Process for Preparing Stealth Nanoparticles

Patent metadata

Field	Value
Publication number	US-2016129132-A1
Application number	US-201414894495-A
Country	US
Kind code	A1
Filing date	May 28, 2014
Priority date	May 28, 2013
Publication date	May 12, 2016
Grant date	—

Abstract

A process for the preparation of targeting nanoparticles of a poly(alkyl cyanoacrylate) homopolymer or copolymer, wherein said method comprises, in a single step, the anionic polymerisation of an oil-in-water miniemulsion as herein defined. The invention also relates to nanoparticles produced from said process and to their use in medicine.

First claim

1 - 18 . (canceled)

19 . A process for the preparation of targeting nanoparticles of a poly(alkyl cyanoacrylate) homopolymer or copolymer, wherein said method comprises, in a single step, the anionic polymerisation of an oil-in-water miniemulsion, wherein said miniemulsion comprises:
(i) at least one alkyl cyanoacrylate monomer; (ii) at least two polyalkylene glycols selected from the group consisting of polyethylene glycols (PEG) and polypropylene glycols (PPG) or mixtures thereof, wherein at least one of said polyalkylene glycols is covalently attached to a targeting moiety; and (iii) optionally one or more active agents.

20 . A process for the preparation of targeting nanoparticles of a poly(alkyl cyanoacrylate) homopolymer or copolymer, wherein said method comprises adding at least two polyalkylene glycols selected from the group consisting of polyethylene glycols (PEG) and polypropylene glycols (PPG) or mixtures thereof, to an oil-in-water miniemulsion, wherein said miniemulsion comprises
(i) at least one alkyl cyanoacrylate monomer; and (ii) optionally one or more active agents; and polymerising the resulting mixture by anionic polymerisation.

21 . The process as claimed in claim 19 , wherein said miniemulsion is prepared by the addition of said at least two polyalkylene glycols to an oil-in water miniemulsion comprising said at least one alkyl cyanoacrylate monomer and optionally said one or more active agents.

22 . The process as claimed claim 21 , wherein at least one of said polyalkylene glycols initiates the anionic polymerisation reaction.

23 . The process as claimed in claim 22 wherein said nanoparticles are stealth nanoparticles.

24 . The process as claimed in claim 21 , wherein said miniemulsion further comprises a radically polymerisable crosslinker, preferably an anhydride or an acrylate.

25 . The process as claimed in claim 21 , wherein said at least one cyanoacrylate monomer is selected from the group consisting of ethyl cyanoacrylate, butyl cyanoacrylate, isohexyl cyanoacrylate, octyl cyanoacrylate and derivatives and mixtures thereof.

26 . The process as claimed in claim 21 , wherein at least one of the polyalkylene glycols is a polyethylene glycol, optionally further comprising a hydrophobic component, e.g. polypropylene oxide component.

27 . The process of claim 26 , wherein at least one of the polyethylene glycols is a block copolymer of a polyethylene glycol and polypropylene glycol and wherein preferably said copolymer comprises a hydroxy or amino end group attached to a polypropylene oxide block.

28 . The process of claim 21 wherein the targeting moieties are selected from the group consisting of peptides, miniproteins, antibody fragments, affibody molecules, nanobodies and aptamers.

29 . The process of claim 21 , wherein the targeting moieties are selected from the group consisting of peptides, antibody fragments, affibody molecules, nanobodies and aptamers.

30 . The process of claim 21 wherein the active agent is a therapeutic agent and is preferably docetaxel, cabazitaxel, paclitaxel, 5-fluorouracil, sorafenib, AMG900, temsirolimus or everolimus.

31 . The process of any claim 21 wherein the active agent is carboplatin, oxaliplatin, picoplatin, tetraplatin, satraplatin, cisplatin, platinum-DACH or ormaplatin.

32 . The process of claim 21 wherein the active agent is an imaging agent and is preferably selected from the group consisting of metals, metal salts, near infrared dyes, fluorescent dyes, PET/SPECT chelating agents, agents suitable for MRI or Raman spectroscopy and radiopharmaceuticals.

33 . A targeting nanoparticle of a poly(alkyl cyanoacrylate) homopolymer or copolymer manufactured by the anionic polymerisation of an oil-in-water miniemulsion, wherein said miniemulsion comprises
(i) at least one alkyl cyanoacrylate monomer; (ii) at least two polyalkylene glycols selected from the group consisting of polyethylene glycols (PEG) and polypropylene glycols (PPG) or mixtures thereof, wherein at least one of said polyalkylene glycols is covalently attached to a targeting moiety; and (iii) optionally one or more active agents.

34 . The targeting molecule of claim 33 :
wherein said miniemulsion is prepared by the addition of said at least two polyalkylene glycols to an oil-in water miniemulsion comprising said at least one alkyl cyanoacrylate monomer and optionally said one or more active agents; wherein at least one of said polyalkylene glycols initiates the anionic polymerisation reaction; wherein said nanoparticles are stealth nanoparticles; wherein said miniemulsion further comprises a radically polymerisable crosslinker, preferably an anhydride or an acrylate; wherein said at least one cyanoacrylate monomer is selected from the group consisting of ethyl cyanoacrylate, butyl cyanoacrylate, isohexyl cyanoacrylate, octyl cyanoacrylate and derivatives and mixtures thereof; wherein at least one of the polyalkylene glycols is a polyethylene glycol, optionally further comprising a hydrophobic component, e.g. polypropylene oxide component; wherein the targeting moieties are selected from the group consisting of peptides, miniproteins, antibody fragments, affibody molecules, nanobodies and aptamers; wherein the targeting moieties are selected from the group consisting of peptides, antibody fragments, affibody molecules, nanobodies and aptamers; wherein the active agent is a therapeutic agent and is preferably docetaxel, cabazitaxel, paclitaxel, 5-fluorouracil, sorafenib, AMG900, temsirolimus or everolimus; the active agent is carboplatin, oxaliplatin, picoplatin, tetraplatin, satraplatin, cisplatin, platinum-DACH or ormaplatin; the active agent is an imaging agent and is preferably selected from the group consisting of metals, metal salts, near infrared dyes, fluorescent dyes, PET/SPECT chelating agents, agents suitable for MRI or Raman spectroscopy and radiopharmaceuticals.

35 . The targeting nanoparticle of claim 35 wherein said miniemulsion further comprises a radically polymerisable crosslinker, preferably an anhydride or an acrylate.

36 . The targeting nanoparticles of claim 35 wherein at least one of the polyethylene glycols is a block copolymer of a polyethylene glycol and polypropylene glycol and wherein preferably said copolymer comprises a hydroxy or amino end group attached to a polypropylene oxide block.

37 . A pharmaceutical composition comprising a targeting nanoparticle as defined in claim 34 and one or more pharmaceutically acceptable carriers, diluents or excipients.

38 . A targeting nanoparticle as defined in claim 34 for use in drug delivery or molecular imaging.

Assignees

• Sintef Tto As
• Sinvent As

Inventors

• Schmid Ruth
• Stenstad Per
• Morch Yrr
• Johnsen Heidi

Classifications

• A61K9/5192

  Processes · CPC title

• A61K47/585

  Ion exchange resins, e.g. polystyrene sulfonic acid resin · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K9/5138

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K9/5146

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title