Micellar nanocomplex

Patent metadata

Field	Value
Publication number	US-10052307-B2
Application number	US-201515309675-A
Country	US
Kind code	B2
Filing date	May 8, 2015
Priority date	May 9, 2014
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

The present invention relates to micellar nanocomplexes and a method of forming the same. The micellar nanocomplex comprises a micelle and an agent encapsulated within said micelle, where the micelle comprises a polymer-flavonoid conjugate, wherein said polymer is bonded to the B ring of said flavonoid. The micellar nanocomplex may have useful applications as a drug-delivery system.

First claim

The invention claimed is:

1. A micellar nanocomplex comprising a micelle and an agent encapsulated within said micelle, said micelle comprising a polymer-flavonoid conjugate, wherein said polymer is bonded to the B ring of said flavonoid.

2. The micellar nanocomplex of claim 1 , wherein at least one flavonoid is bonded to said polymer.

3. The micellar nanocomplex of claim 1 , wherein said polymer is bonded to said flavonoid via a linker.

4. The micellar nanocomplex of claim 3 , wherein said linker is selected from the group consisting of a thioether, imine, amine, azo and 1,2,3-triazole group.

5. The micellar nanocomplex of claim 1 , wherein said flavonoid is a monomeric flavonoid or a dimeric flavonoid.

6. The micellar nanocomplex of claim 2 , wherein when more than one flavonoid is present in said conjugate, at least one of the flavonoid is bonded to said polymer via the B ring.

7. The micellar nanocomplex of claim 6 , wherein the other of said at least one flavonoid is bonded to said polymer via the A ring.

8. The micellar nanocomplex of claim 1 , wherein said polymer is a hydrophilic polymer.

9. The micellar nanocomplex of claim 8 , wherein said hydrophilic polymer comprises monomers selected from the group consisting of acrylamides, alkyls, oxazolines, alkenyls, imines, acrylic acids, methacrylates, diols, oxiranes, alcohols, amines, anhydrides, esters, lactones, carbonates, carboxylic acids, acrylates, hydroxyls, phosphates, terephthalate, amides and ethers.

10. The micellar nanocomplex of claim 8 , wherein said hydrophilic polymer is selected from the group consisting of polyacrylamide, poly(N-isopropylacrylamide), poly(oxazoline), polyethylenimine, poly(acrylic acid), polymethacrylate, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidinone), polyethers, poly(allylamine), polyanhydrides, poly(β-amino ester), poly(butylene succinate), polycaprolactone, polycarbonate, polydioxanone, poly(glycerol), polyglycolic acid, poly(3-hydroxypropionic acid), poly(-hydroxyethyl methacrylate), poly(N-(2-hydroxypropyl)methacrylamide), polylactic acid, poly(lactic-co-glycolic acid), poly(ortho esters), poly(-oxazoline), poly(sebacic acid), poly(terephthalate-co-phosphate) and copolymers thereof.

11. The micellar nanocomplex of claim 8 , wherein said hydrophilic polymer is a polysaccharide.

12. The micellar nanocomplex of claim 8 , wherein said hydrophilic polymer is a polysaccharide selected from the group consisting of hyaluronic acid, dextran, pullulan, chitosan, cellulose, amylose, starch, gelatin, carrageenan, cyclodextrin, dextran sulfate, Ficoll, gellan, guar gum, pectin, polysucrose, pullulan, scleroglucan, xanthan, xyloglucan and alginate.

13. The micellar nanocomplex of claim 1 , wherein said flavonoid is selected from the group consisting of flavones, isoflavones, flavans, proanthocyanidins and anthocyanidins.

14. The micellar nanocomplex of claim 13 , wherein said flavans is selected from the group consisting of (−)-epicatechin, (+)-epicatechin, (−)-catechin, (+)-catechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, Fisetinidol, Gallocatechin, Gallocatechin gallate, Mesquitol and Robinetinidol, ellagitannin, gallotannin, oolongtheanin, phlorotannin, tannin, theacitrin, theadibenzotropolone, theaflavin, theanaphthoquinone, thearubigins, theasinensin and mixtures thereof.

15. The micellar nanocomplex of claim 1 , wherein said agent is a therapeutic agent.

16. The micellar complex of claim 15 , wherein said therapeutic agent is a chemotherapeutic agent selected from the group consisting of alkylating agents, anthracyclines, cytoskeletal disruptors, epothilones, histone deacetylase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, kinase inhibitors, monoclonal antibodies, antibody-drug conjugates, nucleotide analogs, precursor analogs, peptide antibiotics, platinum-based agents, retinoids, vinca alkaloids, cytokines, anti-metabolites, and vinca alkaloids derivatives, and other cytotoxics.

17. The micellar complex of claim 16 , wherein said chemotherapeutic agent is selected from the group consisting of Actinomycin, Afatinib, All-trans retinoic acid, Axitinib, Azacitidine, Azathioprine, Bevacizumab, Bleomycin, Bosutinib, Bortezomib, Carboplatin, Capecitabine, Cetuximab, Cisplatin, Chlorambucil, Crizotinib, Cyclophosphamide, Cytarabine, Dasatinib, Daunorubicin, Docetaxel, Doxifluridine, Doxorubicin, Epirubicin, Epothilone A (C26H39NO6S), Epothilone B (C27H41NO6S), Epothilone C (C26H39NO5S), Epothilone D (C27H41NO5S), Epothilone E (C26H39NO7S), Epothilone F (C27H41NO7S), Erlotinib, Etoposide, Fluorouracil, Fostamatinib, Gefitinib, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Irinotecan, Lapatinib, Lenvatinib, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Nilotinib, Oxaliplatin, Paclitaxel, Panitumumab, Pazopanib, Pegaptanib, Pemetrexed, Ranibizumab, Regorafenib, Ruxolitinib, Sorafenib, Sunitinib, Trastuzumab, Teniposide, Tioguanine, Tofacitinib, Topotecan, Valrubicin, Vemurafenib, Vinblastine, Vincristine, Vindesine, Vinorelbine.

18. The micellar nanocomplex of claim 1 , wherein said micellar nanocomplex has a size in the range of 30 to 300 nm, 50 to 300 nm, 100 to 300 nm, 30 to 50 nm, 30 to 100 nm, 30 to 150 nm, 150 to 300 nm, 200 to 300 nm, 250 to 300 nm, 100 to 150 nm, 100 to 200 nm, 100 to 250 nm, 130 to 180 nm, or 130 to 250 nm.

19. The micellar nanocomplex of claim 1 , wherein the loading efficiency of said agent present within said micelle is more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or 80%.

20. The micellar nanocomplex of claim 1 , wherein the loading content of said agent present within said micelle is in the range of 1 to 10 w/w %, 5 to 25 w/w %, 20 to 45 w/w %, 30 to 50 w/w %, 35 to 50 w/w %, 40 to 50 w/w %, 45 to 50 w/w %, 30 to 35 w/w %, 30 to 40 w/w % or 30 to 45 w/w %.

21. A method for forming a micellar nanocomplex comprising a micelle and an agent encapsulated within said micelle, the method comprising the steps of:
a. adding said agent in a suitable solvent to a polymer-flavonoid conjugate, wherein said polymer is bonded to the B ring of said flavonoid; and
b. allowing the self-assembly of a micelle comprising said polymer-flavonoid conjugate and encapsulation of said agent within said micelle to thereby form said micellar nanocomplex.

22. The method of claim 21 , wherein step (a) further comprises the steps of:
a. removing said solvent to form a dry film of said agent and said polymer-flavonoid conjugate; and
b. hydrating said dry film with an aqueous solvent.

23. The method of claim 21 , further comprising the step of isolating the formed micellar nanocomplex by filtration.

24. The method of claim 21 , wherein step (a) further comprises the step of dialysing the agent in a suitable solvent.

25. The micellar nanocomplex of claim 1 for treating a tumor.

Assignees

• Agency Science Tech & Res

Inventors

• Kurisawa Motoichi
• Nunnarpas Yongvongsoontorn
• Ying Jackie Y
• Chung Joo Eun
• Bae Ki Hyun
• Tan Min-Han
• Lee Esther

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• C08G65/3318

  heterocyclic · CPC title

• A61K47/60 Primary

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

• C08L1/02

  Cellulose; Modified cellulose · CPC title