WO2021113397A1 - Plates-formes et méthodes d'administration de médicament peg polymère - Google Patents

Plates-formes et méthodes d'administration de médicament peg polymère Download PDF

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Publication number
WO2021113397A1
WO2021113397A1 PCT/US2020/062939 US2020062939W WO2021113397A1 WO 2021113397 A1 WO2021113397 A1 WO 2021113397A1 US 2020062939 W US2020062939 W US 2020062939W WO 2021113397 A1 WO2021113397 A1 WO 2021113397A1
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Prior art keywords
pcl
drug
approximately
mpeg
hydrochloride
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PCT/US2020/062939
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English (en)
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Ernest SHIN
Won Jong Kim
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Onselex Inc.
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Publication of WO2021113397A1 publication Critical patent/WO2021113397A1/fr

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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

Definitions

  • the present invention relates generally to amphiphilic diblock and/or triblock copolymers and/or star-shaped block copolymers of biodegradable materials (e.g., PEG-Jb-PCL and PEG-a- PCL) as drug delivery platforms and to methods of producing, evaluating, administering, and treating subjects with the same.
  • biodegradable materials e.g., PEG-Jb-PCL and PEG-a- PCL
  • the present invention provides poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.
  • poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.
  • Block copolymers which comprise hydrophilic and hydrophobic polymers covalently bound to one another are by definition amphiphilic polymers. Above a certain concentration, called the critical micellar concentration (CMC) or critical aggregation concentration (CAC), block copolymers can self-assemble to form supramolecular aggregates (micelles or nanoparticles) in aqueous medium.
  • the micelles consist of two distinct regions: an interior region of hydrophobic polymer chains (the core region), which has the ability to solubilize hydrophobic molecules; and an outer region of well-solvated hydrophilic polymer chains (the shell region), which imparts colloidal stability.
  • Block copolymers can be designed to exhibit low CAC (few milligrams per liter) and high thermodynamic stability, compared to low molecular weight surfactants.
  • the size of block copolymer micelles is of the order of 10-40 nanometers. (See, Reiss, G., et. a!., Block Copolymers, In Encyclopedia of Polymer Science and Engineering; Korschwitz, J. I. Ed.; Wiley-lnterscience, New York, NY (1985)). Due to these properties, block copolymer micelles comprising hydrophilic-biocompatible and hydrophobic biodegradable segments have attracted considerable attention related to their use as nanosized carriers of poorly water-soluble drugs.
  • These micelles can facilitate the solubilization of poorly water-soluble drugs, increase their circulation time in vivo and eventually target them passively or actively by means of targeting ligands to specific tissues (e.g., tumoral tissues).
  • tissues e.g., tumoral tissues.
  • Torchilin, V. P., J. Controlled Rel., 73:137-172 2001
  • Jones, M. C., and Leroux, J. C., Eur. J. Pharm. Biopharm., 48:101-111 (1999) See, Kataoka, K., et al., Adv. Drug Deliv. Rev., 47:113-131 (2001); Torchilin, V. P., J. Controlled Rel., 73:137-172 (2001); and Jones, M. C., and Leroux, J. C., Eur. J. Pharm. Biopharm., 48:101-111 (1999)).
  • Block copolymers having a variety of architectures e.g., A-B, A-B-A, and star-shaped block copolymers are known in the art.
  • A-B type diblock copolymers monomethoxy poly(ethylene glycol)-block-poly(D,L-lact- ide) (MPEG-b-PDLLA) (Yasugi, K., etal., J. Controlled Rel., 62:89-100 (1999)); monomethoxy poly(ethylene glycol)-block-poly(£-caprolactone) (MPEG- b-PCL) (See, Shin, I. G., et aL, J.
  • MPEG- b-PDLLA has been synthesized by ring opening polymerization of D,L-lactide initiated either with potassium monomethoxy poly(ethylene glyco)late at 25 °C in tetrahydrofuran (THF) (See, Jeong, B., etal., Nature, 388:860-862 (1997)) or with MPEG at 110 to 150 °C in the bulk. (Kim, S. Y., et al., J. Controlled Rel., 56:197-208 (1998)).
  • MPEG-b-PCL has also been synthesized by ring opening polymerization of e-caprolactone initiated with potassium MPEG alcoholate in THF at 25 °C (See, Deng, X. M.
  • MPEG-b-PBLA was synthesized by polymerization of N-carboxyanhydride of aspartic acid initiated with MPEG amine, in a solvent at 25 °C. (See, Yokoyama, M., et ai, Makromol. Chem. Rapid Commun., 8:431-435 (1987)).
  • FIG. 1A shows molecular weights (MW) of exemplary mPEG-OH and mPEG-Jb-PCL. The MW was calibrated using polystyrene standards.
  • FIG. 1B shows an exemplary 1 H NMR spectrum of mPEG-b-PCL, mPEG-OH, and e-caprolactone.
  • FIG. 2 shows an exemplary GPC profile of mPEG-b-PCL and mPEG-OH.
  • FIG. 3 shows exemplary UV-visible spectrum and calibration curves of PTX in MeCN; Panel A) absorption spectrum of PTX in MeCN at different concentrations; and Panel B) calibration curve of PTX.
  • FIG. 4 describes exemplary schemes for preparing PTX-loaded micelles, wherein: Panel A) provides a pictorial representation of a scheme for PTX-loaded micelle preparation; and Panel B) provides mixing conditions of reagents for PTX-loaded micelles in one embodiment.
  • FIG. 5 shows an exemplary absorption spectrum of PTX loaded micelle and mPEG-Jb- PCL in MeCN.
  • FIG. 6 shows size analyses of representative PTX loaded micelles, wherien: Panel A) shows a DLS spectrum of PTX loaded micelle; and Panel B) shows a TEM image of PTX loaded micelles.
  • the micelles are about 20 to 30 nm in diameter.
  • FIG. 7 shows an exemplary 1 H NMR spectrum of alkyne-PCL and e-caprolactone.
  • the present invention relates generally to amphiphilic diblock and/or triblock copolymers and/or star-shaped block copolymers of biodegradable materials (e.g., PEG-Jb-PCL and PEG-a- PCL) as drug delivery platforms and to methods of producing, evaluating, administering, and treating subjects with the same.
  • biodegradable materials e.g., PEG-Jb-PCL and PEG-a- PCL
  • the present invention provides poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.
  • poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.
  • polymeric block copolymers of the present invention upon association (e.g., attachment thereto) of one or more active drug substances (or prodrug substances) are useful delivery platforms and carriers for administering compounds of interest to a subject.
  • active drug substances or prodrug substances
  • the drug substances are typically intended to provide a therapeutic benefit to the subject.
  • the present invention relates to polymeric block copolymers based drug delivery platforms and to methods of producing, evaluating, administering, and treating subjects with the same. More particularly, the present invention provides polymeric block copolymers (e.g., PEG-Jb-PCL and PEG-a-PCL) based drug delivery platforms comprising one or more copolymers with controlled molecular weights and/or polydispersities as well as selective methods for associating one or more drug substances to the copolymer.
  • polymeric block copolymers e.g., PEG-Jb-PCL and PEG-a-PCL
  • the drug delivery platforms are polymer compounds that are substantially biocompatible, biodegradable, and hydrophilic, or alternatively, substantially hydrophobic or hydrophilic.
  • the drug delivery platforms comprise copolymer compounds comprising hybrid polymers having a main chain containing nitrogen and phosphorous linked through a plurality of interchangeable C-C single and double bonds and optionally further comprising one or more types of advantageous side-chains.
  • Suitable hybrid polymers compounds are preferentially, though not exclusively, found in the broad class of methoxy poly(ethylene glycol)-block-poly(£-caprolactone) polymers (e.g., PEG-Jb- PCL and PEG-a-PCL) formulated as nanoshperes, microspheres, micelles, films, or hydrogels.
  • the polymeric block copolymers (e.g., PEG-Jb-PCL and PEG-a-PCL) compounds of the present invention are subsequently, or concomitantly with production, derivitized (e.g., loaded) with one or more active drug substances (or prodrug) substances.
  • Suitable therapeutic agents including drugs and drug substances including, but not limited to, one or more anticancer agents (e.g., chemotherapeutic agent(s), hormone therapies, targeted cancer drugs, bisphosphonates, anticancer and/or anti-tumorigenic agents, anti-proliferative agents, antiangiogenic agents, anti metastatic agents, neoadjuvant therapies and agents, and immunological therapies (e.g., “checkpoint inhibitor” agents)).
  • anticancer agents e.g., chemotherapeutic agent(s), hormone therapies, targeted cancer drugs, bisphosphonates, anticancer and/or anti-tumorigenic agents, anti-proliferative agents, antiangiogenic agents, anti metastatic agents, neoadjuvant therapies and agents, and immunological therapies (e.g., “checkpoint inhibitor” agents)).
  • anticancer agents e.g., chemotherapeutic agent(s), hormone therapies, targeted cancer drugs, bisphosphonates, anticancer and/or anti-tumorigenic
  • suitable hybrid polymers compounds are preferentially, though not exclusively, found in the broad class of methoxy poly(ethylene glycol)-block-poly(£- caprolactone) (“mPEG-b-PCL” or “mPEG-PCL”) compounds that are subsequently derivitized with one or more drug substances (pharmacologically active or prodrug) such as one or more anticancer agents or drugs.
  • drug substances pharmaceutically active or prodrug
  • the concentration, loading characteristics, adsorption, absorption, or otherwise the chemical association (e.g., covalent, ionic bonding and the like) of the agent(s) to the drug carrier is analyzed by 1 H NMR, HPLC, GC, MS, GC-MS, and/or immunological techniques.
  • Preferred drug loading ratios of therapeutic agent (e.g., chemotherapeutic agent) to polymeric block copolymer drug carrier(s) is from about % to about 20%, and more preferably, from about 5% to about 10% drug/copolymer ratio (w/w).
  • Aqueous solubility in preferred compositions ranges range from about 1 to about 10%, and when Paclitaxel (“PTX”) is the agent being delivered, the aqueous solubility is from about 1% to about 6%, and more preferably, from about 3% to about 4%.
  • PTX Paclitaxel
  • one or more targeting moieties can be conjugated to chemical active moieties or functional groups on the drug carrier(s) such as pendant functional groups in diblock, triblock, and star block copolymers.
  • at least one targeting moiety may be conjugated to a pendant functional groups in a vinyl polymer segment, said targeting moiety being at least one member selected from the group consisting of vitamins, sugars, lectins, antibodies and antibody fragments, peptides, receptors, ligands, and combinations thereof.
  • the compositions provide one or more targeting comprising folic acid, sugars, and antibodies, and the like.
  • the drug delivery systems when loaded with one or more drugs or therapeutic agents are optionally freeze dried, lyophilized, or otherwise stabilized to enhance storage and logistic considerations and/or safety and efficacy considerations upon administration.
  • one or more cryoprotectants are optionally added to the freeze dried and/or lyophilized products.
  • Suitable cryoprotectants include, but are not limited to, polysaccharides (sugars and sugar alcohols) (e.g., Arabinose, Ribose, Ribulose, Xylose, Xylulose, Lyxose, Allose, Altrose, Fructose, Galactose, Glucose, Gulose, Idose, Mannose, Sorbose, Talose, Tagatose, Sedoheptulose, Mannoheptulose, Sucrose, Maltose, Trehalose, Lactose, Mellibiose, Amylaose, and Mannan and the like).
  • polysaccharides e.g., Arabinose, Ribose, Ribulose, Xylose, Xylulose, Lyxose, Allose, Altrose, Fructose, Galactose, Glucose, Gulose, Idose, Mannose, Sorbose, Ta
  • the present invention contemplates, the use of one or more sugar cryoprotectants, and more preferably, the use of sucrose, to stabilize the drug delivery systems during freeze drying and/or lyophilization processing.
  • Percentages of the cryoprotectants in particular drug delivery systems range from about 0.001% to about 10% or more, from about 0.01% to about 10% or more, from about 0.1% to about 10% or more, from about 0.001% to about 5% or more, from about 0.01% to about 5% or more, from about 0.1% to about 5% or more, from about 0.5% to about 5% or more, from about 0.5% to about 10% or more, from about 1% to about 10% or more, from about 2% to about 8% or more, from about 3% to about 7% or more, and from 4% to about 6% or more, and about 5%.
  • the drug delivery systems and compositions of the present invention further comprise one or more excipients, for example, pharmaceutically, or physiologically, acceptable organic, or inorganic carrier substances suitable for enteral or parenteral application which do not deleteriously react with the composition.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrolidine.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like which do not deleteriously react with the compositions administered to the human.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or aromatic substances and the like which do not deleteriously react with the compositions administered to the human.
  • Certain methods of the present invention provide readily scalable production schemes for producing polymeric block copolymers (e.g., PEG-Jb-PCL and PEG-a-PCL) based drug delivery platforms with enhanced efficiency.
  • polymeric block copolymers e.g., PEG-Jb-PCL and PEG-a-PCL
  • Still other embodiments of the present invention provide production schemes for producing polymeric block copolymers (e.g., PEG-Jb-PCL and PEG-a-PCL) based drug delivery platforms at scale while maintaining current Good Laboratory Practice (“cGLP”), and/or current Good Manufacturing Practice (“cGMP”) standards, related to experimental and non-clinical trial materials, compared to clinical trial materials, respectively.
  • polymeric block copolymers e.g., PEG-Jb-PCL and PEG-a-PCL
  • cGLP current Good Laboratory Practice
  • cGMP current Good Manufacturing Practice
  • Preferred embodiments of the instant compositions provide drug carrier compositions (e.g., nanospheres) that range in size from about 10 nm to about 100 nm, and preferably, having a mean of about 50 nm.
  • Methods are provided herein for producing drug carrier compositions (e.g., nanospheres) with a mean particle size of about 50 nm, as measured, for example by Dynamic Light Scattering (DLS) techniques. Standard techniques can be used to concentration and/or filter nanospheres.
  • DLS Dynamic Light Scattering
  • the present invention relates generally to amphiphilic diblock and/or triblock copolymers and/or star-shaped block copolymers of biodegradable materials (e.g., PEG-Jb-PCL and PEG-a- PCL) as drug delivery platforms and to methods of producing, evaluating, administering, and treating subjects with the same.
  • biodegradable materials e.g., PEG-Jb-PCL and PEG-a- PCL
  • the present invention provides poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.
  • poly(ethylene glycol)-Jb-poly(£-caprolactone) and poly(ethylene glycol)-a-poly(£-caprolactone) copolymers and copolymer-drug conjugates, aggregates, and supramolecular assemblies (e.g., micelles) as well as selective methods for associating one or more therapeutic drug (or prodrug) substances to the polymeric block copolymers.
  • drug refers to organic and/or inorganic molecules including, but not limited to, small molecule drugs, proteins, polysaccharides, nucleoproteins, lipoproteins, synthetic polypeptides, small molecules linked to a protein(s), saccharides, oligosaccharides, carbohydrates, glycoploymers, glycoproteins, steroids, nucleic acids, nucleotides, nucleosides, oligonucleotides (including antisense oligonucleotides), cDNA, nucleic acids, vitamins, including, but not limited to, vitamin C and vitamin E, lipids, or combination and portions thereof, that causes a biological effect when administered in vivo to an animal such as mammal and in particular, a human.
  • these terms more particularly in certain embodiments, further refer to any substance used internally or externally in an animal (e.g., a human) as medicaments, medicines, or prophylactics (i.e., vaccines and immunological active compositions) for the treatment, cure, or prevention of a disease, disorder, or medical condition, including, but not limited to, antifungal, agents (e.g., Fluconazole and Voriconazole), antiepileptic drugs (e.g., Rufinamide and Topiramate), immunosuppressants, antioxidants, anesthetics, chemotherapeutic agents, steroids (e.g., retinoids, hormones and the like), antibiotics, antivirals, antiproliferatives, antihistamines and allergy treatments (e.g., Triamcinolone acetonide), anticoagulants, antiphotoaging agents, biological agents (e.g., nucleotides, oliogonucleotides, polynucleotides, and nucle
  • agents
  • the drug delivery systems of the present invention are formulated and/or optimized to carry and deliver (e.g., release over time) one or more chemotherapeutic agents.
  • suitable chemotherapeutic agents include, but are not limited to, small molecule chemotherapeutic drugs and anticancer and/or anti- tumorigenic agents, antiproliferative agents, antiangiogenic agents, anti-metastatic agents, neoadjuvant therapies and agents, immunological therapies (e.g., “checkpoint inhibitor” agents)).
  • aliphatic refers to a hydrocarbon, typically of Ci , to C20, that can contain one or a combination of alkyl, alkenyl, or alkynyl moieties, and which can be straight, branched, or cyclic, or a combination thereof.
  • a lower aliphatic group is typically from Ci to C5 ⁇
  • alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, preferably of Ci to C20, and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • the alkyl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al. (“Protective Groups in Organic Synthesis,” John Wiley and Sons, Second Edition, 1991).
  • the term “lower alkyl,” as used herein, refers to an alkyl group of Ci to C5.
  • alkylamino or arylamino refers to an amino group that has one or two alkyl or aryl substituents, respectively.
  • protected refers to a group that is added to an oxygen or nitrogen atom to prevent its further reaction during the course of derivatization of other moieties in the molecule in which the oxygen or nitrogen is located.
  • oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
  • amino acid refers to a natural or synthetic amino acid, and includes, but is not limited to alanyl, valinyl, leucinyl, isoleucinyl prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaoyl, lysinyl, argininyl, and histidinyl.
  • amino acid ester refers to the aliphatic, aryl or heteroaromatic carboxylic acid ester of a natural or synthetic amino acid.
  • aryl refers to phenyl, biphenyl, or naphthyl, and preferably phenyl.
  • the aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, etal., "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991.
  • halo includes chloro, bromo, iodo, and fluoro.
  • heteroaryl or “heteroaromatic,” as used herein, refer to an aromatic moiety that includes at least one sulfur, oxygen, or nitrogen in the aromatic ring.
  • Non-limiting examples are furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbozolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl,
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t- butyldiphenylsilyl, trityl, alkyl groups, acyl groups such as acetyl and propionyl, methylsulfonyl, and p-toluylsulfonyl.
  • alkylheterocyclic or “alkylheteroaromatic” refer to a moiety in which the alkyl group is covalently attached to the heteroaromatic, is preferably Ci, to C4 alkylheteroaromatic, and more preferably CH2 -heteroaromatic.
  • aralkyl refers to an aryl group with an alkyl substituent.
  • alkoxy refers to a moiety of the structure -O-alkyl.
  • alkynyl refers to a C2 to C10 straight or branched hydrocarbon with at least one triple bond.
  • protected-oxy refers to an oxygen atom that has been protected from undesired reactions with any of the oxygen protecting group known to those skilled in the art, including but not limited to, for example, a trisubstituted silyl group such as trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl group, acyl groups such as acetyl, propionyl, benzoyl, P-NO2 benzoyl, toluyl, methylsulfonyl, or p-toluylsulfonyl.
  • a trisubstituted silyl group such as trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, alkyl group, acyl groups such as acety
  • heteroalkyl refers to an alkyl group that includes a heteroatom such as oxygen, sulfur, or nitrogen (with valence completed by hydrogen or oxygen) in the carbon chain or terminating the carbon chain.
  • these compounds include a series of lower alkyls interrupted by a heteroatom such as oxygen, sulfur or nitrogen, including -O- [(alkyl)0] x -CH 2 )NH 2 , wherein the alkyl group can vary within the moiety, including -0-[(CH 2 ) x 0] y -CH 2 ) x NH 2 ; -0-[(CH 2 ) x 0] y CH 2 ) x NH(CH 2 ) x S0 3 H, and -0-[(alkyl)-0] y -(alkyl), wherein the alkyl group can vary within the moiety, including -0-[(CH 2 ) x 0] y -(alkyl), wherein the alkyl group can vary within the moiety
  • inventive subject matter may be referred to herein, individually and/or collectively, by the term "invention" merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept if more than one is in fact disclosed.
  • inventive subject matter may be referred to herein, individually and/or collectively, by the term "invention" merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept if more than one is in fact disclosed.
  • inventive subject matter merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept if more than one is in fact disclosed.
  • Tetrahydrofuran (THF, HPLC grade) was obtained from Burdick & Jackson (Muskegon, Ml, USA).
  • THF was used as the eluent at a flow rate of 1 mL/min.
  • the molecular weights were calibrated using polystyrene standards.
  • FIG. 1A The dynamic light scattering (DLS) measurements were performed using a Zetasizer Nano S90 system (Malvern Instruments, Worcestershire, U.K.).
  • FIG. 6, Panel A UV-Visible spectra were acquired by using UV 2550 spectrophotometer (Shimadzu, Japan). (FIG. 3).
  • mPEG-OH (2 g), e-CL (2.283 g) and Sn(Oct)2 (0.081 g) and 10 L of toluene were charged into a flame-dried Schlenk flask equipped with a magnetic stirring bar under dry nitrogen. After deoxygenating the solution by nitrogen purging, polymerization was carried out in a heated oil bath at 110 °C for 24 h. After cooling to room temperature, the polymer was precipitated in excess diethyl ether. The precipitated polymer was redissolved in CH2CI2 and re precipitated in diethylether. The purified polymer was filtered and dried under vacuum at 30 °C.
  • Drug-loaded mPEG-Jb-PCL micelles were prepared by thin film hydration method according to G. Saravanakumar etal., 2018, supra.
  • FIG. 4 Panel A
  • 41 mg of mPEG-Jb-PCL and 3.2 mg of drug (Paclitaxel “PTX”) were dissolved in 3 ml_ THF in a 40 ml_ vial. After complete dissolution, THF was evaporated to form a thin film on the surface of vial.
  • FIG. 4, Panel A and Panel B The film was then rehydrated with distilled water 30 ml_ with sonication.
  • the non-encapsulated drugs were removed by dialysis and filtration through a syringe filter (0.45 pm).
  • This Example describes the preparation of drug loaded mPEG-a-PCL micelles using an acetal/ketal linker and thin film methodology.
  • Tin (II) 2-ethylhexanoate (Sn(Oct)2) was obtained from Alfa Aesar, Haverhill,
  • THF Tetrahydrofuran
  • HPLC grade Tetrahydrofuran
  • CH2CI2, 99.5% acetonitrile
  • MeCN acetonitrile
  • sodium carbonate Na 2 C0 3 , 99.0%
  • anhydrous sodium sulfate Na 2 S0 4 , 99.0%
  • diethyl ether 94.5%) were purchased from Samchun Chemicals Co., Ltd., Seoul, Korea.
  • 2-Chloroethyl vinyl ether (>97.0%) was obtained from Tokyo Chemical Industry CO., LTD.
  • the monomer e-CL was dried over calcium hydride and distilled under reduced pressure prior to use.
  • the molecular weights were calibrated using polystyrene standards.
  • the dynamic light scattering (DLS) measurements were performed using a Zetasizer Nano S90 system (Malvern Instruments, Worcestershire, U.K.). UV-Visible spectra were acquired by using UV 2550 spectrophotometer from Shimadzu Corp. (Kyoto, Japan).
  • Alkyne-PCL was synthesized by ring-opening polymerization of e-CL using propargyl alcohol as an initiator and Sn(Oct)2 as a catalyst using the methods described by G. Saravanakumar et al., and H. Wang etal.
  • N3-a-PEG was synthesized by following a previous synthetic method with modification. (See, Wang, H., et al., 2013, supra).
  • acetal linker was conjugated to the chain end of mPEG-OH.
  • dried mPEG-OH (2 g, 0.4 mmol, mPEG-OH of M n 5 g/mol)
  • PPTS (20 mg. 0.08 mmol
  • 20 mL of anhydrous CH2CI2 were charged into a flame-dried round- bottomed flask. Thereafter, 0.4 mL of 2-chloroethyl vinyl ether (4 mL, 4 mmol) was added dropwise into the flask at 0 °C with constant stirring.
  • the pH-responsive mPEG-a-PCL was synthesized by click chemistry between the synthesized alkyne-PCL and I h-a-PEG.
  • N3-a-PEG (1 g, 0.2 mmol) and alkyne-PCL (780 mg, 0.2 mmol) were dissolved in 25 mL THF.
  • CuBr (28.8 mg, 0.2 mmol) and PMDETA (42 pL, 0.2 mmol) were added into the flask. This solution was then deoxygenated by nitrogen purging or three exhausting-refilling nitrogen cycles. After deoxygenation, the resulting solution was stirred at room temperature for 24 h under N 2 .
  • Drug loaded mPEG-a-PCL micelles were prepared by a thin film hydration method described in G. Saravanakumar. (Saravanakumar, G., et al., 2018, supra). 41 mg of mPEG-a- PCL and 3.2 mg of drug (Paclitaxel) were dissolved in 3 ml_ THF in a 40 ml_ vial. After complete dissolution, THF was evaporated to form a thin film on the surface of vial. The film was then rehydrated with distilled water 30 mL with sonication. The non-encapsulated drugs were removed by dialysis and filtered through a syringe filter (0.45 pm).
  • the loading contents and loading efficiency of PTX in the micelle were determined using UV-Visible spectrophotometer at 227 nm, by the following equation.
  • Drug loading contents (LC) (%) mass of PTX in micelles / mass of the micelles x 100%
  • Drug loading efficiency (LE) (%) actual loading contents / theoretical drug loading contents x 100%.
  • Preferred embodiments of the present polymeric drug carrier and delivery systems are formulated and optimized to delivery one or more anticancer or antitumor drug agents or substances such as, but not limited to: Abemaciclib, Abiraterone Acetate, Acalabrutinib, Adriamycin, Afatinib Dimaleate, Afinitor (Everolimus), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectinib), Alectinib, Alimta (Pemetrexed Disodium), Aliqopa, (Copanlisib Hydrochloride), Aloxi (Palonosetron Hydrochloride), Alpelisib, Alunbrig (Brigatinib), Ameluz (Aminolevulinic Acid Hydrochloride), Amifostine, Aminolevulinic acid hydrochloride, Anastrozole, Apalutamide, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (
  • Thalidomide Thalomid (Thalidomide), Thioguanine, Thiotepa, Tibsovo (Ivosidenib), Tisagenlecleucel, Topotecan Hydrochloride, Toremifene, Torisel (Temsirolimus), Totect (Dexrazoxane Hydrochloride), Trabectedin, Trametinib, Treanda (Bendamustine Hydrochloride), Trexall (Methotrexate), Trifluridine and Tipiracil Hydrochloride, Trisenox (Arsenic Trioxide), Tykerb (Lapatinib Ditosylate), Uridine Triacetate, Valrubicin, Valstar (Valrubicin), Vandetanib, Varubi (Rolapitant Hydrochloride), Veip, Velcade (Bortezomib), Vemurafenib, Venclexta (Venetoclax), Venetoclax, Verzenio
  • Yescarta (Axicabtagene Ciloleucel), Yondelis (Trabectedin), Zaltrap (Ziv-Aflibercept), Zarxio (Filgrastim), Zejula (Niraparib Tosylate Monohydrate), Zelboraf (Vemurafenib), Zinecard (Dexrazoxane Hydrochloride), Ziv-Aflibercept, Zofran (Ondansetron Hydrochloride), Zoladex (Goserelin Acetate), Zoledronic Acid, Zolinza (Vorinostat), Zometa (Zoledronic Acid), Zydelig (Idelalisib), Zykadia (Ceritinib), and Zytiga (Abiraterone Acetate), and the like.
  • Various embodiments of the drug delivery compositions of the present invention are formulated and optimized for treating, ameliorating, or retarding the metastasis thereof regarding a particular type of tumor or cancer, or a tumor or cancer of a particular organ, tisues, or structure, including, but not limited to: Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS-Related Cancers (e.g., Kaposi Sarcoma (Soft Tissue Sarcoma), AIDS-Related Lymphomas, Anal Cancer, Appendix Cancer and Gastrointestinal Carcinoid Tumors, Astrocytomas, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma of the Skin, Bile Duct Cancer (e.g., Cholangiocarcinoma), Bladder Cancer, Bone Cancer (e.g., Ewing Sarcoma and Osteosarcoma and Malignant Fibrous Histi
  • CML Chronic Myelogenous Leukemia
  • AML Acute Myeloid Leukemia
  • AML Chronic Myeloproliferative Neoplasms
  • Nasal Cavity and Paranasal Sinus Cancer Nasopharyngeal Cancer
  • Neuroblastoma Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer
  • Oropharyngeal Cancer Osteosarcoma and Malignant Fibrous Histiocytoma, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors, Papillomatosis, Paraganglioma, Parathyroid Cancer,
  • Penile Cancer Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Prostate Cancer, Rectal Cancer, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Ewing Sarcoma, Kaposi Sarcoma, Osteosarcoma, Soft Tissue Sarcoma, Uterine Sarcoma, Sezary Syndrome, Small Intestine Cancer, Squamous Cell Carcinoma of the Skin, Occult Primary Squamous Neck Cancer, T-Cell Lymphoma, Cutaneous (e.g., Mycosis Fungoides and Sezary Syndrome), Testicular Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Urethral Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Vascular Tumors, and Wilms Tumor, and the like.
  • the drug delivery systems and compositions of the present disclosure are provided as sterile and, optionally, preservative-free formulations.
  • the drug delivery systems and compositions are sterile, optionally preservative- free, and formulated in a single-use or unit-dose formats.
  • the sterile formulations contain one or more preservatives, stabilizers, sugars, or sugar alcohols.
  • the methods and drug delivery systems and compositions of the present invention provide treatments for cancer and other proliferative diseases in a subject in order to confer a medicinal or therapeutic benefit in the subject by the administration of an effective dose of the one or more of compositions described herein. Methods of administering the compounds of the invention may be by metered dose or by one or more controlled release devices.
  • the compositions may be in unit dosage forms suitable for single administration of precise dosages.
  • the concentration of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,
  • the concentration of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%,
  • the concentration of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w/w, w/v or v/v.
  • the concentration of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v.
  • the amount of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g,
  • the amount of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g
  • compositions of the present invention provide, amounts of one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, 1-3 g, or 1-10 g.
  • the target dose may be administered in a single dose. Alternatively, the target dose may be administered in about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or more doses.
  • the administration schedule may be repeated according to any prescribed regimen, including any administration schedule described herein or known in the art.
  • the one or more of the active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention may be administered in one dose or multiple dosages. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the particular compositions used, the purpose of the use, the target cells or tissues being contacted, and the subject being treated.
  • Single or multiple administrations e.g., about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 50, more doses
  • Single or multiple administrations e.g., about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 50, more doses
  • minutes, hours, days, weeks, months, or even years e.g., about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or 50, or more doses
  • one dose of the composition is administered every 1-3, 1-7, 1-10, 1-12, 1-14, 1-28, 1-30, or more, days as prescribed by a physician or as otherwise deemed necessary for therapeutic benefit. Administration can be carried out with the dose level and pattern being selected by the treating physician. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimens is necessary for optimal therapy. Dosing for compositions of the present invention may be found by routine experimentation in light of the instant disclosure and one’s skill in the art.
  • a suitable pharmaceutical preparation may also include, optionally, in addition to one or more compounds of the present invention, other agents, including, but not limited to, excipients, diluents, extenders, stabilizers, colors, flavors, formulating agents (e.g., gels and thickeners), antioxidants (e.g., ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, EDTA, phosphoric acid, sodium ascorbate, sodium metabisulfite, tartaric acid, tertiary butyl hydroquinone), preservatives, sterile aqueous solutions, buffers, sugars, and the like, as are generally known and accepted.
  • excipients e.g., diluents, extenders, stabilizers, colors, flavors, formulating agents (e.g., gels and thickeners), antioxidants (e.g., ascorbic acid, butylated hydroxyanisole, butylated
  • one or more additional small molecule drug and/or biological agents may be preferentially combined in an admixture (or administered concomitantly) with the one or more active drug or therapeutic compounds provided in the drug delivery systems and compositions of the present invention of the present invention to achieve a beneficial, or even synergistic, outcome in the subject.
  • the compositions of the present invention can be formulated for delivery into the subject’s mouth ( e.g ., by ingestion, buccal and/or sublingual deposit).
  • compositions are formulated for injection (e.g., intramuscular, intradermal, intrathecal, intraperitoneal, intra-arterial, and/or subcutaneous, and the like), infusion (e.g., intraosseous and/or intravenous, and the like), irrigation, instillation (e.g., dropwise instillation) and the like.
  • injection e.g., intramuscular, intradermal, intrathecal, intraperitoneal, intra-arterial, and/or subcutaneous, and the like
  • infusion e.g., intraosseous and/or intravenous, and the like
  • irrigation e.g., dropwise instillation
  • instillation e.g., dropwise instillation
  • delivery of the desired formulation is aided by one or more mechanical device(s) such as microneedles and patches, syringes, pumps, catheters, ports, inhalant delivery devices, biolistic delivery devices, and the like.

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Abstract

La présente invention concerne de manière générale des copolymères diblocs et/ou triblocs amphiphiles et/ou des copolymères séquencés en étoile de matériaux biodégradables (par exemple, le PEG-b-PCL et le PEG-a-PCL) en tant que plates-formes d'administration de médicament ainsi que des méthodes de fabrication, d'évaluation, d'administration et de traitement de sujets correspondantes. Plus particulièrement, la présente invention concerne des copolymères et des conjugués copolymère-médicament de poly(éthylène glycol)-b-poly(ε-caprolactone) et de poly(éthylène glycol)-a-poly(ε-caprolactone), des agrégats et des ensembles supramoléculaires (par exemple, des micelles) ainsi que des méthodes sélectives pour associer une ou plusieurs substances médicamenteuses thérapeutiques (ou promédicaments) aux copolymères séquencés polymères.
PCT/US2020/062939 2019-12-03 2020-12-02 Plates-formes et méthodes d'administration de médicament peg polymère WO2021113397A1 (fr)

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Publication number Priority date Publication date Assignee Title
US20080299205A1 (en) * 2004-07-19 2008-12-04 Mayer Lawrence D Particulate Constructs For Release of Active Agents

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080299205A1 (en) * 2004-07-19 2008-12-04 Mayer Lawrence D Particulate Constructs For Release of Active Agents

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BERNABEU: "Paclitaxel: What has been done and what challenges remain ahead", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 526, 2017, pages 474 - 495, XP085057495, DOI: 10.1016/j.ijpharm.2017.05.016 *
HADDADI AZITA, JAHAN SHEIKH TASNIM: "Investigation and optimization of formulation parameters on preparation of targeted anti-CD205 tailored PLGA nanoparticles", INTERNATIONAL JOURNAL OF NANOMEDICINE, vol. 10, pages 7371 - 7384, XP055834654, DOI: 10.2147/IJN.S90866 *
HU JIAN, ZHANG MINGZU, HE JINLIN, NI PEIHONG: "Injectable hydrogels by inclusion complexation between a three-armed star copolymer (mPEG-acetal-PCL-acetal-) 3 and α-cyclodextrin for pH-triggered drug delivery", RSC ADVANCES, vol. 6, no. 47, 1 January 2016 (2016-01-01), pages 40858 - 40868, XP055834653, DOI: 10.1039/C6RA07420K *

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