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, or more than 8 weeks.

In one aspect, the individual being treated is an individual who has already suffered from a disorder (eg, HBV or HDV). Administration of the disclosed pharmaceutical composition to clinically asymptomatic human individuals who are genetically prone to or prone to suffering from diseases (for example, HBV or HDV) are also suitable for preventing the onset of clinical symptoms. A human individual who is genetically prone to or susceptible to suffering from HBV or HDV may be a human individual with close family members or relatives who present or suffer from a disease (such as HBV or HDV). In another aspect, the individual being treated is an individual in which HBV or HDV will be prevented. In another aspect, the individual being treated is prone to or susceptible to a condition (e.g., HBV or HDV). In another aspect, the individual being treated is an individual who has been diagnosed with a disorder (eg, HBV or HDV). In another aspect, the individual has a family member or immediate relative who has been diagnosed with HBV or HDV or exhibits HBV or HDV symptoms. In another aspect, the individual has siblings, parents, or children who have been diagnosed with HBV or HDV or exhibit HBV or HDV symptoms. In another aspect, the individual has not been diagnosed with HBV or HDV and has a family member, close relative, spouse, or sexual partner who has been diagnosed with HBV or HDV or exhibits HBV or HDV symptoms. In one aspect, the individual being treated is a patient in need.

In one aspect, the individual being treated is a human patient. In one aspect, the patient is a male patient. In one aspect, the patient is a female patient. In one aspect, the patient is a premature newborn. In one aspect, the patient is a full-term newborn. In one aspect, the patient is a newborn. In one aspect, the patient is a baby. In one aspect, the patient is an infant. In one aspect, the patient is a young child. In one aspect, the patient is a child. In one aspect, the patient is a youth. In one aspect, the patient is a child patient. In one aspect, the patient is an elderly patient. In one aspect, the human patient is a pediatric patient less than about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In another aspect, the human patient is an adult patient. In another aspect, the human patient is an elderly patient. In another aspect, the human patient is a patient who is greater than about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 years old. In another aspect, the patient is approximately between 1 and 5 years old, between 2 and 10 years old, between 3 and 18 years old, between 21 and 50 years old, between 21 and 40 years old. Between the ages of, between 21 and 30, between 50 and 90, between 60 and 90, between 70 and 90, between 60 and 80, or between Between 65 and 75 years old. In one aspect, the patient is a young elderly patient (65-74 years old). In one aspect, the patient is a moderately elderly patient (75-84 years old). In one aspect, the patient is an elderly patient (>85 years old).

In one aspect, the method comprises administering the pharmaceutical composition orally, by enema, or via rectal suppository. In one aspect, the pharmaceutical composition is formulated as a gelling agent, pill, microcapsule, capsule or lozenge. In one aspect, the pharmaceutical composition is formulated into enteric-coated capsules or microcapsules, acid-resistant capsules or microcapsules, or formulated as one of the following parts or administered together with: food, food additives, based Dairy products, soy-based products or their derivatives, jelly or yogurt. In another aspect, the pharmaceutical composition is formulated as an acid-resistant enteric coated capsule. The pharmaceutical composition may be provided in powder form for sale in combination with food or drink. The food or drink may be a dairy-based product or a soy-based product. In another aspect, the food or food supplement contains an enteric coating containing the pharmaceutical composition and/or acid-resistant microcapsules.

Described herein are kits comprising any of the pharmaceutical compositions disclosed herein and instructions for use. For example, the kit may include a unit dosage form containing a mixture of one or more bacteria. Such kits may include at least one or a mixture of bacteria including at least one of an uncultured fecal bacterial preparation and one or more bacterial isolates, and optionally a delivery device or a combination for administering the composition to the individual. Instructions for administering a dose to an individual via an appropriate route of delivery. In some cases, the dosage form contains live bacteria in any suitable form (fresh, frozen, lyophilized, etc.) and is formulated for oral administration, by nasogastric tube, by colonoscopy, or by anal administration to a human individual . As described herein, dosage forms suitable for the kits provided herein include, but are not limited to, liquid solutions, capsules, lozenges, powders, granules, and lyophilized forms.

The instructions of the kit can describe, for example, the administration information of one or more of the pharmaceutical compositions in the kit. As an example, the administration frequency and dosage of the composition, such as the number of capsules to be administered with the pharmaceutical composition at a predetermined time and the number of administrations per day/week. In situations where the kit contains more than one composition (for example, a mixture of multiple bacteria or other pharmaceutical compositions without a mixture of bacteria), the instructions may describe the administration of each composition. For example, one composition can be administered before the other composition, for example, two pharmaceutical compositions can be administered sequentially at intervals of minutes, hours, days, weeks, months or longer. Alternatively, the two compositions can be administered at the same time.

In another aspect, the use of the bacterial mixture described herein is provided herein for the manufacture of medicaments for the treatment of HBV or HDV or for reducing the severity of one or more indicators or symptoms of HBV or HDV .

The disclosure herein includes the selection of human fecal donors based on the abundance of bacterial taxa (for example, phyla, class, order, family, genus, species, or strains) in the feces of the donor, and subsequent use as a source of fecal bacteria. A method in which the donor collects feces to produce uncultured fecal bacteria preparations. For example, techniques based on nucleic acid hybridization, such as PCR (such as quantitative PCR), can be used to screen the feces or fecal microbiota of potential donors for the existence or abundance of specific relevant taxa, and if the taxa is higher than If the content of the threshold abundance is present in the feces, the donor can be selected as the fecal donor for the preparation of the pharmaceutical composition containing the relevant taxa. In one aspect, the uncultured fecal bacterial preparation prepared from the feces of the donor (that is, containing related taxa) can be supplemented with one or more bacterial isolates to improve the bacterial taxa in the presence of uncultured feces. The abundance in the bacterial mixture of the bacterial preparation.

In another aspect, the fecal donor may ingest one or more bacterial isolates, for example in the form of one or more probiotics, before performing the fecal supply. In one aspect, the fecal donor may ingest the bacterial isolate before supplying the feces to introduce the bacterial isolate into the fecal microbial phase of the supplied feces, that is, as a bacterial strain. Therefore, it is possible to ingest the required bacterial isolates included in the bacterial mixture of the pharmaceutical composition through the fecal donor to introduce the bacterial isolates into the fecal microbial phase of the donor, thereby making the uncultivated fecal bacterial preparation from "ready-made "Feces that have or have included bacterial strains derived from the desired bacterial isolate. Uncultivated fecal bacterial preparations from the feces of donors who have ingested bacterial isolates (for example, in the form of probiotics) can be directly incorporated into the pharmaceutical compositions described herein, without adding any other to the preparations The bacterial isolate, or alternatively, an additional dose of bacterial isolate may be further blended or concentrated. The origin of the fecal microbial phase of the fecal donor is to administer one or more desired bacterial strains of the bacterial isolates of the fecal donor. Endogenously contains bacterial strains of the same classification category (for example, phyla, class, order, family, genus, or species) as bacterial isolates, or does not endogenously contain genes with bacterial isolates higher than the threshold level Consistency (for example, 16S rRNA sequence with bacterial isolates with greater than 97% identity, greater than 98% identity, greater than 99% identity, greater than 99.1% identity, greater than 99.2% identity, greater than 99.3% identity , 16S rRNA sequence greater than 99.4% identity, greater than 99.5% identity, greater than 99.6% identity, greater than 99.7% identity, greater than 99.8% identity or greater than 99.9% identity) bacterial strains. In this article, the bacterial isolate that is incorporated into the fecal microbial phase by ingesting the bacterial isolate through the fecal microbial phase donor is referred to as "bacterial strain" (that is, derived from the ingested bacterial isolate) to exist in vitro The purified bacterial isolates are distinguished.

In one aspect, the donor may ingest probiotics that include bacterial isolates of classification categories that are not detectable or exist in relative abundance below the threshold abundance in the feces of the donor before ingesting the probiotics. For example, the presence of a specific taxa (phyla, class, order, family, genus, species or strain) in the donor microbial phase can be screened for the donor's fecal microbial phase (for example, using PCR such as PCR). Nucleic acid hybridization technology). If the taxa is not found in the microbial phase or exists with a relative abundance below the threshold abundance, the donor can administer or ingest probiotics containing bacterial isolates of the taxa.

In one aspect, the duration between the ingestion of one or more bacterial isolates by the fecal donor and the collection of feces from the donor (that is, including bacterial strains derived from one or more bacterial isolates) can vary; for example, The duration can be at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 20 hours, at least 22 hours. Hours, at least 24 hours, at least 26 hours, at least 28 hours, at least 30 hours, at least 32 hours, at least 34 hours, at least 36 hours, at least 38 hours, at least 40 hours, at least 42 hours, at least 44 hours, at least 46 hours, At least 48 hours, at least 50 hours, at least 52 hours, at least 54 hours, at least 56 hours, at least 58 hours, at least 60 hours, at least 62 hours, at least 64 hours, at least 66 hours, at least 68 hours, at least 70 hours, at least 72 Hours or more than 72 hours.

In one aspect, the donor may ingest a certain dose of the bacterial isolate one or more times to facilitate the incorporation of the bacterial isolate as a bacterial strain into the donor fecal microbial phase. In one aspect, the donor may ingest a certain dose of bacterial isolate at least once or twice a day for at least three consecutive days or weeks. In another aspect, the dose is taken at least once, twice or three times a day, maintained between 1 week and 16 weeks, between 2 weeks and 16 weeks, between 3 weeks and 16 weeks, between 4 weeks and Between 16 weeks, between 5 weeks and 16 weeks, between 6 weeks and 16 weeks, between 7 weeks and 16 weeks, between 8 weeks and 16 weeks, between 10 weeks and 16 weeks, Between 12 weeks and 16 weeks, between 1 week and 12 weeks, between 2 weeks and 12 weeks, between 3 weeks and 12 weeks, between 4 weeks and 12 weeks, between 5 weeks and 12 weeks Between weeks, between 6 weeks and 12 weeks, between 7 weeks and 12 weeks, between 8 weeks and 12 weeks, between 9 weeks and 12 weeks, between 10 weeks and 12 weeks, between Between 1 and 2 weeks, between 2 and 3 weeks, between 3 and 4 weeks, between 4 and 5 weeks, between 5 and 6 weeks, between 6 and 7 weeks Between, between 7 weeks and 8 weeks, between 8 weeks and 9 weeks, between 9 weeks and 10 weeks, or between 10 weeks and 11 weeks.

A method for manufacturing a pharmaceutical composition is disclosed herein. The method comprises: extracting a bacterial population or community from the feces of a healthy human donor; and incorporating the extracted bacterial population or community into a pharmaceutical composition, wherein the bacterial population or community Contains bacterial strains derived from probiotics ingested by healthy human donors.

Disclosed herein is a method of manufacturing a pharmaceutical composition containing a bacterial population or community of a healthy human donor, the method comprising: receiving feces from the donor after the donor has ingested probiotics including bacterial strains; extracting the bacterial population or community from the feces, wherein The bacterial population or community includes bacterial strains; the bacterial population or community is incorporated into a pharmaceutical composition, where the bacterial population or community is not cultured; and where the feces of the donor before the probiotics are ingested by the donor do not contain the bacterial strain.

It should be understood that the compositions, dosage forms and medicaments as described herein include one or more additional compounds or drugs added to the purified fecal microbial phase composition or otherwise together with the purified fecal microbial phase composition Co-administer the combined pharmaceutical composition.

The present invention provides and includes the following embodiments:

Example 1. A method for treating hepatitis B virus (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising administering to the individual a therapeutic composition of a pharmaceutically active dose, the treatment The composition contains a preparation of uncultured fecal bacteria.

Example 2. A method for treating hepatitis B virus (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising administering to the individual a therapeutic composition of a pharmaceutically active dose, the treatment The composition contains a mixture of bacteria.

Example 3. A method for treating hepatitis B virus (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising administering to the individual a therapeutic composition of a pharmaceutically active dose, the treatment The composition contains live non-pathogenic fecal bacteria or non-cellular fecal percolate.

Embodiment 4. The method of embodiment 1, 2 or 3, wherein the individual in need comprises hepatitis steatosis classified as group 1, group 2, or group 3.

Embodiment 5. The method of embodiment 1, 2 or 3, wherein the composition comprises an isolated or purified population of the live non-pathogenic fecal bacteria.

Embodiment 6. The method of embodiment 1, 2 or 3, wherein the composition comprises a non-selective fecal microbial phase.

Embodiment 7. The method of embodiment 1, 2 or 3, wherein the method reduces the hepatitis steatosis of the patient by at least 10%, 20%, 30%, 50%, 60% after 4, 8 or 12 weeks of treatment , 70%, 80% or 90%.

Embodiment 8. The method of embodiment 1, 2 or 3, wherein the method reduces the patient's ALT and/or AST content by at least 10%, 20%, 30%, 50% after 4, 8 or 12 weeks of treatment , 60%, 70%, 80% or 90%.

Embodiment 9. The method of Embodiment 1, 2 or 3, wherein the administration is on a daily or weekly basis.

Embodiment 10. As in the method of embodiment 1, 2 or 3, wherein the administration lasts for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks.

Embodiment 11. As in the method of embodiment 1, 2 or 3, wherein the dose is administered at least once a day or a week for at least continuous 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15 days.

Embodiment 12. As in the method of embodiment 1, 2 or 3, wherein the dose is administered at least once a day or a week for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11 or 12 weeks.

Embodiment 13. As in the method of embodiment 1, 2 or 3, wherein the dose is administered at least once a day or a week, and maintained at most continuously 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 13, 14, 15, 16, 17, 18, 19, or 20 days.

Embodiment 14. As in the method of embodiment 1, 2 or 3, wherein the dose is administered at least once a day or a week, and maintained at most continuously 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11 or 12 weeks.

Embodiment 15. As in the method of embodiment 1, 2 or 3, wherein the dose is administered at least twice a day or a week for at least two consecutive days.

Embodiment 16. As in the method of embodiment 15, wherein the dose is administered at least twice a day or a week, and maintained at least continuously for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 days.

Embodiment 17. As in the method of embodiment 15, wherein the dose is administered at least twice a day or a week for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks.

Embodiment 18. As in the method of embodiment 15, wherein the dose is administered at least twice a day or a week, maintaining at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days.

Embodiment 19. As in the method of embodiment 15, wherein the dose is administered at least twice a day or a week, maintaining at most continuously 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks.

Embodiment 20. Like the method of embodiment 1, 2 or 3, wherein the dose is administered at least three times a day for at least one day.

Embodiment 21. As in the method of embodiment 20, wherein the dose is administered at least three times a day for at least continuous 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 days.

Embodiment 22. As in the method of embodiment 20, wherein the dose is administered at least three times a day and maintained at most continuously for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 days.

Embodiment 23. As in the method of embodiment 1, 2 or 3, wherein the therapeutic composition comprises live non-pathogenic fecal bacteria and non-cellular fecal filter.

Embodiment 24. As in the method of embodiment 3, wherein the therapeutic composition comprises live non-pathogenic fecal bacteria supplemented with non-cellular fecal filter material.

Embodiment 25. As in the method of embodiment 3, wherein the non-cellular fecal filter material contains biologically active proteins or peptides, micronutrients, fats, sugars, small carbohydrates, trace elements, mineral salts, ash, mucus, amino acids, nutrients , Vitamins, minerals or any combination thereof.

Embodiment 26. Like the method of embodiment 23, wherein the non-cellular fecal filter material contains one or more biologically active molecules selected from the group consisting of bacteriocins, lantibiotics, and nisin.

Embodiment 27. As in the method of embodiment 23, wherein the non-cellular fecal filter material contains one or more bacteriocins selected from the group consisting of: colicin, tedurizine, pratadesine, microcin, and subtilis Bactericin A.

Embodiment 28. As in the method of embodiment 23, wherein the non-cellular fecal filter material contains one or more lantibiotics selected from the group consisting of thuringicin, nisin, subtilisin, fibrin, mutated chain Su, medicid, acagadine and cinnamycin.

Embodiment 29. As in the method of embodiment 23, wherein the non-cellular fecal filter material comprises an antispore compound, an antimicrobial compound, an anti-inflammatory compound, or any combination thereof.

Embodiment 30. As in the method of embodiment 23, wherein the non-cellular fecal filter material contains interleukin, cytokine, leukotriene, eicosanoid or any combination thereof.

Embodiment 31. The method as in any one of the preceding embodiments, wherein the method includes a first dosing schedule followed by a second dosing schedule.

Embodiment 32. Like the method of embodiment 31, wherein the second administration schedule includes a maintenance dose that is lower than or equal to the dose of the first administration schedule.

Embodiment 33. Like the method of embodiment 32, wherein the second administration schedule lasts for at least about 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, or 96 months.

Embodiment 34. Like the method of embodiment 32, wherein the second administration schedule lasts permanently.

Embodiment 35. Like the method of embodiment 31, wherein the interval between the first dosing schedule and the second dosing schedule is at least about 1, 2, 3, 4, 5, 6, 7, 8. 9, 10, 11 or 12 weeks.

Embodiment 36. Like the method of embodiment 31, wherein the second administration schedule is a continuous administration schedule.

Embodiment 37. Like the method of embodiment 31, wherein the second administration schedule is an intermittent administration schedule.

Embodiment 38. Like the method of embodiment 37, wherein the intermittent administration schedule includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. The treatment period is followed by a resting period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

Embodiment 39. The method as in any one of the preceding embodiments, wherein the composition is formulated in a delayed or gradual enteric release form.

Embodiment 40. The method as in any one of the preceding embodiments, wherein the administration comprises oral administration, by enema, or via rectal suppository.

Embodiment 41. The method as in any one of the preceding embodiments, wherein the composition is formulated into an enteric-coated capsule, an acid-resistant enteric-coated capsule, and an enteric-coated microcapsule , Or formulated as one of the following: food, food additives, dairy-based products, soy-based products or their derivatives, jelly or yogurt.

Embodiment 42 The method as in any one of the preceding embodiments, wherein the method eliminates or reduces muscle spasms.

Embodiment 43. The method as in any one of the preceding embodiments, wherein the method increases the bacterial diversity in the gastrointestinal tract of the individual.

Embodiment 44. The method of any one of the preceding embodiments, wherein the pharmaceutically active dose comprises at least about 10 ⁵ , 10 ⁶ , 10 ⁷ , 10 ⁸ , 10 ⁹ , 10 ¹⁰ , 10 ¹¹ , 10 ¹² or 10 ¹³ cfu or total number of cells.

Embodiment 45. The method of Embodiments 1, 2, 3, wherein the pharmaceutically active dose contains at most about 10 ⁵ , 10 ⁶ , 10 ⁷ , 10 ⁸ , 10 ⁹ , 10 ¹⁰ , 10 ¹¹ , 10 ¹² or 10 ¹³ cfu or total number of cells.

Embodiment 46. The method of Embodiment 1, 2, 3, wherein the pharmaceutically active dose is selected from the group consisting of 10 ⁵ to 10 ¹⁴ , 10 ⁶ to 10 ¹⁴ , 10 ⁷ to 10 ¹⁴ , 10 ⁸ to 10 ¹⁴ , 10 ⁹ to 10 ¹³ , 10 ¹⁰ to 10 ¹² , 10 ⁹ to 10 ¹⁴ , 10 ⁹ to 10 ¹² , 10 ⁹ to 10 ¹¹ , 10 ⁹ to 10 ¹⁰ , 10 ¹⁰ to 10 ¹⁴ , 10 ¹⁰ to 10 ¹³ , 10 ¹¹ to 10 ¹⁴ , 10 ¹¹ to 10 ¹³ , 10 ¹² to 10 ¹⁴ and 10 ¹³ to 10 ¹⁴ cfu or total number of cells.

Embodiment 47. As in the methods of Embodiments 1, 2, and 3, wherein the composition includes a faecal microorganism phase further supplemented with faecal microorganisms.

Embodiment 48. Like the method of Embodiments 1, 2, and 3, wherein the composition further comprises a non-pathogenic fungal isolate.

Embodiment 49. As in the method of embodiment 48, wherein the fungal isolate in the composition is at least 10%.

Embodiment 50. The method of embodiment 47, wherein the fecal microorganism is selected from the group consisting of: Bacteroides fragilis subsp. common, Collins aerogenes, Bacteroides fragilis subsp. polymorphous, Peptostreptococcus extensii II, Di Parabacteroides, Fusobacterium prausnitzii (Fusobacterium prausnitzii), Coccus regular, Collins aerogenes III, Peptostreptococcus aeruginosa I, Rumencoccus brucella, Bifidobacterium adolescentis, Bacillus formic acid, Bifidobacterium longum , Eubacterium inert, Rumenococcus twisted chain, Eubacterium rectum, Eubacterium fusiformis, Bacteroides escherichia, Clostridium vulgaris, Bacteroides fragilis subspecies A, Eubacterium biformis, Bifidobacterium infantis, Eubacterium rectum III- F. Accompanying Coccus faecalis, Pseudoflavonoids hirsutii, Rumencoccus albicans, Dallella long-chain, Eubacterium hosei, Eubacterium bulgingi I, Clostridium lamellae, Rumenococcus ovale, Eubacterium rectum, Multibranch Clostridium spores, Lactobacillus Leichmannii, Rumencoccus, Vibrio butyricum, Acidococcus spiculata, Eubacterium bulgingis, Bacteroides fragilis subsp. fragilis, Bacteroides AR, Faecococcus dexteris, Ha Anaerobic Corynebacterium, Eubacterium cylindrica, Eubacterium ruminant, Eubacterium CH-1, Staphylococcus epidermidis, Peptostreptococcus BL, Eubacterium mucinum, Typhimurium apothecium, Bacteroides L, Clostridium dysophilus I , Clostridium naviculare, Clostridium innocuous, Clostridium polycladi, Propionibacterium acnes, Rumenococcus chrysogenum, Rumenococcus AT, Peptococcus AU-1, Bacteroides fragilis subspecies ova, Bacteroides fragilis type d Subspecies, Bacteroides fragilis subspecies type f; Bacteroides L-1, Bacteroides L-5; Clostridium nucleatum, Clostridium dysfunction, Escherichia coli, Gemini measles, Fingoldi, Peptococcus G. Peptococcus-AU-2; Streptococcus intermedius, Rumencoccus yoghurt, Rumencoccus COBacterium X, Coccus faecalis BH, Coccus faecalis-CC; Eubacterium gracilis, Mycobacterium mycobacterium, Clostridium fusiformis Species, Bacteroides coagulans, Oral Prevotella, Rumen Prevotella, Oudryella viscera, Desulfovibrio inert, Lactobacillus G, Vibrio succinate A, and combinations thereof.

Embodiment 51. Like the method of Embodiment 6, wherein the fecal microbial phase is further supplemented with bacterial spores.

Embodiment 52. Like the method of embodiment 51, wherein the bacterial spores are Clostridium spores or Bacillus spores.

Embodiment 53 As in the method of Embodiment 6, wherein the preparation of the fecal microbial phase involves treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonic treatment.

Embodiment 54 As in the method of Embodiment 6, wherein the preparation of the fecal microbial phase does not involve treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonic treatment.

Example 55. As in the method of Example 6, wherein the preparation of the fecal microbial phase involves separation steps selected from the group consisting of density gradient, filtration, and chromatography.

Example 56. Like the method of Example 6, wherein the preparation of the fecal microbial phase does not involve separation steps selected from the group consisting of density gradient, filtration and chromatography.

Embodiment 57. As in the method of embodiment 6, wherein the fecal microbial phase includes the complete fecal microbial phase of the donor.

Embodiment 58. As in the method of embodiment 6, wherein the composition is substantially free of eukaryotic cells from the donor of the fecal microbial phase.

Embodiment 59. As in the method of embodiment 6, wherein the fecal microbial phase is derived from restored fecal matter.

Embodiment 60. As in the method of embodiment 6, wherein the fecal microbial phase is derived from synthetic fecal matter.

Embodiment 61. As in the method of embodiment 6, wherein the fecal microbial phase does not include antibiotic-resistant populations.

Embodiment 62. As in the method of Embodiment 6, wherein the fecal microbial phase contains a proportional amount of live biota preparation similar to normal healthy human fecal biota.

Embodiment 63. As in the method of embodiment 6, wherein the fecal microbial phase contains bacteria from at least seven different families.

Embodiment 64. As in the method of embodiment 6, wherein the agricultural diversity index of the manure microbial phase is 0.4-5.0.

Embodiment 65. As in the method of embodiment 6, wherein the fecal microbial phase comprises one or more microorganisms selected from the group consisting of: Clostridium spores, Bacillus, Collins, Bacteroides, Eubacterium, Clostridium, C Acidobacteria, Lactobacillus, Rumenococcus, Escherichia coli, Bud, Desulfomonas, Peptostreptococcus, Bifidobacterium and Candida.

Embodiment 66. As in the method of embodiment 6, wherein the fecal microbial phase does not include live Bacteroides, Clostridium, Propionibacterium, Lactobacillus, Rumenococcus, Escherichia coli, Bacteria, Desulfomonas, Peptostreptococcus, Bifidobacterium, Candida, or any combination thereof.

Embodiment 67. As in the method of embodiment 6, wherein the fecal microbial phase includes one or more microorganisms selected from the group consisting of: Bacteroides fragilis subsp. common, Collins aerogenes, Bacteroides fragilis subsp. polymorphous, extended Peptostreptococcus II, Parabacteroides dienii, Clostridium prasyllis, Faecococcus regularis, Collins aerogenes III, Peptostreptococcus aeruginosa I, Rumenococcus brucella, Bifidobacterium adolescentis, Bacillus formic acid, Long double Mycobacterium, Eubacterium inert, Rumenococcus twisted, Eubacterium rectum, Eubacterium fusiformis, Bacteroides escherichia, Clostridium tenuisii, Bacteroides fragilis subspecies A, Eubacterium biformis, Bifidobacterium infantis, Eubacterium rectum III-F, Accompanying Coccus faecalis, Pseudoflavonoids hirsutii, Rumencoccus albicans, Dallella long-chain, Eubacterium hosei, Eubacterium proboscis I, Clostridium laslerii, Rumenococcus ovale, Eubacterium rectum, Clostridium polymycosporum, Lactobacillus Leichmannii, Rumencoccus clever, Vibrio spikebutyricum, Acidococcus spiculata, Eubacteria protubercula, Bacteroides fragilis subsp. fragilis, Bacteroides AR, Faecococcus dexteris , Anaerobic Corynebacterium harveyi, Eubacterium cylindrica, Eubacterium ruminant, Eubacterium CH-1, Staphylococcus epidermidis, Peptostreptococcus BL, Eubacterium mucinae, Typhimurium extreme, Bacteroides L, Clostridium dead Bacteria I, Clostridium naviculare, Innocuous Bacillus sp Subspecies type d, Bacteroides fragilis subspecies type f; Bacteroides L-1, Bacteroides L-5; Clostridium nucleatum, Clostridium death, Escherichia coli, Gemini measles, Fingoldi, Peptococcus G, Peptococcus-AU-2; Streptococcus intermedius, Rumencoccus yoghurt, Rumencoccus CO, Bacterium X, Coccus faecalis BH, Coccus faecalis-CC; Eubacterium gracilis, Mycobacterium mycobacterium, Clostridium fusiformis Subsp. coliforms, Bacteroides coagulans, Prevotella oral cavity, Prevotella rumen, Oudryella viscera, Desulfovibrio inert, Lactobacillus G, Vibrio succinate A, and combinations thereof.

Embodiment 68. Like the method of embodiment 1, 2, 3, wherein the composition contains at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95% %, 99% or 99.5% bacterial spores.

Example 69. As in the method of Examples 1, 2, and 3, wherein the composition is in the form of liquid, freezing, freeze drying, spray drying, foam dehydration, freeze drying or powder.

Embodiment 70. Like the method of Embodiments 1, 2, and 3, wherein the composition includes excipients, physiological saline, buffer, buffer, or fluid-glucose-cellobiose agar (RGCA) medium.

Embodiment 71. As in the methods of Embodiments 1, 2, and 3, wherein the composition includes a cryoprotective agent.

Embodiment 72. As in the method of embodiment 71, wherein the cryoprotective agent comprises polyethylene glycol, skim milk, erythritol, arabitol, sorbitol, glucose, fructose, alanine, and glycamine Acid, proline, sucrose, lactose, ribose, trehalose, dimethylsulfene (DMSO), glycerin or a combination thereof.

Embodiment 73. The method of Embodiments 1, 2, and 3, wherein the composition further comprises an acid inhibitor, an antacid, an H ₂ antagonist, a proton pump inhibitor, or a combination thereof.

Embodiment 74. Like the methods of Embodiments 1, 2, and 3, wherein the composition contains substantially no non-living substances.

Embodiment 75. Like the method of Embodiments 1, 2, and 3, wherein the composition is substantially free of non-cellular substances selected from the group consisting of residual fibers, DNA, virus coating substances, and non-viable substances.

Example 76. Like the method of Examples 1, 2, and 3, wherein the composition is formulated into enteric coated capsules or microcapsules, acid-resistant capsules or microcapsules, powder suitable for reconstitution, nasal-duodenal infusion Or for delivery as an enema or colonoscopy infusion.

Embodiment 77. As in the method of embodiment 1, 2, 3, wherein the composition is combined with food, liquid beverage, food additive, dairy-based product, soybean-based product or its derivative, jelly or yogurt Co-investing.

Example 78. Like the method of Examples 1, 2, and 3, wherein the individual is pretreated with antibiotics before the composition is administered.

Embodiment 79. As in the method of embodiment 78, wherein the antibiotic is selected from the group consisting of rifabutin, clarithromycin, clofazimine, vancomycin, rifamycin, nitroimidazole, chlorine Mycin and its combination.

Embodiment 80. As in the method of embodiment 78, the antibiotic is selected from the group consisting of rifaximin, rifamycin derivatives, rifamycin, rifabutin, rifapentin, Folazil, dicyclomycin, aminoglycoside, gentamicin, neomycin, streptomycin, paromomycin, prestigmine, mutagen, sisomicin, nettimycin, Rui Termicin, kangmycin, aztreonam, aztreonam, clarithromycin, dirithromycin, roxithromycin, telithromycin, azithromycin, bismuth hyposalicylate, vancomycin Vitamins, streptomycin, fidaxomycin, amikacin, arbekacin, neomycin, nettimycin, paromomycin, erythromycin, tobramycin, apramycin and Its combination.

Embodiment 81. The method as in any one of the preceding embodiments, wherein prior to administration of the composition, the individual is pretreated with an anti-inflammatory drug.

Embodiment 82. The method as in any one of the preceding embodiments, wherein the composition comprises one or more, two or more, three or more, or four or more selected from the group consisting of Non-pathogenic spores of Clostridium sporospores: Clostridium different spores, Clostridium argentino, Clostridium pasteurii, Clostridium botulinum, Clostridium sarcosporum, Clostridium granulosporum, Clostridium crypticans, Emphysema Clostridium anthracis, Clostridium clostridium, Clostridium spores, Clostridium sphaeroides, Clostridium fescinia, Clostridium gordonii, Clostridium ethylene glycol, Clostridium haemolyticus, Clostridium sp Clostridium spores, Clostridium histolyticum, Clostridium indole, Clostridium irregular, Clostridium mucilae, Clostridium notorious, Clostridium novei, Clostridium orotic acid, Clostridium parasporidium Clostridium, Clostridium perfringens, Clostridium trisporum, Clostridium rotundus, Clostridium putrefaction, Clostridium sardinii, Clostridium paniculata, Clostridium scintillum, Clostridium spp. , Clostridium soxhletii, Clostridium cuneiformis, Clostridium spiralis, Clostridium sporogenum, Clostridium proximal spores, Clostridium symbiotic, Clostridium tertiary, Clostridium tetani, Clostridium weierii And Clostridium villus.

Embodiment 83. As in the method of Embodiments 1, 2, and 3, wherein the composition comprises purified, isolated, or cultured live non-pathogenic Clostridium spores and one or more genera selected from the group consisting of Plural kinds of purified, isolated or cultured live non-pathogenic microorganisms: Collins, Coccus, Dallella, Eubacterium and Rumenococcus.

Embodiment 84. Like the method of Embodiments 1, 2, and 3, wherein the composition comprises a plurality of purified, isolated or cultured live non-pathogenic microorganisms, which are selected from one or more of the following groups Genus: Clostridium spores, Collins bacteria, Coccus faecalis, Dallella, Eubacteria and Rumenococcus.

Embodiment 85. As in the method of embodiment 83, wherein the composition comprises two or more genera selected from the group consisting of: Collins, Faecoccus, Dallella, Eubacterium, and Rumenococcus.

Embodiment 86. As in the method of embodiment 83, wherein the composition comprises two or more genera selected from the group consisting of: faecalis, Dallella, Eubacterium, and Rumenococcus.

Embodiment 87. Like the method of embodiment 83 or 84, wherein the plurality of live non-pathogenic microorganisms include one or more, two or more, three or more, four or more, or five Or more species selected from the group consisting of: Faecoccus dexteroides, Faecoccus accompaniment, Dallella long-chain, Eubacterium fusciculata, Eubacterium macrobacteria, Eubacterium hosei, Eubacterium rectum, and Streptococcus ruminans.

Embodiment 88. The method as in any one of the preceding embodiments, wherein the method further comprises administering drugs to treat intestinal dysfunction, obesity, insulin resistance, hyperglycemia, prediabetes, or type 2 diabetes.

Embodiment 89. The method as in any one of the preceding embodiments, wherein the method further comprises administering drugs to treat abdominal pain, red urine, fever, joint pain, loss of appetite, nausea and vomiting, weakness and fatigue or jaundice.

Embodiment 90. Like the method of embodiment 88, wherein the drug for treating intestinal dysfunction is selected from the group consisting of docusate, bisacodyl, and docusate stool softening agent. Laxatives, sodium phosphate, mineral oil, psyllium hydrophilic musilloid, magnesium hydroxide and glycerin or a combination thereof.

Embodiment 91. Same as the method of any one of the preceding embodiments, wherein the method reduces liver steatosis.

Embodiment 92. The method as in any one of the preceding embodiments, wherein the method reduces liver fat.

Embodiment 93. Same as the method in any one of the preceding embodiments, wherein the method reduces the ALT content.

Embodiment 94. Same as the method in any one of the preceding embodiments, wherein the method reduces the AST content.

Embodiment 95. Same as the method in any one of the preceding embodiments, wherein the method reduces the GGT content.

Embodiment 96. As the method of any one of embodiments 91 to 95, wherein the reduction comprises a reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70% compared with the content before the treatment. %, 80% or 90%.

Embodiment 97. The method as in any one of the preceding embodiments, wherein the method eliminates or relieves one or more symptoms selected from the group consisting of: abdominal pain, fever, joint pain, loss of appetite, nausea and vomiting, weakness and fatigue Or jaundice.

Example 98. A method for treating at least one symptom of hepatitis B (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising administering (i) a pharmaceutical composition to the individual, It comprises a bacterial population derived from the feces of a human donor, wherein the bacterial population has not been cultured; and (ii) bacterial isolates.

Embodiment 99. Like the method of embodiment 98, wherein the pharmaceutical composition comprises the bacterial isolate.

Example 100. A method for treating at least one symptom of hepatitis B virus (HBV) in an individual in need, the method comprising administering to the individual a pharmaceutical composition, the pharmaceutical composition comprising a human donor The bacterial colony of the feces, where the bacterial colony has not been cultured.

Embodiment 101. A method comprising: extracting a bacterial colony from the feces of a healthy human donor; and mixing the bacterial colony with a bacterial isolate; wherein the bacterial colony is not cultured.

Embodiment 102. As in the method of embodiment 101, wherein the bacterial isolate is cultured.

Example 103. A method for treating at least one symptom of hepatitis B virus (HBV) in an individual in need, the method comprising administering to the individual (i) a pharmaceutical composition comprising a human donor The bacterial population of the feces, and (ii) at least one, at least two, or all three types of non-pathogenic microorganisms selected from the group consisting of: bacterial isolates, fungal isolates and archaea isolates.

Embodiment 104. Like the method of embodiment 103, wherein the bacterial population is not cultured.

Embodiment 105. Like the method of embodiment 103, wherein the non-pathogenic microorganism type is not cultured.

Embodiment 106. A method comprising: extracting a bacterial population from the feces of a healthy human donor; and mixing the bacterial population with the following: (i) non-pathogenic bacterial isolates, and (ii) at least one or at least two Or all three types of non-pathogenic microorganisms selected from the group consisting of: bacterial isolates, fungal isolates, and archaea isolates.

Embodiment 107. Like the method of embodiment 106, wherein the bacterial population is not cultured.

Embodiment 108. A method for treating the signs or symptoms of hepatitis B virus (HBV) in an individual in need, which comprises: administering a pharmaceutical composition to an individual in need, wherein the pharmaceutical composition comprises human-based The abundance of at least one component in the fecal microbial phase of a fecal donor is derived from a microbial population selected from the donor, wherein the microbial population is uncultured and contains at least one, at least two, or all three selected from the group consisting of Types of non-pathogenic microorganisms: bacterial isolates, fungal isolates and archaea isolates.

Example 109. A method for treating at least one symptom of hepatitis B (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising orally administering a pharmaceutical composition to the individual, the The pharmaceutical composition comprises a bacterial population derived from the feces of a human donor, wherein the bacterial population has not been cultured.

Embodiment 110. The method of embodiment 109, wherein the pharmaceutical composition further comprises a bacterial isolate, a fungal isolate, an archaeal isolate, or any combination thereof.

Embodiment 111. As in the method of embodiment 109 or 110, wherein the pharmaceutical composition is lyophilized.

Embodiment 112. As in the method of any one of embodiments 109 to 111, wherein the pharmaceutical composition is in a capsule.

Embodiment 113. As in the method of any one of embodiments 109 to 112, wherein the bacterial population includes a non-selective fecal microbial phase.

Embodiment 114. As in the method of any one of embodiments 109 to 113, wherein the pharmaceutical composition is administered orally every day.

Embodiment 115. As the method of any one of embodiments 109 to 113, wherein the pharmaceutical composition is administered orally every day, maintaining at least 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 , 28, 32, 40, 50, 60 or 80 weeks.

Embodiment 116. The method of any one of embodiments 109 to 115, wherein the individual has not received antiviral therapy before receiving the pharmaceutical composition.

Embodiment 117. The method of any one of embodiments 109 to 116, wherein the individual does not receive antiviral therapy when receiving the pharmaceutical composition.

Embodiment 118. The method of any one of embodiments 109 to 117, wherein the individual has not received interferon therapy before receiving the pharmaceutical composition.

Embodiment 119. The method of any one of embodiments 109 to 118, wherein the individual does not receive interferon therapy when receiving the pharmaceutical composition.

Embodiment 120. As in the method of any one of embodiments 109 to 119, wherein the individual exhibits HBeAg clearance after treatment.

Embodiment 121. As in the method of any one of embodiments 109 to 119, wherein the individual exhibits a decrease in HBsAg after treatment.

Embodiment 122. As in the method of any one of embodiments 109 to 119, wherein the individual exhibits a decrease in HBeAg after treatment.

The present invention can be better understood by referring to the following non-limiting examples, which are provided as examples of the present invention. The following examples are presented in order to more fully illustrate the preferred aspects of the present invention, however, they should not be construed as limiting the broad scope of the present invention. Therefore, the scope of the attached patent application should not be limited to the description of the aspects contained herein. Examples Example 1. Preparation of Fecal Microorganism Phase

The fecal microbial phase is basically prepared according to the scheme disclosed in US2014/0147417 or WO2014/152484. An exemplary scenario is outlined below.

Screen for potential fecal microbial donors according to the list of criteria used to exclude inappropriate donors. If the potential fecal microbial phase donor has received antibiotics, laxatives, weight-loss drugs, immunomodulators, or chemotherapy within the first three months, it will be excluded. If the potential fecal microbiota donor has the following medical history, it will be excluded: all known infectious diseases, morbid obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, chronic diarrhea, constipation, colorectal polyps or cancer, immunity System defects, metabolic syndrome, chronic fatigue syndrome, major GI surgery, or other diseases or conditions that may be related to specific changes in the fecal microbiota. If the potential fecal microbial phase donor has a positive laboratory test for C-reactive protein, erythrocyte sedimentation rate, hepatitis A, hepatitis B, hepatitis C, human immunodeficiency virus, human T lymphocyte virus or syphilis, it will Its exclusion. If the potential fecal microbial phase donor is positive for fecal eggs, parasites and/or viruses, it will be excluded. Potential fecal microbial donors who participated in high-risk sexual behaviors, were imprisoned, or received any tattoos or piercings in disease-endemic areas in the past three months are excluded.

Collect donor feces (fresh feces) from healthy, screened human donors in a sterile container, and in about 500-1000 mL 0.9% physiological saline solution containing 12-15% trehalose and 0.025% cysteine Medium homogenization. The resulting suspension was filtered at a pore size between 0.2 and 0.5 mm to produce an uncultured fecal bacterial preparation. If the preparation is to be stored, place it at -80 degrees Celsius. If a frozen preparation is to be used, it is thawed at room temperature before administration to the patient. Example 2. Capsules for oral treatment regimen of HBV or HDV

Divide patients into four groups (groups 1 to 4). Pretreatment with antibiotics (such as vancomycin and Metronidazole) was administered to patients in group 1. Group 2 did not receive antibiotics. Groups 1 and 2 all received bowel preparation before colonoscopy, followed by capsule fecal microbiota therapy. Groups 3 and 4 did not receive bowel preparation, while group 3, but not group 4, also received antibiotic pretreatment. A single capsule contains 10 ⁹ to 10 ¹² live cells. The capsules were administered for 18 weeks as follows: two capsules twice a day for 14 days; two capsules twice a day every other day for 14 days; 4 capsules twice a week for 14 days; and weekly 4 capsules at a time (e.g. every Monday) for 12 weeks. Use high-dose capsules (total cell count of approximately 10 ¹² ) in the initial dose (also called the therapeutic dose) for the first 4 weeks. Use lower dose capsules (total cell count of approximately ¹⁰⁹ ) in the maintenance dose for the following 14 weeks. In patients who received antibiotic pretreatment, capsules were administered on the first day after antibiotics were stopped. Observe patient symptoms and perform clinical examinations before, during and after oral capsule treatment. DNA environmental genomics before, during and after treatment (2-4 days; 1 week; 6 weeks; 12 weeks) are also performed. Capsule treatment can reverse the patient's symptoms and cause clinically normal desire and bowel movements.

Since various changes can be made and illustrated in the structure and method described herein without departing from the scope of the present invention, it is intended that all the content contained in the foregoing description should be interpreted illustratively and not restrictively. The breadth and scope of the present invention should not be limited by any of the above-mentioned exemplary embodiments, but should only be defined according to the scope of the following patent applications and their equivalents. All patent cases and non-patent documents cited in this specification are incorporated herein by reference in their entirety.

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Claims (122)

A method for treating hepatitis B virus (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising administering to the individual a pharmaceutically active dose of a therapeutic composition, the therapeutic composition comprising not Cultured fecal bacteria preparation. A method for treating hepatitis B virus (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising administering to the individual a pharmaceutically active dose of a therapeutic composition, the therapeutic composition comprising bacteria mixture. A method for treating hepatitis B virus (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising administering to the individual a pharmaceutically active dose of a therapeutic composition, the therapeutic composition comprising living The non-pathogenic fecal bacteria or non-cellular fecal filter material. The method of 2 or 3, wherein the individual in need comprises hepatitis steatosis classified as group 1, group 2, or group 3. The method of 2 or 3, wherein the composition comprises an isolated or purified population of the live non-pathogenic fecal bacteria. The method of 2 or 3, wherein the composition comprises a non-selective fecal microbial phase. The method of 2 or 3, wherein the method reduces the patient’s hepatitis steatosis by at least 10%, 20%, 30%, 50%, 60%, 70%, 80% or 90% after 4, 8 or 12 weeks of treatment . The method of 2 or 3, wherein the method reduces the patient's ALT and/or AST content by at least 10%, 20%, 30%, 50%, 60%, 70%, 80% after 4, 8 or 12 weeks of treatment Or 90%. The method of 2 or 3, wherein the administration is on a daily or weekly basis. The method of 2 or 3, wherein the administration lasts for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks. The method of 2 or 3, wherein the dose is administered at least once a day or a week for at least continuous 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 days . The method of 2 or 3, wherein the dose is administered at least once a day or a week for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. The method of 2 or 3, wherein the dose is administered at least once a day or a week for at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days. The method of 2 or 3, wherein the dose is administered at least once a day or a week for at most consecutive 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. The method of 2 or 3, wherein the dose is administered at least twice a day or a week for at least two consecutive days. The method of claim 15, wherein the dose is administered at least twice a day or a week for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive days . The method of claim 15, wherein the dose is administered at least twice a day or a week for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. The method of claim 15, wherein the dose is administered at least twice a day or a week for at most 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days. The method of claim 15, wherein the dose is administered at least twice a day or a week for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. The method of 2 or 3, wherein the dose is administered at least three times a day for at least one day. The method of claim 20, wherein the dosage is administered at least three times a day for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 consecutive days. The method of claim 20, wherein the dosage is administered at least three times a day for at most consecutive 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 days. The method of 2 or 3, wherein the therapeutic composition comprises live non-pathogenic fecal bacteria and a non-cellular fecal filter. The method of claim 3, wherein the therapeutic composition comprises live non-pathogenic fecal bacteria supplemented with a non-cellular fecal filter. The method of claim 3, wherein the non-cellular fecal filter contains biologically active proteins or peptides, micronutrients, fats, sugars, small carbohydrates, trace elements, mineral salts, ash, mucus, amino acids, nutrients, vitamins, minerals Substance or any combination thereof. The method of claim 23, wherein the non-cellular fecal filter material comprises one or more biologically active molecules selected from the group consisting of bacteriocins, lantibiotics, and nisin. Such as the method of claim 23, wherein the non-cellular fecal filter material contains one or more bacteriocins selected from the group consisting of: colicin, troudulixine, putaindicine, Microcin and subtilosin A. Such as the method of claim 23, wherein the non-cellular fecal filter material contains one or more lantibiotics selected from the group consisting of thuricin, nisin, subtilin, Fibrin (epidermin), mutacin, mersacidin, actagardine and cinnamycin. The method of claim 23, wherein the non-cellular fecal filter material comprises an anti-spore compound, an anti-microbial compound, an anti-inflammatory compound, or any combination thereof. The method of claim 23, wherein the non-cellular fecal filter material comprises interleukin, cytokine, leukotriene, eicosanoid or any combination thereof. A method according to any one of the preceding claims, wherein the method comprises a first dosing schedule followed by a second dosing schedule. The method of claim 31, wherein the second administration schedule comprises a maintenance dose lower than or equal to the dose of the first administration schedule. The method of claim 32, wherein the second administration schedule lasts for at least about 2, 4, 6, 8, 10, 12, 18, 24, 36, 48, 72, or 96 months. The method of claim 32, wherein the second administration schedule lasts permanently. The method of claim 31, wherein the interval between the first dosing schedule and the second dosing schedule is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks. The method of claim 31, wherein the second administration schedule is a continuous administration schedule. The method of claim 31, wherein the second administration schedule is an intermittent administration schedule. The method of claim 37, wherein the intermittent administration schedule comprises a treatment period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, and then A dormancy period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. The method according to any one of the preceding claims, wherein the composition is formulated as a delayed or gradual enteric release form. The method according to any one of the preceding claims, wherein the administration comprises oral administration, administration by enema or via rectal suppository. The method according to any one of the preceding claims, wherein the composition is formulated into an enteric coated capsule, an acid-resistant coated enteric coated capsule, an enteric coated microcapsule, or One of the following: food, food additives, dairy-based products, soy-based products or their derivatives, jelly or yogurt. The method of any one of the preceding claims, wherein the method eliminates or reduces muscle spasms. The method of any one of the preceding claims, wherein the method increases the bacterial diversity in the gastrointestinal tract of the individual. The method of any one of the preceding claims, wherein the pharmaceutically active dose comprises at least about 10 ⁵ , 10 ⁶ , 10 ⁷ , 10 ⁸ , 10 ⁹ , 10 ¹⁰ , 10 ¹¹ , 10 ¹² or 10 ¹³ cfu or a total of cell. 2. The method of 3, wherein the pharmaceutically active dose contains at most about 10 ⁵ , 10 ⁶ , 10 ⁷ , 10 ⁸ , 10 ⁹ , 10 ¹⁰ , 10 ¹¹ , 10 ¹² or 10 ¹³ cfu or total number of cells. 2. The method of 3, wherein the pharmaceutically active dose is selected from the group consisting of 10 ⁵ to 10 ¹⁴ , 10 ⁶ to 10 ¹⁴ , 10 ⁷ to 10 ¹⁴ , 10 ⁸ to 10 ¹⁴ , 10 ⁹ to 10 ¹³ , 10 ¹⁰ to 10 ¹² , 10 ⁹ to 10 ¹⁴ , 10 ⁹ to 10 ¹² , 10 ⁹ to 10 ¹¹ , 10 ⁹ to 10 ¹⁰ , 10 ¹⁰ to 10 ¹⁴ , 10 ¹⁰ to 10 ¹³ , 10 ¹¹ to 10 ¹⁴ , 10 ¹¹ to 10 ¹³ , 10 ¹² to 10 ¹⁴ and 10 ¹³ to 10 ¹⁴ cfu or total number of cells. 2. The method of 3, wherein the composition comprises a fecal microorganism phase further supplemented with fecal microorganisms. 2. The method of 3, wherein the composition further comprises a non-pathogenic fungal isolate. The method of claim 48, wherein the fungal isolate in the composition is at least 10%. The method 47 of such request entries, wherein the fecal microorganism selected from the group consisting of the group: Bacteroides fragilis ordinary subspecies (Bacteroides fragilis ssp vulgatus.), Collinsella aerofaciens (Collinsella aerofaciens), Bacteroides fragilis polymorphonuclear subspecies ( Bacteroides fragilis ssp. thetaiotaomicron , Peptostreptococcus productus II, Parabacteroides distasonis , Fusobacterium prausnitzii , Coprococcus eutactus , Collins III ( Collinsella aerofaciens III), Peptostreptococcus productus I (Peptostreptococcus productus I), Ruminococcus bromii , Bifidobacterium adolescentis , Gemmiger formicilis , Bifidobacterium longum ( Bifidobacterium longum , Eubacterium siraeum , Ruminococcus torques , Eubacterium rectale , Eubacterium eligens , Bacteroides eggerthii , Clostridium tenuipes ( Clostridium leptum ), Bacteroides fragilis ssp. A, Eubacterium biforme , Bifidobacterium infantis , Eubacterium rectale III-F (Eubacterium rectale III-F) , Coprococcus comes , Pseudoflavonifractor capillosus , Ruminococcus albus , Dorea formicigenerans , Eubacterium hallii ), Eubacterium ventriosum I, Fusobacterium russi , Ruminococcus obeum , Eubacterium rectale , Clostridium ramosum , Lactobacillus leichmannii , Ruminococcus callidus , Butyrivibrio crossotus , Acidaminococcus fermentans , Eubacterium ventriosum , Bacteroides fragilis ssp. fragilis , Bacteroides AR, Coprococcus catus , Aerostipes hadrus , Eubacterium cylindroides , Eubacterium ruminantium, Eubacterium CH-1, Staphylococcus epidermidis , Peptostreptococcus BL, Eubacterium limosum , Eubacterium limosum Tissierella praeacuta , Bacteroides L, Fusobacterium mortiferum I, Fusobacterium naviforme , Clostridium innocuum , Clostridium ramosum , Propionibacterium acnes , Ruminococcus flavefaciens , Ruminococcus AT, Peptococcus AU-1, Bacteroides fragilis ssp. ovatus ), fragile imitation pole Bacterium d subspecies, Bacteroides fragilis subspecies f; Bacteroides L-1 ( Bacteroides L-1), Bacteroides L-5 ( Bacteroides L-5); Fusobacterium nucleatum (Fusobacterium nucleatum), death bacteria Fusobacterium mortiferum , Escherichia coli , Gemella morbillorum , Finegoldia magnus , Peptococcus G, Peptococcus G, Peptococcus-AU-2; Intermediate chain Streptococcus intermedius , Ruminococcus lactaris , Ruminococcus CO Gemmiger X, Coprococcus BH, Coprococcus- CC; Eubacterium tenue , Micro branch Eubacterium (Eubacterium ramulus), fusiform fusiform Bacteroides subspecies (Bacteroides clostridiiformis ssp. clostridliformis), coagulation Bacteroides (Bacteroides coagulans), oral Prevotella bacteria (Prevotella oralis), rumen habitat Prevotella (Prevotella ruminicola ), Odoribacter splanchnicus , Desuifomonas pigra , Lactobacillus G, Succinivibrio A, and combinations thereof. The method of claim 6, wherein the fecal microbial phase is further supplemented with bacterial spores. The method according to item 51 of the request, wherein the bacterial spore such as Clostridium (Clostridium) spores or Bacillus (Bacillus) spores. The method of claim 6, wherein the preparation of the fecal microbial phase involves treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonic treatment. Such as the method of claim 6, wherein the preparation of the fecal microbial phase does not involve treatment selected from the group consisting of ethanol treatment, detergent treatment, heat treatment, irradiation, and sonic treatment. The method of claim 6, wherein the preparation of the fecal microbial phase involves separation steps selected from the group consisting of density gradient, filtration and chromatography. The method of claim 6, wherein the preparation of the fecal microbial phase does not involve separation steps selected from the group consisting of density gradient, filtration and chromatography. The method of claim 6, wherein the fecal microbial phase comprises the complete fecal microbial phase of the donor. The method of claim 6, wherein the composition is substantially free of eukaryotic cells from the donor of the fecal microbial phase. The method of claim 6, wherein the fecal microbial phase is derived from restored fecal matter. The method of claim 6, wherein the fecal microbial phase is derived from synthetic fecal material. The method of claim 6, wherein the fecal microbiota does not include antibiotic-resistant populations. The method of claim 6, wherein the fecal microbial phase comprises a living biotas preparation similar to a normal healthy human fecal biota in a proportional content. The method of claim 6, wherein the fecal microbial phase contains bacteria from at least seven different families. Such as the method of claim 6, wherein the Shannon Diversity Index (Shannon Diversity Index) of the manure microbial phase is 0.4-5.0. The method of the requested item 6, wherein the microorganism fecal phase comprises one or more microorganism selected from the group consisting of: Clostridium, Bacillus, bacteria Collins (Collinsella), Bacteroides (Bacteroides), Eubacterium (Eubacterium), Fusobacterium, Propionibacteriu , Lactobacillus , Ruminococcus , Escherichia coli, Gemmiger , Desulfomonas , Peptostreptococcus ), Bifidobacterium (Bifidobacterium) and Candida ( Monilia ). The method of claim 6, wherein the fecal microbial phase does not contain live Bacteroides, Clostridium, Propionibacterium, Lactobacillus, Rumenococcus, Escherichia coli, Bud, Dethiomonas, Peptostreptococcus, Bifidobacterium, Candida, or any combination thereof. The method of claim 6, wherein the fecal microbial phase comprises one or more microorganisms selected from the group consisting of: Bacteroides fragilis subsp. common, Collins aerogenes, Bacteroides fragilis subsp. polymorphous, Peptostreptococcus expansii II , Parabacteroides diundi, Clostridium prasyllium, Faecococcus regularis, Collins aerogenes III, Peptostreptococcus aeruginosa I, Rumen brucellus, Bifidobacterium adolescentis, Bacillus formate, Bifidobacterium longum, Inert Eubacterium, Rumenococcus twisted, Eubacterium rectum, Eubacterium fusiformis, Bacteroides escherichia, Clostridium tenuisii, Bacteroides fragilis subsp. A, Eubacterium biformis, Bifidobacterium infantis, Eubacterium rectum III-F, Accompanying Coccus faecalis, Pseudoflavtobacillus pluvialis, Rumencoccus albicans, Dallella long-chain, Eubacterium hosei, Eubacterium bulgingi I, Clostridium lavendere, Gastrococcus ovatus, Eubacterium rectum, Clostridium multicladosporum Bacteria, Lactobacillus Leichmannii, Clever Rumenococcus, Vibrio butyricum, Acidococcus spike, Eubacterium bulgingis, Bacteroides fragilis subsp. fragilis, Bacteroides ar Corynebacterium, Eubacterium cylindrica, Eubacterium ruminant, Eubacterium CH-1, Staphylococcus epidermidis, Peptostreptococcus BL, Eubacterium mucinum, Typhimurium acuminatum, Bacteroides L, Clostridium dysfunction I, Navicula Clostridium microflora, innocuous clostridium spores, Clostridium polysporum, Propionibacterium acnes, Rumenococcus chrysogenum, Rumenococcus AT, Peptococcus AU-1, Bacteroides fragilis subsp. ova, Bacteroides fragilis subsp. d , Bacteroides fragilis subspecies type f; Bacteroides L-1, Bacteroides L-5; Clostridium nucleatum, Clostridium dead, Escherichia coli, Gemini measles, Fingoldi, Peptococcus G, Peptococcus-AU-2; Streptococcus intermedius, Rumencoccus yoghurt, Rumencoccus CO, Bacteria X, Coccus faecalis BH, Coccus faecalis-CC; Eubacterium gracilis, Mycobacterium mycobacterium, Bacteroides fusiformis subsp. fusiformis, Bacteroides coagulans, Prevotella oral cavity, Prevotella rumen, Odrelia viscera, Desulfovibrio inert, Lactobacillus G, Vibrio succinate A and combinations thereof. 2. The method of 3, wherein the composition comprises at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99% or 99.5% bacterial spores . 2. The method of 3, wherein the composition is in the form of liquid, freezing, freeze drying, spray drying, foam dehydration, freeze drying or powder. 2. The method of 3, wherein the composition comprises excipient, physiological saline, buffer, buffer or fluid-glucose-cellobiose agar (RGCA) medium. 2. The method of 3, wherein the composition contains a cryoprotectant. The method of claim 71, wherein the cryoprotective agent comprises polyethylene glycol, skimmed milk, erythritol, arabitol, sorbitol, glucose, fructose, alanine, glycine, and proline Acid, sucrose, lactose, ribose, trehalose, dimethylsulfene (DMSO), glycerin or a combination thereof. 2. The method of 3, wherein the composition further comprises an acid inhibitor, an antacid, an H ₂ antagonist, a proton pump inhibitor, or a combination thereof. 2. The method of 3, wherein the composition contains substantially no non-living substances. 2. The method of 3, wherein the composition is substantially free of non-cellular materials selected from the group consisting of residual fibers, DNA, virus coating materials, and non-viable materials. 2. The method of 3, wherein the composition is formulated into enteric-coated capsules or microcapsules, acid-resistant capsules or microcapsules, powders suitable for reconstitution, nasal-duodenal infusion, or used for enema or Delivery in the form of colonoscopy infusion. 2. The method of 3, wherein the composition is co-administered with foods, liquid beverages, food additives, dairy-based products, soybean-based products or derivatives thereof, jellies or yogurt. 2. The method of 3, wherein the subject is pretreated with antibiotics before administering the composition. Such as the method of claim 78, wherein the antibiotic is selected from the group consisting of: rifabutin (rifabutin), clarithromycin (clarithromycin), clofazimine (clofazimine), vancomycin (vancomycin), Lifu Rifampicin, nitroimidazole, chloramphenicol, and combinations thereof. Such as the method of claim 78, wherein the antibiotic is selected from the group consisting of rifaximin, rifamycin derivatives, rifamycin, rifabutin, and rifapentin (Rifapentine), rifalazil, bicyclomycin (bicozamycin), aminoglycoside, gentamycin, neomycin, streptomycin, paromomycin (Paromomycin), verdamicin, mutamicin, sisomicin, netilmicin, retymicin, kanamycin, safe Trinan (aztreonam), antreonam macrolide, clarithromycin, dirithromycin, roxithromycin, telithromycin, azithromycin, sub Bismuth salicylate, vancomycin, streptomycin, fidaxomicin, amikacin, arbekacin, neomycin, nettimycin, paromomycin ( Paromomycin, rhodostreptomycin, tobramycin, apramycin, and combinations thereof. The method according to any one of the preceding claims, wherein the individual is pretreated with an anti-inflammatory drug before administering the composition. The method of any one of the preceding claims, wherein the composition comprises one or more, two or more, three or more, or four or more species of Clostridium spores selected from the group consisting of Non-pathogenic spores: Clostridium absonum , Clostridium argentinense , Clostridium baratii , Clostridium botulinum , Clostridium botulinum, Clostridium botulinum Clostridium cadaveris), meat Clostridium (Clostridium carnis), hidden Clostridium (Clostridium celatum), emphysema, gangrene Clostridium (Clostridium chauvoei), spindle Clostridium (Clostridium clostridioforme), spatulate Clostridium (Clostridium cochlearium , Clostridium fallax , Clostridium felsineum , Clostridium ghonii , Clostridium glycolicum , Clostridium hemolyticum ( Clostridium haemolyticum ), Clostridium hastiforme (Clostridium hastiforme ), Clostridium histolyticum (Clostridium histolyticum ), Clostridium indolis (Clostridium indolis ), Clostridium irregulare , Clostridium mucous Clostridium limosum , Clostridium malenominatum , Clostridium novyi , Clostridium oroticum , Clostridium paraputrificum , Perfringens Clostridium (Clostridium perfringens), hairy Clostridium (Clostridium piliforme), corruption Clostridium (Clostridium putrefaciens), corruption Clostridium (Clostridium putrificum), Clostridium Sardinia (Clo stridium sardiniense), fried disc Clostridium (Clostridium sartagoforme), scintillation Clostridium (Clostridium scindens), septicemia Clostridium (Clostridium septicum), Soxhlet Clostridium (Clostridium sordellii), wedge Clostridium (Clostridium sphenoides ), Clostridium spiroforme , Clostridium sporogenes , Clostridium subterminale , Clostridium symbiosum , Clostridium tertium , Clostridium tetani , Clostridium welchii and Clostridium villosum . 2. The method of 3, wherein the composition comprises purified, isolated or cultured live non-pathogenic Clostridium spores and a plurality of species from one or more genera selected from the group consisting of purified, isolated or cultured Living non-pathogenic microorganisms: Collins, Coprococcus , Dorea, Eubacterium and Rumenococcus. 2. The method of 3, wherein the composition comprises a plurality of purified, isolated or cultured live non-pathogenic microorganisms, which are from one or more genera selected from the group consisting of: Clostridium spores, Collins, Faecococcus, Dallella, Eubacterium and Rumenococcus. The method of claim 83, wherein the composition comprises two or more genera selected from the group consisting of Collins, Faecoccus, Dallella, Eubacterium, and Rumenococcus. The method of claim 83, wherein the composition comprises two or more genera selected from the group consisting of: faecalis, Dallella, Eubacterium, and Rumenococcus. Such as the method of claim 83 or 84, wherein the plurality of live non-pathogenic microorganisms comprise one or more, two or more, three or more, four or more, or five or more the selected species groups consisting of: smart fecal bacteria, accompanied by fecal bacteria, long chain Dole coli, Bacillus fastidious really, really huge bacillus (Eubacterium hadrum), E. hallii, twist and Eubacterium rectal chain Ruminococcus. The method according to any one of the preceding claims, wherein the method further comprises administering a drug to treat intestinal dysfunction, obesity, insulin resistance, hyperglycemia, prediabetes or type 2 diabetes. The method according to any one of the preceding claims, wherein the method further comprises administering drugs to treat abdominal pain, red urine, fever, joint pain, loss of appetite, nausea and vomiting, weakness and fatigue, or jaundice. Such as the method of claim 88, wherein the drug for treating intestinal dysfunction is selected from the group consisting of docusate, bisacodyl, docusate stool softening laxative, phosphoric acid Sodium, mineral oil, psyllium hydrophilic musilloid, magnesium hydroxide and glycerin or a combination thereof. The method according to any one of the preceding claims, wherein the method reduces liver steatosis. The method of any one of the preceding claims, wherein the method reduces liver fat. The method according to any one of the preceding claims, wherein the method reduces the content of ALT. The method according to any one of the preceding claims, wherein the method reduces the AST content. The method according to any one of the preceding claims, wherein the method reduces the GGT content. The method according to any one of claims 91 to 95, wherein the reduction comprises a reduction of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% compared with the content before treatment Or 90%. The method according to any one of the preceding claims, wherein the method eliminates or alleviates one or more symptoms selected from the group consisting of abdominal pain, fever, joint pain, loss of appetite, nausea and vomiting, weakness and fatigue, or jaundice. A method for treating at least one symptom of hepatitis B (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising administering to the individual (i) a pharmaceutical composition, which comprises The bacterial population of the feces of human donors, wherein the bacterial population has not been cultured; and (ii) bacterial isolates. The method of claim 98, wherein the pharmaceutical composition comprises the bacterial isolate. A method for treating at least one symptom of hepatitis B virus (HBV) in an individual in need, the method comprising administering a pharmaceutical composition to the individual, the pharmaceutical composition comprising bacteria derived from the feces of a human donor Population, where the bacterial population has not been cultivated. A method comprising: extracting a bacterial colony from the feces of a healthy human donor; and mixing the bacterial colony with a bacterial isolate; wherein the bacterial colony is not cultured. The method of claim 101, wherein the bacterial isolate is cultured. A method for treating at least one symptom of hepatitis B virus (HBV) in an individual in need, the method comprising administering to the individual (i) a pharmaceutical composition comprising bacteria derived from the feces of a human donor Population, and (ii) at least one, at least two, or all three types of non-pathogenic microorganisms selected from the group consisting of: bacterial isolates, fungal isolates, and archaea isolates. Such as the method of claim 103, wherein the bacterial population is not cultivated. Such as the method of claim 103, wherein the non-pathogenic microorganism type is not cultured. A method comprising: extracting a bacterial population from the feces of a healthy human donor; and mixing the bacterial population with: (i) non-pathogenic bacterial isolates, and (ii) at least one, at least two, or all three options Free of non-pathogenic microorganism types from the following groups: bacterial isolates, fungal isolates, and archaea isolates. Such as the method of claim 106, wherein the bacterial population is not cultivated. A method for treating the signs or symptoms of hepatitis B virus (HBV) in an individual in need, which comprises: administering a pharmaceutical composition to the individual in need, wherein the pharmaceutical composition comprises a human fecal donor-based The abundance of at least one component in the fecal microbial phase is derived from a microbial population selected from the donor, wherein the microbial population is uncultured and contains at least one, at least two, or all three non-pathogenic microorganisms selected from the group consisting of Type: bacterial isolates, fungal isolates and archaea isolates. A method for treating at least one symptom of hepatitis B (HBV) or hepatitis D virus (HDV) in an individual in need, the method comprising orally administering to the individual a pharmaceutical composition, the pharmaceutical composition comprising A bacterial population derived from the feces of a human donor, where the bacterial population has not been cultured. The method of claim 109, wherein the pharmaceutical composition further comprises a bacterial isolate, a fungal isolate, an archaeal isolate, or any combination thereof. The method of claim 109 or 110, wherein the pharmaceutical composition is lyophilized. The method of any one of claims 109 to 111, wherein the pharmaceutical composition is in a capsule. The method of any one of claims 109 to 112, wherein the bacterial population comprises a non-selective fecal microbial phase. The method according to any one of claims 109 to 113, wherein the pharmaceutical composition is administered orally every day. The method according to any one of claims 109 to 113, wherein the pharmaceutical composition is administered orally every day to maintain at least 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, 40, 50, 60 or 80 weeks. The method of any one of claims 109 to 115, wherein the individual has not received antiviral therapy before receiving the pharmaceutical composition. The method of any one of claims 109 to 116, wherein the individual does not receive antiviral therapy when receiving the pharmaceutical composition. The method of any one of claims 109 to 117, wherein the individual has not received interferon therapy before receiving the pharmaceutical composition. The method of any one of claims 109 to 118, wherein the individual does not receive interferon therapy when receiving the pharmaceutical composition. The method of any one of claims 109 to 119, wherein the individual exhibits HBeAg clearance after treatment. The method of any one of claims 109 to 119, wherein the individual exhibits a decrease in HBsAg after treatment. The method of any one of claims 109 to 119, wherein the individual exhibits a reduction in HBeAg after treatment.