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WO2016144637A1 - Conjugués de co-médicament à base d'ester oxyacétate de tocophéryle - Google Patents

Conjugués de co-médicament à base d'ester oxyacétate de tocophéryle Download PDF

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WO2016144637A1
WO2016144637A1 PCT/US2016/020398 US2016020398W WO2016144637A1 WO 2016144637 A1 WO2016144637 A1 WO 2016144637A1 US 2016020398 W US2016020398 W US 2016020398W WO 2016144637 A1 WO2016144637 A1 WO 2016144637A1
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compound
anticancer
acid
nanoparticles
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Ivan Alferiev
Michael Chorny
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Childrens Hospital of Philadelphia CHOP
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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • 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
    • A61K47/6905—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 colloid or an emulsion
    • A61K47/6907—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 colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
    • 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
    • A61K47/6937—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 the polymer being PLGA, PLA or polyglycolic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • the invention relates to co-drugs containing tocopheryloxyacetic acid esters of anticancer agents and antiproliferative agents.
  • TOA Tocopheryloxyacetic acid
  • mitochondria-targeting compounds from the bench to the bedside? Mol Nutr Food Res 2009; 53(1): 129- 139). It was synthesized and reported as a non-cleavable, hydrolytically stable analogue of tocopherol succinate, the best characterized compound in this series (Lawson KA et al. Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastasis. Mol Cancer Ther 2003;2:437-444).
  • tocopheryloxyacetic acid and other tocopherol derivatives show promise as anticancer and antiproliferative agents, enhancing their effects with pharmacologically complementary compounds and enabling their effective delivery in active form remains a challenge and improvements in this respect would be welcome.
  • the invention provides a compound including an ester of tocopheryloxyacetic acid with an anticancer or antirestenotic agent selected from the group consisting of SN38, paclitaxel, camptothecin, 7-ethylcamptothecin, etoposide, fenretinide, and lestaurtinib, wherein if the anticancer or antirestenotic agent includes at least two hydroxyl groups, the compound may optionally further include an ester group formed between a carboxylic acid and the anticancer or antirestenotic agent moiety in the compound.
  • an anticancer or antirestenotic agent selected from the group consisting of SN38, paclitaxel, camptothecin, 7-ethylcamptothecin, etoposide, fenretinide, and lestaurtinib, wherein if the anticancer or antirestenotic agent includes at least two hydroxyl groups, the compound may optionally further include an ester group formed between
  • the invention provides an oil-in-water nanoemulsion wherein the emulsified oily phase includes an oil having dissolved therein a compound as described above. In some embodiments, the invention provides a nanoparticle including a compound as described above.
  • the invention provides a method of treating a diagnosed medical condition in a patient, including administering to the patient one or more dosages of the compound, nanoparticles, dispersion of solid nanoparticles, or oil-in-water nanoemulsions described above, wherein the one or more dosages constitute an amount therapeutically effective to treat the medical condition.
  • FIG. 1 shows the effect of SN38 co-drug-loaded nanoparticles on IMR-32 neuroblastoma cell growth according to the invention, compared with the effect of free SN38, measured 7 days post-treatment.
  • FIG. 2 shows growth profiles of two neuroblastoma cell types, IMR-32 and BE(2)- C, treated for 24 hours with SN38 in co-drug-loaded nanoparticles according to the invention, compared with untreated cells and cells treated with free SN38 and with blank nanoparticles as controls.
  • FIG. 3 shows particle size distributions of small (85 nm) and large ( 160 nm) sized polylactide-based nanoparticles containing a D-a-tocopheryloxyacetic acid conjugate with paclitaxel according to the invention.
  • FIG. 4 shows the antiproliferative effect of 160 nm nanoparticles loaded with D-a- tocopheryloxyacetic acid conjugate with paclitaxel (PTX), according to the invention.
  • FIG. 5 shows the antiproliferative effect of 85 nm nanoparticles loaded with D-a- tocopheryloxyacetic acid conjugate with paclitaxel (PTX), according to the invention.
  • tocopheryloxyacetic acid is uniquely suited for creating rapidly activatable ester-linked co-drug conjugates with anticancer and/or antirestenotic agents having hydroxyl functions available for esterification, non-limiting examples of which include paclitaxel, camptothecin, 7-ethyl-lO-hydroxycamptothecin (SN38), 7-ethylcamptothecin (SN22), etoposide, fenretinide, and lestaurtinib.
  • the accelerated hydrolytic activation of such conjugates is a special property of the tocopheryloxyacetate esters that does not extend to other redox-silent tocopherol derivatives.
  • Conjugates of ⁇ , ⁇ , ⁇ and ⁇ -tocopheryloxyacetic acids (any one or more of these) with any hydroxy-functionalized anticancer or antirestenotic agent can be prepared analogously, for example using the methods disclosed in the Examples, and all of these compounds and their therapeutic uses are contemplated according to the invention.
  • esters based on tocopheryloxyacetic are the only ones enjoying both accelerated and directed hydrolytic activation, thereby providing a unique advantage when such esters are used in co-drug combinations with alcohols, such as paclitaxel, camptothecin, SN38, 7-ethylcamptothecin, CEP-701, fenretinide etc.
  • alcohols such as paclitaxel, camptothecin, SN38, 7-ethylcamptothecin, CEP-701, fenretinide etc.
  • This increased susceptibility to hydrolytic cleavage is essential for effectively outcompeting the breakdown of the chemically and metabolically unstable pharmacophores and for achieving quantitative recovery of the parent compounds.
  • the compound may optionally further comprise an ester group formed between a carboxylic acid and the anticancer or antirestenotic agent moiety in the compound.
  • PhBu-SN38-TOA shown in Scheme 2 below, where the conjugate of SN38 with tocopheryloxyacetic acid (“SIM38-TOA”) is in turn conjugated via its phenolic hydroxyl on the SN38 moiety with 4-phenylbutyric acid, a potent histone deacetylase inhibitor.
  • SIM38-TOA conjugate of SN38 with tocopheryloxyacetic acid
  • Another example is SN38-TOA conjugated to a macromolecule, for example a polycarboxylic acid macromolecule.
  • polyglutamate as shown in Scheme 4 below.
  • the polycarboxylic acid macromolecule may optionally be further esterified with one or more C1-C18 alcohols, which may be used singly or in any combination. If used, the C1-C18 alcohols will typically be linear primary alcohols.
  • Examples include methanol, ethanol, n-propanol, and n-butanol. Other examples include oleyl alcohol and stearyl alcohol.
  • tocopheryloxyacetic acid ester co-drugs stems from the increased lipophilicity associated with the tocol moiety (logP 0/w of conjugates several units higher compared to that of parent alcohol compounds), which makes the resultant derivatives particularly well-suited for incorporation into cell membranes or encapsulation and delivery in micro- or nanoparticles (NP), thus offering important advantages for treating cancer, arterial restenosis and other proliferative conditions.
  • this hydrophobizing effect may facilitate effective intratumoral accumulation and retention of the conjugate by enabling its stable association with cell membrane lipids or with particulate carriers, thus leading to substantially increased site-specificity of the pharmacological effect mediated by the two co-drug forming active moieties.
  • this hydrophobizing effect may facilitate effective intratumoral accumulation and retention of the conjugate by enabling its stable association with cell membrane lipids or with particulate carriers, thus leading to substantially increased site-specificity of the pharmacological effect mediated by the two co-drug forming active moieties.
  • regeneration of the two drug molecules exhibiting complementary antiproliferative activities can provide additive or synergistic effects, which in turn can translate into lower therapeutically effective doses, help reduce systemic exposure, and further minimize toxicity.
  • the tocopheryloxyacetic acid ester co-drugs may be present as nanoparticles in the form of a nanosuspension; i.e., a suspension in an aqueous medium where the suspended nanoparticles are colloidally stabilized, for example via an ionic or steric stabilizer (e.g., albumin), but in which the nanoparticles do not include a water-insoluble matrix material in addition to the drug substance.
  • a nanosuspension i.e., a suspension in an aqueous medium where the suspended nanoparticles are colloidally stabilized, for example via an ionic or steric stabilizer (e.g., albumin), but in which the nanoparticles do not include a water-insoluble matrix material in addition to the drug substance.
  • the nanoparticles may additionally include a water-insoluble matrix material, provided that it is biodegradable or bioeliminable, IMonlimiting examples include aliphatic polyesters (e.g ., polylactides and copolymers thereof) and aliphatic polyanhydrides.
  • Exemplary matrix materials include poly(D,L-lactide), poly(D,L-lactide)- poly(ethylene glycol) block copolymer, poly(L-lactide), poly(L-lactide)-poly(ethylene glycol) block copolymer, poly(epsilon-caprolactone), poly(epsilon-caprolactone)- poly(ethylene glycol) block copolymer, poly(lactide-co-glycolide), and poly(lactide-co- glycolide)-poly(ethylene glycol) block copolymer.
  • the term "nanoparticle” means a particle whose largest linear dimension is less than 1000 nm.
  • the nanoparticles are approximately spherical and the largest linear dimension is therefore the diameter.
  • the nanoparticles typically have an average diameter less than 200 nm, or less than 150 nm, or less than 100 nm, or less than 75 nm.
  • the average diameter is at least 10 nm, or at least 20 nm, or at least 40 nm.
  • the tocopheryloxyacetic acid ester co-drugs may be present in the oil phase of colloidally stable oil-in-water emulsions, particularly nanoemulsions (i.e., particles less than 1 Mm diameter).
  • the co-drug may be dissolved in an oil, thus forming the dispersed internal oily phase of the emulsion.
  • oils can be suitable for dissolving the co-drug, with non-limiting examples being tocopherols (alpha, beta, gamma, delta), tocopherol acetate (also a liquid, but less susceptible to oxidation than tocopherols, thus offering improved stability and longer shelf-life), triolein (glycerol trioleate), and other biocompatible oils suitable for parenteral administration.
  • Suitable nanoemulsions can be prepared using methods known in the art, for example solvent displacement.
  • D-a-tocopheryloxyacetic acid was prepared from D-a-tocopherol and ethyl bromoacetate by the method of Karla A. Lawson, Kristen Anderson, Maria Menchaca, Jeffrey Atkinson, LuZhe Sun, Vernon Knight, Brian E. Gilbert, Claudio Conti, Bob G. Sanders, and Kimberly Kline. Molecular Cancer Therapeutics Vol. 2, 437-444, May
  • Conjugate (1) of D-a-tocopheryloxyacetic acid with SN38 at the 20-OH position was prepared by direct coupling of 10-Boc-SN38 with D-a-tocopheryloxyacetic acid, as shown
  • Triple conjugate (3) of D-g-tocopheryloxyacetic acid and 4-phenylbutyric acid with SIM38 Triple conjugate (3) of D-o-tocopheryloxyacetic acid and 4-phenylbutyric acid with SN38 was prepared by acylation of SN38 at the 10-OH position with 4-phenylbutyric acid, followed by similar acylation at the 20-OH position in the intermediate 4 with D-o- tocopheryloxyacetic acid, as shown in Scheme 2.
  • D-a-tocopheryloxyacetic acid 165 mg, 0.34 mmol
  • fenretinide 113 mg, 0.29 mmol
  • DPTS catalyst 113 mg, 0.38 mmol
  • Conjugate (1) was attached by its phenolic OH to poly-L-glutamic acid via ester bonds as shown in Scheme 4, and the unreacted carboxylic groups on the polymer were then esterified with ethanol .
  • conjugate (1) 169 mg, 0.19 mmol
  • DPTS catalyst 92 mg
  • Biodegradable PEGylated nanoparticles suitable for intravenous administration of SN38 tocopheryloxyacetate-based co-drugs were prepared using a nanoprecipitation method optimized for producing sub- 100 nm sized particulates.
  • Ten mg of the conjugate, 20 mg of PLURONIC® F-68 surfactant and 200 mg of poly(D,L-lactide)-poly(ethylene g lycol) block copolymer ( 15 kDa : 5 kDa) were dissolved in 12 mL of organic solvent (acetone and tetrahydrofuran for SN38-TOA and PolyG(SN38-TOA), respectively) .
  • the co-drugs were assayed spectrophotometrically against suitable calibration cu rves after nanoparticle dilution with aqueous sodium chloride (5 N) and two-step extraction in 2-butanol or a 1 : 1 : 1 mixture of n-octanol, sec-butanol and acetonitrile, respectively.
  • the co-drug loadings in the nanoparticle formulations were found to be 1.50 and 1.42 mg/mL, respectively.
  • the particle size determined by dynamic light scattering was 80-90 nm.
  • Nanoemulsion of SN22-TOA dissolved in D-alpha-tocopherol A tocopherol-based nanoemulsion with a 100-nm droplet size containing 7- ethylcamptothecin tocopheryloxyacetate (SN22-TOA) was prepared using a modification of the solvent displacement method. Ten mg of the conjugate, 40 mg of PLURONIC® F- 68 surfactant and 100 mg of D-alpha-tocopherol were dissolved in a mixture of 8 mL of acetone and 12 mL ethanol (alternatively, 20 mL ethanol without acetone could also be used). The organic phase was rapidly added to 50 mL of water with magnetic stirring.
  • the mixture was transferred into an evaporation flask, and the solvents were removed by gradually reducing the pressure from 120 mbar to 40 mbar at 30°C.
  • the formulation was additionally concentrated, glucose was added to the nanoparticle suspension at 5% w/v to adjust the tonicity, and the volume was brought to 5.0 mL.
  • the resulting nanoemulsion was sterilized by passing it through a 0.22 ⁇ filter unit.
  • the co-drug was assayed spectrophotometrically against a suitable calibration curve after dilution with aqueous sodium chloride (5 N) and two-step extraction in 2- butanol.
  • the co-drug loading was found to be 1.8-2.2 mg/mL, respectively.
  • the emulsion droplet size determined by dynamic light scattering was 100-130 nm.
  • a luciferase-based method was applied to longitudinally study the effect of the SN38 co-drug-loaded nanoparticles on neuroblastoma cell growth.
  • neuroblastoma IMR-32 cells (a cell line that has features characteristic of high-risk neuroblastoma including MYCN amplification and chromosome lp deletion) were seeded on day -1 on 96-well plates at 40,000 cells per well. On day 0, the cells were incubated with indicated doses of free SN38 (plate 1), blank NP (plate 2), NP loaded with SN38- TOA or NP loaded with PolyG(SN38-TOA) diluted in culture medium. Blank NP were applied as a control at doses equivalent to those of co-drug-loaded NP. After the indicated exposure time, the medium was replaced with fresh culture medium containing 100 Mg/mL of luciferin.
  • FIG. 2 Growth profiles of two neuroblastoma cell types, IMR-32 and BE(2)-C treated for 24 hours with 25 ng/well equivalent dose of SN38 in co-drug-loaded NP or free SN38 compared to untreated cells and blank NP controls are shown in FIG. 2. While the less proliferative cell line BE(2)-C was not responsive to NP loaded with PolyG(SN38-TOA), marked growth inhibition was observed with NP loaded with SN38-TOA for both cell types. Formulation of small (85 nm) and large ( 160 nm) sized polylactide-based nanoparticles containing D-a-tocopheryloxyacetic acid conjugate with paclitaxel
  • Biodegradable NP for intra-arterial delivery of paclitaxel tocopheryloxyacetate co- drug were prepared using a nanoprecipitation protocol optimized for producing differently sized submicronial particles.
  • Ten mg of the conjugate, 100 of mg poly(D,L- lactide) (Mw 63 kDa) and 40 mg PLURONIC® F-68 surfactant were dissolved in a) 10 mL of acetone followed by 10 mL of ethanol after complete dissolution of the components, or b) 8 mL of acetone for making small (85 nm) and large ( 160 nm) NP, respectively.
  • the organic solutions were quickly added to 50 mL of water with magnetic stirring.
  • the resultant mixture was transferred into an evaporation flask, and the solvents were removed by gradually reducing the pressure from 125 mm to 40 mm Hg, 30°C.
  • the formulation was additionally concentrated, glucose was added to the nanoparticle suspension at 5% w/v to adjust the tonicity, and the volume was brought to 5.0 mL.
  • the resulting nanoparticles were sterilized by passing them through a 0.22 pm filter unit.
  • the particle sizes as determined by dynamic light scattering are depicted in FIG. 3.
  • the co-drug content was assayed spectrophotometrically against a suitable calibration curve after nanoparticle dilution with aqueous sodium chloride (5 N) and two- step extraction in 2-butanol.
  • the co-drug loadings in the 85- and 160-nm sized nanoparticle formulations were found to be 960 and 860 pg/mL, respectively.
  • Inhibition of vascular smooth muscle cell proliferation contributing to intimal hyperplasia can potentially prevent injury-triggered arterial renarrowing (restenosis) and significantly improve the outcomes of angioplasty procedures used clinically to reopen obstructed blood vessels.
  • permeability and retention of NP in the injured arterial wall is a promising approach of achieving sustained therapeutically adequate local drug levels while minimizing systemic drug exposure.
  • PTX-TOA D-o-tocopheryloxyacetic acid conjugate with paclitaxel
  • paclitaxel equivalent doses of the co-drug-loaded NP diluted in cell culture medium DMEM supplemented with 2% fetal bovine serum and 40 ng per mL of platelet-derived growth factor BB for 1 hr, 4 hr and 24 hr. Blank NP applied at equivalent doses were used as controls. At the end of the incubation period, NP were removed and the cells were incubated under fresh culture medium. Cell viability was determined using the Alamar Blue assay 8 days after treatment. The results, shown in FIG. 4 (160 nm NP) and FIG. 5 (85 nm NP), indicate exposure time-dependent, extensive A10 cell growth inhibition by paclitaxel tocopheryloxyacetate-loaded NP, with a stronger antiproliferative effect exhibited by smaller sized NP.

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Abstract

L'invention concerne un composé comprenant un ester d'acide tocophéryloxyacétique avec un agent anticancéreux ou antiresténose choisi dans le groupe constitué de SN38, du paclitaxel, de la camptothécine, de la 7-éthylcamptothécine, de l'étoposide, du fenrétinide et du lestaurtinib. Si l'agent comprend au moins deux groupes hydroxyle, le composé peut éventuellement comprendre en outre un groupe ester formé entre un acide carboxylique et la partie agent anticancéreux ou antiresténose dans le composé. Le médicament peut se présenter sous la forme d'une nanoparticule. L'invention concerne une nanoémulsion huile dans l'eau constituée d'une phase huileuse émulsionnée qui comprend une huile dans laquelle est dissous un composé décrit ci-dessus. L'invention concerne un procédé de traitement d'une pathologie diagnostiquée chez un patient, qui comprend l'administration au patient d'une ou plusieurs doses du composé, de nanoparticules, d'une dispersion de nanoparticules solides ou de nanoémulsions huile-dans-l'eau décrits ci-dessus, dans lesquels la ou les doses constituent une quantité thérapeutiquement efficace pour traiter la pathologie.
PCT/US2016/020398 2015-03-06 2016-03-02 Conjugués de co-médicament à base d'ester oxyacétate de tocophéryle Ceased WO2016144637A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018169934A1 (fr) 2017-03-14 2018-09-20 The Children's Hospital Of Philadelphia Esters clivables pour une thérapie anticancéreuse basée sur des nanovecteurs
WO2024042043A1 (fr) 2022-08-24 2024-02-29 Boehringer Ingelheim International Gmbh Procédé évolutif pour la préparation d'un inhibiteur de glyt-1
US12441707B2 (en) 2019-12-30 2025-10-14 Tyra Biosciences, Inc. Indazole compounds

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Publication number Priority date Publication date Assignee Title
US20110105437A1 (en) * 2008-03-14 2011-05-05 Stephen John Ralph Mitochondrially Delivered Anti-Cancer Compounds
US20130296285A1 (en) * 2010-12-28 2013-11-07 The Childrens Hospital Of Philadelphia Design of Hydrolytically Releasable Prodrugs for Sustained Release Nanoparticle Formulations
WO2013188727A2 (fr) * 2012-06-15 2013-12-19 The Children's Hospital Of Philadelphia Nouveaux dérivés pro- et co-médicaments pour la délivrance par nanoparticules d'agents anticancer sélectionnés, formés en utilisant des ponts esters phénoliques rapidement clivables

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Publication number Priority date Publication date Assignee Title
US20110105437A1 (en) * 2008-03-14 2011-05-05 Stephen John Ralph Mitochondrially Delivered Anti-Cancer Compounds
US20130296285A1 (en) * 2010-12-28 2013-11-07 The Childrens Hospital Of Philadelphia Design of Hydrolytically Releasable Prodrugs for Sustained Release Nanoparticle Formulations
WO2013188727A2 (fr) * 2012-06-15 2013-12-19 The Children's Hospital Of Philadelphia Nouveaux dérivés pro- et co-médicaments pour la délivrance par nanoparticules d'agents anticancer sélectionnés, formés en utilisant des ponts esters phénoliques rapidement clivables

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018169934A1 (fr) 2017-03-14 2018-09-20 The Children's Hospital Of Philadelphia Esters clivables pour une thérapie anticancéreuse basée sur des nanovecteurs
CN110691605A (zh) * 2017-03-14 2020-01-14 费城儿童医院 用于基于纳米载体的癌症治疗的可裂解酯
EP3595697A4 (fr) * 2017-03-14 2020-11-18 The Children's Hospital of Philadelphia Esters clivables pour une thérapie anticancéreuse basée sur des nanovecteurs
US11633485B2 (en) 2017-03-14 2023-04-25 The Children's Hospital Of Philadelphia Cleavable esters for nanocarrier-based cancer therapy
US12441707B2 (en) 2019-12-30 2025-10-14 Tyra Biosciences, Inc. Indazole compounds
WO2024042043A1 (fr) 2022-08-24 2024-02-29 Boehringer Ingelheim International Gmbh Procédé évolutif pour la préparation d'un inhibiteur de glyt-1

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