Nanospheres for therapeutic agent delivery

• US 9,724,304 B2
• Filed: 06/14/2013
• Issued: 08/08/2017
• Est. Priority Date: 06/14/2012
• Status: Active Grant

• Current Assignee: Temple University of The Commonwealth System of Higher Education
• Original Assignee: Temple University of The Commonwealth System of Higher Education
• Inventors: Wong, Ho Lun, Narvekar, Mayuri, Xue, Hui Yi
• Primary Examiner(s): ZISKA, SUZANNE E
• Application Number:
  US13/918,019
• Publication Number:
  US 20130337077A1
• Time in Patent Office: 1,516 Days
• CPC Class Codes: A61K 31/203 Retinoic acids ; Salts thereof
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)

Abstract

Provided is a nanosphere for delivery of a therapeutic agent comprising: a polymer matrix; discrete liquid oil droplets dispersed in the polymer matrix; and a therapeutic agent dissolved or dispersed in the oil. In some embodiments, the nanosphere is pegylated. In some embodiments, the nanosphere has a diameter of from about 100 nm to about 300 nm. In further preferred embodiments, the nanosphere has a diameter of from about 150 nm to about 250 nm. In yet further embodiments, the nanosphere has a diameter of from about 180 nm to about 220 nm. In some embodiments, the oil comprises a lipid or a phospholipid. In further embodiments, the lipid or the phospholipid has a melting point below 20° C. In some embodiments, the polymer is a natural, modified or synthetic polymer. In further embodiments, the polymer is biodegradable.

Claims

1. A nanosphere for delivery of a therapeutic agent comprising:

a polymer matrix;

discrete liquid oil droplets dispersed in the polymer matrix; and

a therapeutic agent dissolved or dispersed in the oil droplets.

2. The nanosphere of claim 1 wherein said nanosphere is pegylated.

3. The nanosphere of claim 1 wherein said nanosphere has a diameter of from about 100 nm to about 300 nm.

4. The nanosphere of claim 1 wherein said oil comprises a lipid or a phospholipid.

5. The nanosphere of claim 1 wherein said oil is selected from the group consisting of palmitoleic acid, oleic acid, linoleic acid, α

-linoleic acid, arachidonic acid, propylene glycol monocaprylate, propylene glycol dicaprylate, propylene glycol dicaprate, glycerol monocaprate and glycerol monooleate.

6. The nanosphere of claim 4 wherein said lipid or said phospholipid has a melting point below 20°

C.

7. The nanosphere of claim 1 wherein said polymer is a natural, modified or synthetic polymer.

8. The nanosphere of claim 1 wherein said polymer is biodegradable.

9. The nanosphere of claim 1 wherein said polymer is selected from the group consisting of a polylactic acid polymer, a polyglycolic acid polymer, a poly(lactic-co-glycolic acid) copolymer, an acrylic polymer, a polyhydroxyalkanoate polymer, a polyethylenimine polymer, an acrylamide polymer and a chitosan polymer.

10. The nanosphere of claim 1 wherein said therapeutic agent is a poorly water soluble drug.

11. The nanosphere of claim 10 wherein said poorly water soluble drug is an antineoplastic agent, a steroidal hormone, a sex hormone, an anti-fungal drug, an anti-viral drug, an antibiotic, an opioid agonist, an opioid antagonist, a calcium channel blocker, an antiangiogenic drug, a diagnostic compound, a vitamin or a cosmetic compound.

12. The nanosphere of claim 1 wherein said therapeutic agent is interferon, macrophage activation factor, an interleukin, colony stimulating factor, tumor degenerating factor, epidermal growth factor, erythropoietin, tissue plasminogen activator, insulin, luteinizing hormone releasing hormone, an enzyme, a vaccine or an antibody.

13. The nanosphere of claim 12 wherein said enzyme is urokinase or superoxide dismutase.

14. The nanosphere of claim 1 wherein said nanosphere is prepared by emulsion-solvent evaporation of a solvent for said polymer.

15. A method for preparing a nanosphere according to claim 1 comprising the steps of:

dissolving or dispersing a therapeutic agent in an oil;

adding a solvent for the therapeutic agent and the oil to form a solution;

adding a polymer to said solution with mixing to form a mixture;

adding said mixture to a solvent for the polymer with mixing; and

evaporating the solvent for the polymer to obtain a nanosphere comprising said therapeutic agent dissolved or dispersed in discrete liquid oil droplets dispersed in a matrix formed by said polymer.

16. The method of claim 15 wherein said solvent for the polymer is an alcohol.

17. The method of claim 15 wherein said nanosphere has a diameter of from about 100 nm to about 300 nm.

18. The method of claim 15 wherein said oil comprises a lipid or a phospholipid.

19. The method of claim 18 wherein said lipid or said phospholipid has a melting point below 20°

C.

20. The method of claim 15 wherein said polymer comprises a natural, modified or synthetic polymer.

21. The method of claim 15 wherein said polymer is biodegradable.

22. The method of claim 15 wherein said therapeutic agent is a poorly water soluble drug.

23. The method of claim 22 wherein said poorly water soluble drug is an antineoplastic agent, a steroidal hormone, a sex hormone, an anti-fungal drug, an anti-viral drug, an antibiotic, an opioid agonist, an opioid antagonist, a calcium channel blocker, an antiangiogenic drug, a diagnostic compound, a vitamin or a cosmetic compound.

24. The method of claim 15 wherein said therapeutic agent is interferon, macrophage activation factor, an interleukin, colony stimulating factor, tumor degenerating factor, epidermal growth factor, erythropoietin, tissue plasminogen activator, insulin, luteinizing hormone releasing hormone, an enzyme, a vaccine or an antibody.

25. The method of claim 24 wherein said enzyme is urokinase or superoxide dismutase.

26. The nanosphere of claim 1 wherein the glass transition temperature of the nanosphere is lower than that of the polymer matrix alone.

27. The nanosphere of claim 1 wherein said nanosphere is amorphous.

28. The method of claim 15 wherein the glass transition temperature of the nanosphere is lower than that of the polymer matrix alone.

29. The method of claim 15 wherein said nanosphere is amorphous.