Semi-fluorinated block copolymers for delivery of therapeutic agents

• US 8,900,562 B2
• Filed: 01/10/2008
• Issued: 12/02/2014
• Est. Priority Date: 01/12/2007
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Mecozzi, Sandro, Kwon, Glen S.
• Primary Examiner(s): ROGERS, JAMES WILLIAM
• Application Number:
  US11/972,061
• Publication Number:
  US 20080194500A1
• Time in Patent Office: 2,518 Days
• Field of Search: 424/78.08, 424/78.17, 424/78.37
• US Class Current: 424/78.17
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/395 having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
• CPC Class Codes: A61K 31/4353 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 8/90 Block copolymers A61K8/89 takes precedence
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: C08L 2666/02 Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 51/003 grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds C08L51/04, C08L51/06 take precedence
• CPC Class Codes: C08L 53/00 Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers

Abstract

The present invention provides semi-fluorinated block copolymers and related methods of synthesizing and using semi-fluorinated block copolymers for drug delivery and drug formulation applications. Semi-fluorinated block copolymers of this aspect of the invention include block copolymers having discrete hydrophilic, fluorophilic and hydrophobic structural domains that are capable of forming supramolecular structures in aqueous solutions, such as micelles, for encapsulating hydrophobic and/or fluorophilic therapeutic agents. Encapsulation by semi-fluorinated block copolymers of the present invention allows for enhanced solubilization and stabilization of hydrophobic and/or fluorophilic therapeutic agents relative to conventional drug delivery compositions and methods.

Claims

1. A therapeutic formulation for delivering a hydrophobic drug or fluorophilic therapeutic agent to a patient, said formulation comprising:

said hydrophobic drug or fluorophilic therapeutic agent; and

semi-fluorinated block copolymers, wherein each of said semi-fluorinated block copolymers comprises a hydrophilic block, a fluorophilic block, and a hydrophobic group;

wherein said fluorophilic block of each of said semi-fluorinated block copolymers is positioned between said hydrophilic block and said hydrophobic group,

wherein said hydrophobic group is a distearoyl-glycero-phosphoethanolamine;

wherein said hydrophilic block is a poly(ethylene glycol) block having a molecular weight selected over the range of 1000 g mol−

1 to 12,000 g mol−

1; and

wherein said fluorophilic block is a perfluorinated alkyl chain having a length of 6 to 20 carbons.

2. The therapeutic formulation of claim 1 wherein said perfluorinated alkyl chain has between 12 to 40 carbon-fluorine bonds.

3. The therapeutic formulation of claim 1 wherein said perfluorinated alkyl chain has a length of 8 carbons.

4. The therapeutic formulation of claim 1 wherein said hydrophilic block is a poly(ethylene glycol) block having a molecular weight of 5000 g mol⁻

1.

5. The therapeutic formulation of claim 1 wherein said hydrophobic group is 1,2-distearoyl-S,N-glycero-3-phosphoethanolamine.

6. The therapeutic formulation of claim 1 wherein said semi-fluorinated block copolymers have the chemical formula:

7. The therapeutic formulation of claim 6 wherein said semi-fluorinated block copolymers have the chemical formula:

8. The therapeutic formulation of claim 1 wherein said hydrophobic drug is paclitaxel, rapamycin, geldanamycin, doxorubicin, or amophotericin-B.

9. The therapeutic formulation of claim 1 wherein said hydrophobic drug is functionalized via addition of a fluorophilic group.

10. The therapeutic formulation of claim 1 further comprising an aqueous solution.

11. The therapeutic formulation of claim 1 wherein said semi-fluorinated block copolymers self assemble in aqueous solution to form a supramolecular structure that at least partially encapsulates said hydrophobic drug.

12. The therapeutic formulation of claim 11 wherein said supramolecular structure is selected from the group consisting of a micelle, a vesicle, a bilayer, a folded sheet and a tubular micelle.

13. The therapeutic formulation of claim 11 wherein said supramolecular structure has an interior hydrophobic core comprising hydrophobic groups of said semi-fluorinated block copolymers, an intermediate fluorophilic portion comprising fluorophilic blocks of said semi-fluorinated block copolymers and an exterior hydrophilic portion comprising hydrophilic blocks of said semi-fluorinated block copolymers;

wherein said hydrophilic portion is separated from said hydrophobic core by said intermediate fluorophilic portion.

14. The therapeutic formulation of claim 13 wherein said hydrophobic drug encapsulated by said supramolecular structure is provided in said hydrophobic core, in said intermediate fluorophilic portion or in both said hydrophobic core and intermediate fluorophilic portion supramolecular structure.

15. The therapeutic formulation of claim 1 wherein said semi-fluorinated block copolymers have a critical micelle concentration less than or equal to 1 μ

M.

16. The therapeutic formulation of claim 11 wherein said supramolecular structure has a cross sectional physical dimension selected over the range of about 10 nanometers to about to about 100 nanometers.

22. The therapeutic formulation of claim 1 wherein said hydrophobic drug is Paclitaxel.

23. The therapeutic formulation of claim 1 wherein said hydrophobic drug is Rapamycin.

24. The therapeutic formulation of claim 1 wherein said hydrophobic drug is 17-AAG.

25. The therapeutic formulation of claim 1 wherein said hydrophobic drug is Amphotericin B.

17. A method of administering a hydrophobic drug or fluorophilic therapeutic agent to a patient in need of treatment;

said method comprising the steps of;

providing a therapeutic formulation comprising

said hydrophobic drug or fluorophilic therapeutic agent,

and semi-fluorinated block copolymers in an aqueous solution, wherein each of said semi-fluorinated block copolymers comprise a hydrophilic block, a fluorophilic block, and a hydrophobic group;

wherein said fluorophilic block of each of said semi-fluorinated block copolymers is positioned between said hydrophilic block and said hydrophobic group,

wherein said hydrophobic group is 1,2-distearoyl-S,N-glycero-3-phosphoethanolamine;

wherein said hydrophilic block is a poly(ethylene glycol) block having a molecular weight selected over the range of 1000 g mol−

1 to 12,000 g mol−

1; and

wherein said fluorophilic block is a perfluorinated alkyl chain having a length of 6 to 20 carbons; and

delivering said therapeutic formulation to said patient.

18. A method of solubilizing a hydrophobic drug or fluorophilic therapeutic agent, said method comprising the steps of:

providing said hydrophobic drug or fluorophilic therapeutic agent,

and semi-fluorinated block copolymers in an aqueous solution, wherein each of said semi-fluorinated block copolymers comprises a hydrophilic block, a fluorophilic block, and a hydrophobic group;

wherein said fluorophilic block of each of said semi-fluorinated block copolymers is positioned between said hydrophilic block and said hydrophobic group,

wherein said hydrophobic group is 1,2-distearoyl-S,N-glycero-3-phosphoethanolamine;

wherein said hydrophilic block is a poly(ethylene glycol) block having a molecular weight selected over the range of 1000 g mol−

1 to 12,000 g mol−

1; and

wherein said fluorophilic block is a perfluorinated alkyl chain having a length of 6 to 20 carbons; and

wherein said semi-fluorinated block copolymers self assemble in said aqueous solution to form a supramolecular structure that at least partially encapsulates said hydrophobic drug or fluorophilic therapeutic agent, thereby solubilizing said hydrophobic drug or fluorophilic therapeutic agent.

19. A method of decreasing the toxicity of a hydrophobic drug or fluorophilic therapeutic agent, said method comprising the steps of:

providing said hydrophobic drug or fluorophilic therapeutic agent, and semi-fluorinated block copolymers in an aqueous solution, wherein each of said semi-fluorinated block copolymers comprises a hydrophilic block, a fluorophilic block, and a hydrophobic group;

wherein said fluorophilic block of each of said semi-fluorinated block copolymers is positioned between said hydrophilic block and said hydrophobic group,

wherein said hydrophobic group is 1,2-distearoyl-S,N-glycero-3-phosphoethanolamine;

wherein said hydrophilic block is a poly(ethylene glycol) block having a molecular weight selected over the range of 1000 g mol−

1 to 12,000 g mol−

1; and

wherein said fluorophilic block is a perfluorinated alkyl chain having a length of 6 to 20 carbons; and

wherein said semi-fluorinated block copolymers self assemble in said aqueous solution to form a supramolecular structure that at least partially encapsulates said hydrophobic drug or fluorophilic therapeutic agent, thereby decreasing the toxicity of said hydrophobic drug or fluorophilic therapeutic agent.

20. A semi-fluorinated block copolymer having the chemical formula:

21. The semi-fluorinated block copolymer of claim 20 having the chemical formula: