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WO2025090548A1 - Traitement au butyrate ciblé du côlon pour la réduction du n-oxyde de triméthylamine - Google Patents

Traitement au butyrate ciblé du côlon pour la réduction du n-oxyde de triméthylamine Download PDF

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Publication number
WO2025090548A1
WO2025090548A1 PCT/US2024/052475 US2024052475W WO2025090548A1 WO 2025090548 A1 WO2025090548 A1 WO 2025090548A1 US 2024052475 W US2024052475 W US 2024052475W WO 2025090548 A1 WO2025090548 A1 WO 2025090548A1
Authority
WO
WIPO (PCT)
Prior art keywords
tmao
composition
patient
butyrate
colon
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/052475
Other languages
English (en)
Inventor
Jerzy Ryszard Szewczyk
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biokier Inc
Original Assignee
Biokier Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biokier Inc filed Critical Biokier Inc
Publication of WO2025090548A1 publication Critical patent/WO2025090548A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method of reducing trimethylamine-N-oxide (TMAO) by the administration of at least 500mg of a colon targeted butyrate.
  • TMAO trimethylamine-N-oxide
  • TMOA is a gut microbiota metabolite produced from dietary nutrients. Circulating
  • TMAO arises from endogenous liver and gut production, TMAO levels in blood plasma are associated with prevalent cardiovascular disease.
  • the coion is known to be a production site associated with TMAO production in the body.
  • Colon targeted butyrate has been described in iiterature.
  • application number 110106622 (Taiwan) and PCT/US21/23841 incorporated herein by reference.
  • it consists of a butyrate core coated with a neutral polymer coating and the polymer coating is coated with a composition that essentially dissolves in the colon when given orally. Coatings that dissolve essentially in the colon and are well known.
  • the present invention relates to the discovery that administration of at least 500mg of a colon targeted butyrate reduces the blood concentration of TMAO below 6.2 ⁇ M.
  • a method of reducing blood plasma TMAO below 6.2 ⁇ M in a patient comprising: a) selecting a composition for oral administration to the patient comprising butyric acid, the composition formulated to release butyric acid in a colon targeted delivery system; and b) administering an effective amount of at least 500mg of the composition to the patient at least once per day sufficient to lower blood plasma levels of TMAO below 6.2 ⁇ M.
  • the terms “a” or “an”, as used herein, are defined as one or as more than one.
  • the term “plurality”, as used herein, is defined as two or as more than two.
  • the term “another”, as used herein, is defined as at least a second or more.
  • the terms “including” and/or “having”, as used herein, are defined as comprising (i.e., open language).
  • the term “coupled”, as used herein, is defined as connected, although not necessarily directly, and not necessarily mechanically.
  • treating refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression of the condition and preventing or delaying the initial occurrence of the condition in a subject, or reoccurrence of the condition in a previously afflicted subject.
  • treating refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression of the condition and preventing or delaying the initial occurrence of the condition in a subject, or reoccurrence of the condition in a previously afflicted subject.
  • the butyrate compounds of the present invention may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms (“polymorphs”) are within the scope of the present invention.
  • Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystaliization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as x-ray diffraction patterns, solubility, and melting point.
  • the compounds herein include the salts of the present compositions and include the pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may include acid addition salts.
  • Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavuianate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphat
  • the term “administration” of a composition of the present invention refers to oral, in a formulation designed to only deliver the drug to the colon. As described elsewhere herein, the compounds are so formulated to be taken so as to bypass the upper digestive tract and stomach and essentially deliver all the composition in the colon.
  • the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. In one embodiment, the effective amount is at least 500mg. In another, it is between 500mg to 3,000mg.
  • the term "therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes, within its scope, amounts effective to enhance normal physiological function. A therapeutically effective amount will produce a "therapeutic effect”.
  • a compound of the present invention for use in therapy, therapeutically effective amounts of a compound of the present invention, as well as salts thereof, are presented as a pharmaceutical composition formulated to release in a colon targeted delivery system, specifically with a neutral first layer and a colon releasing outer layer.
  • the present invention provides pharmaceutical compositions that include effective amounts of a compound as herein described, or a salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the carrier(s), diluent(s), or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition and consistent with the mode of administration, i.e. , oral or rectal.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the type of colon targeted delivery system, are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant, physician, or veterinarian. Regardless, an effective amount of a gut hormone compound of the present invention for the treatment of humans suffering from high levels of TMAO and associated conditions generally should be at least 500mg Thus, for a 70 kg adult mammal, the actual amount per day would usually be 21 mg.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt or solvate thereof may be determined as a proportion of the effective amount of the compound of the present invention per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein.
  • Pharmaceutical formulations of a tablet presented herein are presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain as a non-limiting example, at least 500mg of butyrate of the present invention depending on the age, weight, and severity of the condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • the compounds of the present invention, or a salt thereof, are administered by a colon targeted coating drug delivery system.
  • the delivery systems may be employed for targeting drug delivery to the colon and bypassing the upper digestive system and stomach.
  • Such drug delivery systems include coatings of the outer layer with one or more covalent linkage compositions, polymer coated compositions, compositions embedded in matrices, time released compositions, redox-sensitive polymer compositions, bioadhesive compositions, micropartical coating compositions, and osmotic delivery compositions.
  • Suitable compositions include those containing polysaccharides, such as chitosan, pectin, chondroitin sulphate, cyclodexthn, dextrans, guar gum, inulin, amylose, and locust bean gum.
  • the compounds may also be coupled with soluble polymers.
  • Such polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl- aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • the targeted matrix in matrix systems comprising a formulation of a hydrophilic first matrix, comprising a lipophilic phase and an amphiphilic phase, wherein the lipophilic phase and the amphiphilic phase are in a second matrix together, and the second matrix is dispersed throughout the hydrophilic first matrix, and wherein the pharmaceutical composition containing the compound is at least partially incorporated into the amphiphilic phase.
  • a formulation of a hydrophilic first matrix comprising a lipophilic phase and an amphiphilic phase, wherein the lipophilic phase and the amphiphilic phase are in a second matrix together, and the second matrix is dispersed throughout the hydrophilic first matrix, and wherein the pharmaceutical composition containing the compound is at least partially incorporated into the amphiphilic phase.
  • the compounds of the present invention or a salt thereof may be employed alone or in combination with other therapeutic agents.
  • the compound(s) of the present invention and the other pharmaceutically active agent(s) may be administered together in the same tablet or administered in separate tablets or when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compound(s) of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention or a salt or solvate thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition, including both compounds; or (2) separate pharmaceutical compositions, each including one of the compounds.
  • the combination may be administered separately in a sequential manner, wherein one treatment agent is administered first and the other second, or vice versa. Such sequential administration may be close in time or remote in time.
  • neutral polymer refers in one embodiment to hydroxypropyl methylcellulose (HPMC) type polymers, gelatin, etc.
  • HPMC hydroxypropyl methylcellulose
  • the neutral polymer should have a thickness of 5 to 100 microns such that it dissolves in the colon after the outer layer is removed.
  • the polymer coating is from 0.5% to about 10% the weight of the butyrate core.
  • it is Opadry® Clear (PVA- based, polyvinyl alcohol).
  • composition of the invention shows a reduction of TMAO to below recommended max concentration.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un traitement d'une personne souffrant de TMAO sur 6,2 micromolaire avec une composition de butyrate ciblant le côlon peut abaisser le TMAO inférieur à 6,2 micromolaire.
PCT/US2024/052475 2023-10-23 2024-10-23 Traitement au butyrate ciblé du côlon pour la réduction du n-oxyde de triméthylamine Pending WO2025090548A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363592366P 2023-10-23 2023-10-23
US63/592,366 2023-10-23

Publications (1)

Publication Number Publication Date
WO2025090548A1 true WO2025090548A1 (fr) 2025-05-01

Family

ID=95516390

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/052475 Pending WO2025090548A1 (fr) 2023-10-23 2024-10-23 Traitement au butyrate ciblé du côlon pour la réduction du n-oxyde de triméthylamine

Country Status (1)

Country Link
WO (1) WO2025090548A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200390798A1 (en) * 2016-12-06 2020-12-17 Kaleido Biosciences, Inc. Glycan polymers and related methods thereof
US20210267919A1 (en) * 2020-02-28 2021-09-02 Biokier, Inc. Stabilized coated butyrate for colon release

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200390798A1 (en) * 2016-12-06 2020-12-17 Kaleido Biosciences, Inc. Glycan polymers and related methods thereof
US20210267919A1 (en) * 2020-02-28 2021-09-02 Biokier, Inc. Stabilized coated butyrate for colon release

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