WO2021233549A1 - Cleavable polymer drug conjugates for viral diseases - Google Patents

Cleavable polymer drug conjugates for viral diseases Download PDF

Info

Publication number
WO2021233549A1
WO2021233549A1 PCT/EP2020/064230 EP2020064230W WO2021233549A1 WO 2021233549 A1 WO2021233549 A1 WO 2021233549A1 EP 2020064230 W EP2020064230 W EP 2020064230W WO 2021233549 A1 WO2021233549 A1 WO 2021233549A1
Authority
WO
WIPO (PCT)
Prior art keywords
peg
vitamin
nanoparticle
sars
polymer
Prior art date
Application number
PCT/EP2020/064230
Other languages
French (fr)
Inventor
Hamdi Sena NOMAK
Original Assignee
Rs Arastirma Egitim Danismanlik Ilac Sanayi Ticaret Anonim Sirketi
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 Rs Arastirma Egitim Danismanlik Ilac Sanayi Ticaret Anonim Sirketi filed Critical Rs Arastirma Egitim Danismanlik Ilac Sanayi Ticaret Anonim Sirketi
Priority to PCT/EP2020/064230 priority Critical patent/WO2021233549A1/en
Publication of WO2021233549A1 publication Critical patent/WO2021233549A1/en

Links

Classifications

    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6933—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
    • C08F220/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
    • C08F220/285—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing a polyether chain in the alcohol moiety
    • C08F220/286—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing a polyether chain in the alcohol moiety and containing polyethylene oxide in the alcohol moiety, e.g. methoxy polyethylene glycol (meth)acrylate

Definitions

  • This invention relates to nanoparticles or microparticles comprising polymer drug conjugates according to formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PEG and/or PLA and/or PLGA and/or PF-127.
  • chloroquine or its derivative hydroxychloroquine and some antiviral drugs are considered as treatment options.
  • some of these drugs have serious side effects and can be as fatal as the virus itself.
  • Present invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I, optionally in conjugation with or as a blend with chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat, chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PEG and/or PL A and/or PLGA and/or PF-127 wherein; Ri and R2 are independently selected from H or -C3 ⁇ 4; R 3 is selected from -H or -C3 ⁇ 4; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising chloroquine, hydroxychloroqu
  • microparticles or nanoparticles prepared according to present invention is suitable for local delivery, such as through inhalation, and because of the cleavable bond on the polymer drug conjugate the drugs are released at the target site and thus much less systemic administration and toxicity is observed.
  • polymer-drug conjugate refers to a polymeric structure having a therapeutic agent covalently attached to the polymer.
  • polymer-drug conjugate as shown with formula I refers to the structure shown with formula I wherein; Ri and R2 are independently selected from H or - CH 3 ; R 3 is selected from -H or -CH 3 ; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS- CoV-2 or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null; B is an end group that is optionally
  • polymeric backbone and “polymer backbone” can be used interchangeably and refer to a polymer chain having side chains or pendant groups.
  • a side chain may have an oligo ethylene glycol unit and a pendant group may be bearing one therapeutic agent or any other group that can be utilized to attach a therapeutic and/or diagnostic agent or a targeting group.
  • acrylate refers to derivatives of acrylic acids. These derivatives include the parent acid (CH2CHCO2H) and esters, thus the term “acrylate based” defines functional groups having any of the abovementioned acrylate derivatives.
  • methacrylate refers to derivatives of methacrylic acids. These derivatives include the parent acid (CH 2 C(CH 3 )C0 2 H) and esters. Thus the term “methacrylate based” defines functional groups having any of the abovementioned methacrylate derivatives.
  • (meth)acrylate refers to the terms “acrylate” and “methacrylate”.
  • (meth)acrylate can be used interchangeably with “acrylate” and “methacrylate” and comprises all features of these terms as described above.
  • (meth)acrylate should be construed to mean “methacrylate and/or acrylate”
  • the term “the polymer-drug conjugate of the invention” should be construed to mean “a polymer-drug conjugate according to formula I” or “a polymer-drug conjugate of formula I” or “formula I” and these terms can be used interchangeably.
  • PEG refers to a polyether compound having the structure of H-(0-CH 2 -CH 2 )n-0R 3 , n being a natural number between 1-200 and R 3 selected from H or -CH 3.
  • PEG is defined as an oligomer or polymer of ethylene oxide.
  • PEG polyethylene glycol
  • PEO polyethylene oxide
  • POE polyoxyethylene
  • the polymer-drug conjugate of the invention comprises PEG side chains.
  • the side chains provide important physicochemical properties to the polymer-drug conjugate of the invention and leads to a polymer-drug conjugate that has better physicochemical properties in comparison to the conjugates that does not have said side chains.
  • n is a natural number between 1-20, preferably 1-10, most preferably 1-4.
  • N can be for example 1 or 2 or 3 or 4 or 5 or 6 or 7.
  • the inventors have found that, polymer-drug conjugates of formula I having an n value in between 1-4 readily forms desirable microparticles or nanoparticles without the need for further steps such as spray drying etc.
  • L in formula I denotes a cleavable linker.
  • the term “Cleavable linker” refers to a group that spatially separates drug or a targeting group from the carrier molecule.
  • the terms “linker”, “L” and “cleavable linker” refer to the same entity and can be used interchangeably.
  • R 2 -CH 3
  • R 3 -CH 3
  • random copolymer refers to a copolymer wherein the monomers forming the copolymer follow in any order.
  • block copolymer refers to a copolymer wherein all of one type of monomer is grouped together and the all of the other type of monomers are grouped together.
  • the polymer-drug conjugates of the invention can be in the form of block copolymer or random copolymers. In a preferred embodiment the polymer-drug conjugates of the invention are in the form of random copolymer.
  • the linkers are cleavable so that the therapeutic agent can be released, for example, under reducing conditions, oxidizing conditions or by hydrolysis of an ester, amide, hydrazide, or similar linkage that forms the covalent bond between the linker and the therapeutic agent.
  • Said cleavable linker can be any hydrocarbon or substituted hydrocarbon based compound which is capable of dissociating under physiological conditions.
  • the linker can be selected from compounds that are cleaved under the physiological conditions of the target site or with the help of the overexpressed enzymes present in the target site.
  • the target site is the lungs.
  • the linker can also be a Ci-Cio hydrocarbon or a Ci-Cio substituted or hetero substituted hydrocarbon such that it comprises a functional group that dissociates under physiological conditions, such as an, ester, imine, amide, disulfide, carbonate, carbamate,.
  • Ci-Cio hydrocarbon refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone.
  • Ci-Cio substituted hydrocarbon refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein one or more of its hydrogen atoms replaced by atoms of groups of other elements such as alcohol, amine, carboxyl, thiol etc.
  • Ci-Cio heterosub stituted hydrocarbon refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein at least one of the C atoms is substituted with an atom other than C such as nitrogen, oxygen, phosphorus, sulfur or a halogen atom.
  • substituents include but not limited to lower alkoxy such as methoxy, ethoxy, butoxy; ethers;;; esters; hetroaryl; heterocyclic; hydroxyl; protected hydroxyl; acyl; acyloxy; amino; amido; imine, disulfide, carbonate, carbamate, , hydrazine.
  • the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one disulfide functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one ester functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one imine functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one amide functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one carbonate functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one carbamate functional group.
  • the linker may comprise a Ci-Cio substituted or hetero substituted hydrocarbon comprising two or more functional groups selected from the group comprising, ester, imine, amide, disulfide, carbonate, carbamate,.
  • any other agent known to be effective for a disease caused by SARS-CoV and/or SARS-CoV-2 refers to any agent that prevents or leads to alleviation of at least one of the symptoms of a disease caused by SARS-CoV and/or SARS-CoV-2.
  • Chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof can be present in an amount in between 1% to 50% by weight of the polymer-drug conjugate, preferably in an amount between 2% to 45% by weight of the drug-polymer conjugate and most preferably in an amount between 3% to 40% by weight of the drug-polymer conjugate.
  • the therapeutic agent can be present in an amount in the range of for example; 4% to 45% or 5% to 40% or 6% to 38% or 7% to 35% or 8% to 30% by weight of the drug-polymer conjugate.
  • a preferred embodiment of the invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 wherein; Ri and R2 are independently selected from H or -CH 3 ; R 3 is selected from -H or -CH 3 ; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or
  • a preferred embodiment of the invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I as described above wherein x:y have a ratio in between 5:1 to 1:1, preferably in between 4,5:1 to 1:1, most preferably between 4:1 to 1,5:1.
  • the inventors have found that when the monomers forming the polymer-drug conjugate of formula I are such that x:y are in a ratio in between 5:1 to 1:1 the polymer-drug conjugate that forms is in the form of a nanoparticle or microparticle without addition of other chemicals.
  • the term “end group” refers to functionalities or constitutional units that are at the extremity of a polymer.
  • the end groups shown as A and B can be identical to or different from one another.
  • a and B can optionally be a polymerization initiator or a fragment thereof. Particularly when an initiator is used in the polymerization reaction, the initiator fragment may stay as an end group to the polymer.
  • the initiator used herein may be any material suitable for initiating the polymerization reaction known in the art.
  • fragment refers to compounds that form due to breaking of one or more of the covalent bonds forming the initiator molecule.
  • a and/or B is optionally null.
  • A is null and B is a polymerization initiator or a fragment of a polymerization initiator.
  • B is null and A is a polymerization initiator or a fragment of a polymerization initiator.
  • a and B are both fragments of a polymerization initiator however they are structurally different from one another. In other words, A and B are different fragments of the same initiator. In another embodiment A and B are both fragments of a polymerization initiator and they have the same chemical structure.
  • the measurement of the amount of drug in the polymer conjugate of the invention is made by using conventional techniques well-known in the art, for example by calculation of the drug ratio from an 'H-NMR of the polymer-drug conjugate.
  • the polymer-drug conjugate of the invention has an average molecular weight in between 3 kDa to 150 kDa, preferably between 4kDa to 120 kDa, most preferably between 5 kDa to 100 kDa.
  • Molecular weight of the polymer-drug conjugate of the invention is determined by using conventional techniques known in the art for example by using gel permeation chromatography (GPC).
  • Polymer-drug conjugate of the invention can be prepared by using conventional methods disclosed in the art.
  • the cleavable linker according to present invention can be obtained from commercial sources or may be prepared according to known methods provided in literature.
  • the polymer-drug conjugate of the invention can be prepared by any of the known polymerization methods. Any suitable initiators and/or catalysts known in the art can be used for the preparation of the polymer-drug conjugate of the present invention. Where a polymerization initiator is used, the initiator or a fragment thereof may be present in the resulting polymer-drug conjugate.
  • the polymer backbone of the polymer-drug conjugate of the invention can be obtained by for example bulk polymerization, solution polymerization and/or suspension polymerization techniques known in the art.
  • the polymerization technique used for the preparation of the polymer-drug conjugate of the present invention may propagate through free-radical polymerization or controlled/living free radical polymerization.
  • controlled/living free radical polymerization refers to atom transfer radical polymerization (ATRP), Reversible addition fragmentation chain transfer (RAFT) polymerization, iodine transfer polymerization (ITP), selenium centered radical mediated polymerization, telluride mediated polymerization (TERP), nitroxide mediated polymerization (NMP).
  • RAFT polymerization is used to prepare the polymer-drug conjugates of the invention.
  • a polymerization initiator as used herein refers to a chemical compound that reacts with a monomer to form an intermediate compound capable of linking successively with a large number of other monomers into a polymeric compound.
  • the present invention relating to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I may further comprise a targeting group.
  • Said targeting agent can be as attached to the polymer-drug conjugate as shown with formula I or can be embedded into the nanoparticle of microparticle structure or in the case that the microparticle or nanoparticle comprises a coating it can be in the coating mixture or can be embedded into the coating layer.
  • targeting group means a molecule which serves to deliver the polymer-drug conjugate of the invention to a specific site for the desired activity, i.e. it provides localization of the compound.
  • Targeting ligands include, for example, molecules that bind to molecules on a targeted cell surface.
  • Exemplary targeting ligands include antibodies, antibody fragments, small organic molecules, peptides, peptoids, proteins, polypeptides, oligosaccharides, transferrin, HS- glycoprotein, coagulation factors, serum proteins, beta-glycoprotein and the like.
  • the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I wherein said nanoparticles or microparticles are coated with a compound selected from the group comprising glucose, sucrose, maltose, fructose, trehalose, lactose, dextrose, tagatose, raffmose, erythritol, maltitol, maltodextrin mannitol, sorbitol,, polydextrose, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PEG, PLGA, PLA, PF-127.
  • the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I wherein polymer-drug conjugate as shown with formula I is blended with a first compound and then the formed nanoparticles or microparticles are coated with a second compound.
  • the first compound is selected from a group comprising chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PLA, PLGA, PF-127, chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or their pharmaceutically acceptable derivatives thereof.
  • the second compound is selected from a group comprising glucose, sucrose, maltose, fructose, trehalose, lactose, dextrose, tagatose, raffmose, erythritol, maltitol, maltodextrin mannitol, sorbitol,, polydextrose, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PEG, PLGA, PLA, PF-127.
  • the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I in conjugation with chitosan wherein said conjugate is coated with alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PL A and/or PLGA and/or PF127.
  • the nanoparticles according to the invention can have a size in the range of 1-999 nm, preferably in the range of 10-900 nm, most preferably 50-850 nm. Any sample wherein at least 90% of the particles have a size in the range of 1-999 nm is considered as a nanoparticle.
  • microparticles according to the invention can have a size in the range of 1-15 pm, preferably in the range of 1-10 pm, most preferably 1-6 pm. Any sample wherein at least 90% of the particles have a size in the range of 1-5 pm is considered as a microparticle.
  • Chitosan is a linear polysaccharide composed of randomly distributed P-(l 4)-linked D- glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). Chitosan can have an average molecular weight in between 2kDa to 300kDa.
  • Alginate is a salt of alginic acid which is a linear copolymer with homopolymeric blocks of (1- 4)-linked b-D-mannuronate (M) and its C-5 epimer a-L-guluronate (G) residues, respectively, covalently linked together in different sequences or blocks.
  • Alginate can preferably be in the form of sodium alginate.
  • Alginate, preferably sodium alginate can have an average molecular weight in between lkDa to 200kDa.
  • PLGA refers to a co polymer comprising the monomers of lactide and glycolide in various ratios.
  • the ratio of lactide to glycolide is prefereably 50:50 is a preferred embodiment of the invention.
  • the PLGA polymer can have a molecular weight in the range of 5-20 kDa, preferably 7-17 kDa.
  • PEG-PLGA refers to a block copolymer wherein one block is polyethylene glycol and the other block is a random copolymer of polylactide-co-glycolide.
  • the blocks can be attached to one another with any conventional means known to a person skilled in the art.
  • PLA refers to a polymer comprising the monomer of lactide.
  • the PLA polymer can have a molecular weight in the range of 5-20 kDa, preferably 7-17 kDa.
  • PEG-PLA refers to a block copolymer wherein one block is polyethylene glycol and the other block is a polylactide.
  • the blocks can be attached to one another with any conventional means known to a person skilled in the art.
  • PF127 also known as poloxamer 407 refers to a triblock copolymer made up of hydrophobic residue of polyoxypropylene (POP) between the two hydrophilic units of polyoxyethylene (POE) also known as polyethylene glycol (PEG).
  • POP polyoxypropylene
  • POE polyoxyethylene
  • PEG polyethylene glycol
  • PEG that forms a block copolymer with PLA or PLGA can be a linear or branched PEG, for example can be randomly branched or can be in star shape or can have multiple arms, such as at least two arms.
  • PEG that forms a block copolymer with PLA or PLGA can have a molecular weight in the range of 2-50 kDa.
  • Another embodiment of the present invention provides a method for delivering a therapeutic agent, comprising administering to a subject an effective amount of a microparticle or nanoparticle comprising polymer-drug conjugate shown with formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or
  • PEG-PF127 and/or PLA and/or PLGA and/or PF127 Another embodiment of the invention is the microparticle or nanoparticle comprising polymer- drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and/or PLGA and/or PF127 for use in treatment of a variety of disorders that require the delivery of chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or
  • the invention is related to microparticle or nanoparticle comprising a polymer-drug conjugate shown with formula I optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG- PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 for use as a medicament for treatment of a disease caused by SARS-CoV and/or SARS-CoV-2 viruses.
  • treat means to inhibit, reduce, modulate, ameliorate, or block at least one symptom that characterizes a pathologic condition, in a subject threatened by, or afflicted with, the condition
  • a pharmaceutical composition comprising a microparticle or nanoparticle comprising polymer-drug conjugate according to formula I optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 and at least one pharmaceutically acceptable diluent, excipient and/or carrier.
  • treatment includes either therapeutic or prophylactic therapy.
  • the composition comprising a microparticle or nanoparticle comprising the polymer-drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 may be in any suitable form depending upon the desired method of administering it to a patient.
  • composition comprising polymer drug conjugates of the invention can be formulated to be administered orally, e.g. in the form of liquid dispersions or aqueous or oily suspensions or they can formulated for parenteral administration, for example for subcutaneous, intravenous, intramuscular, intrastemal, intraperitoneal, intradermal, transdermal or other infusion techniques.
  • composition comprising the polymer drug conjugates of the invention can also be formulated for administration by inhalation in form of an aerosol, dry powder or solution for administration with an inhaler or nebulizer.
  • the polymer-drug conjugates of the invention are preferably administered to a subject transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intratumorally or via inhalation.
  • the most suitable route for administration in any given case will depend on the particular therapeutic agent present in the polymer-drug conjugate of the present invention, the subject, and the nature and severity of the disease and the physical condition of the subject.
  • a microparticle or nanoparticle comprising the polymer-drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG- PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 is formulated in form of a dry powder or aerosol or solution for for administration with an inhaler or nebulizer.
  • the inventors were able to deliver the therapeutics agents of chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof directly to the target site, that is lungs and any systemic absorption of the active agents and possible side effects originating from them are prevented. Furthermore, a more effective treatment is provided.
  • micro or nanoparticles comprising the polymer-drug conjugates shown with formula I may be administered in combination, e.g. simultaneously, sequentially or separately, with one or more other therapeutically active compounds selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS- CoV-2, vitamins known in the arts such as vitamin A, Vitamin Bl, Vitamin B2, Vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D2, vitamin D3, vitamin E, vitamin K and minerals such as potassium, chlorine, sodium, calcium, phosphorus, magnesium, iron, zinc, manganese, copper, iodine, chromium, molybdenum, selenium, cobalt and antioxidants known in the art such as quercetin, coenzyme Q
  • Said second therapeutic agent can be selected from the therapeutic agents listed above on the condition that it is different from the one present in the polymer-drug conjugate of the invention.
  • Comprising in the context of the present specification is intended to meaning including.
  • Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.
  • Example 1 Synthesis and Characterization of Copolymer P(OEGMA-HCQ-CB).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Polymers & Plastics (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to nanoparticles or microparticles comprising polymer drug conjugates according to formula (I) optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PEG and/or PLA and/or PLGA and/or PF-127.

Description

CLEAVABLE POLYMER DRUG CONJUGATES FOR VIRAL DISEASES
This invention relates to nanoparticles or microparticles comprising polymer drug conjugates according to formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PEG and/or PLA and/or PLGA and/or PF-127.
BACKGROUND OF THE INVENTION
Several viral diseases affect the respiratory system of humans leading to severe pneumonia and in some cases even death. In the last 20 years there has been two major epidemics caused by viruses, specifically SARS-CoV and SARS-CoV-2. The diseases caused by these viruses, namely SARS and Covid-19, lead to several deaths around the globe. At the moment there is no vaccine specific for these viruses and also there is no drug indicated for the treatment.
Even in the present circumstances some previously known molecules indicated for treatment of different unrelated diseases are considered as helpful with minimum clinical data. For example, chloroquine or its derivative hydroxychloroquine and some antiviral drugs are considered as treatment options. However, some of these drugs have serious side effects and can be as fatal as the virus itself.
One downside of these conventional drugs, specifically chloroquine and its derivatives is that they are administered systemically and therefore they are distributed to the entire body and accumulate in organs other then the lungs and even cause heart failure upon prolonged use. The inventors aim to solve the problem of systemic distribution of the candidate molecules and prevent side effects.
BRIEF DESCRIPTION OF THE INVENTION
Present invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I, optionally in conjugation with or as a blend with chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat, chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PEG and/or PL A and/or PLGA and/or PF-127 wherein; Ri and R2 are independently selected from H or -C¾; R3 is selected from -H or -C¾; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null; B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null.
Figure imgf000003_0001
The inventors have surprisingly found that the microparticles or nanoparticles prepared according to present invention is suitable for local delivery, such as through inhalation, and because of the cleavable bond on the polymer drug conjugate the drugs are released at the target site and thus much less systemic administration and toxicity is observed. DETAILED DESCRIPTION OF THE INVENTION
The term “polymer-drug conjugate” refers to a polymeric structure having a therapeutic agent covalently attached to the polymer.
Within the present invention the term “polymer-drug conjugate as shown with formula I” refers to the structure shown with formula I wherein; Ri and R2 are independently selected from H or - CH3; R3 is selected from -H or -CH3; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS- CoV-2 or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null; B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null.
The terms “polymeric backbone” and “polymer backbone” can be used interchangeably and refer to a polymer chain having side chains or pendant groups. For example, a side chain may have an oligo ethylene glycol unit and a pendant group may be bearing one therapeutic agent or any other group that can be utilized to attach a therapeutic and/or diagnostic agent or a targeting group. The term “acrylate” refers to derivatives of acrylic acids. These derivatives include the parent acid (CH2CHCO2H) and esters, thus the term “acrylate based” defines functional groups having any of the abovementioned acrylate derivatives.
The term “methacrylate” refers to derivatives of methacrylic acids. These derivatives include the parent acid (CH2C(CH3)C02H) and esters. Thus the term “methacrylate based” defines functional groups having any of the abovementioned methacrylate derivatives.
The term “(meth)acrylate” refers to the terms “acrylate” and “methacrylate”. Thus, the term “(meth)acrylate” can be used interchangeably with “acrylate” and “methacrylate” and comprises all features of these terms as described above. The term “(meth)acrylate” should be construed to mean “methacrylate and/or acrylate”
Throughout the text, the term “the polymer-drug conjugate of the invention” should be construed to mean “a polymer-drug conjugate according to formula I” or “a polymer-drug conjugate of formula I” or “formula I” and these terms can be used interchangeably.
The term “PEG” refers to a polyether compound having the structure of H-(0-CH2-CH2)n-0R3, n being a natural number between 1-200 and R3 selected from H or -CH3. PEG is defined as an oligomer or polymer of ethylene oxide. The terms “PEG”, “polyethylene glycol”, “polyethylene oxide”, “PEO”, “polyoxyethylene” and “POE” refer to the same structure and may be used interchangeably within this text.
As shown by formula I the polymer-drug conjugate of the invention comprises PEG side chains. The side chains provide important physicochemical properties to the polymer-drug conjugate of the invention and leads to a polymer-drug conjugate that has better physicochemical properties in comparison to the conjugates that does not have said side chains. In a preferred embodiment n is a natural number between 1-20, preferably 1-10, most preferably 1-4. N can be for example 1 or 2 or 3 or 4 or 5 or 6 or 7. The inventors have found that, polymer-drug conjugates of formula I having an n value in between 1-4 readily forms desirable microparticles or nanoparticles without the need for further steps such as spray drying etc.
As mentioned above “L” in formula I denotes a cleavable linker. The term “Cleavable linker” refers to a group that spatially separates drug or a targeting group from the carrier molecule. The terms “linker”, “L” and “cleavable linker” refer to the same entity and can be used interchangeably. In one embodiment Ri=H, R.2=H, R.3=H; In another embodiment Ri=H, R2=H, R3= -CIR; In another embodiment Ri=H, R2= -CH3, R3=H; In another embodiment Ri=H, R2= -CH3, R3— CH3; In another embodiment R1—CH3, R2= H, R3=H; In another embodiment R1—CH3, R2= H, R3—CH3; In another embodiment R1—CH3, R2= -CH3, R3=H; In another embodiment R1—CH3,
R2= -CH3, R3= -CH3. The term “random copolymer” refers to a copolymer wherein the monomers forming the copolymer follow in any order. The term “block copolymer” refers to a copolymer wherein all of one type of monomer is grouped together and the all of the other type of monomers are grouped together. The polymer-drug conjugates of the invention can be in the form of block copolymer or random copolymers. In a preferred embodiment the polymer-drug conjugates of the invention are in the form of random copolymer. The linkers are cleavable so that the therapeutic agent can be released, for example, under reducing conditions, oxidizing conditions or by hydrolysis of an ester, amide, hydrazide, or similar linkage that forms the covalent bond between the linker and the therapeutic agent.
Said cleavable linker can be any hydrocarbon or substituted hydrocarbon based compound which is capable of dissociating under physiological conditions. In a preferred embodiment the linker can be selected from compounds that are cleaved under the physiological conditions of the target site or with the help of the overexpressed enzymes present in the target site. In a preferred embodiment of the invention the target site is the lungs.
The linker can also be a Ci-Cio hydrocarbon or a Ci-Cio substituted or hetero substituted hydrocarbon such that it comprises a functional group that dissociates under physiological conditions, such as an, ester, imine, amide, disulfide, carbonate, carbamate,.
The term “Ci-Cio hydrocarbon” refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone.
The term “Ci-Cio substituted hydrocarbon” refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein one or more of its hydrogen atoms replaced by atoms of groups of other elements such as alcohol, amine, carboxyl, thiol etc.
The term “Ci-Cio heterosub stituted hydrocarbon” refers to a hydrocarbon chain having 1 to 10 C atoms in the backbone wherein at least one of the C atoms is substituted with an atom other than C such as nitrogen, oxygen, phosphorus, sulfur or a halogen atom. These substituents include but not limited to lower alkoxy such as methoxy, ethoxy, butoxy; ethers;;; esters; hetroaryl; heterocyclic; hydroxyl; protected hydroxyl; acyl; acyloxy; amino; amido; imine, disulfide, carbonate, carbamate, , hydrazine.
In an embodiment of the invention, the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one disulfide functional group.. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one ester functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one imine functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one amide functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one carbonate functional group. In an embodiment of the invention the linker is a Ci-Cio hetero substituted hydrocarbon comprising at least one carbamate functional group.
In another embodiment of the invention the linker may comprise a Ci-Cio substituted or hetero substituted hydrocarbon comprising two or more functional groups selected from the group comprising, ester, imine, amide, disulfide, carbonate, carbamate,. The term “any other agent known to be effective for a disease caused by SARS-CoV and/or SARS-CoV-2” refers to any agent that prevents or leads to alleviation of at least one of the symptoms of a disease caused by SARS-CoV and/or SARS-CoV-2.
Chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof can be present in an amount in between 1% to 50% by weight of the polymer-drug conjugate, preferably in an amount between 2% to 45% by weight of the drug-polymer conjugate and most preferably in an amount between 3% to 40% by weight of the drug-polymer conjugate. The therapeutic agent can be present in an amount in the range of for example; 4% to 45% or 5% to 40% or 6% to 38% or 7% to 35% or 8% to 30% by weight of the drug-polymer conjugate.
A preferred embodiment of the invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 wherein; Ri and R2 are independently selected from H or -CH3; R3 is selected from -H or -CH3; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null; B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null.
Figure imgf000009_0001
A preferred embodiment of the invention relates to a nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I as described above wherein x:y have a ratio in between 5:1 to 1:1, preferably in between 4,5:1 to 1:1, most preferably between 4:1 to 1,5:1. The inventors have found that when the monomers forming the polymer-drug conjugate of formula I are such that x:y are in a ratio in between 5:1 to 1:1 the polymer-drug conjugate that forms is in the form of a nanoparticle or microparticle without addition of other chemicals. The term “end group” refers to functionalities or constitutional units that are at the extremity of a polymer. The end groups shown as A and B can be identical to or different from one another.
A and B can optionally be a polymerization initiator or a fragment thereof. Particularly when an initiator is used in the polymerization reaction, the initiator fragment may stay as an end group to the polymer. The initiator used herein, may be any material suitable for initiating the polymerization reaction known in the art. The term “fragment” as used herein refers to compounds that form due to breaking of one or more of the covalent bonds forming the initiator molecule.
A and/or B is optionally null.
In an embodiment of the invention A is null and B is a polymerization initiator or a fragment of a polymerization initiator. In another embodiment B is null and A is a polymerization initiator or a fragment of a polymerization initiator. In another embodiment A and B are both fragments of a polymerization initiator however they are structurally different from one another. In other words, A and B are different fragments of the same initiator. In another embodiment A and B are both fragments of a polymerization initiator and they have the same chemical structure.
The measurement of the amount of drug in the polymer conjugate of the invention is made by using conventional techniques well-known in the art, for example by calculation of the drug ratio from an 'H-NMR of the polymer-drug conjugate. In another embodiment the polymer-drug conjugate of the invention has an average molecular weight in between 3 kDa to 150 kDa, preferably between 4kDa to 120 kDa, most preferably between 5 kDa to 100 kDa.
Molecular weight of the polymer-drug conjugate of the invention is determined by using conventional techniques known in the art for example by using gel permeation chromatography (GPC).
Polymer-drug conjugate of the invention can be prepared by using conventional methods disclosed in the art.
The cleavable linker according to present invention can be obtained from commercial sources or may be prepared according to known methods provided in literature.
The polymer-drug conjugate of the invention can be prepared by any of the known polymerization methods. Any suitable initiators and/or catalysts known in the art can be used for the preparation of the polymer-drug conjugate of the present invention. Where a polymerization initiator is used, the initiator or a fragment thereof may be present in the resulting polymer-drug conjugate.
The polymer backbone of the polymer-drug conjugate of the invention can be obtained by for example bulk polymerization, solution polymerization and/or suspension polymerization techniques known in the art.
The polymerization technique used for the preparation of the polymer-drug conjugate of the present invention may propagate through free-radical polymerization or controlled/living free radical polymerization. Herein the term “controlled/living free radical polymerization” refers to atom transfer radical polymerization (ATRP), Reversible addition fragmentation chain transfer (RAFT) polymerization, iodine transfer polymerization (ITP), selenium centered radical mediated polymerization, telluride mediated polymerization (TERP), nitroxide mediated polymerization (NMP). In a preferred embodiment of the invention RAFT polymerization is used to prepare the polymer-drug conjugates of the invention.
A polymerization initiator as used herein refers to a chemical compound that reacts with a monomer to form an intermediate compound capable of linking successively with a large number of other monomers into a polymeric compound.
In an embodiment the present invention relating to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I may further comprise a targeting group. Said targeting agent can be as attached to the polymer-drug conjugate as shown with formula I or can be embedded into the nanoparticle of microparticle structure or in the case that the microparticle or nanoparticle comprises a coating it can be in the coating mixture or can be embedded into the coating layer. The term "targeting group" means a molecule which serves to deliver the polymer-drug conjugate of the invention to a specific site for the desired activity, i.e. it provides localization of the compound. The localization is mediated by specific recognition of molecular determinants, molecular size of the targeting agent or conjugate, ionic interactions, hydrophobic interactions, and the like. Other mechanisms of targeting an agent to a particular tissue or region are known to those of skill in the art. Targeting ligands include, for example, molecules that bind to molecules on a targeted cell surface. Exemplary targeting ligands include antibodies, antibody fragments, small organic molecules, peptides, peptoids, proteins, polypeptides, oligosaccharides, transferrin, HS- glycoprotein, coagulation factors, serum proteins, beta-glycoprotein and the like.
The terms “targeting agent”, “targeting group” or “targeting ligand” refers to the same entity and can be used interchangeably within the context of the present invention. In an embodiment, the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I wherein said nanoparticles or microparticles are coated with a compound selected from the group comprising glucose, sucrose, maltose, fructose, trehalose, lactose, dextrose, tagatose, raffmose, erythritol, maltitol, maltodextrin mannitol, sorbitol,, polydextrose, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PEG, PLGA, PLA, PF-127.
In an embodiment, the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I wherein polymer-drug conjugate as shown with formula I is blended with a first compound and then the formed nanoparticles or microparticles are coated with a second compound. The first compound is selected from a group comprising chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PLA, PLGA, PF-127, chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or their pharmaceutically acceptable derivatives thereof. The second compound is selected from a group comprising glucose, sucrose, maltose, fructose, trehalose, lactose, dextrose, tagatose, raffmose, erythritol, maltitol, maltodextrin mannitol, sorbitol,, polydextrose, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PEG, PLGA, PLA, PF-127.
In an embodiment, the present invention relates to nanoparticles or microparticles comprising a polymer-drug conjugate as shown with formula I in conjugation with chitosan wherein said conjugate is coated with alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PL A and/or PLGA and/or PF127.
The nanoparticles according to the invention can have a size in the range of 1-999 nm, preferably in the range of 10-900 nm, most preferably 50-850 nm. Any sample wherein at least 90% of the particles have a size in the range of 1-999 nm is considered as a nanoparticle.
The microparticles according to the invention can have a size in the range of 1-15 pm, preferably in the range of 1-10 pm, most preferably 1-6 pm. Any sample wherein at least 90% of the particles have a size in the range of 1-5 pm is considered as a microparticle.
Chitosan is a linear polysaccharide composed of randomly distributed P-(l 4)-linked D- glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). Chitosan can have an average molecular weight in between 2kDa to 300kDa.
Alginate is a salt of alginic acid which is a linear copolymer with homopolymeric blocks of (1- 4)-linked b-D-mannuronate (M) and its C-5 epimer a-L-guluronate (G) residues, respectively, covalently linked together in different sequences or blocks. Alginate can preferably be in the form of sodium alginate. Alginate, preferably sodium alginate, can have an average molecular weight in between lkDa to 200kDa.
PLGA refers to a co polymer comprising the monomers of lactide and glycolide in various ratios. The ratio of lactide to glycolide is prefereably 50:50 is a preferred embodiment of the invention. The PLGA polymer can have a molecular weight in the range of 5-20 kDa, preferably 7-17 kDa. PEG-PLGA refers to a block copolymer wherein one block is polyethylene glycol and the other block is a random copolymer of polylactide-co-glycolide. Herein the blocks can be attached to one another with any conventional means known to a person skilled in the art.
PLA refers to a polymer comprising the monomer of lactide. the PLA polymer can have a molecular weight in the range of 5-20 kDa, preferably 7-17 kDa.
PEG-PLA refers to a block copolymer wherein one block is polyethylene glycol and the other block is a polylactide. Herein the blocks can be attached to one another with any conventional means known to a person skilled in the art.
PF127 also known as poloxamer 407 refers to a triblock copolymer made up of hydrophobic residue of polyoxypropylene (POP) between the two hydrophilic units of polyoxyethylene (POE) also known as polyethylene glycol (PEG). The approximate lengths of the two PEG blocks is 101 repeat units while the approximate length of the propylene glycol block is 56 repeat units.
PEG that forms a block copolymer with PLA or PLGA can be a linear or branched PEG, for example can be randomly branched or can be in star shape or can have multiple arms, such as at least two arms. PEG that forms a block copolymer with PLA or PLGA can have a molecular weight in the range of 2-50 kDa.
Another embodiment of the present invention provides a method for delivering a therapeutic agent, comprising administering to a subject an effective amount of a microparticle or nanoparticle comprising polymer-drug conjugate shown with formula I optionally in conjugation with or as a blend with chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or
PEG-PF127 and/or PLA and/or PLGA and/or PF127. Another embodiment of the invention is the microparticle or nanoparticle comprising polymer- drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and/or PLGA and/or PF127 for use in treatment of a variety of disorders that require the delivery of chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof. In a preferred embodiment, the invention is related to microparticle or nanoparticle comprising a polymer-drug conjugate shown with formula I optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG- PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 for use as a medicament for treatment of a disease caused by SARS-CoV and/or SARS-CoV-2 viruses.
As used herein, "treat" or "treating" means to inhibit, reduce, modulate, ameliorate, or block at least one symptom that characterizes a pathologic condition, in a subject threatened by, or afflicted with, the condition
Thus, according to the invention there is provided a pharmaceutical composition comprising a microparticle or nanoparticle comprising polymer-drug conjugate according to formula I optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 and at least one pharmaceutically acceptable diluent, excipient and/or carrier. The term “treatment” includes either therapeutic or prophylactic therapy. The composition comprising a microparticle or nanoparticle comprising the polymer-drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG-PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 may be in any suitable form depending upon the desired method of administering it to a patient. The composition comprising polymer drug conjugates of the invention can be formulated to be administered orally, e.g. in the form of liquid dispersions or aqueous or oily suspensions or they can formulated for parenteral administration, for example for subcutaneous, intravenous, intramuscular, intrastemal, intraperitoneal, intradermal, transdermal or other infusion techniques. The composition comprising the polymer drug conjugates of the invention can also be formulated for administration by inhalation in form of an aerosol, dry powder or solution for administration with an inhaler or nebulizer. The polymer-drug conjugates of the invention are preferably administered to a subject transdermally, subcutaneously, intranasally, intravenously, intramuscularly, intratumorally or via inhalation. The most suitable route for administration in any given case will depend on the particular therapeutic agent present in the polymer-drug conjugate of the present invention, the subject, and the nature and severity of the disease and the physical condition of the subject. In a most preferred embodiment of the invention a microparticle or nanoparticle comprising the polymer-drug conjugate of the invention optionally in conjugation with or as a blend with chloroquine and/or hydroxychloroquine and/or mefloquine and/or remdesivir and/or nafamostat and/or favipiravir and/or camostat and/or chitosan and/or alginate and/or PEG-PLA and/or PEG- PLGA and/or PEG-PF127 and/or PLA and or PLGA and/or PEG and/or PF-127 is formulated in form of a dry powder or aerosol or solution for for administration with an inhaler or nebulizer. This way the inventors were able to deliver the therapeutics agents of chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof directly to the target site, that is lungs and any systemic absorption of the active agents and possible side effects originating from them are prevented. Furthermore, a more effective treatment is provided.
The micro or nanoparticles comprising the polymer-drug conjugates shown with formula I may be administered in combination, e.g. simultaneously, sequentially or separately, with one or more other therapeutically active compounds selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS- CoV-2, vitamins known in the arts such as vitamin A, Vitamin Bl, Vitamin B2, Vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D2, vitamin D3, vitamin E, vitamin K and minerals such as potassium, chlorine, sodium, calcium, phosphorus, magnesium, iron, zinc, manganese, copper, iodine, chromium, molybdenum, selenium, cobalt and antioxidants known in the art such as quercetin, coenzyme Q-10, ubiquinol, glutathione, astaxanthin, lutein, catechin, gallocatechin, anthocyanins, reservatrol, curcumin or an agent selected from the group of antivirals, antiinfectives, antimicrobials, immunomodulatory agents.
Said second therapeutic agent can be selected from the therapeutic agents listed above on the condition that it is different from the one present in the polymer-drug conjugate of the invention. Comprising in the context of the present specification is intended to meaning including.
Where technically appropriate, embodiments of the invention may be combined.
Embodiments are described herein as comprising certain features/elements. The disclosure also extends to separate embodiments consisting or consisting essentially of said features/elements.
Technical references such as patents and applications are incorporated herein by reference. Any embodiments specifically and explicitly recited herein may form the basis of a disclaimer either alone or in combination with one or more further embodiments.
The invention will now be described with reference to the following examples, which are merely illustrative and should not in any way be construed as limiting the scope of the present invention.
EXAMPLES: Example 1: Synthesis and Characterization of Copolymer P(OEGMA-HCQ-CB).
P(OEGMA) (1.22 mmol) and HCQ-MA (0.40 mmol) were dissolved in anhydrous DMF (4 mL) and the mixture was stirred for 30 min under N2. 4-cyano-4-(thiobenzoylthio)pentanoic acid (0.028 mmol) as a chain trasfer reagent and AIBN (5.6 x 103 mmol) as an initiator were added to polymer the polymer solution under N2. The reaction was sealed and heated at 70 °C for 21 hours. To purify the copolymer; it was precipitated in diethyl ether (100 mL) and then it was washed with diethyl ether (3 x 25 mL). The product was dried under vacuo and obtained as a pink viscous solid. ¾ NMR (400 MHz, CDC13): d/ppm = 8.48 (br s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.36 (br s, 1H); 6.43 (br s, 1H); 4.27-4.08 (br s, 2H), 3.65 (br s, 14H); 3.55 (br s, 2H), 3.36 (s, 3H), 1.01-0.87 (m, CH2 ve CH3 polymer backbone). GPC: Mn = 20 kDa; Mw / Mn = 1.26.
It was seen that the particles obtained with this method readily forms nanoparticles as confirmed with the DLS data (Figure 1).
Example 2: Synthesis and Characterization of Copolymer P(OEGMA-HCQ-CB).
P(OEGMA) (1.22 mmol) and HCQ-MA (0.40 mmol) were dissolved in anhydrous DMF (4 mL) and the mixture was stirred for 30 min under N2. 4-cyano-4-(thiobenzoylthio)pentanoic acid (0.012 mmol) as a chain trasfer reagent and AIBN (2.51 x 10-3 mmol) as an initiator were added to polymer the polymer solution under N2. The reaction was sealed and heated at 70 oC for 21 hours. To purify the copolymer; it was precipitated in diethyl ether (100 mL) and then it was washed with diethyl ether (3 x 25 mL) The product was dried under vacuo and obtained as a yellow viscous. 1H NMR (400 MHz, CDC13): d/ppm = 8.48 (br s, 1H), 7.91 (s, 1H), 7.82 (br s, 1H); 7.35 (br s,lH); 6.43 (br s, 1H); 4.27-4.07 (br s, 2H), 3.65 (br s, 14H); 3.55 (br s, 2H), 3.36 (s, 3H), 1.01-0.87 (m, CH2 ve CH3 polymer backbone). GPC: Mn = 49 kDa; Mw / Mn = 1.52.
It was seen that the particles obtained with this method readily forms microparticles as confirmed with the DLS data (Figure 2).

Claims

1. A nanoparticle or microparticle comprising a polymer-drug conjugate as shown with formula I
Figure imgf000021_0001
wherein;
Ri, R2 and R3 are independently selected from H or -CH3; x is a natural number between 1-250; y is a natural number between 1-70; n is a natural number between 1-200 and L is a cleavable linker and D is at least one therapeutic agent selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, camostat, favipiravir or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof, Z is selected from N or O; A is an end group that is optionally a polymerization initiator or a fragment thereof or A may be null; B is an end group that is optionally a polymerization initiator or a fragment thereof or B may be null.
2. A nanoparticle or microparticle according to claim 1 wherein said microparticles are coated with a compound selected from the group comprising glucose, sucrose, maltose, fructose, trehalose, lactose, dextrose, tagatose, raffmose, erythritol, maltitol, maltodextrin mannitol, sorbitol,, poly dextrose, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PEG, PLA, PLGA, PF-127.
3. A nanoparticle or microparticle according to claims 1 wherein polymer-drug conjugate as shown with formula I is blended with a first compound and coated with a second compound.
4. A nanoparticle or microparticle according to claim 3 wherein the first compound is selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, camostat, favipiravir, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PEG, PLA, PLGA, PF-127.
5. A nanoparticle or microparticle according to claim 3 wherein the second compound is selected from a group comprising glucose, sucrose, maltose, fructose, trehalose, lactose, dextrose, tagatose, raffmose, erythritol, maltitol, maltodextrin mannitol, sorbitol,, poly dextrose, chitosan, alginate, PEG-PLA, PEG-PLGA, PEG-PF127, PLA, PLGA, PF- 127 or PEG.
6. A nanoparticle or microparticle according to claims 1 to 5 wherein chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof can be present in an amount in between 1% to 50% by weight of the polymer-drug conjugate.
7. A nanoparticle or microparticle according to claims 1 to 6 wherein the polymer-drug conjugate shown with formula I has an average molecular weight in between 3 kDa to
150 kDa.
8. A nanoparticle or microparticle according to claims 1 to 7 wherein x:y have a ratio in between 5:1 to 1:1.
9. A nanoparticle or microparticle according to claims 1 to 8 wherein n is a natural number between 1-20, preferably 1-10, most preferably 1-4.
10. A microparticle or nanoparticle according to claims 1-9 for use in treatment of a variety of disorders that require the delivery of chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-CoV-2 or their pharmaceutically acceptable derivatives thereof.
11. A microparticle or nanoparticle according to claims 1-10 for use in treatment of a disease caused by SARS-CoV and/or SARS-CoV-2 viruses.
12. A pharmaceutical composition comprising a microparticle or nanoparticle according to claims 1-9 and at least one pharmaceutically acceptable diluent, excipient and/or carrier.
13. A pharmaecutical composition according to claim 12 wherein said composition is formulated for oral, parenteral, intranasal or transdermal, administration.
14. A pharmaecutical composition according to claims 12 and 13 wherein said composition is formulated in form of a dry powder or aerosol or solution for administration with an inhaler or nebulizer.
15. A microparticle or nanoparticle according to claims 1-9 is administered in combination, with one or more other therapeutically active compounds selected from a group comprising chloroquine, hydroxychloroquine, mefloquine, remdesivir, nafamostat, favipiravir, camostat or vitamins selected from vitamin A, Vitamin Bl, Vitamin B2, Vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, vitamin C, vitamin D2, vitamin D3, vitamin E, vitamin K or minerals selected from potassium, chlorine, sodium, calcium, phosphorus, magnesium, iron, zinc, manganese, copper, iodine, chromium, molybdenum, selenium, cobalt or antioxidants selected from quercetin, coenzyme Q-10, ubiquinol, glutathione, astaxanthin, lutein, catechin, gallocatechin, anthocyanins, reservatrol, curcumin or any agent selected from the group of antivirals, antiinfectives, antimicrobials, immunomodulatory agents or any other agent known to be effective for or indicated for a disease caused by SARS-CoV and/or SARS-
CoV-2.
PCT/EP2020/064230 2020-05-21 2020-05-21 Cleavable polymer drug conjugates for viral diseases WO2021233549A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2020/064230 WO2021233549A1 (en) 2020-05-21 2020-05-21 Cleavable polymer drug conjugates for viral diseases

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2020/064230 WO2021233549A1 (en) 2020-05-21 2020-05-21 Cleavable polymer drug conjugates for viral diseases

Publications (1)

Publication Number Publication Date
WO2021233549A1 true WO2021233549A1 (en) 2021-11-25

Family

ID=70977930

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/064230 WO2021233549A1 (en) 2020-05-21 2020-05-21 Cleavable polymer drug conjugates for viral diseases

Country Status (1)

Country Link
WO (1) WO2021233549A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018092048A1 (en) * 2016-11-16 2018-05-24 Rs Arastirma Egitim Danismanlik Ilac Sanayi Ticaret Anonim Sirketi Self-assembled diblock copolymers composed of pegmema and drug bearing polymeric segments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018092048A1 (en) * 2016-11-16 2018-05-24 Rs Arastirma Egitim Danismanlik Ilac Sanayi Ticaret Anonim Sirketi Self-assembled diblock copolymers composed of pegmema and drug bearing polymeric segments

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COLSON PHILIPPE ET AL: "Chloroquine and hydroxychloroquine as available weapons to fight COVID-19", INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, ELSEVIER, AMSTERDAM, NL, vol. 55, no. 4, 4 March 2020 (2020-03-04), XP086143459, ISSN: 0924-8579, [retrieved on 20200304], DOI: 10.1016/J.IJANTIMICAG.2020.105932 *
FEI YU ET AL: "Chloroquine-Containing HPMA Copolymers as Polymeric Inhibitors of Cancer Cell Migration Mediated by the CXCR4/SDF-1 Chemokine Axis", ACS MACRO LETTERS, vol. 5, no. 3, 17 February 2016 (2016-02-17), pages 342 - 345, XP055644514, ISSN: 2161-1653, DOI: 10.1021/acsmacrolett.5b00857 *
PRUIJSSERS ANDREA J ET AL: "Nucleoside analogues for the treatment of coronavirus infections", CURRENT OPINION IN VIROLOGY, vol. 35, 1 April 2019 (2019-04-01), United Kingdom, pages 57 - 62, XP055772499, ISSN: 1879-6257, DOI: 10.1016/j.coviro.2019.04.002 *

Similar Documents

Publication Publication Date Title
Khutoryanskiy Beyond PEGylation: alternative surface-modification of nanoparticles with mucus-inert biomaterials
Marasini et al. Polymer-drug conjugates as inhalable drug delivery systems: A review
Harugade et al. Chitosan: A review on properties, biological activities and recent progress in biomedical applications
Abd Elgadir et al. Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems: A review
Hu et al. Advances in chitosan-based drug delivery vehicles
Cortes et al. Xanthan gum in drug release
TWI314461B (en) Amphiphilic block copolymers and nano particles comprising the same
Das et al. RAFT polymerization of ciprofloxacin prodrug monomers for the controlled intracellular delivery of antibiotics
Chen et al. Glycan targeted polymeric antibiotic prodrugs for alveolar macrophage infections
EP3344232B1 (en) Micelles for mucoadhesive drug delivery
EP3478323B1 (en) Cleavable polymer drug conjugates
Yao et al. Poly (ethylene glycol) alternatives in biomedical applications
US20150366975A1 (en) Thermosensitive injectable hydrogel for drug delivery
US9861704B2 (en) Polymeric prodrug of disulfiram and application thereof
EP1877446A1 (en) Method for removal of toxins from mucosal membranes
US20240108736A1 (en) Self-assembled diblock copolymers composed of pegmema and drug bearing polymeric segments
Desbrieres et al. Chemically modified polysaccharides with applications in nanomedicine
Yin et al. Anticancer camptothecin-N-poly (lactic acid) nanoconjugates with facile hydrolysable linker
Liu et al. Biodegradable brush-type copolymer modified with targeting peptide as a nanoscopic platform for targeting drug delivery to treat castration-resistant prostate cancer
Vinjamuri et al. Polymer applications in pulmonary drug delivery
WO2021233549A1 (en) Cleavable polymer drug conjugates for viral diseases
US20230381112A1 (en) Compositions and Methods of Manufacturing Amphiphilic Block Copolymers that Form Nanoparticles in Situ
EP4203968A1 (en) Dendrimer-drug conjugate
CN110917149A (en) Polymer micelle freeze-drying preparation for encapsulating insoluble antitumor drug
Kantaria et al. A new generation of biocompatible nanoparticles made of resorbable poly (ester amide) s

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20730578

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20730578

Country of ref document: EP

Kind code of ref document: A1