EP4514360A1 - Composition destinée à être utilisée dans le traitement d'une maladie - Google Patents

Composition destinée à être utilisée dans le traitement d'une maladie

Info

Publication number
EP4514360A1
EP4514360A1 EP23795796.4A EP23795796A EP4514360A1 EP 4514360 A1 EP4514360 A1 EP 4514360A1 EP 23795796 A EP23795796 A EP 23795796A EP 4514360 A1 EP4514360 A1 EP 4514360A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
conjugate
decarboxylated
activity
subject
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
EP23795796.4A
Other languages
German (de)
English (en)
Inventor
Iyad Khamaysi
Salim Hadad
Zaid Abassi
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.)
Technion Research and Development Foundation Ltd
Rambam Med Tech Ltd
Original Assignee
Technion Research and Development Foundation Ltd
Rambam Med Tech Ltd
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 Technion Research and Development Foundation Ltd, Rambam Med Tech Ltd filed Critical Technion Research and Development Foundation Ltd
Publication of EP4514360A1 publication Critical patent/EP4514360A1/fr
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Definitions

  • Acute pancreatitis is a common disease in gastroenterology with an increasing global incidence, where it accounts for about 2% of all hospitalized patients.
  • AP is a complex inflammatory syndrome that results from many etiologies where gallstones, alcohol and ERCP are the leading causes.
  • About 20% of patients who experienced first AP-attack will develop recurrent attacks (RAP) and approximately one third of the latter continue to end-stage chronic pancreatitis (CP).
  • RAP recurrent attacks
  • CP chronic pancreatitis
  • pancreas edema and inflammation, as well as the induction of cytokines and signaling molecules following cerulein administration were attenuated markedly by PG545 and SST0001, selective heparanase inhibitors, implying that heparanase plays a significant role in AP.
  • all the above features appear even more pronounced in transgenic mice over expressing heparanase, suggesting that these mice can be utilized as a sensitive model system to reveal the molecular mechanism by which heparanase functions in AP. Therefore, there is an ongoing need to develop novel medications for specific and efficient treatment of AP.
  • Inflammatory brain disease also referred to as inflammatory disease of the central nervous system (CNS) is a condition where the brain and/or spinal cord become inflamed. Inflammation in the brain causes irritation and swelling of brain tissue or blood vessels and can lead to brain damage over the long term.
  • CNS central nervous system
  • Non-Steroidal Anti-inflammatory Drug are extensively used for the treatment of inflammation and pain. NSAIDs act by inhibiting Cyclooxygenase (COX)-l and/or COX-2 activity, thereby reducing intracellular synthesis of prostaglandins, being associated with inflammation and/or pain.
  • COX Cyclooxygenase
  • most NSAIDs are not able to cross the blood brain barrier (BBB) in an amount sufficient for inducing a therapeutic effect. Therefore, there is an ongoing need to develop methods for enhancing BBB penetration of known NSAIDs, e.g., for use in the treatment of brain inflammation and for reducing COX activity within the brain.
  • trehalose is covalently bound to a carboxy group of said NSAID.
  • covalently bound is via a bond selected from an ester, an amide, a thioester, a carbamate, a carbonate ester, a carbamide, a thiocarbamate, a phosphonate, a phosphodiester, a sulfonate ester, or any combination thereof.
  • trehalose is covalently bound via a hydroxy group at position 2, at position 6 or both.
  • the conjugate is represented by Formula 1: wherein each R independently comprises decarboxylated diclofenac, decarboxylated naproxen, decarboxylated diflunisal, decarboxylated salsalate, decarboxylated paracetamol, decarboxylated ibuprofen, decarboxylated indomethacin, decarboxylated mefenamic acid, decarboxylated meclofenamic acid, decarboxylated clonixin, or decarboxylated licofelone, and each X or
  • Xi independently comprises O, S, or NH.
  • a pharmaceutical composition comprising a therapeutically effective amount of a conjugate and a pharmaceutically acceptable carrier, wherein the conjugate comprises trehalose covalently bound to a Non-Steroidal Antiinflammatory Drug (NSAID).
  • NSAID Non-Steroidal Antiinflammatory Drug
  • the NS AID is selected from aspirin, diclofenac, naproxen, diflunisal, salsalate, ibuprofen, indomethacin, mefenamic acid, meclofenamic acid, clonixin, licofelone, a COX-2 inhibitor including any pharmaceutically acceptable salt, pharmaceutically active derivative or a combination thereof.
  • the conjugate is the conjugate of the invention.
  • the pharmaceutical composition is for use in the prevention or treatment of a disease or disorder in a subject in need thereof.
  • disease or disorder is or comprises inflammation, pain, or both.
  • disease or disorder is or comprises pancreatitis.
  • the pharmaceutical composition is for use in the inhibition and/or the reduction of cyclooxygenase (COX) activity, heparinase (Hep) activity, or both within a subject in need thereof.
  • COX cyclooxygenase
  • Hep heparinase
  • the disease or disorder is associated with COX activity, Hep activity, or both.
  • a method for inhibiting or reducing enzymatic activity within a subject in need thereof comprising administering the pharmaceutical composition the invention to said subject, wherein the enzymatic activity comprises COX activity, Hep activity, or both.
  • reducing enzymatic activity comprises preventing or treating a condition selected from inflammation and pain in said subject.
  • inflammation comprises pancreatitis.
  • Figures 1A-C are bar graphs showing effects of either PG545, SST0001, Aspirin or combined therapy on cerulein -induced pancreatitis as evident by serum levels of lipase (1A), amylase (IB) and pancreatic index (Pancreas /Body weight ratio) (1C) in WT mice and Hpa-Tg animals.
  • Figures 2A-E and 2A’-G’ are micrographs showing histopathology images of WT and Hpa-Tg mice injected with either saline or cerulein in the presence or absence of PG545, SST0001, Asp or combined pretreatment. Pancreas tissues were collected 24 h thereafter, and 5micron sections from formalin-fixed, paraffin-embedded samples were stained for H&E. Shown are representative photomicrographs at X20 original magnification.
  • Figures 2A-E present Hematoxylin stained samples of WT and Hpa-Tg mice injected with either saline (2A) or cerulein (2B) in the presence or absence of Asp (2C), PG545 (2D) or combined pretreatment PG545+Asp (2E).
  • Figures 2A’-G’ present Eosin stained samples of WT and Hpa-Tg mice injected with either saline (2A’) or cerulein (2B’) in the presence or absence of PG545 (2C’), SST0001 (2D’), Asp (2E’) or combined pretreatment PG545+Asp (2F’) and PG545+Asp+ SST0001 (2G’).
  • Figures 3A-D are bar graphs and micrographs showing the effect of pretreatment with Aspirlose (mono or Diester) on cerulein -induced pancreatitis as evident by serum levels of lipase (3A), amylase (3B) and pancreatic index (Pancreas /Body weight ratio) (3C) and histological alterations (3D) in WT mice and Hpa-Tg animals.
  • Aspirlose mono or Diester
  • pancreatic index Pancreas /Body weight ratio
  • 3D histological alterations
  • Figures 4A-C are bar graphs showing the effect of post-treatment with Aspirlose (mono or Diester) on cerulein -induced pancreatitis as evident by serum levels of lipase (4A), amylase (4B) and pancreatic index (Pancreas /Body weight ratio) (4C) in Hpa-Tg animals.
  • Aspirlose mono or Diester
  • pancreatic index Pancreas /Body weight ratio
  • Figures 5A-D are bar graphs and micrographs showing the effect of pretreatment with Indose (conjugate of Indomethacin and Trehalose) or Diclose (conjugate of Diclofenac and Trehalose) (16 or 32 mg/kg, ip) cerulein -induced pancreatitis as evident by serum levels of lipase (5A), amylase (5B) pancreatic index (Pancreas /Body weight ratio(P/M)) (5C) and histological analysis (5D) in WT animals.
  • Indose conjuggate of Indomethacin and Trehalose
  • Diclose conjuggate of Diclofenac and Trehalose
  • Figures 6A-C are bar graphs and micrographs showing the effect of pretreatment with Indose (conjugate of Indomethacin and Trehalose) or Diclose (conjugate of Diclofenac and Trehalose) (16 or 32 mg/kg, ip) cerulein -induced pancreatitis as evident by serum levels of lipase (6A), amylase (6B) and pancreatic index (Pancreas /Body weight ratio(P/M)) (6C) in Hpa-Tg animals.
  • Indose conjuggate of Indomethacin and Trehalose
  • Diclose conjuggate of Diclofenac and Trehalose
  • pancreatic index Pancreas /Body weight ratio(P/M)
  • conjugate comprising a disaccharide covalently bound to a compound selected from the group comprising diclofenac, naproxen, diflunisal, salsalate, paracetamol, ibuprofen, indomethacin, mefenamic acid, meclofenamic acid, clonixin, and licofelone or any combination thereof.
  • non-limiting examples of the disaccharide are: Sucrose, Lactose , Maltose, Trehalose, Cellobiose, Chitobiose, Kojibiose, Nigerose, Isomaltose, 3,
  • the disaccharide comprises two monosaccharide units connected to each other via a glycosidic bond, wherein each of the monosaccharide units is independently selected from a hexose and a pentose. In some embodiments, each of the monosaccharide units is a hexose. In some embodiments, the disaccharide is trehalose or a derivative thereof (e.g., a conformer, a diastereomer, an enantiomer).
  • the conjugate comprises trehalose covalently bound to a compound selected from the group comprising diclofenac, naproxen, diflunisal, salsalate, ibuprofen, paracetamol, indomethacin, mefenamic acid, meclofenamic acid, clonixin, and licofelone or any combination thereof.
  • the compound is or comprises at least one NSAID selected from diclofenac, naproxen, ibuprofen, indomethacin, and paracetamol, or any combination thereof.
  • the conjugate comprises trehalose covalently bound to a plurality of compounds, wherein the compound is as described hereinabove. In some embodiments, the compound is devoid of aspirin.
  • trehalose is covalently bound via a hydrolysable bond.
  • trehalose is covalently bound via a biodegradable or biocleavable bond.
  • biodegradable or biocleavable bonds are well-known in the art and comprise inter alia an amide bond, an ester bond, and a disulfide bond.
  • the covalent bond is selected from an ester, an amide, a thioester, a carbamate, a carbonate ester, a carbamide, a thiocarbamate, a phosphonate, a phosphodiester, a sulfonate ester, or any combination thereof.
  • the covalent bond is selected from an ester, an amide, a thioester, or any combination thereof.
  • the conjugate comprises trehalose covalently bound to one or more compounds via an ester bond.
  • the conjugate is of Formula 1:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne de manière générale le domaine des compositions comprenant un ou plusieurs conjugués de tréhalose et concerne des méthodes d'utilisation de celles-ci par ex. pour le traitement d'une maladie ou d'un trouble chez un sujet.
EP23795796.4A 2022-04-28 2023-04-27 Composition destinée à être utilisée dans le traitement d'une maladie Pending EP4514360A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263335978P 2022-04-28 2022-04-28
PCT/IL2023/050433 WO2023209722A1 (fr) 2022-04-28 2023-04-27 Composition destinée à être utilisée dans le traitement d'une maladie

Publications (1)

Publication Number Publication Date
EP4514360A1 true EP4514360A1 (fr) 2025-03-05

Family

ID=88518068

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23795796.4A Pending EP4514360A1 (fr) 2022-04-28 2023-04-27 Composition destinée à être utilisée dans le traitement d'une maladie

Country Status (4)

Country Link
EP (1) EP4514360A1 (fr)
JP (1) JP2025514339A (fr)
CA (1) CA3248113A1 (fr)
WO (1) WO2023209722A1 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030105144A1 (en) * 2001-04-17 2003-06-05 Ping Gao Stabilized oral pharmaceutical composition

Also Published As

Publication number Publication date
JP2025514339A (ja) 2025-05-02
WO2023209722A1 (fr) 2023-11-02
CA3248113A1 (fr) 2023-11-02

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