WO2022272181A1 - Self-assembling amphiphilic polymers as anti-covid-19 agents - Google Patents
Self-assembling amphiphilic polymers as anti-covid-19 agents Download PDFInfo
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- WO2022272181A1 WO2022272181A1 PCT/US2022/035210 US2022035210W WO2022272181A1 WO 2022272181 A1 WO2022272181 A1 WO 2022272181A1 US 2022035210 W US2022035210 W US 2022035210W WO 2022272181 A1 WO2022272181 A1 WO 2022272181A1
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- 238000003809 water extraction Methods 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
Classifications
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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 block copolymers, and more specifically to the use of such copolymers for drug delivery.
- 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.
- PAMAM PEG-conjugated polyamidoamine
- 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.
- One aspect of the invention relates to a method for the treatment of viral diseases comprising the administration of antiviral agents encapsulated in polyethylene glycol based polymeric micelles.
- the invention also concerns formulations of polyethylene glycol based polymeric micelles for the treatment of viral diseases and more particularly for the treatment of infections caused by viruses like SARS-CoV-2.
- the formulations are composed of polyethylene glycol-based polymeric micelles and contain an encapsulated drug effective against the viral disease with good in vitro antiviral activity. Encapsulation according to the present invention provides a marked improvement in the pharmacokinetics of the encapsulated drugs, and improves their aqueous solubility.
- the present invention provides improved biocompatible comb-type polymers of structures (4) and (5) below, and methods for producing the improved polymers:
- each instance of X is individually either OH or NHR, with R being a C10-C18, preferably C14-C16, hydrophobic moiety.
- the proportion of substitutents X that are OH ranges from 10% to 90%, is preferably 20-65%, and more preferably is 25-60%.
- 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 100 and is preferably between 20 and 50.
- 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.
- 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 polymer (4) may be modified by covalent attachment of cell-, tissue-, or virus-specific targeting ligands to provide polymer (5). Attachment of ligands to the repeating units of the polymers of the invention affords multivalent display of the ligand on the polymer (5) chains and on the nanoparticles.
- the invention also provides a method for the treatment or prevention of an infection of a human or other animal by a virus, which comprises administering to said animal a suspension of self-assembled nanoparticles which comprise a comb-type polymer having structure (4) or (5).
- 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 or denature the outer coating of virus particles. This activity is enhanced by the binding affinity of the multiple carboxylate groups and/or ligands L 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.
- Fig. 4 is a plot of cell survival as a function of unencapsulated drug or prodrug concentrations.
- Fig. 5 is a plot of cell survival as a function of encapsulated host concentration.
- Fig. 6 is a plot of cell survival as a function of encapsulated guest concentration.
- Comb polymers having the general structure of the polymers of the present invention have been described in US Patent application serial Nos. 12/223,052 and 12/518,411 (publication Nos. 2010/0260743 and 2010/0008938), both of which are incorporated herein by reference in their entireties. It is a feature of these materials, referred to as “pi-polymers”, that the side chains R are neither randomly nor uniformly distributed along the polymer chain, but rather occur in pairs, each pair being spaced more or less regularly along the polymer chain, depending on the degree of monodispersity of the PEG monomer.
- 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 CIO to Cl 8 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., 10%, 20%, 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 X is individually either OH or NHR, with R being a C10-C18 hydrophobic moiety, and 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 100 and is preferably between 20 and 50, while the value of n ranges from 5 to 25.
- structure (5) is an idealized representation, and that any of the depicted carboxy groups, including those at the polymer end caps, may be coupled to the ligand L.
- 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 CO2RI.
- the comb polymers described above When dissolved in water or an aqueous medium, the comb polymers described above self-assemble into core-corona type 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 self-assembled nanoparticles described above, both with and without antiviral drugs, or prodrugs thereof, dissolved therein.
- the invention provides a method of treating or preventing viral infections in humans and other animals, in particular infections caused by coronaviruses, including SARS- CoV-2, by administering effective amounts of the comb polymers and pharmaceutical compositions described above.
- a feature of the present invention is the enhanced combined activity of the polymer and the encapsulated drugs.
- the polymeric micelle (host) has the property of dismantling the virus by binding to and denaturing its envelope glycoproteins, thus blocking the re-infection part of the virus’s life cycle, i.e., the infection of new cells by newly-released viral particles.
- the encapsulated drug (guest) meanwhile, is capable of blocking the replication part of the life cycle, in which the virus generates progeny inside cells. With both life cycle processes sufficiently blocked, a synergistic reduction in viral replication and viral load is obtained.
- Another feature of the present invention is the improvement in drug pharmacokinetics and pharmacodynamics provided by the encapsulation of the drug within the polymer nanoparticles.
- Remdesivir for example, is known to be more effective when injected as a complex with SBECD The extension of this concept to the enhancement of remdesivir' s pharmacokinetics and pharmacodynamics upon encapsulation in polymeric micelles has been discussed in A. Chakraborty, A. Diwan, “Pharmacodynamics of Remdesivir: How to Improve for COVID-19 Res. Environ. Sci. (2020) 1(8):431-438A, with in vivo results reported by A. Chakraborty el al. in bioRxiv preprints https://doi.org/10.1101/2021.10.22.465399 and https://doi.org/10.1101/2021.ll.17.468980.
- the polymers of the invention may be prepared by the process shown in Scheme 1 and in Figure 2.
- 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.
- the amidation reaction is not quantitative, and in practice it is not desired that it be quantitative.
- 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 C18 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, sulfone, sulfoxide, 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, the logP of R-H is greater than 2.5.
- Amidation to produce polymer (3) can be accomplished with any of a variety of carboxyl activating reagents, which are well known in the field of peptide synthesis. Suitable examples include but are not limited to CDI, DCC, DIC, and EDC. N- hydroxysuccinimide or N-hydroxysulfosuccinimide are preferably used with the carbodiimide reagents. Carbonyl diimidazole (CDI) is a preferred reagent. Esterification with maleic anhydride, followed by addition of mercaptosuccinic acid to the resulting maleoyl groups, is then used to introduce up to six additional carboxyl groups at each branch point moiety, as shown in structure (4).
- 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 indefinitely under a dry, inert gas such as nitrogen or argon.
- 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% available from Millipore Sigma, Burlington MA, is also suitable.
- Polyethylene glycols from other vendors are expected to be suitable, provided that the certificate of analysis shows a sufficiently narrow molecular weight dispersion.
- Molecular weight control is important because different molecular weights of the polymer (2) will yield different grades and types of the amidated polymer (3), and of any further derived polymers.
- PEG polymers In the pharmacokinetics of PEG polymers, it is known that smaller polymers are cleared by glomerular filtration via the kidneys, resulting in a lower half life, whereas larger polymers circulate longer and may exhibit fecal excretion, rather than urinary excretion, as the primary elimination pathway.
- FIG. 1 A representative 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.
- 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). The pH of the solution was monitored by a pH probe and viscosity was monitored using in-reactor ultrasonic viscometer probe.
- DTT Dithiothreitol
- the DP (degree of polymerization) of the resulting polymer ranged from 3 to 14 as desired, based on the amount of DTT employed, and the molecular weight (as determined by SEC-MALS) ranged from 4kDa to 18 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 N-hydroxysulfosuccinimide are used, particularly with carbodiimide reagents, to minimize side reactions, such as the conversion of reactive O-acyl ureas to unreactive N-acyl ureas.
- activation agents such as diisopropylcarbodiimide (DIC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide N-hydroxysulfosuccinimide are used, particularly with carbodiimide reagents, to minimize side reactions, such as the conversion of reactive O-acyl ureas to unreactive N-acyl ureas.
- the molar equivalents of activating agent used depends on the alkyl amine substitution desired, and maximum amine substitution is 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 (HDA), tetradecylamine and other CIO to C18 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 reactive group unavailability due to micelle formation 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 (HDA, 0.55-0.65 mmol).
- HDA n-hexadecylamine
- the reaction was stirred at 20-45°C for 2-24 hours, preferably 18-24 hours, or until TLC or mass spectroscopy of the reaction mixture indicated the desired extent 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.
- reaction mixture as is at the end of the reaction was diluted with dichloromethane to 4-10% w/w of starting polymer content, and the 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 extent of removal of amine was followed by TLC and mass spectral analysis.
- the product was isolated by distillation of the dichloromethane 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 excess maleic anhydride in methyl isobutyl ketone is added.
- the amount of maleic anhydride addded is in at least a 20% stoichiometric excess relative to the calculated quantity of hydroxyl groups present, preferably from 80-140% in excess, and may be as much as 300% or more in excess. Care must be taken to avoid sublimation of maleic anhydride when used without a cosolvent such as MEK, MIBK etc. Therefore, maleic anhydride is added when the polymer temperature reaches approximately 50-80°C, preferably about 60-70°C.
- the maleic anhydride pellets are mixed into the polymer melt.
- the temperature of the reactor is then further increased to the reaction temperature.
- the reaction mixture is stirred at 70-140°C, preferably 80-100°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 (diisopropylethylamine) or TEA (triethylamine).
- DIPEA diisopropylethylamine
- TEA triethylamine
- Excess mercaptosuccinic acid (1-2 equivalents per equivalent of added maleic anhydride, preferably 1.2-1.8 equivalents, more preferably 1.4-1.6 equivalents) is then added, and allowed to react with the maleate double bonds at pH 8-9.
- the progress of the reaction may be followed by mass spectroscopy.
- 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 adjusted to between 2 and 4 with hydrochloric acid, and the polymer 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 solid is then oven-dried under vacuum or under nitrogen to obtain the product, P10M2-DTT-C16-(M-MSA), also referred to below as P 10M2-DT-(HD A)x(M-MS A) 2
- 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
- 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, N,N-diisopropylcarbodiimide, or the like, 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 below, where L represents a ligand coupled via amidation of the polymer carboxyl groups, and X represents a mixture of OH and NHR groups as described above. 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 ami dated.
- Dry polymer P10M2-DT-(HDA) X (M-MSA) 2 (4) is dissolved in a suitable inert solvent such as DMF under an atmosphere of nitrogen, at between 15-45°C, and the polymer carboxylic acid groups are activated by addition of CDI (5-30% excess over the number of carboxylic acid groups intended to be amidated.) The activation is carried for 30-60 minutes, and to the activated polymer is added a solution of the ligand L60(OMe)2 in DMF. The pH is maintained at 7.5-9 with TEA or DIPEA. The coupling reaction is continued for 2-20 hrs.
- 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 respective proportions from 3: 1 to 40: 1 by mass, preferably from 10: 1 to 20: 1 by mass, 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
- the physiological EC50 and EC90 cannot be determined accurately, and therefore cell culture-based EC50 and EC90 values are often used.
- the range of encapsulation ratios for a particular guest and host will be preferably in the range of the ratio of their EC50 values or EC90 values respectively.
- 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/or bioavailability.
- Many alkyl and alkoxy carbonyl 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 C18 aliphatic and aromatic acids carbonates derived from Cl to Cl 8 aliphatic and aromatic alcohols, and carbamates derived from Cl to C18 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.
- the new and known drug derivatives (i.e. pro-drugs) of the invention which are preferably lower alkyl esters or lower alkoxy carbonyl esters (i.e. carbonates) of antiviral drugs known in the art, are prepared by known methods of acylation, or modifications thereof.
- acid anhydrides may be employed for esterification.
- Alkoxy carbonyl chlorides may be employed to prepare alkoxy carbonyl esters.
- Preferred solvents for these reactions are dipolar aprotic solvents such as DMSO, DMF and NMP.
- the host polymer and the guest antiviral drug or derivative are dissolved, in appropriate proportion from 3: 1 to 20: 1, depending upon the host and the guest in a mutual solvent and mixed to obtain a clear solution.
- Stirring, or passing through a double barrel or single barrel syringe repeatedly, may achieve the proper mixing.
- Suitable solvents include but are not limited to dimethylsulfoxide (DMSO), ethanol, tetrahydrofuran (THF), dichloromethane (DCM) and acetone.
- DMSO dimethylsulfoxide
- THF tetrahydrofuran
- DCM dichloromethane
- This solution is then evaporated in a vacuum oven, rotary evaporator, or lyophilizer.
- the dried mixture is then reconstituted in water or suitable buffer to give a nanoemulsion of the guest species in the polymer.
- the loading ratio of the guest drug is determined by suitable method such as HPLC or UV -Visible spectroscopy.
- Adenine and uracil 3-hexanoyloxybutoxymethylphosphonates were prepared by reacting the 3-hydroxybutoxymethylphosphonates with hexanoic anhydride in the presence of catalytic quantities of 4-dimethylaminopyridine (DMAP) in dimethyl sulfoxide.
- DMAP 4-dimethylaminopyridine
- Hydroxyl groups in Boc-protected compounds were also esterified with various acid anhydrides in the presence of 4-DMAP, and then the Boc groups were removed, to give esters with varying degrees of hydrophobicity, suitable for encapsulation.
- acid chlorides instead of acid anhydrides, in N,N-dimethylacetamide, were employed without catalyst.
- the methylphosphonate derivative of adenine was prepared by stirring adenine (1 mmol) and sodium hydride (1.5 mmol, 60% suspension in mineral oil) in tetrahydrofuran (5 mL) for 5 minutes, adding diethyl ⁇ 3-hydroxy-4-[(4-methylbenzene- sulfonyl)oxy]butoxy ⁇ methanephosphonate (10 mmol), and refluxing the mixture overnight to complete the reaction. Water (10 mL) was added, and the reaction mixture extracted with ethyl acetate. The ethyl acetate layer was evaporated to dryness.
- the pH was adjusted to 7-7.5 with 1 N aqueous hydrochloric acid, and the solution extracted with three portions of ethyl acetate.
- the organic layer was washed with water (lx).
- the ethyl acetate layer was acidified with 1 N aqueous hydrochloric acid and extracted with water (3x) to extract the product as the HC1 salt.
- the aqueous phase was brought up to pH 7-7.5 with sodium bicarbonate and extracted with ethyl acetate (3x) followed by dichloromethane (lx).
- the mixed dichloromethane-ethyl acetate phases were evaporated under reduced pressure to give the title compound (65 mg, m/z 410).
- a 10-20 % w/w solution of P10M2-DTT-C16-(M-MSA) polymer (4) was prepared in ethyl alcohol. Solid remdesivir, 5 to 20 % by weight of polymer used, was added to the polymer solution. The mixture was well stirred to dissolve remdesivir and then evaporated to dryness under nitrogen at 35-60°C until constant weight was observed. The dried material was then dissolved in PBS or water at pH 6-7, and filter-sterilized for further use. The concentration of remdesivir was determined by HPLC or UV analysis.
- the compound (guest) was dissolved in ethanol. It was mixed with the P10M2DT(HDA)x(M-MSA)y polymer (host) solution in ethanol in a guesthost ratio of 1:20 by weight. The solution was evaporated under nitrogen in an oven at about 50°C. The resulting dry film was then redissolved in PBS containing 5% ethanol, and used for the study. It should be noted that some substances did not dissolve properly in lxPBS, settling out upon refrigeration. Ethanol was added to all samples for purposes of uniformity in the study. [0097] In normal drug formulations, ethanol can be completely avoided.
- formulations can be made in osmotically balanced solutions, pH adjusted solutions, as the case may be for the different routes of drug administration.
- physiologically balanced solutions containing mannitol, sodium chloride, or other osmolality balancing agents can be made for injection, infusion, or inhalation purposes.
- a somewhat acidic taste may be preferred, and sweeteners, taste masking agents, flavoring agents, etc. may be added without disturbing the encapsulation.
- the guest compound was dissolved in DMSO and mixed with a P10M2DT(HDA)x(M-MSA)y host polymer solution in DMSO in a ratio of 1 :20.
- the resulting DMSO solution was lyophilized.
- the lyophilized powder was then dissolved in PBS containing 5% ethanol as above.
- Host polymer and remdesivir served as positive controls; with PBS and DMSO as vehicle controls.
- the drug and prodrug compounds in DMSO solution or encapsulated in P10M2DT(HDA)x(M- MSA)y nanoparticles dissolved in PBS buffer, were exposed to cultured MRC5 lung fibroblast cells (ATCC CCL-171) in a cell culture plate virally infected by hCoV-229E at different drug concentrations.
- the polymeric micelle material P10M2DT(HDA)x(M-MSA)y itself has anti- coronavirus activity of its own, and was also employed in PBS buffer as a positive control.
- Remdesivir a well-known approved SARS-CoV-2 therapeutic drug with broad-spectrum anti- coronavirus activity, was also used as positive control.
- the solution vehicle (PBS) was used as negative control. Remdesivir was dissolved in DMSO due to its poor water solubility, and DMSO was also used as a negative control (results not shown).
- the improvement in cell survival which is correlated with the reduction in growth of the virus, was read out using the CellTiter-GloTM assay (Promega Corp., Madison, WI, USA.)
- Encapsulated and non-encapsulated compounds were applied to the cell cultures without viral infection, and cell survival was read out using the same CellTiter-GloTM assay.
- Figure 4 plots cell survival against non-encapsulated compound concentrations, and shows the selected compounds’ efficacy as antivirals. Almost all of the compounds show substantial concentration-dependent antiviral activity that merits further study.
- Figure 5 plots cell survival against the concentration of host polymer, and shows the compounds’ efficacy as antivirals when encapsulated into P10M2DT(HDA)x(M-MSA)y polymer (4) nanoparticles at a 1:20 ratio.
- the efficacy of some of these encapsulated compounds in terms of maximal survival improvement, exceeds that of remdesivir (Example 17).
- Examples 10, 11, 12 and 13 show a substantial increase in effectiveness compared to the host polymer (4) itself, and are found to be comparable to or superior to remdesivir.
- Figure 6 plots cell survival against the concentration of encapsulated guest compounds. The plots indicate improvements in survival with increasing amounts of compounds, in contrast to the toxicity of remdesivir (Ex. 17) at increasing concentrations.
- Figure 7 compares the efficacies of encapsulated and non-encapsulated compounds when plotted as guest compound concentrations. The plots clearly indicate significant improvements in the effective activities of the guest compounds upon encapsulation.
- Figure 8 plots uninfected cell survival against encapsulated compound host concentrations. The plots show the high cytotoxicity of encapsulated remdesivir, and the relative non-toxicity of the drugs and prodrugs tested.
- remdesivir showed superior maximum viral inhibition and at lower concentrations than the synthesized and encapsulated drugs of this invention, its effectiveness rapidly decreases at slightly higher concentrations due to cytotoxicity. Clinical studies of Remdesivir have shown that its clinical effect was limited yet increasing concentrations is not an option due to its toxicity.
- the examples above are non-limiting, representative examples only.
- the invention contemplates all combinations of known prodrugs, including but not limited to ester, carbonate, ether and carbamate prodrugs, with any known antiviral drugs that are amenable to such derivatization, and the use of any such prodrugs in combination with any of the comb polymers of the invention.
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US5919442A (en) * | 1995-08-11 | 1999-07-06 | Dendritech, Inc. | Hyper comb-branched polymer conjugates |
US20060269479A1 (en) * | 2005-04-19 | 2006-11-30 | Colton Clark K | Amphiphilic polymers and methods of use thereof |
US20100008938A1 (en) * | 2007-01-22 | 2010-01-14 | Anil Diwan | Self assembling amphiphilic polymers as antiviral agents |
US20100239659A1 (en) * | 2007-07-19 | 2010-09-23 | Allexcel., Inc. | Self-assembling amphiphilic polymers as anti-cancer agents |
US20180016352A1 (en) * | 2015-02-05 | 2018-01-18 | The University Of Queensland | Targeting constructs for delivery of payloads |
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US6521736B2 (en) * | 2000-09-15 | 2003-02-18 | University Of Massachusetts | Amphiphilic polymeric materials |
JP5027157B2 (en) * | 2006-01-19 | 2012-09-19 | オールエクセル,インコーポレイティド | Solubilization and targeted introduction of drugs with self-assembling amphiphilic polymers |
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US5919442A (en) * | 1995-08-11 | 1999-07-06 | Dendritech, Inc. | Hyper comb-branched polymer conjugates |
US20060269479A1 (en) * | 2005-04-19 | 2006-11-30 | Colton Clark K | Amphiphilic polymers and methods of use thereof |
US20100008938A1 (en) * | 2007-01-22 | 2010-01-14 | Anil Diwan | Self assembling amphiphilic polymers as antiviral agents |
US20100239659A1 (en) * | 2007-07-19 | 2010-09-23 | Allexcel., Inc. | Self-assembling amphiphilic polymers as anti-cancer agents |
US20180016352A1 (en) * | 2015-02-05 | 2018-01-18 | The University Of Queensland | Targeting constructs for delivery of payloads |
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