WO2023088463A1 - Compositions et procédés de berbérine ursodésoxycholate pour modulation de compositions du microbiome intestinal - Google Patents

Compositions et procédés de berbérine ursodésoxycholate pour modulation de compositions du microbiome intestinal Download PDF

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Publication number
WO2023088463A1
WO2023088463A1 PCT/CN2022/133198 CN2022133198W WO2023088463A1 WO 2023088463 A1 WO2023088463 A1 WO 2023088463A1 CN 2022133198 W CN2022133198 W CN 2022133198W WO 2023088463 A1 WO2023088463 A1 WO 2023088463A1
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pharmaceutically acceptable
budca
gut microbiome
subject
acceptable salt
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PCT/CN2022/133198
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English (en)
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Liping Liu
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Shenzhen Hightide Biopharmaceutical Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

  • the invention generally relates to pharmaceutical compositions and methods for therapeutic uses thereof.
  • the invention relates to pharmaceutical compositions and methods of use of berberine ursodeoxycholate (BUDCA) for modulating gut microbiome and the treatment of associated diseases and disorders, as monotherapy, in combination therapy with other agents or an adjuvant.
  • BUDCA berberine ursodeoxycholate
  • BUDCA is an ionic salt of berberine (BBR) and ursodeoxycholic acid (UDCA) , represented by
  • BUDCA is currently under investigation for the treatment of primary sclerosing cholangitis (PSC) , primary biliary cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH) .
  • PSC primary sclerosing cholangitis
  • PBC primary biliary cirrhosis
  • NASH non-alcoholic steatohepatitis
  • BUDCA is an ionic salt formed between BBR and UDCA with 1: 1 stoichiometry and unique physico-chemical properties including enhanced bioavailability of BBR within the gut.
  • Human gut microbiome a. k. a., gut flora or gut microbiota
  • gut microbiota are the microorganisms (e.g., bacteria, archaea, fungi, and viruses) that live in the digestive tracts of a human.
  • the gut microbiome has broad impacts, including effects on colonization, resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, controlling immune function, and even behavior through the gut–brain axis.
  • gut microbiome The role of gut microbiome in human health has been the subject of extensive research, establishing its involvement in human metabolism, nutrition, physiology, and immune function. Imbalance of the normal gut microbiome have been linked with gastrointestinal conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) , and wider systemic manifestations of disease such as obesity, type 2 diabetes, and atopy. An altered gut microbiome has been associated with the pathogenesis and progression of various metabolic diseases and liver diseases.
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • the invention is based in part on novel compositions and methods of use of BUDCA as well as combinations of BBR and UDCA, for modulating the composition of gut microbiome in a subject and for treating associated diseases and conditions.
  • the invention generally relates to a method for modulating a gut microbiome composition comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDCA.
  • the invention generally relates to a method for reducing one or more pathobionts in gut microbiome, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDCA.
  • the invention generally relates to a method for increasing one or more beneficial microorganisms in gut microbiome, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDCA.
  • the invention generally relates to a method for treating NAFLD comprising administering to a subject in need there of a pharmaceutical composition comprising BUDCA.
  • the invention generally relates to a method for treating diabetes comprising administering to a subject in need there of a pharmaceutical composition comprising BUDCA.
  • the invention generally relates to a method for modulating a gut microbiome composition comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
  • the invention generally relates to a method for reducing one or more pathobionts in gut microbiome, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
  • the invention generally relates to a method for increasing one or more beneficial microorganisms in gut microbiome, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
  • the invention generally relates to use of BUDCA for the manufacture of a medicament.
  • the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.
  • the invention generally relates to use of BUDCA for modulating a subject’s gut microbiome.
  • the invention generally relates to use of BUDCA for reducing one or more pathobionts in a subject’s gut microbiome.
  • the invention generally relates to use of BUDCA for increasing one or more beneficial microorganisms in a subject’s gut microbiome.
  • the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for modulating a gut microbiome.
  • the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for reducing one or more pathobionts in a subject’s gut microbiome.
  • the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for increasing one or more beneficial microorganisms in a subject’s gut microbiome.
  • FIG. 1 Exemplary data on changes in components of gut microbiota before and after treatment with BUDCA in Mouse Model of Dyslipidemia and NAFLD.
  • FIG. 2 Exemplary data on changes in components of gut microbiota before and after treatment with BUDCA in Hamster Model of Dyslipidemia and NAFLD.
  • FIG. 3 Exemplary data on changes in components of gut microbiota before and after treatment with BUDCA in Mouse Model of Diabetes.
  • the term “effective amount” of an active agent refers to an amount sufficient to elicit the desired biological response.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.
  • the term “treating” , “reducing” , or “preventing” a disease or disorder” refers to ameliorating such a condition before or after it has occurred. As compared with an equivalent untreated control, such reduction or degree of prevention is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%as measured by any standard technique.
  • the term “pharmaceutically acceptable excipient, carrier, or diluent” refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • wetting agents such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymer as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • the term “subject” refers to any animal (e.g., a mammal) , including, but not limited to humans, non-human primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • the terms “subject” and “patient” are used interchangeably herein in reference to a human subject.
  • Compounds of the present invention are, subsequent to their preparation, preferably isolated and purified to obtain a composition containing an amount by weight equal to or greater than 95% ( “substantially pure” ) , which is then used or formulated as described herein. In certain embodiments, the compounds of the present invention are more than 99%pure.
  • the present invention is based in part on unexpected discovery that BUDCA, as well as combinations of BBR and UDCA, can be used to modulate the composition of gut microbiome in a subject and for treating associated diseases and conditions.
  • the invention generally relates to a method for modulating a gut microbiome composition comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDCA.
  • the invention generally relates to a method for reducing one or more pathobionts in gut microbiome, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDCA.
  • the one or more pathobionts are selected from the group consisting of Christensenellaceae, S. aureus and Coprococcus.
  • the invention generally relates to a method for increasing one or more beneficial microorganisms in gut microbiome, comprising administering to a subject in need thereof a pharmaceutical composition comprising BUDCA.
  • the one or more beneficial microorganisms are selected from the group consisating of Akkermansia and Parabacteroide.
  • the invention generally relates to a method for treating NAFLD comprising administering to a subject in need there of a pharmaceutical composition comprising BUDCA.
  • the invention generally relates to a method for treating diabetes comprising administering to a subject in need there of a pharmaceutical composition comprising BUDCA.
  • BUDCA is administered at a daily dosage in the range of about 0.1 mg to about 3,00 mg (e.g., about 1 mg to about 3,000 mg, about 10 mg to about 3,000 mg, about 50 mg to about 3,000 mg, about 100 mg to about 3,000 mg, about 0.1 mg to about 2,000 mg, about 0.1 mg to about 1,000 mg, about 0.1 mg to about 500 mg, about 1 mg to about 500 mg) for a time period of about 1 to about 30 days (e.g., about 1 to about 21 days, about 1 to about 14 days, about 1 to about 7 days, about 7 to about 30 days, about 14 to about 30 days, about 21 to about 30 days, about 7 to 21 days) .
  • BUDCA is administered at a daily dosage in the range of about 1 mg to about 500 mg (e.g., about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 5 mg to about 250 mg, about 10 mg to about 200 mg) for a time period of about 1 to about 30 days (e.g., about 1 to about 21 days, about 1 to about 14 days, about 1 to about 7 days, about 7 to about 30 days, about 14 to about 30 days, about 21 to about 30 days, about 7 to 21 days) .
  • 1 mg to about 500 mg e.g., about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 5 mg
  • the pharmaceutical composition of BUDCA disclosed herein comprises a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to a method for modulating a gut microbiome composition comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
  • the invention generally relates to a method for reducing one or more pathobionts in gut microbiome, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
  • the one or more pathobionts are selected from the group consisting of Christensenellaceae, S. aureus and Coprococcus.
  • the invention generally relates to a method for increasing one or more beneficial microorganisms in gut microbiome, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof.
  • the one or more beneficial microorganisms are selected from the group consisating of Akkermansia and Parabacteroide.
  • compositions disclosed herein for modulating gut microbiome and the treatment of associated diseases and disorders may be employed as monotherapy, in combination therapy with other agents, or as an adjuvant.
  • the total amount of BBR and UDCA are administered at a daily dosage in the range of about 0.1 mg to about 3,000 mg (e.g., about 1 mg to about 3,000 mg, about 10 mg to about 3,000 mg, about 50 mg to about 3,000 mg, about 100 mg to about 3,000 mg, about 0.1 mg to about 2,000 mg, about 0.1 mg to about 1,000 mg, about 0.1 mg to about 500 mg, about 1 mg to about 500 mg) for a time period of about 1 to about 30 days (e.g., about 1 to about 21 days, about 1 to about 14 days, about 1 to about 7 days, about 7 to about 30 days, about 14 to about 30 days, about 21 to about 30 days, about 7 to 21 days) .
  • about 1 to about 3,000 mg e.g., about 1 mg to about 3,000 mg, about 10 mg to about 3,000 mg, about 50 mg to about 3,000 mg, about 100 mg to about 3,000 mg, about 0.1 mg to about 2,000 mg, about 0.1 mg to about 1,000 mg, about 0.1 mg to about 500 mg
  • the total amount of BBR and UDCA is administered at a daily dosage in the range of about 1 mg to about 500 mg (e.g., about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 5 mg to about 250 mg, about 10 mg to about 200 mg) for a time period of about 1 to about 30 days (e.g., about 1 to about 21 days, about 1 to about 14 days, about 1 to about 7 days, about 7 to about 30 days, about 14 to about 30 days, about 21 to about 30 days, about 7 to 21 days) .
  • about 1 mg to about 500 mg e.g., about 5 mg to about 500 mg, about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 1 mg to about 250 mg, about 1 mg to about 200 mg about 1 mg to about 100 mg, about 1 mg
  • the weight ratio of BBR to UDCA is in the range of about 3: 1 to about 1: 3 (e.g., 2: 1 to 1: 3, 1: 1 to 1: 3, 3: 1 to 1: 2, 3: 1 to 1: 1, about 1: 1) .
  • the pharmaceutical composition of BBR and UDCA disclosed herein comprises a pharmaceutically acceptable excipient, carrier, or diluent.
  • the invention generally relates to use of BUDCA for the manufacture of a medicament.
  • the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.
  • the medicament is for modulating a subject’s gut microbiome.
  • the medicament is for reducing one or more pathobionts in a subject’s gut microbiome (e.g., Christensenellaceae, S. aureus and/or Coprococcus) .
  • the medicament is for increasing one or more beneficial microorganisms (e.g., Akkermansia and Parabacteroide) in a subject’s gut microbiome.
  • the invention generally relates to use of BUDCA for modulating a subject’s gut microbiome.
  • the invention generally relates to use of BUDCA for reducing one or more pathobionts in a subject’s gut microbiome.
  • the invention generally relates to use of BUDCA for increasing one or more beneficial microorganisms in a subject’s gut microbiome.
  • the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for modulating a gut microbiome.
  • the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for reducing one or more pathobionts in a subject’s gut microbiome.
  • the invention generally relates to use of BBR, or a pharmaceutically acceptable salt thereof, and UDCA, or a pharmaceutically acceptable salt thereof, for increasing one or more beneficial microorganisms in a subject’s gut microbiome.
  • BUDCA Various solid and crystalline forms of BUDCA may be employed in the invention disclosed herein.
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • the solid or crystalline form (e.g., Form A of BUDCA) is a hydrate of BUDCA. In certain embodiments, the solid or crystalline form (e.g., Form A of BUDCA) is a hemi-nonahydrate of BUDCA.
  • the solid or crystalline form (e.g., Form A of BUDCA) is crystalline.
  • the crystalline form is characterized in a monoclinic crystal system and P2 1 space group.
  • each unit cell contains two asymmetric units and there are two BBR cations, two UDCA anions and nine H 2 O molecules per asymmetric unit, and four BBR cations, four UDCA anions and eighteen H 2 O molecules per unit cell.
  • Possible formulations include those suitable for oral, sublingual, buccal, parenteral (for example subcutaneous, intramuscular, or intravenous) , rectal, topical including transdermal, intranasal and inhalation administration. Most suitable means of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and on the nature of the active compound.
  • Model 1 (mouse model of dyslipidemia/NAFLD) ; C57BL/6J mice fed a high fat/cholesterol diet for 4 weeks (wks) and then treated with BUDCA 30-300 mg/kg by gavage for 6 wks.
  • Model 2 (hamster model of dyslipidemia/NAFLD) ; golden Syrian hamsters fed a high fat/cholesterol diet for 2 wks and then treated with BUDCA 100 mg/kg by gavage for 8 wks.
  • Model 3 (mouse model of diabetes) , C57BL/6J mice fed a high fat/cholesterol diet for 4 wks, then injected intraperitoneally with 100 mg/kg streptozotocin followed by an additional 4 wks of high fat/cholesterol diet. Mice with fasting glucose between 7.8 and 16.1 mmol/L were treated with intragastric BUDCA at 300 mg/kg for 4 wks. 16SrRNA gene pyrosequencing was used to determine differences in the microbiome composition from fecal samples at the end of treatment.
  • the gut microbiome is involved in the pathogenesis of hepatic and metabolic diseases such as non-alcoholic fatty liver disease (NAFLD) .
  • NAFLD non-alcoholic fatty liver disease

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  • Diabetes (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions et des procédés de modulation des compositions du microbiome intestinal, ainsi que des méthodes de traitement ou de réduction de maladies et d'états associés.
PCT/CN2022/133198 2021-11-22 2022-11-21 Compositions et procédés de berbérine ursodésoxycholate pour modulation de compositions du microbiome intestinal WO2023088463A1 (fr)

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