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WO2022271183A1 - Polymères amphiphiles à auto-assemblage en tant qu'agents anti-covid-19 - Google Patents

Polymères amphiphiles à auto-assemblage en tant qu'agents anti-covid-19 Download PDF

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Publication number
WO2022271183A1
WO2022271183A1 PCT/US2021/039050 US2021039050W WO2022271183A1 WO 2022271183 A1 WO2022271183 A1 WO 2022271183A1 US 2021039050 W US2021039050 W US 2021039050W WO 2022271183 A1 WO2022271183 A1 WO 2022271183A1
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Prior art keywords
polymer
polymers
nanoparticles
comb polymer
self
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PCT/US2021/039050
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Inventor
Anil R. Diwan
Jayant G. Tatake
Rajesh K. PANDEY
Vietha CHINIGA
Neelamkumar RAJ HOLKAR
Preetamkumar RAJ HOLKAR
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Allexcel Inc
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Allexcel Inc
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Priority to PCT/US2021/039050 priority Critical patent/WO2022271183A1/fr
Priority to PCT/US2022/035210 priority patent/WO2022272181A1/fr
Priority to IL309697A priority patent/IL309697A/en
Priority to JP2023580351A priority patent/JP2024529267A/ja
Priority to CN202280057875.8A priority patent/CN118488854A/zh
Priority to CA3224103A priority patent/CA3224103A1/fr
Priority to AU2022297600A priority patent/AU2022297600A1/en
Priority to BR112023027392A priority patent/BR112023027392A2/pt
Priority to MX2024000185A priority patent/MX2024000185A/es
Priority to EP22829466.6A priority patent/EP4547278A1/fr
Publication of WO2022271183A1 publication Critical patent/WO2022271183A1/fr
Anticipated expiration legal-status Critical
Priority to JP2025107411A priority patent/JP2025169240A/ja
Ceased legal-status Critical Current

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    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • A61K47/6935—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 otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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

Definitions

  • the present invention relates to the fields of amphiphilic polymers, and specifically to biocompatible micelle-forming comb-type polymers.
  • the invention also relates to the field of targeted antiviral agents.
  • Amphiphilic block copolymers comprising a hydrophobic block and a hydrophilic block have been well studied in recent years, because of their capacity for self-assembly into a variety of nanostructures as the surrounding solvent is varied. See Cameron et al., Can. J. Chem./Rev. Can. Chim. 77:1311-1326 (1999).
  • the hydrophobic compartment of an amphiphilic polymer has a tendency to self-assemble in order to avoid contact with water and to minimize the free interfacial energy of the system.
  • the hydrophilic blocks form a hydrated “corona” in the aqueous environment, and so the aggregates maintain a thermodynamically stable structure. The result is a stable, latex-like colloidal suspension of polymer aggregate particles having hydrophobic cores and hydrophilic coronas.
  • Comb-type amphiphilic co-polymers differ from block co-polymers in that the backbone is largely hydrophobic or hydrophilic, with polymer chains of opposite polarity pendant from the backbone rather than incorporated into it.
  • Comb-type copolymers have been prepared with hydrophobic backbones and hydrophilic branches (Mayes et al., US Patent No. 6,399,700), and also with hydrophilic backbones and hydrophobic branches (Watterson et al., U.S. Patent No. 6,521,736). The former were used to provide multivalent presentation of ligands for cell surface receptors, while the latter were used to solubilize drugs and deliver them to cells.
  • Amphiphilic polymer aggregates have been studied as carriers for solubilizing insoluble drugs, targeted drug delivery vehicles, and gene delivery systems. They spontaneously self-assemble into a core-corona structure that is more stable than conventional low-molecular-weight micelles, due to chain entanglement and/or the crystallinity of the interior hydrophobic region.
  • the polymeric nature of the vehicle renders the aggregates relatively immune to the disintegration that ordinary liposomes suffer when diluted below their critical micelle concentration.
  • the absence of a bilayer membrane enables them to more readily fuse with cell membranes and deliver their payload directly to the cell.
  • the amphiphilic nature of the aggregates also confers detergent-like activity, and appropriately targeted aggregates appear to be capable fusing with and disrupting viral coat proteins.
  • PEG-conjugated polyamidoamine (“PAMAM”) dendrimers suitable for delivery of polynucleotides.
  • Comb-type polymers generated by random functionalization or co-polymerization are mixtures of thousands of different species of differing molecular weights and branching patterns.
  • the absence of a single, consistent structure presents problems in characterization and quality control, and can be an obstacle when regulatory approval is sought.
  • Regular, consistently-structured amphiphilic comb polymers have been introduced to overcome this shortcoming (Diwan et al., U.S. Patent No. 8,173,764), but there remains a need for tight control of the molecular weight of such polymers.
  • the present invention provides improved biocompatible comb-type polymers of structure (4) below, and methods for producing the improved polymers.
  • the value of m ranges from 10 to 50 and is preferably between 20 and 25.
  • the value of n ranges from 5 to 25, and the overall molecular weight of the polymer (4) may range from 2,000 to 25,000 daltons, and is preferably between 5,000 and 15,000 daltons.
  • R represents a mixture of H and C8-C18 hydrophobic side chains, with the proportion of H ranging from 30% to 90%, preferably 40-90%, and more preferably 50-90%.
  • the invention provides aqueous suspensions of core-corona nanoparticles, which self-assemble from the polymer (4), and provides methods for solubilizing antiviral drugs, by incorporating such drugs (and prodrugs thereof) in the hydrophobic cores of the polymer particles.
  • the invention further provides hydrophobic prodrugs tailored to be soluble in the hydrophobic cores of the nanoparticles.
  • the invention provides polymers (4) to which a plurality of viral -targeting ligands have been covalently attached. Attachment of ligands to the repeating units of the polymers of the invention affords multivalent display of the ligand on the polymer chain and on the nanoparticles surface.
  • the invention also provides a method for the treatment or prevention of an infection of an animal by a virus, which comprises administering to said animal a suspension of corecorona type nanoparticles which comprise a comb-type polymer having structure (4).
  • the polymer particles preferably have an antiviral drug or prodrug dissolved or dispersed in the hydrophobic nanoparticle core.
  • the self- assembled nanoparticles have inherent antiviral properties.
  • This antiviral activity is thought to be due to the detergent-like ability of the amphiphilic polymers to disrupt the outer coating of virus particles. This activity is enhanced by the binding affinity of the multiple carboxylate groups for the surface of the targeted virus.
  • the invention further provides methods for the preparation of the polymers, nanoparticles, and drug complexes described herein.
  • the polymers of the invention self-assemble into polymer aggregates that efficiently solubilize, distribute, and deliver drugs in vivo; have inherent antiviral activity; and are non-toxic, biocompatible, and stable.
  • the invention also relates to a method for the treatment of viral diseases comprising the administration of antiviral agents encapsulated in the self-assembled nanoparticles of the invention.
  • the invention also concerns pharmaceutical compositions comprising antiviral agents encapsulated in the self-assembled nanoparticles of the invention, and the use of these compositions for the treatment of viral diseases and more particularly for the treatment of infections caused by coronaviruses like SARS-CoV-2.
  • the formulations provide a marked improvement in the pharmacokinetics of the encapsulated drugs and improve their aqueous solubility. The improvements in distribution and solubility enable the administration of a wide variety of prodrugs that would not otherwise be effective.
  • Fig. 1 is a graph showing the molecular weight of pi-polymer as a function of the ratio of DTT to PEG dimaleate.
  • Fig. 2 is a synthetic scheme for preparing the polymers of the invention.
  • Fig. 3 is the legend for Fig. 2, and identifies the R groups.
  • the polymers of the invention have a comb-type architecture, with a backbone formed of alternating branch-point moieties and hydrophilic, water-soluble PEG blocks; and a plurality of hydrophobic side chains R attached to each branch-point moiety, as shown in Formula (4).
  • the hydrophobic side chains R are preferably C8 to C18 alkyl groups, but may incorporate heteroatoms to provide dipole-dipole or hydrogen-bonding interactions with encapsulated drugs or prodrugs. Ether, ester, amide, sulfoxide and sulfonyl groups, for example, can be incorporated into some or all of the groups R.
  • the improved polymers of the present invention feature a narrow molecular weight distribution, controlled chain terminal structures, a lowered level of hydrophobic substituents R, and a high density of carboxylate groups, which act as affinity ligands for viral coat proteins.
  • the polymers having lower levels of hydrophobic substitution e.g., 30%. 40% or 50% of R being hydrophobic have been found to be more water-soluble, and more suitable for injectable formulations.
  • Attachment of ligands to the repeating units of the polymers of the invention affords multivalent display of the ligand on the polymer chain and on the nanoparticles surface, which can result in great increases in affinity for the ligands’ target.
  • multivalent antibodies can be far more effective in clearance of their targets than the normal divalent antibodies.
  • Carbohydrate-binding proteins and carbohydrates are known to be multivalent in nature, and ineffective if monovalent.
  • multivalent peptide and carbohydrate targeting moieties will be far more effective than the monomer alone.
  • the increase in MW due to attachment to the polymer results in reduced renal clearance rates of peptides and other ligands.
  • the PEG backbone affords to the peptide benefits similar to those of PEGylation, including evasion of immune surveillance.
  • a multivalent targeting moiety will decorate a multivalent target (say, a virus particle) and neutralize it far more effectively than the monomeric targeting moiety.
  • the invention provides a comb polymer having the following structure:
  • each instance of R is individually either OH or a C8-C18 hydrophobic moiety
  • each instance of L is individually either OH or a ligand having specific binding affinity for the surface of a virus.
  • the average value of m ranges from 10 to 50; and the average value of n ranges from 5 to 25.
  • Each ligand L is may be, for example, one of the following moieties:
  • each R1 is individually H or C1-C4 alkyl
  • each R2 is individually H, COR1, or CO 2 R1.
  • the comb polymers described above When dissolved in water or an aqueous medium, the comb polymers described above self-assemble into core-corona nanoparticles.
  • the invention provides such nanoparticles having dissolved or dispersed within their hydrophobic cores an antiviral drug or a prodrug thereof.
  • compositions which comprise a pharmaceutically acceptable aqueous carrier and the core-corona nanoparticles described above, both with and without antiviral drugs or pro-drugs dissolved therein.
  • the invention provides a method of treating or preventing viral infections in animals (including humans) by administering the comb polymers and pharmaceutical compositions described above, in particular infections by coronaviruses, including SARS-CoV-2.
  • the polymers of the invention may be prepared by the process shown in Scheme 1 and in Figure 2. In practice, the chemical reactions illustrated proceed with statistical product distributions and with less-than-perfect efficiency, and it should be understood that the polymer products shown in the schemes and in the claims are ideal representations rather than typical or average structures. For example, in the treatment of 3 with maleic anhydride (step D in Figure 2), the yield of adduct ranges from 30-50%, which the inventors believe is due to competing Michael addition of side chain hydroxyl groups to form lactone rings.
  • step E in Figure 2 The subsequent reaction with mercaptosuccinic acid (step E in Figure 2) may proceed with yields ranging from 20% to 100%, depending upon the amount of reagent, time, and temperature; these variables can be manipulated to control the density of carboxyl groups on the final product.
  • the invention thus encompasses compositions that are mixtures of regioisomers at the succinate moieties. Due to the asymmetric carbons at the sulfur-bearing carbons, the invention also encompasses polymers which contain mixtures of any or all of the possible regio- and stereo-isomeric possibilities.
  • the hydrophobic moieties R are preferably derived from C8 to Cl 8 aliphatic amines RNH2, and are most conveniently linked to the polymer by amidation of the carboxylic acid groups of polymer (2) as illustrated in Scheme 1.
  • the hydrophobic groups R are preferably C8-C20 hydrocarbon moieties, which may be linear or branched or contain one or more rings. Examples of the group R include but are not limited to n-octyl, 2-ethylhexyl, n-dodecyl, n-hexadecyl, and the like.
  • the solvent power of the hydrophobic core of the self-assembled nanoparticles can be increased by introducing halogen, ether, ester, amide, or nitrile moieties into the hydrophobic group R.
  • hydrophobic when applied to R means that the logP value (octanol -water) of the molecule R-H is greater than 2. In preferred embodiments, logP is greater than 2.5.
  • the invention provides processes for the preparation of the comb polymers of the invention.
  • the key starting material is polyethylene glycol, which is preferably dried before use by stirring under vacuum at an elevated temperature. This may take 8-12 hours, depending on the quality of the PEG. Once dried, the PEG can be stored under argon indefinitely.
  • the PEG is preferably of low dispersity.
  • PEG polymers that are >95% monodisperse, such as are commercially available from Nektar Therapeutics (formerly Shearwater Polymers), Huntsville AL, and Polypure AS, Oslo, Norway.
  • An example of a monodisperse PEG is “PEG-28” from Polypure, which is >95% H0(CH2CH20)28H, molecular weight 1252.
  • Polyethylene glycol 1000 for synthesis available from Millipore Sigma, Burlington MA, is suitable.
  • a repreesentative plot is shown in Fig. 1.
  • the DTT/PEG dimaleate ratio required to obtain a desired MW from this particular batch PEG dimaleate can be obtained from this plot, and by using this ratio in the production process, the desired MW is reliably achieved.
  • the plot is considered a specific characteristic associated with the given batch of PEG dimaleate under the specified process conditions. For a different batch of PEG dimaleate, the process is repeated and a new plot generated, so as to provide the operating polymerization characteristic for that batch.
  • PM2-DTT polymer (2) [41] PEG dimaleate (1) (“P10M2”) was prepared from polyethylene glycol 1000 using the method described in US 2010/0260743. The polymer was melted under nitrogen at 60- 80°C, water was added to 40-50% w/v final concentration, and the solution was adjusted to pH 6-8.5 by addition of DIPEA. Dithiothreitol (DTT), 1.02 to 1.5 mmol per mmol of maleate double bonds, was added as a solution or as a solid. The molar ratio of DTT to P10M2 was based on the desired MW of the P10M2-DTT polymer (2).
  • DTT Dithiothreitol
  • the pH of the solution was monitored by a pH probe and viscosity was monitored using in-reactor ultrasonic viscometer probe. The viscosity plateaued in about 15 minutes and remained essentially unchanged for next 30 minutes. Unreacted DTT and terminal sulfhydryl groups were quenched by the addition of maleic acid until the mixture gave a negative test with Ellman’s reagent.
  • the reaction mixture was acidified to pH 2-4 with 6 N hydrochloric acid.
  • the product PI 0M2- DTT (2) was purified by extraction into dichloromethane (DCM); the low-molecular-weight impurities formed by reaction of DTT with maleic acid and salts remain in the aqueous layer and are removed.
  • the DP (degree of polymerization) of the resulting polymer ranged from 3 to 10 as desired, based on the amount of DTT employed, and the molecular weight (as determined by SEC-MALS) ranged from 4kDa to 14 kDa.
  • Dry polymer (2) (P10M2-DTT) is dissolved in a solvent such as dichloromethane and the carboxyl groups are activated by reaction with activation agents such as diisopropylcarbodiimide (DIC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ( EDC.HCL ) or N,N’-carbonyldiimidazole (CDI).
  • activation agents such as diisopropylcarbodiimide (DIC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ( EDC.HCL ) or N,N’-carbonyldiimidazole (CDI).
  • N-hydroxysuccinimide and N-hydroxysulfosuccinimide are used, particularly with carbodiimide reagents, to minimize side reactions, such as the conversion of reactive O-acyl ureas to
  • the molar equivalents of activating agent used depends on the alkyl amine substitution; desired and maximum amine substitution are not more than the equivalents of activating agent used.
  • the activation time can be between 15 minutes and 2 hrs.
  • alkyl amines such as hexadecylamine (HD A), tetradecylamine and other C8 to Cl 8 alkyl amines, 0.1 to 0.2 molar excess of activating agent are used.
  • the amidation reaction is carried out between 20- 60°C, preferably between 30-50°C, depending upon the amine. Larger amines were found to react better at higher temperatures, possibly because of micelle fomation in the reaction mixture at lower temperatures.
  • the reaction is quenched with water or acidified water to decompose residual activated carboxy groups, and the amidated polymer (3) is extracted into DICHLOROMETHANE or a suitable water immiscible solvent, and washed with water and dilute acid to remove water-soluble and basic impurities.
  • the amidated polymer is further freed from residual alkyl amine by treating with a strong cation exchange resin, and the solvent is removed by distillation in vacuo.
  • Apparent molecular weights are determined by SEC-MALS.
  • the alkyl amine content is determined by acid hydrolysis of the polymer, followed by estimation of alkyl amine by reaction with a suitable amine reactive reagent such as fluorescamine. Unreacted carboxylic groups are estimated by determination of the polymer’s acid value.
  • P10M2-DTT (1 mmol carboxy groups) was dissolved in DICHLOROMETHANE in a reactor set up with a stirrer, a condenser and a thermometer. The solution pH was adjusted to 2-4 with a tertiary base such as triethylamine or diisopropylethylamine. Carbonyldiimidazole (CDI, 0.5 mmol) was added with stirring at a temperature of 10-30°C, controlling the evolution of carbon dioxide generated. The reaction mixture was stirred at ambient temperature for 15-60 minutes to activate the carboxy groups on the polymer. To the activated polymer was then added n-hexadecylamine (HD A, 0.55-0.65 mmol).
  • HD A n-hexadecylamine
  • the reaction was stirred at 20-45°C for 2-18 hours, or until the TLC or mass spectroscopy of the reaction mixture showed the desired progress of the reaction.
  • the reaction was terminated by careful addition of aqueous HC1 to decompose residual activated carboxylates. Additional aqueous HC1 was added, and the aqueous layer (containing imidazole, water-soluble salts, and other water-soluble impurities) was removed. The isolated organic phase was washed again with water.
  • Ethanol was added to a 30-60% final concentration, and the polymer solution was treated (in column or in batch mode) with a strong cation exchange resin (H+ form, 3 to 10 equivalents per equivalent of hexadecylamine) to remove the unreacted amine.
  • a strong cation exchange resin H+ form, 3 to 10 equivalents per equivalent of hexadecylamine.
  • the efficiency of removal of amine was followed by TLC and mass spectral analysis.
  • the product was isolated by distillation of the dichloromethane-ethanol solvent in vacuo, to give P10M2-DTT-C16 (3) as a waxy solid.
  • P10M2-DTT-C16 (3) is heated to 90-120°C under a nitrogen atmosphere, to form a stirrable melt, and a solution of maleic anhydride (1.0 equivalents per equivalent of hydroxy groups) in methyl isobutyl ketone is added. The reaction mixture is stirred at 90-140°C to form the maleate esters of the DTT hydroxyl groups.
  • reaction mixture is then cooled to about 40-70°C, diluted with water, and the pH raised to 8-9 by addition of DIPEA.
  • Mercaptosuccinic acid (1 equivalent per equivalent of maleic anhydride) is then added, and allowed to react with the maleate double bonds at pH 8- 9.
  • the reaction mixture is then cooled to room temperature and extracted with 1 : 1 dichloromethane-isopropyl acetate to remove low molecular weight organic contaminants.
  • the pH is adjsuted to between 2 and 4 with hydrochloric acid, and the polymer (“P10M2- DTT-C16-(M-MSA)”) is extracted from water into DICHLOROMETHANE, and precipitated by addition of 1-4 volumes of n-heptane.
  • the solid is dissolved in butanol or isoamyl alcohol, and re-precipitated by addition of n-heptane.
  • the representative virus-targeting ligands disclosed below have a primary amino group that is used to conjugate the ligand with the polymer carboxylic acids to give the active drug.
  • the methods illustrated are representative, and other means of attachment will be apparent to those of skill in the art, using any of the many linkers and coupling reactions known in the field of small molecule-polymer conjugates.
  • the ligands presented here fall into a few categories:
  • Methyl 6-chloronicotinate is dissolved in THF or MEK as solvent.
  • a molar equivalent of Boc-l-cysteine methyl ester is added followed by addition of potassium carbonate or a tertiary organic base such as triethylamine or DIPEA.
  • Water is added to precipitate the product as a solid, which is isolated by filtration.
  • the filter cake is washed with methanol-water.
  • the dried product is dissolved in dichloromethane and then treated with HC1 in dioxane to remove the t-Boc group.
  • the product is isolated as a hydrochloride salt.
  • cysteic amide derivative (general procedure): Boc-l-cysteic acid and the nicotinyl ester (a) above are dissolved in dimethylformamide. The pH is adjusted with triethylamine to 7-8. A slight molar excess N-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HC1) or 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) is added with an equivalent amount of N-hydroxysuccinimide. After the reaction is complete, the mixture is partitioned between ethyl acetate and aqueous sodium carbonate. The cysteic amide is preciptated from the aqueous solution by neutralization.
  • EDC.HC1 N-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • DTMM 4-(4,6-dime
  • the de-esterified material is extracted into alkali, and acidified to pH 3-5 to precipitate the acid as a solid, which is isolated by filtration to yield caffeoyl-lysine(Boc)-OH.
  • the Boc group is then removed as described above.
  • the caffeic acid (b) is amidated with cysteic acid as described above.
  • the product is purified by water washes.
  • the protective t-Boc group is then removed with HCl-dioxane as described earlier.
  • This compound is prepared from L60(OMe)2 and Boc-l-cysteic acid by the general procedure described earlier.
  • the t-boc protection group is removed by HCl-dioxane using the general procedure described.
  • the above ligands are illustrated as their methyl esters, but ethyl, n-propyl, and butyl esters are contemplated as well.
  • One or both catechol OH groups of caffeic acid may esterified, as carboxymethyl, carboxyethyl), acetate, propionate, and the like.
  • Standard peptide coupling techniques are used to activate carboxy groups of polymers (4) with carbonyldiimidazole or N,N-diisopropylcarbodiimide, followed by addition of the desired ligand.
  • the various virus-specific ligands described above can be conjugated to the polymer through amide linkages.
  • the amounts of ligand can be varied as desired.
  • a representative structure (5) is illustrated above, where L represents a ligand coupled via amidation of the polymer carboxyl groups. Coupling to the least sterically hindered carboxyl groups is illustrated, but it will be appreciated that any of the available carboxy groups, including those at the polymer end caps, may be amidated.
  • a suitable inert solvent such as DMF under an atmosphere of nitrogen
  • the pH is adjusted to 3.5-4.5 with hydrochloric acid, followed by excess water to precipitate the polymer-ligand conjugate.
  • the polymer-ligand conjugate is then purified by either solvent-water extractions or by dialysis or tangential flow filtration with an appropriate cut-off membrane.
  • the host polymer and the guest drug are dissolved, in proportions from 3: 1 to 20: 1, in a mutual solvent, such as dimethylsulfoxide (DMSO), ethanol, tetrahydrofuran (THF) or dichloromethane (DCM), and mixed to produce a clear solution.
  • a mutual solvent such as dimethylsulfoxide (DMSO), ethanol, tetrahydrofuran (THF) or dichloromethane (DCM)
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • DCM dichloromethane
  • This solution is then evaporated in an oven or on a rotary evaporator, or lyophilized, depending upon the solvent used.
  • the dried mixture is then reconstituted in water or suitable buffer to give an emulsion of the guest drug distributed within the self-assembled polymer nanoparticles.
  • the loading ratio of the guest drug is then determined by suitable method such as HPLC or UV-Visible spectroscopy.
  • the self-assembled nanoparticles by virtue of having a hydrophobic core, are capable of dissolving or suspending hydrophobic drugs and pro-drugs that are otherwise not readily formulated into effective pharmaceutical compositions. They enable pro-drugs to be designed for optimal pharmacokinetics, without having to make compromises in the interest of aqueous solubility and bioavailability.
  • Many alkyl and alkoxycarbonyl prodrugs are known in the art, and methods for their manufacture are well known and largely routine. Representative examples are provided below, but most known methods can be adapted to a variety of substrates.
  • esters of Cl to Cl 8 aliphatic and aromatic acids carbonates derived from Cl to Cl 8 aliphatic and aromatic alcohols, and carbamates derived from Cl to Cl 8 aliphatic and aromatic amines, is considered to be within the scope of the invention.
  • the invention makes possible the administration of hydrophobic drugs and prodrugs that might not otherwise be considered as clinical candidates.
  • Suitable antiviral drugs, pro-drugs and drug candidates for use in the invention include, but are not limited to, remdesivir, acyclovir, molnupiravir, PF-00835231, ivermectin, colcicine, mebendazole, CDI-45205, and GC-376, and various prodrug esters, amides and carbamates thereof.
  • a 10-20 % w/w solution of P10M2-DTT-C16-(M-MSA) polymer (4) is prepared in ethyl alcohol. Solid remdesivir, 5 to 20 % by weight of polymer used, is added to the polymer solution. The mixture is well stirred to dissolve remdesivir and then evaporated to dryness under nitrogen at 35-60°C until constant weight is observed. The dried material is then dissolved in PBS or water at pH 6-7, and filter-sterilized for further use. The concentration of remdesivir is determined by HPLC or UV analysis.
  • the new and known drug derivatives (i.e. pro-drugs) of the invention which are lower alkyl esters or lower alkoxy carbonyl esters (i.e. carbonates) of antiviral drugs known in the art, are prepared by analogous methods.
  • Alkoxycarbonyl chlorides may be employed to prepare alkoxycarbonyl esters, and in those cases the preferred solvents are DMF or NMP.

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Abstract

La présente invention concerne des polymères en peigne amphiphiles améliorés, comprenant un squelette hydrophile avec des fractions hydrophobes pendantes espacées régulièrement, ayant des masses moléculaires bien contrôlées, des structures et des groupes terminaux. Les polymères s'auto-assemblent en nanoparticules noyau-couronne dans des environnements aqueux, qui sont susceptibles de perturber des protéines d'enveloppe virale, et qui sont susceptibles d'encapsuler des médicaments antiviraux et des promédicaments. Des fractions de ciblage espacées régulièrement assurent éventuellement la médiation de l'adhérence des nanoparticules à l'enveloppe virale.
PCT/US2021/039050 2021-06-25 2021-06-25 Polymères amphiphiles à auto-assemblage en tant qu'agents anti-covid-19 Ceased WO2022271183A1 (fr)

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PCT/US2021/039050 WO2022271183A1 (fr) 2021-06-25 2021-06-25 Polymères amphiphiles à auto-assemblage en tant qu'agents anti-covid-19
CA3224103A CA3224103A1 (fr) 2021-06-25 2022-06-28 Polymeres amphiphiles a auto-assemblage utilises en tant qu'agents anti-covid-19
IL309697A IL309697A (en) 2021-06-25 2022-06-28 Self-assembled amphiphilic polymers as anti-COVID-19 agents
JP2023580351A JP2024529267A (ja) 2021-06-25 2022-06-28 抗 ｃｏｖｉｄ－１９ 剤としての自己集合両親媒性ポリマー
CN202280057875.8A CN118488854A (zh) 2021-06-25 2022-06-28 作为抗covid-19试剂的自组装两亲性聚合物
PCT/US2022/035210 WO2022272181A1 (fr) 2021-06-25 2022-06-28 Polymères amphiphiles à auto-assemblage utilisés en tant qu'agents anti-covid-19
AU2022297600A AU2022297600A1 (en) 2021-06-25 2022-06-28 Self-assembling amphiphilic polymers as anti-covid-19 agents
BR112023027392A BR112023027392A2 (pt) 2021-06-25 2022-06-28 Polímeros anfifílicos automontáveis como agentes anti-covid-19
MX2024000185A MX2024000185A (es) 2021-06-25 2022-06-28 Polímeros anfifílicos autoensambables como agentes anti covid 19.
EP22829466.6A EP4547278A1 (fr) 2021-06-25 2022-06-28 Polymères amphiphiles à auto-assemblage utilisés en tant qu'agents anti-covid-19
JP2025107411A JP2025169240A (ja) 2021-06-25 2025-06-25 抗ｃｏｖｉｄ－１９剤としての自己組織化両親媒性ポリマー

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US6399700B2 (en) * 1998-04-13 2002-06-04 Massachusetts Institute Of Technology Comb copolymers for regulating cell-surface interactions
US6521736B2 (en) * 2000-09-15 2003-02-18 University Of Massachusetts Amphiphilic polymeric materials
US8173764B2 (en) * 2006-01-19 2012-05-08 Allexcel Inc. Solubilization and targeted delivery of drugs with self-assembling amphiphilic polymers

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EP0844891A4 (fr) * 1995-08-11 2004-05-06 Dow Chemical Co Conjugues de polymeres hyper-ramifies en peigne
EP1879626A4 (fr) * 2005-04-19 2011-03-23 Massachusetts Inst Technology Polymeres amphiphiles et leurs procedes d'utilisation
EA026125B1 (ru) * 2007-01-22 2017-03-31 Элексел, Инк. Самособирающиеся амфифильные полимеры в качестве противовирусных средств
MX341715B (es) * 2007-07-19 2016-08-23 Allexcel Inc Polímeros anfifílicos de autoensamblaje como agentes anticáncer.
US20180016352A1 (en) * 2015-02-05 2018-01-18 The University Of Queensland Targeting constructs for delivery of payloads

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6399700B2 (en) * 1998-04-13 2002-06-04 Massachusetts Institute Of Technology Comb copolymers for regulating cell-surface interactions
US6521736B2 (en) * 2000-09-15 2003-02-18 University Of Massachusetts Amphiphilic polymeric materials
US8173764B2 (en) * 2006-01-19 2012-05-08 Allexcel Inc. Solubilization and targeted delivery of drugs with self-assembling amphiphilic polymers

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AU2022297600A1 (en) 2024-02-01
JP2025169240A (ja) 2025-11-12
BR112023027392A2 (pt) 2024-03-12
CN118488854A (zh) 2024-08-13
WO2022272181A1 (fr) 2022-12-29
IL309697A (en) 2024-02-01

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