EP3589122A1 - Mikrobiom-transplantation - Google Patents
Mikrobiom-transplantationInfo
- Publication number
- EP3589122A1 EP3589122A1 EP18709501.3A EP18709501A EP3589122A1 EP 3589122 A1 EP3589122 A1 EP 3589122A1 EP 18709501 A EP18709501 A EP 18709501A EP 3589122 A1 EP3589122 A1 EP 3589122A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- microbiome
- sample
- microbiome sample
- stabilized
- preferred
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0278—Physical preservation processes
- A01N1/0284—Temperature processes, i.e. using a designated change in temperature over time
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0236—Mechanical aspects
- A01N1/0242—Apparatuses, i.e. devices used in the process of preservation of living parts, such as pumps, refrigeration devices or any other devices featuring moving parts and/or temperature controlling components
- A01N1/0252—Temperature controlling refrigerating apparatus, i.e. devices used to actively control the temperature of a designated internal volume, e.g. refrigerators, freeze-drying apparatus or liquid nitrogen baths
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/37—Digestive system
- A61K35/38—Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
- B30B15/06—Platens or press rams
- B30B15/062—Press plates
- B30B15/064—Press plates with heating or cooling means
Definitions
- the present invention relates to a method of producing a stabilized microbiome sample, a press cooling apparatus for providing a stabilized microbiome sample, and a stabilized, preferably storage and reusable microbiome sample, especially for use in a method of non-therapeutic or therapeutic treatment of the human or animal body.
- the composition of the intestinal flora (microbiome) of a human being has a significant influence on his health. Above all, the complex composition of the microbiome plays a decisive role. This composition is influenced by a variety of factors, including nutrition, stress, infections and chronic diseases. Each person has an individual microbiome that can change over the course of a lifetime.
- the human gut microbiota contains approximately 3.3 million genes of microbial flora compared to 25,000 human genes.
- the normal or healthy microbiome contains 1200 to 1500 different species of bacteria, yeasts, fungi and also viruses.
- the human intestinal flora contains proteins, carbohydrates, mineral salts, trace elements, fat, dead microorganisms and undigested food.
- dysbiosis can lead to a change in the composition of the microorganisms, in the long run also the loss of some bacterial species and bring growth benefits for other bacterial species.
- dysbiosis can be caused by long-term and / or broad-spectrum antibiotics (Winek et al., 2016). An antibiotic affects all bacteria present, not just the pathogenic germs.
- microbiome intestine In addition to the known functions of the intestine or the microbiome in the intestine, including digestion and the close connection to the immune system, there are also close mutual interactions between the microbiome and the brain (microbiome intestine). Brain axis, engl, gut-brain-axis). Thus, neurological problems and behaviors can be influenced by the microbiome composition, which may include behavior, memory, learning ability, up to microglia activation in the brain or the integrity of the blood-brain barrier. However, this influence is not just one-sided. Damage to the brain, for example, can also have an impact on the microbiome.
- microbiome-brain-brain axis are not only limited to stroke as a neurological disorder, but may also affect other neurological disorders. Alone by antibiosis-induced dysbiosis in the intestine cognitive damage could be caused in the animal model (Fröhlich et al. 2016). This is also in line with the findings that patients with depression have altered microbiome composition (Kelly et al., 2016).
- microbiome transplant It is still only partially known which represents the optimal composition of a healthy microbiome and the risks associated with allogeneic microbiome transplantations.
- the microbiome is likely to have a significant impact on the pathogenesis and progression of a variety of diseases, including autoimmune diseases and chronic inflammatory diseases, e.g. Multiple sclerosis (Haghikia et al., 2015).
- the microbiome may have a maldevelopment or become out of balance, for example, being infected by microorganisms, in particular by parasites, viruses, fungi, yeasts or bacteria.
- Such a misdeveloped or out of balance microbiome requires restoration of the natural state. This can be achieved by a microbiome transplant, for example a stool transplant.
- Transplantation of the microbiome is one of the most successful treatment options for producing the original or healthy microbiome in the patient.
- the microbiome sample administered should come as close as possible to the composition of the original, in particular healthy, microbiome with all its components, ie should be as unchanged as possible.
- lactobacilli of the genera Lactobacillus and Bifidobacterium.
- Oral application is usually in pill form, with a shell material that dissolves only in the intestine and thus allows a targeted release.
- a few bacterial strains are given at the same time, which do not reflect the complexity of a human, healthy microbiome.
- microbiome may play a role in a variety of diseases, including autoimmune diseases such as: Multiple sclerosis (Haghikia et al., 2015) or diabetes. It is therefore not foreseeable which long-term consequences can cause allogeneic microbiome transplants.
- autoimmune diseases such as: Multiple sclerosis (Haghikia et al., 2015) or diabetes. It is therefore not foreseeable which long-term consequences can cause allogeneic microbiome transplants.
- WO 2014/197562 A1 relates to compositions for the remediation of microbial flora and methods for the preparation, processing and administration of such compositions.
- the preparation of such microbial flora remediation compositions includes, for example, collecting a fecal sample and diluting this sample to obtain a diluted sample.
- microbiome compositions available to date for the treatment of gastrointestinal diseases do not correspond in their composition to the composition of the microbiome which is advantageous for the particular organism.
- microbiome compositions since microbiome compositions have been taken from another organism, on the other hand, since microbiome compositions no longer correspond to the original composition in the starting organism at a defined time, in particular with regard to the presence of individual microorganisms but also the proportion of the respective microorganisms in the microbiome composition.
- the invention is therefore based on the technical problem of providing a method for producing a stabilized microbiome, which makes it possible to obtain a microbiome from a starting organism, in particular from a healthy starting organism, optionally to prepare or prepare specifically for the transport and subsequent storage, to store and at a later date, for example, in the loss of the current microbiome of the organism, for example, for pathological, traumatic or other reasons, if possible in an unchanged state compared to the time of recovery an organism, especially the starting organism to administer.
- the present invention solves the technical problem by providing a method for producing, in particular a method for preparing or providing a stabilized microbiome sample, the method comprising in particular the following method steps: a) providing an initial temperature of 35 to 39 ° C microbiome sample derived from the gut of an organism, ie a parent organism, b) packaging the microbiome sample into a microbiome sample container, c) forming a microbiome sample layer with a layer thickness of 2 to 6 mm in the microbiome sample container, d) homogeneously cooling the microbiome sample layer to a final temperature of 4 to 10 ° C, and e) obtaining a stabilized microbiome sample at a final temperature of 4 to 10 ° C.
- the method according to the invention for the production comprises the following method steps: a) providing an initial temperature of 35 to 39 ° C, from the intestine of an organism, ie b) packaging the microbiome sample into a, preferably closable and / or flexible, in particular closable and flexible, microbiome sample container, c) forming a microbiome sample layer with a layer thickness of 2 to 6 mm in the microbiome sample container, d) homogeneous Cooling the microbiome sample layer to a final temperature of 4 to 10 ° C, and e) obtaining a stabilized microbiome sample at a final temperature of 4 to 10 ° C.
- the method according to the invention for the preparation comprises the following method steps: a) providing an initial temperature of 35 to 39 ° C. from the intestine of an organism, ie a starting organism, derived microbiome sample, b) packaging the microbiome sample into a sealable, shape-flexible microbiome sample container, c) forming a microbiome sample layer having a layer thickness of 2 to 6 mm in the microbiome sample container, d) homogeneously cooling the microbiome sample layer to a final temperature of 4 to 10 ° C, and e) Obtain a stabilized microbiome sample at a final temperature of 4 to 10 ° C.
- the invention thus provides that, in a method step a), a microbiome sample originating from an organism, that is to say a starting organism, for example a microbiome sample obtained, that is to say removed or naturally precipitated, is provided and fed to a sequence of method steps, in the context of which one stabilized microbiome sample is prepared.
- the method according to the invention makes it possible to stabilize a microbiome sample, ie to put it in a storable state, this stabilized microbiome sample advantageously corresponding quantitatively and qualitatively completely or substantially completely to the sample which was provided in process step a) is directly derived from an initial organism, that is, was derived from it, for example, excreted by this or was taken from this.
- microorganisms react differently to changes, in particular temperature changes, the biochemical interaction of the microbiome sample must be brought to a standstill or largely brought to a standstill by controlled, rapid, but not too rapid, homogeneous cooling down to the final temperature according to the invention.
- the metabolism of the microorganisms in the microbiome sample is reduced to a minimum, but there are still no damages, as they can occur by uncontrolled freezing.
- the microbiome sample thus corresponds to or largely corresponds to the initial state of the microbiome directly after excretion or removal from the starting organism.
- the invention is thus based on the surprising finding that the method according to the invention for the preparation, in particular the method for preparing or providing a stabilized microbiome sample, the quantitative and qualitative composition of the microbiome sample obtained, ie the composition of the various microorganisms in the Mikrobiomprobe in accordance with Step a), unchanged or largely unchanged, that is, that the quantitative proportions of the individual microorganisms in the inventively stabilized Mikrobiomprobe hardly or not changed and also the qualitative composition of the microorganisms still that of the microorganisms in the microbiome immediately after winning, ie directly after removal or withdrawal, corresponds or largely corresponds.
- the stabilized microbiome sample produced according to the invention has little or no altered composition of the microbiome after production, in particular after preparation and storage, compared to the composition of the microbiome in the starting organism, in particular healthy starting organism, ie it corresponds biostic and in its proportion structure So qualitatively and quantitatively, the unchanged or almost unchanged microbiome of the parent organism, ie the original microbiome, preferably a healthy human, in time directly after winning.
- the same or substantially the same composition of the stabilized Mikrobiomprobe compared to the microbiome of the starting organism advantageously allows a therapeutic or non-therapeutic treatment of an organism, in particular a patient, in particular a treatment of the organism, especially patients from whom the Mikrobiomprobe was originally obtained for example, originally taken or excreted.
- the microbiome sample stabilized according to the invention can advantageously be stored over a long period of time without the composition of this microbiome sample changing significantly compared with the composition of the original microbiome, ie the composition of the microbiome in the starting organism.
- the stability of a microbiome sample stabilized according to the invention is surprisingly increased and advantageously makes it possible to take a microbiome sample from a starting organism, in particular a healthy starting organism, preferably healthy humans, and their subsequent administration to a diseased or an unnatural, state-containing organism, preferably patients, in particular, the patient from whom the microbiome sample was taken, that is, originally removed or excreted.
- the present invention therefore makes it possible to provide microbiome samples on their own to healthy organisms, in particular healthy people, in particular those which are possibly predisposed or susceptible to certain diseases, in which the microbiome sample is in the original, in particular healthy, condition of the microbiome sample Organism corresponds to and store them, especially in a Bio-Bank, until a time when a disease occurs and a transplantation of the original, especially healthy, microbiome is desirable.
- the present invention also provides a process for the preparation, in particular a process for the preparation or preparation, of a storable stabilized microbiome.
- microbiome is understood to mean the totality of all microorganisms colonizing the intestine of an organism, in particular of the human organism.In a preferred embodiment, the totality of all microbial genes or genomes in the intestine of the organism under the microbiome , in particular of the human organism.
- a starting organism for the production of a stabilized microbiome may be either a healthy parent organism or such an organism having one or more diseases or unnatural conditions in addition to a disease to be treated, or an unnatural condition occurring later, that is after obtaining the microbiome sample and their existence is of minor importance with regard to the disease to be treated later or the unnatural state to be treated.
- An original microbiome may therefore preferably be a healthy microbiome, that is to say originate from a healthy starting organism, or be a microbiome from a starting organism which has a disease or an unnatural state.
- a parent organism may have an unnatural condition or disease
- an original microbiome sample may also be derived from such a parent organism, with this parent organism later having a different unnatural state or possibly more severe at another Illness diseased, the microbiome from such a parent organism can still be used advantageously for therapeutic success.
- a healthy parent organism is preferably a parent organism that has not been treated with antibiotics or that has little or no qualitative and quantitative change in the original composition of the microbiome.
- an original state is also understood to mean a natural state.
- the term "stabilized microbiome” is understood to mean a microbiome which has the properties of a native microbiome, ie of a microbiome from a starting organism directly and immediately after obtaining, ie in particular excretion or removal, in particular of an original, in particular healthy, Microbiome, in spite of further process steps such as removal, packaging, pressing, cooling and / or storage, at the same time in comparison to this native microbiome but characterized by an increased shelf life.
- transplantation is understood to mean an autologous or allogeneic transplantation of a sample previously excreted from a starting organism or taken from a starting organism, the sample being in native or processed form, into an organism, preferably a patient, ie the transplantation of a transplant into the original source organism or into another organism.
- a microbiome sample is understood to be a sample obtained from a starting organism, that is to say a sample taken or precipitated, of the microbiome present there in the intestine, in particular of a healthy organism.
- the microbiome sample is obtained from the gastrointestinal region of a starting organism, that is to say taken or eliminated, more preferably the microbiome sample is a stool sample.
- the sample excreted from the intestine, in particular the stool sample, or the specimen taken from the intestine represents a summative or integral microbiome sample which has extensive immune components for later retransplantation.
- the sample excreted from the intestine, in particular the stool sample, or the sample taken from the intestine may already be dehydrated or compressed.
- the method according to the invention is a method for producing a stabilized stool sample.
- the microbiome sample provided in process step a) is obtained from a starting organism, that is to say taken or excreted, in particular from a starting organism of a mammal, in particular from a human starting organism, preferably such a starting organism is an original, in particular healthy, starting organism.
- the microbiome sample provided from the starting organism in method step a) has an initial temperature of 35 to 39 ° C., preferably 33 to 39 ° C., preferably 33 to 40 ° C., preferably 35 to 40 ° C., or preferably more than 39 ° C.
- the microbiome sample obtained from the intestine of a parent organism, obtained in process step a), can be prepared by removal from different areas of the gastrointestinal tract and by precipitation in the form of stool samples for the process according to the invention.
- the removal of the microbiome sample can not be done invasively, for example from stool samples.
- the microbiome sample can also be taken from defined areas of the gastrointestinal tract in a minimally invasive manner using endoscopic and colonoscopic instrumentation.
- the provided microbiome sample is packed in a, preferably closable and / or form-flexible, in particular closable and form-flexible, microbiome sample container.
- microbiome sample container means a preferably closable, in particular a form-flexible, container which preferably does not permit the exchange of gaseous or liquid compounds, and in particular the formation of a thin layer of the microbiome sample, ie the microbiome sample layer allows, preferably by a volume supernatant in, preferably form-flexible, microbiome sample container.
- the microbiome sample container is a shape-flexible sample container, in particular a form-flexible sample bag.
- preferred embodiment of the microbiome sample container is closed, preferably the Mikrobiomproben disposer is closed without a complete evacuation of the air.
- the volume and surface size of the microbiome sample container allows a sample to be distributed flat by roller or plate pressing without being compressed or compacted.
- the microbiome sample container prevents contamination and mass and gas exchange of the microbiome sample.
- the microbiome sample container can be inserted and pressed between two plane-parallel plates.
- the microbiological sample container is sterile. In a preferred embodiment according to the invention, the microbiome sample container is sterile closable.
- the microbiome sample container has a lyophilizing and / or adhesion-inhibiting coating.
- the invention further provides that after packaging the microbiome sample in a, preferably closable and / or form-flexible, in particular closable and flexible microbiome sample container according to method step b) forming a Mikrobiomproben für with a layer thickness of 0.5 to 10 mm, preferably 1 to 8 mm, preferably 2 to 6 mm in the Mikrobiomproben employer is effected.
- the microbiome sample layer according to method step c) has a layer thickness of 0.5 to 10 mm, preferably 1 to 8 mm, preferably 2 to 10 mm, preferably 2 to 8 mm, preferably 2 to 6 mm, preferably 2 to 4 mm, preferably 3 to 10 mm, preferably 3 to 8 mm, preferably 3 to 6 mm, or preferably 3 to 5 mm.
- the microbiome sample layer is formed in method step c) by rolling, winding or planar pressing.
- process step c) takes place in a press-cooling device according to the invention.
- the metabolic process is stopped by reducing the temperature to a layer thickness according to the invention, in particular by contact with a highly heat-conducting jacketed cooling region and the associated temperature reduction and / or thermal insulation.
- the microbiome sample layer in method step d) is cooled homogeneously to a final temperature of 4 to 10 ° C, preferably 4 to 8 ° C, preferably 4 to 6 ° C, preferably 2 to 10 ° C, preferably 2 to 8 ° C, preferably 2 to 6 ° C, preferably 0 to 10 ° C, preferably 0 to 8 ° C, preferably 0 to 6 ° C, preferably 0 to 4 ° C, preferably 0 to -10 ° C, preferably 0 to -6 ° C, preferably, 0 to -4 ° C, preferably -10 to 10 ° C, preferably -10 to 6 ° C, or preferably -10 to 0 ° C.
- a “homogeneous cooling” is understood to mean uniform cooling, in particular spatially uniform cooling, of a sample, ie cooling, during cooling within the sample, in particular over the entire volume of the sample including its edge regions , no or hardly any temperature differences occur.
- the homogeneous cooling of the microbiome sample layer in process step d) takes place over a period of 0.5 to 10 minutes, preferably 0.5 to 6 minutes, preferably 0.5 to 4 minutes, preferably 0.5 to 2 minutes, preferably 1 to 20 minutes, preferably 1 to 10 minutes, preferably 1 to 6 minutes, preferably 1 to 4 minutes, or preferably 1 to 2 minutes.
- the homogeneous cooling of the microbiome sample layer in process step d) takes place over all outer surfaces of the Microbiome Proben GmbH, preferably over cooled outer surfaces, in particular over two outer surfaces of the microbiome sample layer.
- the homogeneous cooling of the microbiome sample layer in process step d) takes place at a cooling rate of 1 to 60 ° C. per minute, preferably 1 to 50 ° C. per minute, preferably 1 to 40 ° C. per minute, preferably 1 to 30 ° C per minute, preferably 1 to 10 ° C per minute, preferably 1 to 20 ° C per minute, or preferably 1 ° C per minute.
- the stabilized microbiome sample in process step e) is obtained at a final temperature of 4 to 10 ° C, preferably 4 to 8 ° C, preferably 0 to 8 ° C, preferably 0 to 4 ° C, preferably -4 to 8 ° C, preferably -4 to 4 ° C, or preferably -4 to 2 ° C.
- the process steps b), c), d) and e) take place simultaneously.
- process steps d) and e) take place simultaneously.
- the stabilized microbiome sample is freeze-dried in a further method step, preferably according to one of method steps c) d) or e), particularly preferably according to one of method steps d) or e).
- the microbiome sample layer is comminuted, preferably a cutting into thinner slices.
- At least one additional component preferably a liquid medium
- the at least one component for the preparation of the microbiome sample is added, preferably for processing before process step b), during or after process step d) and / or after process step e).
- the at least one component is added for storage of the microbiome sample, preferably for storage according to method step e).
- the addition of the at least one further component to the microbiome sample can serve to achieve a quantitative and / or qualitative change, in particular optimization, of the stabilized microbiome sample obtained.
- microbiome sample obtained in process step e) or optionally after storage is subsequently changed quantitatively and / or qualitatively, in particular optimized.
- the at least one further component is selected from the group consisting of microorganisms, in particular bacteria, yeasts and fungi, prebiotics, probiotics, binders, in particular starch, digestible or indigestible filling material, adhesive material, shaping agents and antiinflammatory agents.
- the microorganisms selected from the group consisting of Actinobacteria, Firmicutes, Bacteroidetes, Proteobacteria, Bacillus thuringiensis, Lactobacillus, Bifidobacterium, Enterococcus, E. coli and mixtures thereof.
- an additional shaping of the microbiome sample takes place before or during method step b), before or during method step c), before or during method step d) and / or before, during or after step e).
- the shaping and / or addition of at least one further component preferably serves to improve the mechanical and / or kinetic movement properties and the surface properties of the stabilized microbiome sample, in particular the adhesion and adhesive function on the intestinal wall.
- preparation of the microbiome sample takes place before method step b), after method step d) and / or after method step e).
- the preparation of the microbiome sample comprises the separation of food constituents, the adjustment of the pH, the addition of at least one further component and / or a filtration.
- the microbiome sample, preferably the stabilized microbiome sample can thereby be further optimized as a retransplantation unit.
- food components preferably undigested food components, more preferably food components> 3 mm, are separated by suspension, skimming and subsequent drying.
- storage of the stabilized microbiome sample takes place after process step e).
- storage is understood as storage or asservation.
- the storage of the stabilized microbiome sample is therapy-related and / or non-therapy-related.
- the stabilized microbiome sample is stored at the final temperature according to the invention, preferably at a final temperature of 4 to 10 ° C.
- the stabilized microbiome sample is stored for one day, preferably 2 days, preferably 3 days, preferably one week, preferably 2 weeks, preferably 3 weeks, preferably one month, preferably 2 months, preferably 3 months, preferably 4 months, preferably 5 months, preferably 6 months, preferably one year or more.
- the microbiome sample stabilized according to the invention is immediately after transport and / or storage immediately after the time Implementation of the process step e), that is before storage and / or transport ago.
- the microbiome sample stabilized according to the invention is particularly suitable for the long-term preservation of the microbiome of a parent organism.
- the storage of the stabilized microbiome sample takes place in a Bio-Bank.
- bio-bank is understood to mean a collection of substances such as body fluids, blood samples, stool samples or tissue samples, for example hair samples or skin samples, or DNA samples with associated data managed in databases, for example background information such as Starting organism, ie the donor, medical history, living conditions of the donor or collecting point
- the bio-bank according to the invention is a disease-specific bio-bank.
- the microbiome sample does not change from the provision of the microbiome sample, preferably from the withdrawal or withdrawal from the starting organism, until it is introduced into the bio-bank or until it is retransplanted into a patient, in particular the sample remains in its original, especially patient-specific, condition received.
- no chemical or biochemical interactions occur with the microbiome sample container.
- the metabolic activity in the stabilized microbiome sample preferably by lyophilization and / or cryopreservation, is prevented or largely prevented.
- the present invention therefore enables to provide a bio-bank containing stabilized microbiome samples, in particular for the transplantation of microbiome samples, preferably for autologous transplantation.
- the storage of the stabilized microbiome sample takes place without the addition of further components, particularly preferably without addition of a cryopreservative.
- the storage of the stabilized microbiome sample is carried out with the addition of at least one further component.
- the storage of the stabilized microbiome sample is carried out with the addition of at least one cryopreservative.
- the stabilized microbiome sample is aliquoted, preferably the formation of a retransplantation unit, in particular for the later galenic or endoscopic retransplantation.
- an analysis of the microbiome sample is carried out before method step b) or method step e), preferably an analysis of the microbiome sample for the quantitative and qualitative composition of the microorganisms, particularly preferably an analysis for the detection of pathogenic microorganisms Detection of antibiotic-resistant germs and / or detection of viruses.
- the analysis of the microbiome sample is a quantifying and / or qualifying analysis of the microbiome.
- Those skilled in the art will appreciate methods for analyzing the microbiome, particularly high throughput nucleic acid sequencing technologies to identify and quantify the relative composition of microorganisms.
- an analysis of the microbiome sample preferably an analysis of the microbiome sample on the quantitative and or qualitative composition of the microbiome sample including a quantitative and / or qualitative composition of the microorganisms present in the microbiome sample to determine the qualitative and / or quantitative composition of the microbiome sample.
- the analysis of the microbiome sample is based on its quantitative and / or qualitative composition for determining the qualitative and / or quantitative composition of the entire microbiome sample, preferably with the aim of making a derived microbiome sample identical or different As closely as possible qualitative and / or quantitative composition, in particular an artificial microbiome sample produce.
- this relates to a method according to the method according to step e) or in an alternative embodiment after storage of the stabilized microbiome obtained in step e) in a method step f) an analysis of the microbiome sample on its qualitative and / or quantitative composition, including a qualitative and / or quantitative composition of the microorganisms contained in the microbiome sample, to determine the qualitative and / or quantitative composition of the microbiome sample carried out and subsequently in a method step g) a derived microbiome sample, in particular artificial microbiome sample prepared which in the qualitative and / or quantitative composition matches or resembles the microbiome sample obtained in step e).
- a derived microbiome sample in particular a beneficial microbiome sample, is produced, which resembles the qualitative and / or quantitative composition of the microbiome sample obtained in method step e), wherein the derived microbiome sample without a pathogenic and / or a produced in an unnatural microbiome composition of microorganisms is produced.
- This particularly preferred embodiment makes it possible to provide larger quantities of microbiome samples derived from optionally present minimal amounts of a microbiome sample obtained in method step e) by determining the qualitative and / or quantitative composition, ie artificial microbiome samples, in particular of identical type.
- the derived microbiome sample is based on the quantitative and / or qualitative composition obtained in process step f) from a large number of microbiome samples derived from starting organisms.
- the present invention therefore also relates, of course, to microbiome samples and biobanks containing these microbiome samples which contain microbiome samples obtained by means of the above process steps a), b), c), d), e), f) and g) and to processes for the preparation of Microbiome samples using method steps a) through g); and therapeutic and non-therapeutic uses of the microbiome samples so prepared described in the present disclosure.
- the present invention also relates to a press cooling apparatus (100) for providing a stabilized microbiome sample comprising a first (25) and a second (50) press plate interconnected by at least one hinge or diverter hinge (3), at least one of the two Press plates in the peripheral region of the other press plate facing the inside has an over the circumference of the press plate extending expansion limiter (5), characterized in that both press plates have at least one cooling device (2) and that the mutually facing inner sides of the two press plates highly thermally conductive coatings (7) or corresponding material properties and the outer sides have highly insulating coatings (8) or corresponding material properties.
- the present invention relates to a press cooling apparatus (300) for providing a stabilized microbiome sample comprising a lower pressure plate (50) and an upper pressure roller (80), the upper pressure roller (80) being disposed at a first end of the lower pressure plate (50 ), wherein the upper press roll (80) is movable parallel to the surface of the lower press plate (50) from the first end of the lower press plate (50) to the second end of the lower press plate (50), characterized in that the lower pressing plate (50) has a cooling device (2) arranged over the entire surface, and that the upper pressing roller (80) facing side of the lower pressure plate (50) highly thermally conductive coatings (7) or corresponding material properties and the outer sides highly insulating coatings (8) or has corresponding material properties.
- the lower pressure plate (50) preferably has, in the peripheral region of its side facing the press roller (80), an expansion limiter (5) which extends over at least part of the circumference of the lower pressure plate (50).
- the press roll (80) is a tube or a solid rod.
- the press roller (80) has its own cooling, in particular cooling filling.
- the cooling device (2) is a coolant-conducting device, a cooling battery or a cooling gel, in particular a liquid-based, sol-based and / or CCV-based cooling system.
- the press cooling device (100, 200) has two plane-parallel plates with highly heat-conductive coatings (7) or two plane-parallel plates of highly heat-conductive material.
- the highly heat-conductive coating or the highly heat-conductive material of the plates, in particular pressing plates is selected from the group consisting of aluminum, molybdenum, tungsten or combinations thereof.
- the press-cooling device (100, 200) has two plane-parallel plates with highly insulating coatings (8) or two plane-parallel plates made of highly insulating material.
- the highly insulating coating or the highly insulating material of the plates in particular press plates, selected from the group consisting of alumina, silica, zirconia, polytetrafluoroethane, phenolic resin, polyacrylonitrile, polyamide, polystyrene or combinations thereof.
- the cooling battery or cooling gel has a heat capacity of 2 to 6 kJ / kg K for liquid compositions, preferably 3 to 5 kJ / kg K, and from 1 to 4 kJ / kg K for solid compositions 1 to 3 kJ / kg K.
- the cooling battery or the cooling gel has a latent heat of 200 to 500 kJ / kg, preferably 250 to 450 kJ / kg, preferably 300 to 400 kJ / kg, or preferably 300 to 350 kJ / kg.
- the present invention relates to a stabilized microbiome sample preparable, in particular produced by the method according to the invention.
- the present invention relates to the use of the microbiome sample stabilized in accordance with the invention in a food or nutritional supplement.
- the present invention relates to the use of the microbiome sample stabilized in accordance with the invention in a pharmaceutical composition.
- the pharmaceutical composition is a liquid, suspension, gel, tablet, pellet, sachet, capsule, suppository or powder.
- the present invention relates to the use of the stabilized microbiome sample according to the invention in a method for the non-therapeutic or therapeutic treatment of an organism, in particular of the human or animal body, in particular for non-therapeutic or therapeutic treatment, preferably for prevention, an unnatural condition or a disease.
- the present invention therefore also relates to a microbiome sample stabilized according to the invention for use in a non-therapeutic or therapeutic method for the treatment of the human or animal body, in particular for the prevention of an unnatural condition or a disease.
- the present invention relates to a method for the therapeutic or non-therapeutic treatment of the human or animal body, in particular for the prevention of an unnatural condition or a disease, wherein a stabilized microbiome sample according to the invention is administered to an organism, in particular a patient.
- the unnatural state or disease is selected from the group consisting of intestinal dysfunction or concomitant congestion, constipation, chronic or inflammatory bowel disease, Crohn's disease, hepatic encephalopathy, enteritis, colitis, ulcerative colitis, irritable bowel syndrome, depression, hypromyalgia, chronic fatigue, ADHD, multiple sclerosis (MS), diarrhea, bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency, infections, especially Clostridium infections, intoxications, diverticulitis, type I diabetes, type II diabetes, allergies, asthma, autoimmune diseases, obesity, rheumatoid arthritis , Hypertension, stroke or cancer.
- the method for the non-therapeutic or therapeutic treatment of the organism is a method for galenic or endoscopic retransplantation.
- the stabilized microbiome sample is used in a method of non-therapeutic or therapeutic treatment of an unnatural condition or disease in an organism, especially a patient, even if such condition or disease is not present in the organism, particularly the patient, was detected but an existing injury and / or abnormal composition of the microbiome of the organism, in particular of the patient, in particular in comparison to an original, in particular healthy, microbiome.
- such a treatment ie a regeneration of the microbiome of the organism
- the method according to the invention reduces high infection rates and gastrointestinal disorders after a stroke.
- the stabilized microbiome sample is applied in a method of non-disease specific therapy.
- the method for the non-therapeutic or therapeutic treatment of an organism is a method for stool transplantation.
- the galenic retransplantation is an oral retransplantation, preferably by a pharmaceutical composition according to the invention, a food or a dietary supplement.
- the method for the non-therapeutic or therapeutic treatment of an organism is an autologous method, in particular a patient-specific method.
- the stabilized microbiome sample is thus preferably administered to the organism, in particular patients, to whom it was previously removed, in particular at a time when it was originally, in particular healthy, preferably the starting organism.
- the stabilized microbiome sample is administered to the parent organism, in particular, patients as soon as it has an unnatural condition or disease.
- an autologous procedure there is no risk of infection or other side effects, such as the induction of obesity.
- a stabilized microbiome sample is administered to an organism, in particular a patient, in particular an organism which has an unnatural state or a disease, in particular patients, who belong to a other source organism, that is not patient-specific, preferably from an original, especially healthy, organism, in particular healthy patients.
- the stabilized microbiome sample is for use in the retransplantation of the patient-specific microbiome, preferably for autologous retransplantation. In another preferred embodiment of the invention, the stabilized microbiome sample is for use in allogeneic retransplantation.
- the organism in particular patients, is administered at least 10 mg of the stabilized microbiome sample, preferably at least 20 mg, preferably at least 50 mg, preferably at least 100 mg, preferably at least 200 mg, preferably at least 500 mg, preferably at least 1 g, preferably at least 2 g, preferably at least 3 g, preferably at least 5 g, preferably at least 10 g, or preferably at least 20 g.
- the present invention relates to the treatment or prevention of an unnatural condition or disease of an organism, in particular a patient, by a microbiome sample stabilized according to the invention.
- the microbiome sample stabilized according to the invention is for stabilizing the digestive system, in particular the intestine, in particular for regenerating an abnormal composition of the microbiome or for building up the intestinal flora, in particular an abnormal distribution of the microflora in the digestive tract, in particular after taking antibiotics.
- the microbiome sample stabilized according to the invention is administered once to the organism, in particular the patient, preferably the stabilized microbiome sample is administered several times, preferably daily, or preferably weekly.
- the stabilized microbiome sample is for use in a method for non-therapeutic or therapeutic treatment, preferably for the prevention, preferably of diabetes, hypertension or obesity, since by these diseases usually the risk of stroke is increased.
- the stabilized microbiome sample is for use in a method for the non-therapeutic or therapeutic treatment of strokes.
- the present invention relates to a bio-bank, comprising at least one microbiome sample stabilized according to the invention, and to the use of the at least one microbiome sample stabilized according to the invention for the construction of a bio-bank.
- the stabilized microbiome sample is for use for non-therapeutic purposes.
- the stabilized microbiome sample is for use for therapeutic purposes.
- the Bio-Bank contains autologous and allogenic samples. In a preferred embodiment according to the invention, the Bio-Bank according to the invention contains stabilized microbiome samples for allogeneic retransplantation. In a preferred embodiment of the invention, the Bio-Bank according to the invention contains stabilized microbiome samples for autologous retransplantation.
- Figures 1 to 16 show: Figure 1 Figure 1 shows a press cooling device (100) according to the invention. Between the upper pressure plate (25) and the lower pressure plate (50), after taking a stool sample (12), an expandable sample bag (6) (microbiome sample container) containing it is placed. The upper (25) and lower (50) pressing plates are connected by a rotary hinge (3) and unfold over a pressing lever action.
- the lower pressure plate (50) has, in its peripheral region, that is to say in its edge region, an inner surface facing the upper pressure plate (25) and an expansion limiter (5) extending over its entire circumference.
- the expansion limiter (5) defines together with the upper (25) and the lower (50) Press plate the compression chamber (70) for the expandable sample bag (6) with the stool sample (12).
- a reservoir (2) for cooling liquid arranged over the entire surface of the pressing plates (25, 50) can be hermetically sealed and the sample bag (6 ) are kept constant in temperature (transport pack size 22 x 28 x 3 cm).
- Figure 2 shows that the upper press plate (25) has on its outwardly facing surface a highly insulating coating (8) or corresponding material properties.
- the outer surface of the lower press plate (50) is also provided with such a highly insulating coating (8).
- the upper (25) and lower (50) press plates have highly thermally conductive non-adhesive coatings (7) or corresponding material properties (e.g., nanogel hydrophobized molybdenum coating on aluminum) on their facing inner surfaces.
- the highly heat-conductive coating (7) the temperature is dissipated very quickly in the direction of the reservoir (2) for the cooling liquid and the stool sample (12) cooled down to about 3 to 4 ° C, see Figure 1.
- FIG. 3 shows a closed press cooling device (100) with a sample bag (6) forming a microbiome sample layer with a layer thickness of 2 to 6 mm. Via an interface region (14), not shown in more detail, and the connections (4), an external fluidic coolant system, not shown, can be connected to the press cooling device (100).
- FIG. 4 shows in a plan view (top) and in a side view (bottom) a toilet seat (9) and an open toilet seat without cover, on which a support unit (10) can be pushed and fixed with the sample bag (6), see FIG , FIG. 5
- FIG. 5 shows the support unit (10) pushed onto the toilet seat (9) with integrated, expandable sample bag (6) and sample receiving area (11) in plan view.
- FIG. 6 shows the support unit (10) pushed onto the toilet seat (9) and folded around the toilet seat (9) with an integrated, expandable sample bag (6) in side view.
- the bag area with expandable sample receiving area (11) picks up the stool sample (12) (folded about 20-22 cm deep and 40-45 cm wide).
- Figure 7 shows the bag area with expandable sample receiving area (11) with the stool sample (12) after removal of the toilet seat (9), the down and folded inside and fixed to the toilet seat (9) according to Figure 6 terminal areas high and to Folded in the middle (package size 22 x 22 cm).
- FIG. 8 By horizontal transverse folding and optionally by means of overlapping adhesive closures, the sealed sample bag (6) is obtained.
- the arrows in Figure 8 indicate the folding directions.
- FIG. 9 shows the hermetically sealed sample bag (6) obtained according to FIGS. 5 to 8 after being introduced into a press cooling device (100) shown in FIG. 1 after pressing, thus after the formation of the microbiome sample layer.
- Figure 10 shows a press cooler (300) comprising a lower pressure plate (50) with expansion limiters (5), a reservoir (2) for cooling liquid disposed over the entire surface of the pressure plate (50) and over the edges of the lower pressure plate (50) Closures (4) for a coolant.
- a press cooler 300
- a lower pressure plate 50
- expansion limiters (5)
- a reservoir (2) for cooling liquid disposed over the entire surface of the pressure plate (50) and over the edges of the lower pressure plate (50) Closures (4) for a coolant.
- a pressure roller (80) for example a tube or a solid rod, running parallel along the lower pressure plate (50) towards a second end of the lower pressing plate (50) is movable and allows the molding and the compression of the sample bag (6).
- FIG. 11 shows the process of rolling pressing of the sample bag (6) located on the lower pressing plate (50) with a stool sample (12) (see FIG. 10).
- the press roll (80) rolls in parallel along the lower press plate (50), preferably at a certain distance from the lower press plate (50) (not shown), from the first end to the second end of the lower press plate (50), thereby forming and pressing the sample bag (6) with the stool sample (12) planar to form a microbiome sample layer.
- the press roller (80) forms the counterpart to the lower press plate (50) during the pressing operation by parallel movement to the lower press plate (50).
- the distance of the press roll (80) to the lower press plate (50) ensures a constant press thickness of the microbiome sample layer.
- FIG. 12 shows a press-cooling device with a lower press plate (50) and an upper press plate (25).
- the lower pressure plate (50) has, in its peripheral region, that is to say in its edge region, an inner surface facing the upper pressure plate (25) and an expansion limiter (5) extending over its entire circumference.
- the expansion limiter (5) defines, together with the upper (25) and lower (50) pressure plates, the compression chamber (70) for the expandable sample bag (6) with the stool sample (12).
- the upper press plate (25) is arranged plane-parallel to the lower press plate (50). It is movable and unfolds by a vertical movement in the direction of the lower pressure plate (50) a pressing action on the sample bag (6).
- the thereby closed press cooling device (200) forms by molding and pressing the sample bag (6) a Mikrobiomproben für with a defined, adjustable layer thickness of 2 to 6 mm.
- closures (4) for a cooling liquid arranged at the edges of the upper (25) and lower (50) pressing plates a reservoir (2) for cooling liquid arranged over the entire surface of the pressing plates (25, 50) can be hermetically sealed and the sample bag (6 ) are kept constant in temperature.
- FIG. 13 shows a microbiome sample layer obtained in a press cooling device on a lower press plate (50) in a sample bag (6) with the stool sample (12) in a layer thickness of 2 to 6 mm.
- the microbiome sample layer formed in the sample bag (6) can be taken out of the press-cooling device in the obtained form and then stored.
- FIG. 14 shows the application of a pressed and shaped sample bag (6) with a microbiome sample layer having a layer thickness of 2 to 6 mm (see FIGS. 9, 12 and 13) onto a carrier (90), for example a film, in particular an insulating and non-adhesive film ,
- the carrier (90) is preferably a flexible cooling battery or a bag with cooling gel.
- FIG. 15 shows the pressed and formed sample bag (6) with the microbiome sample layer applied to the carrier (90) (see FIG. 14).
- the carrier (90) is flexible and can be rolled together with the applied sample bag (6) with the microbiological sample layer.
- Figure 16 shows the pressed and formed sample bag (6) applied to a support (90) with the microbiome sample layer after rolled in rolled form (110) (see Figure 15).
- the microbiological sample layer sample bag (6) rolled into the carrier (90) can be placed in a container for storage and storage.
- the method for producing, in particular for preparing and providing, a stabilized microbiome comprises in an exemplary embodiment the following method steps: 1. Controlled sampling / removal procedure and device
- the acquisition of patient-specific, especially original, microbiomas can be done by removal from different areas of the gastrointestinal tract of a parent organism, ie from different intestinal sections, as well as stool samples.
- the procedure of sampling from stool specimens is non-invasive.
- the procedure of sampling from defined areas of the gastrointestinal tract is usually minimally invasive via endoscopic and colonoscopic device technology.
- the provided stool samples (12) are packed in sample bags (6), but can be closed without a total evacuation of the air.
- the sample bag (6) should be designed in terms of volume and surface size so that a sample by roll, winding or plate crushing / pressing distributed as flat as possible and thereby can not be compressed / compressed, for example between 2 to 6 mm.
- the sample bag (6) is closable to prevent contamination, substance and gas exchange of the sample. It should be sandwiched between two plane-parallel plates (25 and 50) of highly heat-conductive material (7), e.g. Aluminum, can be inserted and pressed, on the back or inside of portable refrigeration units / cooling liquids (2) for the formation of cooling surfaces should be integrated or attached.
- highly heat-conductive material (7) e.g. Aluminum
- the sample After forming the microbiome sample layer by rolling, wrapping or planar pressing to the desired size and thickness by means of suitable press plates (25, 50) or a roll plate displacement, the sample is placed between the press plates (25, 50) or in a winding with integrated or adaptable cooling device (2) fixed.
- the sample bag (6) with the sample (12) and the cooling device (2) should be hygienically closed and shipped.
- the sample bag (6) can also be coated on its inner surface or designed so that a later sampling and further processing from the sample bag (6) without major sample losses is made possible (see Figure 1). This can be achieved with a lyophilizing, adhesion-inhibiting coating.
- the cooling device (2) must keep the cooling up to max. 48h ensure at a final temperature above the freezing temperature, for example 4 to max. 10 ° C.
- a uniform distribution of the sample (12) with a defined thickness between two plane-parallel or roll-parallel plates (25, 50) or rollable layers between the cooling surfaces can be achieved in order to ensure rapid and uniform cooling and a dispatching. / to enable transportable presence of the sample and to provide a directly transportable sample cooling transport module.
- the immediate and even cooling of the sample is designed to minimize microbial division and metabolic activities to a minimum and prevent storage / preservation, consistent quantitative and qualitative composition and distribution of microorganisms and biofuel constituents.
- the closely spaced cooling surfaces with a small spacing allow optimum thickness of the microbiome sample layer while maintaining the qualitative and quantitative composition and distribution of the sample itself.
- the cold-technical adsorption properties serve to avoid non-slow or even shock-freezing and nevertheless the fastest possible derivation of the body-specific temperature of the microbiome without a structural change of the sample.
- there is a rapid reduction of division, growth and metabolic activities and the individual microbiome is preserved in its original and time-specific quality and composition without the microbiome on the one hand dying or at least partially dying and, on the other hand, being able to adapt to the changed environmental conditions.
- the period for transporting the stabilized microbiome sample should be limited to 48 hours, as otherwise a more complex sample preparation at the place of sampling and the place of dispatch must be preceded.
- Transport should take place in a cool box or in the transportable sample cooling transport module and should not fall below or exceed the temperature range of approx. 4 to maximum 10 ° C over a longer period of time.
- microbiome sample for example a stool sample
- the microbiome sample must be separated from undigested food ingredients, for example by flooding, skimming and subsequent drying.
- the patient-specific microbiome sample is lyophilized while maintaining the viability of the microbiome.
- the process of lyophilization proceeds under controlled temperature conditions in low pressure.
- samples containing a patient-safe cryopreservative may be stored in a buffered solution at -80 ° C or in nitrogen (gas phase, liquid phase).
- An aliquoting of the microbiome sample is carried out, which later enables the use for the retransplantation, analysis, diagnosis and / or the quantitative and qualitative optimization of the composition, for example by dietary supplements.
- the storage can take place within the framework of a commercial bio-bank.
- microbiome samples can be made available to the patient in different forms. Freeze-dried microbiome samples can be given as a pill, depending on the material composition, a release of the microbiome (dissolution of the pill) can be targeted in the intestine (galenic).
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Abstract
Description
Claims
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Application Number | Priority Date | Filing Date | Title |
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DE102017203234.0A DE102017203234B4 (de) | 2017-02-28 | 2017-02-28 | Mikrobiom-Transplantation |
PCT/EP2018/054867 WO2018158284A1 (de) | 2017-02-28 | 2018-02-28 | Mikrobiom-transplantation |
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JP2008541009A (ja) | 2005-04-30 | 2008-11-20 | オークビル・ホンコン・カンパニー・リミテツド | サンプルの採取および分析のための装置および方法 |
DE102006007315A1 (de) | 2006-02-16 | 2007-08-30 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Probensammelverfahren und Probensammeleinrichtung |
EP4234011A3 (de) | 2013-06-05 | 2023-09-20 | Rebiotix, Inc. | Mikrobiotawiederherstellungstherapie (mrt), zusammensetzungen und verfahren zur herstellung |
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DE102017203234B4 (de) | 2018-11-15 |
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