WO2024170669A1 - Préparation probiotique multi-souche pour le traitement de troubles immunologiques et allergiques - Google Patents

Préparation probiotique multi-souche pour le traitement de troubles immunologiques et allergiques Download PDF

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WO2024170669A1
WO2024170669A1 PCT/EP2024/053821 EP2024053821W WO2024170669A1 WO 2024170669 A1 WO2024170669 A1 WO 2024170669A1 EP 2024053821 W EP2024053821 W EP 2024053821W WO 2024170669 A1 WO2024170669 A1 WO 2024170669A1
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composition
lacticaseibacillus
strain preparation
paracasei
subsp
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Bastian BAASCH
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Futrue R&S 2 Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • 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
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • 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
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus
    • C12R2001/23—Lactobacillus acidophilus
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus
    • C12R2001/24—Lactobacillus brevis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/225—Lactobacillus
    • C12R2001/25—Lactobacillus plantarum
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/46—Streptococcus ; Enterococcus; Lactococcus

Definitions

  • the present invention provides a novel multi-strain probiotic preparation and relates to said multi-strain preparation for use in therapy, particularly for use in treating or preventing an immunological disease/disorder or an allergic disease/disorder, such as, e.g., allergic rhinitis or allergic conjunctivitis.
  • an immunological disease/disorder or an allergic disease/disorder such as, e.g., allergic rhinitis or allergic conjunctivitis.
  • Allergic rhinitis is one of the most common chronic conditions globally affecting approximately 400 million people. AR often co-occurs with asthma and conjunctivitis and is a global health problem causing major burden and disability worldwide (Pawankar et al., World Allergy Organ J, 2014, 7(1), 12, doi: 10.1186/1939-4551-7-12). It is characterized by allergic symptoms such as rhinorrhea, nasal itching, sneezing and nasal congestion, and is typically caused by immunoglobulin E (IgE)-mediated reactions to inhaled allergens (e.g., plant pollen).
  • IgE immunoglobulin E
  • AR can be divided into two types depending on the timing of its occurrence: seasonal allergic rhinitis (SAR) as well as perennial allergic rhinitis (PAR) (see, e.g., Galli SJ et al., Nature, 2008, 454(7203): 445-454, doi: 10.1038/nature07204; or Mims JW, Facial Plast Surg Clin North Am, 2012, 20(1): 11-20, doi: 10.1016/j.fsc.2O11.10.002).
  • AR is often accompanied by an allergic conjunctivitis (AC) with the typical allergic symptoms causing disturbances and inflammatory reactions of the eye (e.g., itching, burning, redness, teary eyes).
  • AC allergic conjunctivitis
  • ARC allergic rhinoconjunctivitis
  • ARC allergic rhinoconjunctivitis
  • the nasal mucosa is the primary air conditioner of the respiratory tract and the first line of defense against airborne infectious agents. For these roles, maintaining and restoring epithelial integrity and the ability to initiate immune responses are essential.
  • the immune response generally protects the human body from potentially pathogenic substances and simultaneously distinguishes between non-threatening antigens, such as self-antigens, food antigens and environmental allergens, to maintain an equilibrium (Martin-Orozco E et al., Front Pediatr, 2017, 5: 117, doi: 10.3389/fped.2017.00117). Harmless, environmental substances, such as grass pollen or house dust mite, normally do not affect the human body notably. This distinction between harmful and harmless antigens is disturbed in patients with AR. The exact mechanisms which contribute to disease manifestation have not yet been fully elucidated.
  • an allergen e.g., grass pollen
  • APC antigen-presenting cell
  • dendritic cells in the nasal mucosa take up the allergen, process it and transport it to the draining lymph node, in which the processed allergen is presented to naive CD4+ T-cells.
  • naive CD4+ T cells are activated and differentiate into allergenspecific type 2 T helper cells (TH2 cells) that induce the activation of B cells and IgE class switching, which leads to B cell differentiation into plasma cells that produce allergen-specific IgE.
  • TH2 cells allergenspecific type 2 T helper cells
  • the IgE-antibodies reactive for said allergen bind to the surface of granulocytes and mast cells. These processes lead to the formation of a pool of memory allergen specific TH2 cells and B cells. When a patient who has been sensitized by previous exposure to the allergen reencounters the causative allergen, the allergen binds to allergen specific IgE on mast cells in the nasal mucosa, resulting in mast cell activation and degranulation. This leads to the release of prestored and newly synthesized mediators, including histamine, leukotrienes (leukotriene C4 and leukotriene D4), prostaglandin D2 and other products.
  • mediators including histamine, leukotrienes (leukotriene C4 and leukotriene D4), prostaglandin D2 and other products.
  • SIT SIT modifies the allergic immune mechanism by inducing desensitization to the allergen. This is achieved by a constant administration of the specific allergen at increasing dosages throughout the immune therapy period.
  • the procedure is rather elaborate, requiring many physician visits and several years of treatment to achieve maximum efficacy.
  • the drop-out rate in the first year of treatment is 56% and increasing further, so that by year three only 15% of patients remain on immunotherapy (Savi E et al., Allergy, 2013, 68(9): 1193-1195, doi: 10.1111/all.12198).
  • Dysbiosis is a term referring to a pathogenic imbalance of the microbiome or a reduced bacterial number and diversity (Wilkins LJ et al., Sc/ Rep, 2019, 9: 12918, doi: 10.1038/s41598-019- 49452-y). Research efforts have tried to reveal the cause of the occurrence of these severe changes in biodiversity, and the main hypothesis is that modern Western lifestyle with its high hygiene and sanitation standards may steadily contribute to the overall diminished human microbiome. Additional contributors include the consumption of highly processed food, increased urbanization, use of antibiotics and increasing rates of caesarian sections.
  • Hua et al. Hua X et al., EBioMedicine, 2016, 3: 172-179, doi: 10.1016/j.ebiom.2015.11.038) using data of the American Gut Project, which is a worldwide open access database for researchers containing analyzed microbiome data of millions of stool samples across the globe (McDonald D et al., mSystems, 2018, 3(3): e00031-18, doi: 10.1128/mSystems.00031-18).
  • Hua et al. Hua et al.
  • probiotic bacteria has gained substantial scientific interest in recent years.
  • trials investigating the efficacy of probiotics in the treatment of allergy have yielded inconsistent results. This is mainly related to differing compositions, as well as strain-specific properties and effects of probiotics.
  • it is difficult to compare study results because of several limitations, such as different durations of treatment, heterogeneity of the populations studied, and diversity of the scoring system used to determine the symptoms of AR.
  • probiotic bacteria work in a strain-specific manner. Characteristics of specific strains can differ significantly even within the same species and hence may not show similar therapeutic effects (McFarland LV et al., Front Med (Lausanne), 2018, 5: 124, doi: 10.3389/fmed.2018.00124). Accordingly, based on the characteristics of a specific strain and the pathophysiology of the disease in question, even closely related strains may differ considerably in their efficacy or may even cause contradictory effects. Up to date, it is still not possible to predict the effectiveness of a probiotic strain or a combination of strains based on certain properties or in-vitro studies. Correspondingly, the effectiveness of a specific probiotic strain or combination of probiotic strains always needs to be demonstrated in well-designed clinical trials.
  • L paracasei LP-33 could demonstrate efficacy in improving the symptom frequency of AR (Ahmed M et al., Pak J Med Sci, 2019, 35(6): 1538-1543, doi: 10.12669/pjms.35.6.744), while, contrarily, treatment with L paracasei HF.A00232 (Lin WY et al., Pediatr Neonatol, 2014, 55(3): 181-188, doi: 10.1016/j. pedneo.2013.10.001) or L paracasei NCC2461 (Nembrini C et al., Clin Transl Allergy, 2015, 5: 41, doi: 10.1186/s 13601-015-0085-4) had no positive effect on AR symptoms. Thus, despite their close biological relationship, probiotic strains may differ significantly in their effectiveness.
  • the present invention addresses these shortcomings in the prior art and provides a solution to the problem of providing a clinically proven probiotic formulation for the therapy of allergic rhinitis and other immunological or allergic diseases/disorders.
  • the present invention relates to a novel multi-strain preparation (particularly a probiotic preparation) comprising the following bacterial strains:
  • the multi-strain preparation comprising the above-mentioned 53 bacterial strains listed in Table 1 is also referred to herein as "SYN-AR".
  • the novel multi-strain preparation according to the invention preferably contains 53 unique bacterial strains of different species including Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, Lacticaseibacillus casei, Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, Lactobacillus acidophilus, Lactobacillus crispatus, Lactobacillus delbrueckii, Lactobacillus helveticus, Lactococcus lactis, Latilactobacillus sakei, Lentilactobacillus buchneri, Levilactobacillus brevis, Ligilactobacillus salivarius, Limosilactobacillus fermentum, Limosilactobacillus reuter
  • Table 1 Deposited bacterial strains (which are preferably all contained in the multi-strain preparation according to the present invention)
  • the invention provides a multi-strain preparation comprising the first five bacterial strains listed in Table 1 above (and likewise in claim 1), preferably comprising all 53 of the bacterial strains listed in Table 1.
  • the multi-strain preparation according to the invention may also contain one or more further microorganisms, particularly one or more (e.g., one, two, three, four, or five) further bacterial strains.
  • the multi-strain preparation does not contain any bacterial strains other than the 53 strains listed in Table 1 .
  • the multi-strain preparation does not contain any microorganisms other than the 53 strains listed in Table 1.
  • the present invention particularly provides a multi-strain preparation consisting of the 53 bacterial strains listed in Table 1 above.
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • Lacticaseibacillus casei LC11 at least one, preferably at least two, more preferably at least three, more preferably at least four, more preferably at least five, even more preferably at least 10, more preferably at least 15, more preferably at least 20, more preferably at least 25, more preferably at least 30, more preferably at least 35, more preferably at least 40, even more preferably at least 45, yet even more preferably at least 47, or most preferably all, of the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • Lactococcus lactis ssp. lactis SL97 wherein the above preparation preferably further comprises at least 4 other bacterial strains from Table 1, more preferably at least 10 other bacterial strains from Table 1, even more preferably at least 15 other bacterial strains from Table 1, yet even more preferably at least 20 other bacterial strains from Table 1, still more preferably at least 24 other bacterial strains from Table 1 .
  • the multi-strain preparation according to the present invention comprises the following bacterial strains: - Bifidobacterium bifidum BB02;
  • Lactococcus lactis ssp. lactis SL97 wherein the above preparation preferably further comprises at least 4 other bacterial strains from Table 1, more preferably at least 10 other bacterial strains from Table 1, even more preferably at least 15 other bacterial strains from Table 1, yet even more preferably at least 20 other bacterial strains from Table 1, still more preferably at least 24 other bacterial strains from Table 1 .
  • the multi-strain preparation according to the present invention comprises the following bacterial strains:
  • Lactococcus lactis ssp. lactis SL97 wherein the above preparation preferably further comprises at least 4 other bacterial strains from Table 1 , more preferably at least 10 other bacterial strains from Table 1, even more preferably at least 15 other bacterial strains from Table 1 , yet even more preferably at least 20 other bacterial strains from Table 1, still more preferably at least 24 other bacterial strains from Table 1 .
  • concentrations and relative amounts of the different bacterial strains comprised in the multi-strain preparation according to the invention are not particularly limited.
  • each of the first 5 bacterial strains listed in Table 1 (or, preferably, each of the 53 different bacterial strains listed in Table 1) is present at a concentration of at least 10 5 colony forming units (CFU) per dosage unit (e.g., per capsule), whereby the total viable cell count for the multi-strain preparation is preferably at least 1 x10 10 CFU per dosage unit (e.g., per capsule).
  • CFU colony forming units
  • the concentration of each of said 5 bacterial strains (preferably each of said 53 strains) in the multi-strain preparation (or the composition) and the total viable cell count are as defined for the formulation "SYN-AR-A” in Table 4 (see Example 1 below).
  • the multi-strain preparation is preferably a probiotic multi-strain preparation and, accordingly, that each of the above-mentioned bacterial strains in the multi-strain preparation is viable.
  • the bacterial strains are comprised in the multi-strain preparation of the invention in equal amounts. It is, however, preferred that certain bacterial strains are comprised in the multi-strain preparation of the invention in higher amounts than others.
  • Bifidobacterium animalis ssp. lactis Bi 1 and/or Lacticaseibacillus paracasei subsp. paracasei I MC 502 are comprised in the multi-strain preparation of the invention in higher amounts than the remaining strains of said preparation.
  • the amount of Bifidobacterium animalis ssp. lactis Bi1 and/or Lacticaseibacillus paracasei subsp. paracasei IMG 502 in the multistrain preparation of the invention is at least one, preferably at least two, more preferably at least three orders of magnitude higher than the average amount of the remaining strains comprised in said multi-strain preparation.
  • At least 50%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, or yet even more preferably at least 90% of the bacterial strains comprised in the multi-strain preparation of the invention are Bifidobacterium animalis ssp. lactis Bi 1 and/or Lacticaseibacillus paracasei subsp. paracasei IMG 502.
  • compositions of the invention are provided.
  • the present invention provides a novel multi-strain preparation comprising 5 specific bacterial strains (preferably a novel multi-strain preparation comprising 53 specific bacterial strains as listed in Table 1 above), as well as a composition comprising said multi-strain preparation.
  • the invention particularly relates to a probiotic composition comprising said multi-strain preparation.
  • the composition can be provided, e.g., in the form of a pharmaceutical composition or a food composition.
  • the present invention also relates to a composition comprising the multi-strain preparation provided herein.
  • the composition comprises, as an active ingredient, the multi-strain preparation of the invention.
  • the composition may optionally comprise further molecules.
  • Such further molecules can be active ingredients themselves, or can be inert, and can be included to fulfil diverse functions, such as e.g. for the stabilization of the multi-strain preparation of the invention, or for delaying, modulating and/or activating its function, or for providing an additional benefit (e.g., an additional health benefit) to the patient provided with said composition.
  • Non-limiting examples of such further molecules include pharmaceutically acceptable and/or ingestible carriers, adjuvants, other bacterial components, pharmacologically active agents, proteins and/or peptides (in particular proteins and/or peptides that are rich in glutamine and/or glutamate), lipids, carbohydrates, vitamins, minerals and/or trace elements.
  • the composition is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier relates to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • carrier vehicles include water, saline, Ringer's solution, and dextrose solution.
  • Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.
  • the carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability.
  • Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten amino acid residues) (poly)peptides, e.g.
  • polyarginine, or tripeptides proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, starch (e.g., maize starch), glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.
  • hydrophilic polymers such as polyvinylpyrrolidone
  • amino acids such as glycine, glutamic acid, aspartic acid, or arginine
  • monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, starch (e.g., maize star
  • Particularly preferred carriers in accordance with the present invention include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions, and organic solvents, including DMSO.
  • ingestible carrier relates to a carrier that is suitable for the oral administration of the composition and that helps ingesting the ingredients of the composition.
  • Appropriate carriers can be chosen by the skilled person without further ado, depending on the form in which the composition is to be administered.
  • cellulose may be used as a carrier material for tablet or capsule forms; maltodextrin may be used for powder forms, or milk products may be used for administration in the form of a food product, as detailed herein below.
  • adjuvant relates to a compound that modifies the effect of other compounds, such as e.g. any of the bacterial strains comprised in the multi-strain preparation of the invention, while having few - if any - direct effects when given alone.
  • Adjuvants are often added to promote an earlier, more potent response, and/or more persistent response to the active ingredient, thereby allowing for the use of a lower dosage.
  • Non-limiting examples of adjuvants include e.g. aluminum hydroxide and aluminium phosphate, the organic compound squalene but also compounds currently being tested or already qualified as adjuvants, such as e.g.
  • pharmacologically active agents relates to chemical or biological compounds that are pharmaceutically active while being pharmaceutically tolerable to the patient.
  • Non-limiting examples include bisacodyl, loperamide, aminosalicylate, sulfasalazine, 5-aminosalicylic acid, 4-aminosalicylic acid, benzalazine, olsalazine, balsalazide, or bismuth subsalicylate.
  • the pharmacologically active agents can be selected from medicaments known to be useful in the treatment of gastrointestinal diseases. Examples of such pharmacologically active agents are known in the art and are recorded and continuously updated in pharmaceutical registers, such as e.g. the "Rote Liste” in Germany.
  • peptide describes a molecule consisting of up to 30 amino acids
  • protein describes a molecule consisting of more than 30 amino acids.
  • Peptides and proteins may further form dimers, trimers and higher oligomers, i.e. consisting of more than one molecule which may be identical or nonidentical.
  • the corresponding higher-order structures are, consequently, termed homo- or heterodimers, homo- or heterotrimers etc.
  • peptide and protein (wherein “protein” is interchangeably used with “polypeptide”) also refer to naturally modified peptides/proteins wherein the modification is affected e.g. by glycosylation, acetylation, phosphorylation and the like.
  • proteins and/or peptides that are rich in glutamine and/or glutamate are used, as glutamine/glutamate is helpful in building up intestinal cells and in the reconstruction of damaged intestinal mucosa.
  • Proteins and/or peptides that are rich in glutamine/glutamate include, e.g., milk protein, soy protein or wheat protein.
  • lipids as used herein, is defined in accordance with the pertinent art.
  • Non-limiting examples of lipids suitable as additional compounds include, e.g., olive oil, soy oil, rape seed oil or fish oil.
  • Carbohydrates are organic compounds consisting only of carbon, hydrogen and oxygen.
  • Non-limiting examples of carbohydrates suitable as additional compounds include cellulose, lactose, maltodextrin, inulin, dextrose, mannitol, fructooligosaccharide, mannit, maltose, dextrin, sorbitol or fructose.
  • vitamins include water-soluble as well as water-insoluble vitamins.
  • vitamins suitable as additional compounds include vitamin A (e.g. retinol, retinal and carotenoids including beta carotene), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (e.g. niacin, niacinamide, nicotinamide), vitamin B5 (pantothenic acid), vitamin B6 (e.g. pyridoxine, pyridoxamine, pyridoxal), vitamin B7 (biotin), vitamin B9 (e.g. folic acid, folinic acid), vitamin B 12 (e.g.
  • vitamins B1 thiamine
  • vitamin B2 riboflavin
  • vitamin B3 e.g. niacin, niacinamide, nicotinamide
  • vitamin B5 pantothenic acid
  • vitamin B6 e.g.
  • the composition according to the invention comprises vitamin B7 (biotin).
  • Non-limiting examples of "minerals” suitable as additional compounds include magnesium, calcium, zinc, selenium, iron, copper, manganese, chromium, molybdenum, potassium, vanadium, boron, and titanium. Particularly preferred minerals are magnesium and calcium.
  • trace element relates to a chemical element that is only needed in very low quantities for the growth, development and/or physiology of the organism, preferably of a human organism.
  • trace elements suitable as additional compounds include iodine, copper or iron.
  • the composition of the present invention can be provided in the form of a prebiotic composition.
  • the composition according to the invention additionally comprises a "prebiotic compound”.
  • prebiotic compound relates to a non-digestible compound that, upon ingestion by a subject, brings benefits to said subject because of a selective stimulation of growth and/or activation of one or more beneficial bacteria that are present in the intestine of said subject.
  • the prebiotic compound enables a rebalancing of the bacterial flora.
  • the prebiotic composition of the present invention comprises, inulin and/or a fructooligosaccharide as a prebiotic compound.
  • Inulin is a soluble compound that belongs chemically to the family of fructans, i.e. polysaccharides that are formed by linear chains of fructose (up to 100 fructose molecules) with a terminal glucose residue. It has been established in the art that the consumption of inulin results in an increased presence of bifidobacteria and lactobacilli in the intestine. Lactobacilli produce milk enzymes that are important for correct digestion and for the health of the colon. At the same time, a reduction in the number of harmful bacteria in the intestine is observed. Fructooligosaccharides are shorter oligosaccharide fructans (up to 10 fructose molecules), which are resistant to hydrolysis by salivary and intestinal digestive enzymes. In the colon, they are fermented by anaerobic bacteria, thereby increasing the overall health of the gastrointestinal tract.
  • fructans i.e. polysaccharides that are formed by linear chains of fructose (up to 100 fructose molecules) with
  • the amount of prebiotic compound(s) is at least 0.3 g, more preferably at least 0.5 g, even more preferably at least 0.7 g, yet even more preferably at least 1 g, and still more preferably at least 1.5 g of prebiotic compound(s) per 1 g of the bacterial strains contained in the multi-strain preparation (or the corresponding composition).
  • the composition of the present invention can also be in the form of a food composition.
  • the term "food composition”, as used herein, relates to any food suitable for consumption by humans or animals.
  • Non-limiting examples of such "food compositions” thus include e.g. animal food, e.g., extruded and pelleted animal food, or coarse mixed food as well as food for human consumption, both as solid and liquid foods, such as drinks, including drinking water and dairy products, as described in more detail below.
  • the term includes, without being limiting, a food product, a dietary supplement, a nutrient supplement, a medical food, or a food for special medical purposes (FSMP).
  • FSMP food for special medical purposes
  • dietary supplement refers to a manufactured product intended to supplement the diet of a human or animal when taken orally and is typically provided in the form of a pill, capsule, tablet, or liquid, packaged in single or multiple dose units. Dietary supplements typically do not provide significant amounts of calories, but may contain other micronutrients, such as, e.g., vitamins or minerals.
  • nutritional supplement in accordance with the present invention, refers to a composition comprising a dietary supplement in combination with a source of calories.
  • nutritional supplements can be meal replacements or supplements, such as e.g. nutrient or energy bars, nutrient beverages or concentrates.
  • FSMP food for special medical purposes
  • EU Regulation
  • the food composition is a milk product.
  • milk products include acidified milk, milkbased desserts, humanised milk, milk powder, milk concentrate, milk-based dressings, milk beverages as well as fermented milk products such as e.g. yoghurt, including frozen yoghurt, yoghurt preparations, such as yoghurt drinks, fermented cream, kefir, sour cream, creme fraiche, cheese and cheese spread.
  • milk product includes products of either animal (i.e., dairy products) or plant origin (i.e., non-dairy products).
  • Milk products of animal origin include products prepared from milk obtained from e.g. cow, sheep, goat or buffalo.
  • Milk products of plant origin include fermented products of plant origin, such as products prepared from soy milk, rice milk, almond milk, coconut milk or cereal milk (e.g., milk made from oats).
  • the composition may be in solid or liquid form and can be formulated by conventional methods.
  • methods for the formulation of pharmaceutical compositions have been described in the art, e.g., in "Remington: The Science and Practice of Pharmacy”, Pharmaceutical Press, 22 nd edition.
  • compositions are prepared by contacting the components of the composition uniformly and intimately with the desired additional compounds. Then, if necessary, the product is shaped into the desired formulation.
  • compositions can be formulated in various forms.
  • pharmaceutical, as well as prebiotic compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration.
  • parenteral such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration.
  • Dosage forms for oral administration are particularly preferred.
  • the composition is to be administered by oral ingestion, particularly by swallowing. The composition can thus be administered to pass through the mouth into the gastrointestinal tract.
  • Non-limiting examples of preferred forms for oral administration include coated and uncoated tablets, soft gelatine capsules, hard gelatine capsules, lozenges, troches, cachet, wafer, capsule, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules (e.g. aseptically packed powders or granules), medicated gums, chewing tablets and effervescent tablets, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the composition may also be incorporated into food products, in order to provide a food composition.
  • Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatine and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatine capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium star
  • Preferred excipients in this regard include lactose, starch (particularly maize starch), cellulose, or high molecular weight polyethylene glycols.
  • the multi-strain preparation of the invention may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerine, and combinations thereof.
  • the multi-strain preparation of the invention is comprised in a capsule.
  • the term "capsule” as used herein refers to the pharmaceutically inactive enclosure intended to contain at least one pharmaceutically active ingredient.
  • the capsule shell is typically made from aqueous solutions of gelling agents, such as animal protein (mainly gelatin) or plant polysaccharides or their derivatives.
  • the capsule shell is made of gelatin.
  • the capsule shell is made of hydroxypropyl methylcellulose (HPMC).
  • the capsule may further comprise a filling agent.
  • the filing agent is a carbohydrate, such as maize starch.
  • the capsule may further comprise one or more anti-caking agents.
  • anti-caking agent refers to an additive placed in powdered or granulated material to prevent the formation of lumps.
  • anticaking agents include but are not limited to tricalcium phosphate, powdered cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, bone phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminium silicate, calcium aluminosilicate, bentonite, aluminium silicate, stearic acid and polydimethylsiloxane. It is preferred herein that the capsule comprises magnesium stearate and silicon dioxide as anti-caking agent.
  • the capsule comprising the multi-strain preparation of the invention has the following composition:
  • Table 3 Composition of an exemplary capsule of the invention
  • one capsule comprises between 10 8 and 10 12 viable bacteria (CFU), preferably between 10 8 and 10 11 viable bacteria (CFU), more preferably between 10 9 and 10 11 viable bacteria (CFU), even more preferably between 10 10 and 10 11 viable bacteria (CFU), most preferably about 5x10 10 viable bacteria (CFU).
  • CFU viable bacteria
  • one capsule comprises between 10 9 and 10 11 viable bacteria (CFU), wherein the bacterial strains Bifidobacterium animalis ssp. lactis Bi1 and/or Lacticaseibacillus paracasei subsp. paracasei IMG 502 are each comprised in an amount between 10 8 and 8x10 10 CFU. Even more preferably, one capsule comprises between 10 9 and 10 11 viable bacteria (CFU), wherein the bacterial strains Bifidobacterium animalis ssp. lactis Bi1 and/or Lacticaseibacillus paracasei subsp. paracasei IMG 502 are each comprised in an amount between 10 8 and 8x10 10 CFU and wherein the remaining bacterial strains listed in Table 1 are each comprised in an amount between 10 4 and 10 8 CFU.
  • CFU viable bacteria
  • one capsule comprises between 10 10 and 10 11 viable bacteria (CFU), wherein the bacterial strains Bifidobacterium animalis ssp. lactis Bi 1 and/or Lacticaseibacillus paracasei subsp. paracasei IMG 502 are each comprised in an amount between 5x10 9 and 5x10 10 CFU and wherein the remaining bacterial strains listed in Table 1 are each comprised in an amount between 1 x10 5 and 1 x10 7 CFU.
  • one capsule comprises all 53 bacterial strains in the amounts as indicated for the formulation "SYN-AR-A” in Table 4.
  • the capsule further comprises a vitamin.
  • the capsule comprises vitamin B7 (biotin).
  • one capsule may comprise between 1 and 1000 pg of vitamin B7 (biotin), preferably between 10 and 500 pg of vitamin B7 (biotin), more preferably between 10 and 100 pg of vitamin B7 (biotin), most preferably 50 pg of vitamin B7 (biotin).
  • the multi-strain preparation of the invention or the composition comprising the multi-strain preparation of the invention is provided for use in therapy (i.e., for use as a medicament).
  • the multi-strain preparation of the invention can be provided in any suitable form that allows it to be administered to a patient and to unfold its therapeutic potential.
  • the multi-strain preparation of the invention can be formulated into any composition as detailed herein above, including a pharmaceutical composition, a cosmetic composition, a prebiotic composition, or a food composition.
  • the multi-strain preparation according to the invention can be used in therapy, e.g., in the treating or preventing an immunological disease/disorder, particularly for use in treating or preventing an allergic disease/disorder.
  • the invention relates to the multi-strain preparation (or a composition comprising said multi-strain preparation) for use in treating or preventing an immunological disease/disorder, particularly for use in treating or preventing an allergic disease/disorder.
  • the invention likewise relates to the use of the multi-strain preparation (or of a composition comprising said multi-strain preparation) in the manufacture of a medicament (or a pharmaceutical composition) for treating or preventing an immunological disease/disorder, particularly for treating or preventing an allergic disease/disorder.
  • the invention also provides a method of treating or preventing a disease/disorder, particularly an immunological disease/disorder or an allergic disease/disorder, the method comprising administering the multi-strain preparation (or a composition comprising said multi-strain preparation) to a subject in need thereof. It will be understood that this method comprises the administration of a therapeutically effective amount (or dose) of the multi-strain preparation.
  • the allergic disease/disorder to be treated or prevented in accordance with the present invention is preferably selected from allergic rhinitis, allergic conjunctivitis, allergic rhinoconjunctivitis, atopic dermatitis, contact urticaria, allergic bronchial asthma, anaphylaxis, and an allergy-related gastrointestinal condition (such as, e.g., nausea, vomiting, abdominal pain, meteorism, or diarrhea). More preferably, the disease/disorder to be treated or prevented is allergic rhinitis, allergic conjunctivitis, or allergic rhinoconjunctivitis. Most preferably, the disease/disorder to be treated or prevented is allergic rhinoconjunctivitis.
  • the novel multi-strain probiotic preparation provided herein was highly effective in alleviating ARC symptoms in a double-blinded, randomized, placebo-controlled clinical trial with ARC patients, as shown in Example 1.
  • the high effectiveness of this novel multi-strain probiotic preparation was an unexpected result as it is known and widely accepted in the art that the effectiveness of a multistrain preparation is highly strain-specific and thus cannot be predicted.
  • the subject or patient to be treated in accordance with the present invention may be an animal (e.g, a non-human animal).
  • the subject/patient is a mammal. More preferably, the subject/patient is a human (e.g, a male human, or a female human) or a non-human mammal (such as, e.g, a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig).
  • the subject/patient to be treated in accordance with the invention is a human.
  • treatment refers to curing, alleviating, reducing or preventing one or more symptoms or clinically relevant manifestations of a disease or disorder, or to alleviating, reversing or eliminating the disease or disorder, or to preventing the onset of the disease or disorder, or to preventing, reducing or delaying the progression of the disease or disorder.
  • the "treatment” of a subject or patient in whom no symptoms or clinically relevant manifestations of the respective disease or disorder have been identified is a preventive or prophylactic treatment
  • the "treatment” of a subject or patient in whom symptoms or clinically relevant manifestations of the respective disease or disorder have been identified may be, e.g., a curative or palliative treatment.
  • Each one of these forms of treatment may be considered as a distinct aspect of the present invention.
  • the "treatment” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only).
  • the "treatment” of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease. Accordingly, the "treatment” of a disorder or disease may also refer to an amelioration of the disorder or disease, which may, e.g., lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (such as the exemplary responses as described herein above).
  • the treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease), palliative treatment (including symptomatic relief), or prophylactic treatment (including prevention) of the disorder or disease.
  • the present invention particularly provides the multi-strain preparation of the invention (or the composition comprising said multi-strain preparation) for use in therapy, more preferably, for use in treating or preventing an allergic disease/disorder. It will be understood that a therapeutically effective amount of the multi-strain preparation is to be used for this purpose.
  • the dosage needed to observe changes, and the interval following treatment for responses to occur may vary depending on the specific medical use.
  • the particular amounts and times may be determined by conventional tests which are well known to the person skilled in the art.
  • the dosage regimen is typically determined by the attending physician and depends on clinical factors.
  • dosages for any one patient depend upon many factors, including the patient's size, body surface area, age, the composition to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently.
  • the therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skills and judgement of the ordinary clinician or physician.
  • a proposed, yet non-limiting dose for oral administration to a human may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, more preferably 1 mg to 1000 mg, even more preferably 10 to 1000 mg, most preferably 100 to 1000 mg of the active ingredients per unit dose.
  • the unit dose may be administered, e.g., 1 to 3 times per day over a course of 3 consecutive days.
  • the 3-day treatment cycle can be repeated at intervals of, for example, 1 to 4 weeks. Similar amounts and administration intervals are also appropriate for other types of compositions, such as prebiotic or food compositions.
  • the multi-strain preparation is to be administered orally in a weekly amount of at least about 10 5 CFU. More preferably, the multi-strain preparation is to be administered orally in a weekly amount of at least about 10 6 CFU, such as at least about 10 7 CFU, at least about 10 8 CFU, at least about 10 9 CFU, or at least about 10 10 CFU, even more preferably in a weekly amount of at least about 10 11 CFU, yet even more preferably in a weekly amount of at least about 3 x 10 11 CFU, most preferably in a weekly amount of about 4.5 x 10 11 CFU.
  • any suitable dosage regimen to reach this weekly amount may be applied. That is, the multi-strain preparation of the invention or the composition comprising the multi-strain preparation of the invention may be administered one or more times per week until the weekly amount defined herein is reached.
  • the unexpectedly good efficacy of this treatment regime results from the unique composition of the novel multi-strain preparation according to the invention, comprising 5 (preferably 53) specific bacterial strains, in combination with the high dose that is administered over a short period of time, which makes this treatment regime particularly suitable for restoring an altered gut microbiota composition as repeatedly seen in ARC patients.
  • the multi-strain preparation according to the invention is preferably administered according to a treatment or intake regimen which comprises one or more (e.g., one to ten, particularly one, two, three, four, or five) consecutive short-term treatment cycles.
  • Each short-term treatment cycle may, e.g., last for a period of more than 1 day and less than 5 days, such as 2 to 4 days, preferably for 3 days (which is also referred to as a "3-day treatment cycle”). While the duration of each short-term treatment cycle may be the same or different (i.e., may be independently selected from the above-mentioned periods), it is preferred that all short-term treatment cycles have the same duration.
  • any two or more consecutive short-term treatment cycles may be separated by a period (a "break”) of at least 2 days, particularly of several days, weeks or months (e.g., 3 days, 5 days, 7 days (i.e., 1 week), 2 weeks, 3 weeks, 4 weeks, 1 month, or 2 months; preferably at least 3 days, more preferably 4 days), during which the multi-strain preparation (or the corresponding composition) is not administered.
  • the multi-strain preparation or the composition comprising the multi-strain preparation
  • is administered at least once on each day of each short-term treatment cycle e.g., once, twice or three times daily, particularly once daily).
  • the daily dose of the multi-strain preparation (or of the composition comprising the multistrain preparation) to be administered may be, e.g., at least about 10 5 CFU, preferably at least about 10 6 CFU, at least about 10 7 CFU, at least about 10 8 CFU, at least about 10 9 CFU, or at least about 10 10 CFU, more preferably at least about 10 11 CFU, even more preferably about 1.5 x 10 11 CFU (relating to the total viable cell count of the bacterial strains of the multi-strain preparation).
  • a short-term treatment cycle lasts for three days and the daily dose of the multi-strain preparation (or of the composition comprising the multi-strain preparation) to be administered (preferably by the oral route) is about 1.5 x 10 11 CFU (relating to the total viable cell count of the bacterial strains of the multi-strain preparation).
  • each 3-day treatment cycle is separated by a period of four days.
  • the multi-strain preparation of the invention, or the composition comprising the multi-strain preparation of the invention may be administered daily.
  • the dose of the multi-strain preparation (or of the composition comprising the multi-strain preparation) to be administered may be, e.g., at least about 10 5 CFU, preferably at least about 10 6 CFU, at least about 10 7 CFU, at least about 10 8 CFU, at least about 10 9 CFU, more preferably at least about 10 10 CFU, even more preferably at least about 0.2 x 10 11 CFU (relating to the total viable cell count of the bacterial strains of the multi-strain preparation).
  • the multi-strain preparation of the invention or the composition comprising the multi-strain preparation of the invention is administered daily, it is preferably co-administered with vitamin B7 (biotin) as described elsewhere herein.
  • the multi-strain preparation or the composition of the invention can be administered in monotherapy (e.g., without concomitantly administering any further therapeutic agents, or without concomitantly administering any further therapeutic agents against the same disease that is to be treated or prevented with the multi-strain preparation or the composition of the invention).
  • the multi-strain preparation or the composition of the invention can also be administered in combination with one or more further therapeutic agents.
  • the dose of each substance may differ from that when the corresponding substance is used alone, in particular, a lower dose of each substance may be used.
  • the combination of the multi-strain preparation or the composition of the invention with one or more further therapeutic agents may comprise the simultaneous/concomitant administration of the multi-strain preparation or the composition of the invention and the further therapeutic agent(s) (either in a single pharmaceutical formulation or in separate pharmaceutical formulations), or the sequential/separate administration of multi-strain preparation or the composition of the invention and the further therapeutic agent(s). If administration is sequential, either the multi-strain preparation or the composition of the invention or the one or more further therapeutic agents may be administered first. If administration is simultaneous, the one or more further therapeutic agents may be included in the same pharmaceutical formulation as the multi-strain preparation or the composition of the invention, or they may be administered in two or more different (separate) pharmaceutical formulations.
  • viable cells can be grown in a protein-rich liquid growth medium.
  • a suitable medium for growing and/or fermenting the bacterial strains comprises at least water, dextrose, yeast extract and minerals. The skilled person is well aware of the fact that also other media may be used for growing, fermenting and pre-culture of bacterial organisms.
  • a volume of at least 200 mL, preferably of at least 300 mL, more preferably of at least 400 mL, even more preferably of at least 500 mL and most preferably of at least 600 mL of standard medium is inoculated with at least one cell of the bacterial strain and the culture is grown over night anaerobically, e.g., at 37 °C at 220 rpm. Additional fermentation steps, such as e.g., in higher volumes may additionally be carried out. Further processing includes one or more additional method steps, for example for harvesting and/or purification.
  • Means and methods for such harvesting and/or purification steps are well known in the art and include, e.g., centrifugation such as e.g., centrifugation by using a disc centrifuge or separator (e.g., as provided by GEA Westfalia Separator Group GmbH (Oelde, Germany)).
  • the cells may then be stabilised, freeze- dried, milled and sieved using standard means and methods.
  • the cells are optionally mixed with one or more prebiotic compounds and/or one or more members of the group consisting of a pharmaceutically acceptable compound, an ingestible carrier, an adjuvant, a bacterial component, a drug entity, a biological compound and/or a protein and/or peptide and/or mixtures thereof, in particular a protein and/or peptide that is rich in glutamine/glutamate, a lipid, a carbohydrate, a vitamin, mineral and/or trace element; optionally said at least one pharmaceutically acceptable compound is a member selected from the group consisting of one or more vitamins, such as vitamins of the B group, one or more minerals, such as calcium or magnesium, one or more carbohydrates, such as lactose, maltodextrin, inulin, dextrose, mannitol, maltose, dextrin, sorbitol, fructose, and a mixture thereof in different amounts.
  • a pharmaceutically acceptable compound such as vitamins of the B group, one or more minerals, such
  • compositions comprising "a” specific compound, e.g. a carrier, can be interpreted as referring to a composition comprising "one or more” of said specific compound, e.g. one or more carriers.
  • the term "about” preferably refers to ⁇ 10% of the indicated numerical value, more preferably to ⁇ 5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint.
  • the term “about” is used in connection with the endpoint of an open-ended range, it preferably refers to the corresponding range starting from the lower endpoint -10% or from the upper endpoint +10%, more preferably to the range starting from the lower endpoint -5% or from the upper endpoint +5%, and even more preferably to the open-ended range defined by the exact numerical value of the corresponding endpoint. If the term “about” is used in connection with a parameter that is quantified in integers, the numbers corresponding to ⁇ 10% or ⁇ 5% of the indicated numerical value are to be rounded to the nearest integer (using the tie-breaking rule "round half up”).
  • the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia”, i.e., “containing, among further optional elements, ". In addition thereto, this term also includes the narrower meanings of “consisting essentially of' and “consisting of'.
  • a comprising B and C has the meaning of "A containing, inter alia, B and C”, wherein A may contain further optional elements (e.g., "A containing B, C and D” would also be encompassed), but this term also includes the meaning of "A consisting essentially of B and C” and the meaning of "A consisting of B and C” (i.e., no other components than B and C are comprised in A).
  • the present invention particularly relates to the following items:
  • a multi-strain preparation comprising:
  • composition comprising the multi-strain preparation of item 1 or 2.
  • composition of item 3 wherein said composition is a probiotic composition.
  • composition of item 3 or 4 wherein said composition is a pharmaceutical composition, a food supplement composition, or a food composition.
  • the allergic disease/disorder is selected from allergic rhinitis, allergic conjunctivitis, allergic rhinoconjunctivitis, atopic dermatitis, contact urticaria, allergic bronchial asthma, anaphylaxis, and an allergy- related gastrointestinal condition.
  • Figure 1 Timeline of treatment cycles and exposures during the clinical study described in Example 1 .
  • FIG. 1 Mean Total Symptom Score (TSS) during V1 (a) and V3 (b) in SYN-AR-A, SYN-AR-B, SYN-AR-C and placebo groups.
  • TSS Total Symptom Score
  • FIG. 3 Difference in the Total Symptom Score (TSS) at V3 phase compared to baseline exposure V1 phase in SYN-AR-A, SYN-AR-B, SYN-AR-C and placebo groups.
  • TSS Total Symptom Score
  • Example 1 Investigation of the benefit of SYN-AR in three different compositions in the treatment of patients with allergic rhinoconjunctivitis due to grass pollen and associated symptoms against placebo
  • SYN-AR-A is a mixture of 53 probiotic strains with a high concentration (5x1O 10 CFU per capsule).
  • SYN-AR-B is the same mixture of 53 probiotic strains as SYN-AR-A, but contains an increased concentration of Lacticaseibacillus rhamnosus SP1 and an overall lower concentration (6x10 9 CFU per capsule).
  • SYN-AR-C contains the 4 core probiotic strains of the above mixture at a high concentration (4x1O 10 CFU per capsule).
  • placebo is without any probiotics and contains only the excipients (corn starch, magnesium stearate and silicon dioxide).
  • the aim of the study was to investigate the benefit of the 3 different compositions (SYN-AR-A, SYN-AR-B, and SYN- AR-C) in individuals with ARC due to grass pollen and associated symptoms (mild and severe) during exposure to grass pollen in an allergen exposure chamber (AEC) versus placebo.
  • the study compared the importance of probiotic mixtures' composition and concentration for alleviation allergic symptoms associated with ARC.
  • the entire study is divided into a screening phase (VO) for the selection of suitable subjects, a baseline exposure (V1) in the AEC including a follow-up safety phone call (V2), 3 treatment cycles of 3 days per week within the span of 3 weeks, a final exposure (V3) in the AEC with the associated follow-up safety phone call (V4), and a follow-up subjectbased questionnaire regarding overall treatment effect (V5).
  • VO screening phase
  • V1 baseline exposure
  • V2 3 treatment cycles of 3 days per week within the span of 3 weeks
  • V3 a final exposure
  • V4 follow-up safety phone call
  • V5 follow-up subjectbased questionnaire regarding overall treatment effect
  • the AEC allows to expose participants under controlled conditions to a defined number of a specific allergens.
  • the AEC was developed to counteract typical problems of clinical trials during pollen season, where natural allergen exposure can vary in concentration, duration, and purity.
  • standardized grass pollen provided by Stallergenes Greer (Lenoir, USA) were used. At each exposure, participants were exposed to 4000 grass pollen/m 3 for 120 minutes at room temperature (20°C) and 55% relative humidity. The participants recorded symptom severity every 10 minutes during the 120-min exposure time.
  • the treatment phase started at least 1 week after the baseline exposure (V1) and lasted for 3 weeks. Participants underwent 3 treatment cycles (one per week), with each treatment cycle spanning 3 days. In each treatment cycle, participants were treated with either SYN-AR-A, SYN-AR-B, SYN-AR-C or placebo taking 3 capsules per day for 3 consecutive days with daily dose of 1.5x10 11 , 1.8x1O 10 , 1.2x10 11 and 0 CFU, respectively. The final exposure (V3) was followed a week after the final treatment cycle (see Figure 1). 1.2 Study population
  • the study population consisted of individuals affected by seasonal ARC to grass pollen. Only individuals aged between 18 and 65 years with a known grass pollen allergy history of at least 2 years and a positive skin prick test to grass pollen (with wheal diameter > 3 mm and not older than 8 months) were included. Additionally, clinically relevant sensibilization towards grass pollen was assessed by exposure in the AEG. The final study population only included participants with a Maximum Total Symptom Score TSSMAX ⁇ 6 (see section 1.4 for a definition of the TSS) after allergen exposure in the AEG at baseline (V1).
  • Exclusion criteria were acute infections, current cancer diagnosis, autoimmune diseases, gastrointestinal diseases causing diminished metabolic processing of orally taken substances or severe types of the following chronic diseases: neurologic diseases, metabolic diseases, severe asthma, severe pulmonary obstruction, innate anomalies of the heart or gastrointestinal tract or lung.
  • people suffering from psychological diseases e.g., depression
  • eating disorders e.g., bulimia
  • alcohol or drug addiction allergic reactions to any of the ingredients of the formulations tested and counter indication against adrenaline or any other rescue medication (especially cetirizine) were excluded.
  • Pregnant or breastfeeding women heavy smokers, people who had undergone allergen-specific immune therapy in the past 5 years, people who had participated in clinical trials in the past 3 months and people currently housed in waivers due to court order were also excluded.
  • Subjects that develop following criteria during the study were also excluded: occurrence or detection of one or more exclusion criteria during the course of the study, occurrence of UEs and/or SUEs attributable to the investigational product, discovery of a pregnancy, permanent loss of contact of the investigator with the subject, serious violation of the study protocol, surgery, which, due to the extent of the surgery and the length of the sick leave, cannot ensure intake of the investigational product and exposure to the AEG.
  • the study product was a multi-strain, multi-species product.
  • the product contained 53 probiotic strains at a concentration of at least 5x1O 10 CFU per capsule, for SYN-AR-B 53 probiotic strains including an increased amount of Lacticaseibacillus rhamnosus SP1 at a concentration of at least 6x10 9 CFU per capsule and for SYN-AR- C 4 probiotic strains at a concentration of at least 4x10 10 CFU per capsule, respectively (see Table 4 for more details).
  • the total dose per treatment cycle equaled at least 4.5x 10 11 , 5.4x1O 10 and 3.6x10 11 CFU per week for SYN-AR-A, SYN-AR-B and SYN-AR-C, respectively. Further ingredients are listed in Table 5.
  • the placebo solely contained maize starch as filling agent, magnesium stearate and silicon dioxide as anti-caking agents, and hydroxypropyl methylcellulose as capsule shell. Study product and placebo were similarly packaged and differed neither in appearance nor taste.
  • Table 4 Composition of the probiotic mixtures SYN-AR-A, SYN-AR-B, and SYN-AR-C, as used in the clinical study ("CFU”: colony-forming units)
  • Table 5 Composition of one capsule for SYN-AR-A, SYN-AR-B, SYN-AR-C and placebo, respectively, as used in the clinical study
  • the Total Symptom Score (TSS), as described by Pfaar et al. (Pfaar 0 et al., Allergy, 2014, 69(7): 854-867, doi: 10.1111/all.12383), was used to determine symptom severity every ten minutes during the 120-minute allergen exposure in the AEC.
  • Table 6 Detailed description of symptoms covered by the Total Eye Symptom Score (TESS)
  • TNSS Total Nasal Symptom Score
  • the TSSMAX was determined for each exposure in the AEG as the maximum TSS recorded at any timepoint during the defined 120 minutes of exposure. To determine the effectiveness of the treatment, the difference of TSSMAX during exposure after the treatment phase (V3) compared to the TSSMAX recorded at baseline exposure (V1) was determined (d_TSSMAx).
  • a total of 247 patients were screened for the study. Only 166 patients full-filled all inclusion criteria, and they were randomized in 4 groups: 41 patients in placebo group, 42 patients in SYN-AR-A group, 41 patients in SYN-AR-B group, and 42 patients in SYN-AR-C group. Out of 166 patients, a total number of n 8 patients dropped out in the course of the study due to different reasons that were all unrelated to the treatment, and only 158 patients could be included in the final exposure (V3) visit.
  • a modified ITT dataset was prepared: 39 in placebo, 37 in SYN-AR-A, 41 in SYN-AR-B, and 41 in SYN-AR-C.
  • Table 8 Difference in maximum Total Symptom Score (d_TSSMAx) from baseline and after the treatment are shown for all 4 groups. Values are presented as mean ⁇ StD. Wilcoxon Rank Sum test, p ⁇ 0.05.
  • the present study shows that the novel combination of 53 specific bacterial strains provided in accordance with the present invention, particularly SYN-AR-A, represents a new therapy option for patients with ARC and is not only very effective but is also very well tolerated.
  • the study shows that 3 treatment cycle of 3 days/week spanning 3 weeks i.e., only nine days of intake of medication, with the given multi-strain, multi-species preparation SYN-AR-A is sufficient to reduce the typical symptoms of ARC when compared to placebo. This finding is of great importance when considering that it was previously assumed that a continuous, daily intake of probiotic preparations for several weeks or months would be necessary to achieve a good effect.
  • novel multi-strain, multi-species preparation according to the present invention is not only highly effective and well tolerated but also allows a particularly advantageous shortterm treatment regime.
  • the composition contains Bifidobacterium bifidum B B02, Lacticaseibacillus rhamnosus SP1 , Bifidobacterium animalis ssp. lactis Bi1, Lacticaseibacillus paracasei subsp. paracasei IMG 502, and Lacticaseibacillus casei LC11 at a respective number per probiotic strain of at least 1 x10 6 CFU per unit.
  • the term unit is defined as a preselected intake form such as capsule.
  • Further optional components include 120 mg of maize starch as filling agents, and 10 mg of magnesium stearate and 0.05 mg of silicon dioxide as anti-caking agents.
  • the capsule shell and the probiotic mixture weigh 60 mg and 144 mg, respectively.
  • the composition contains the strains Bifidobacterium bifidum BB02, Lacticaseibacillus rhamnosus SP1, Bifidobacterium animalis ssp. lactis Bi1, Lacticaseibacillus paracasei subsp. paracasei IMG 502, Lacticaseibacillus casei LC11 , Lactococcus lactis ssp. lactis SL97, Lactobacillus helveticus SP27, Levilactobacillus brevis SP48, Streptococcus thermophilus SP4, Bifidobacterium longum ssp.
  • unit is defined as a preselected intake form such as capsule.
  • Further optional components include 120 mg of maize starch as filling agents, and 10 mg of magnesium stearate and 0.05 mg of silicon dioxide as anti-caking agents.
  • the capsule shell and the probiotic mixture weigh 60 mg and 144 mg, respectively.
  • the composition contains the strains Bifidobacterium bifidum BB02, Lacticaseibacillus rhamnosus SP1, Bifidobacterium animalis ssp. lactis Bi1, Lacticaseibacillus paracasei subsp. paracasei IMG 502, Lacticaseibacillus casei LC11, Lactobacillus helveticus LH102, Levilactobacillus brevis SP48, Streptococcus thermophilus SP4, Lacticaseibacillus rhamnosus LRH14, Lacticaseibacillus paracasei subsp.
  • unit is defined as a preselected intake form such as capsule.
  • Further optional components include 120 mg of maize starch as filling agents, and 10 mg of magnesium stearate and 0.05 mg of silicon dioxide as anti-caking agents.
  • the capsule shell and the probiotic mixture weigh 60 mg and 144 mg, respectively.

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Abstract

La présente invention concerne une nouvelle préparation probiotique multi-souche et concerne ladite préparation multi-souche destinée à être utilisée en thérapie, en particulier pour une utilisation dans le traitement ou la prévention d'une maladie/d'un trouble immunologique ou d'une maladie/d'un trouble allergique, tel que, par exemple, une rhinite allergique ou une conjonctivite allergique. En outre, la présente invention concerne un nouveau régime de traitement facile à suivre faisant appel à la préparation probiotique de l'invention.
PCT/EP2024/053821 2023-02-15 2024-02-15 Préparation probiotique multi-souche pour le traitement de troubles immunologiques et allergiques WO2024170669A1 (fr)

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