FLUOROPOLYMER-BASED EMULSIONS FOR THE INTRAVENOUS DELIVERY OF FLUORINATED VOLATILE ANESTHETICS

• US 20080234389A1
• Filed: 11/28/2007
• Published: 09/25/2008
• Est. Priority Date: 11/28/2006
• 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, Fast, Jonathan P., Pearce, Robert A.
• Granted Patent: US 9,000,048 B2
• Time in Patent Office: Days
• US Class Current: 514/722
• CPC Class Codes: A61K 31/08 acyclic, e.g. paraformaldehyde
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/02 for peripheral neuropathies

Abstract

The present invention provides therapeutic formulations, including therapeutic emulsions and nanoemulsions, and related methods for the delivery of fluorinated therapeutic compounds, including an important class of low boiling point perfluorinated and/or perhalogenated volatile anesthetics. Emulsion-based fluorinated volatile anesthetic formulations compatible with intravenous administration are provided that are capable of delivering and releasing amounts of fluorinated volatile anesthetic compounds effective for inducing and maintaining anesthesia in patients. Intravenous delivery of the present emulsion-based fluorinated volatile anesthetic formulations permits anesthetic levels in a patient to be selectively adjusted very rapidly and accurately without the need to hyperventilate patients and without the use of irritating agents.

Claims

1. A therapeutic formulation comprising:

an aqueous solution;

semi-fluorinated block copolymers having a hydrophilic block and a fluorophilic block;

a fluorinated therapeutic compound; and

a stabilizing additive.

2. The therapeutic formulation of claim 1 wherein said fluorophilic block is a fluorinated alkyl chain.

3. The therapeutic formulation of claim 1 wherein said fluorophilic block is a perfluorinated alkyl chain having a length of 6 to 16 carbons.

4. The therapeutic formulation of claim 1 wherein said hydrophilic block comprises a polyoxygenated block.

5. The therapeutic formulation of claim 1 wherein said hydrophilic block is a poly(ethylene glycol) block having a molecular weight selected over the range of 500 g mol⁻

1 to 12,000 g mol<sup>−

1</sup>.

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

C_mF_2m+1-L₁-(—

CH₂CH₂—

O—

)_n—

R;

 

 

(FX1)

wherein m is selected from the range of 5 to 25;

n is selected from the range of 10 to 270,

L₁ is a linking group; and

wherein R is a hydrogen, a methyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkenyl;

or a substituted or unsubstituted alkynyl group.

7. The therapeutic formulation of claim 6 wherein said linking group (L₁) is a C_1-10 alkyl group.

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

C_mF_2m+1-(CH₂)_p—

O—

(—

CH₂CH₂—

O—

)_n—

R;

or 

 

(FX2)

C_mF_2m+1—

O—

(—

CH₂CH₂—

O—

)_n—

R;

 

 

(FX3)

wherein m is selected from the range of 5 to 25;

n is selected from the range of 10 to 270;

p is selected from the range 1 to 10; and

wherein R is a hydrogen, a methyl group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted alkenyl;

or a substituted or unsubstituted alkynyl group.

9. The therapeutic formulation of claim 1 wherein said fluorinated therapeutic compound is an anesthetic

10. The therapeutic formulation of claim 1 wherein said fluorinated therapeutic compound is selected from the group consisting of sevoflurane, isoflurane, desflurane, enflurane and methoxyflurane.

11. The therapeutic formulation of claim 1 wherein said stabilizing additive is a perhalogenated fluorocarbon.

12. The therapeutic formulation of claim 11 wherein said perhalogenated fluorocarbon stabilizing additive has between 12 to 25 carbon-fluorine bonds.

13. The therapeutic formulation of claim 11 wherein said perhalogenated fluorocarbon stabilizing additive has a solubility in water less than or equal to 20 nanomolar.

14. The therapeutic formulation of claim 11 wherein said perhalogenated fluorocarbon stabilizing additive has a molecular weight selected over the range of 460 amu to 520 amu.

15. The therapeutic formulation of claim 11 wherein said perhalogenated fluorocarbon stabilizing additive is selected from the group consisting of:

a perfluorocarbon;

a bromine substituted perfluorocarbon;

a chlorine substituted perfluorocarbon; and

a bromine and chlorine substituted perfluorocarbon.

16. The therapeutic formulation of claim 11 wherein said perhalogenated fluorocarbon is selected from the group consisting of perfluorooctyl bromide;

perfluorononyl bromide, perfluorodecyl bromide, perfluorodecalin;

perfluorodichlorooactane; and

bis-perfluorobutyl ethylene and perfluoro(methyldecalin).

17. The therapeutic formulation of claim 1 further comprising one or more additional fluorocarbon stabilizing additives.

18. The therapeutic formulation of claim 1 wherein the fluorinated therapeutic compound is 5% to 25% by volume of said therapeutic formulation, wherein the stabilizing additive is a perhalogenated stabilizing additive and is 1% to 20% by volume of said therapeutic formulation;

and wherein the semi-fluorinated block copolymers have a concentration selected over the range of 1 mg ml<sup>−

1</sup> to 45 mg ml<sup>−

1</sup>.

19. The therapeutic formulation of claim 1 comprising a therapeutic emulsion comprising:

a continuous phase comprising said aqueous solution provides; and

a dispersed phase comprising said semi-fluorinated block copolymers and said fluorinated therapeutic compound.

20. The therapeutic formulation of claim 19 wherein said dispersed phase further comprises said stabilizing additive.

21. The therapeutic formulation of claims 20 wherein said dispersed phase comprises a plurality of droplets dispersed in said continuous phase.

22. The therapeutic formulation of claim 21 wherein said droplets have an average diameter less than or equal to 1000 nanometers.

23. The therapeutic formulation of claim 21 wherein said droplets have an average diameters less than or equal to 400 nanometers.

24. The therapeutic formulation of claim 21 wherein said droplets dispersed in said continuous phase comprise self assembled supramolecular structures.

25. The therapeutic formulation of claim 24 wherein said supramolecular structures comprises an interior fluorous core of said fluorinated therapeutic compound;

wherein said interior fluorous core comprise droplets of fluorinated therapeutic compound encapsulated by said semi-fluorinated block copolymers.

26. The therapeutic formulation of claim 25 wherein said fluorophilic block of said semi-fluorinated block copolymers is oriented proximate to said interior fluorous core of said particles;

and wherein said hydrophilic block is oriented distal to said interior fluorous core of said particles.

27. The therapeutic formulation of claim 25 wherein said droplets of fluorinated therapeutic compound have an average diameter ranging from 100 nm to 1 micron.

28. The therapeutic formulation of claim 19 comprising a nanoemulsion.

29. The therapeutic formulation of claim 19 wherein said fluorinated therapeutic compound is 5% to 50% by volume of said therapeutic emulsion.

30. The therapeutic formulation of claim 19 wherein said fluorinated therapeutic compound is greater than 5% by volume of said therapeutic emulsion.

31. The therapeutic formulation of claim 19 wherein said therapeutic emulsion capable of administration to a patient via intraveneous injection.

32. A method of administering a fluorinated therapeutic compound to a patient, said method comprising the steps of:

providing a therapeutic formulation comprising;

an aqueous solution;

semi-fluorinated block copolymers having a hydrophilic block and a fluorophilic block;

a fluorinated therapeutic compound; and

a stabilizing additive;

emulsifying said therapeutic formulation, thereby making a therapeutic emulsion; and

delivering said therapeutic emulsion to said patient.

33. The method of claim 32 wherein said stabilizing additive is a perhalogenated fluorocarbon stabilizing additive.

34. The method of claim 32 wherein said therapeutic emulsion is delivered to said patient via intravenous injection.

35. The method of claim 32 wherein a volume of therapeutic emulsion selected over the range of 1 ml to 100 ml is delivered to said patient.

36. The method of claim 32 wherein said therapeutic emulsion is delivered to said patient at a rate selected over the range of 0.1 ml min⁻

1 to 5 ml min<sup>−

1</sup>.

37. The method of claim 32 wherein said step of emulsifying said therapeutic formulation comprises the steps of:

adding said fluorinated therapeutic compound and said stabilizing additive to said aqueous solution having said semi-fluorinated block copolymers therein, thereby generating a therapeutic mixture; and

homogenizing said therapeutic mixture, thereby generating said therapeutic emulsion.

38. The method of claim 37 further comprising the step of lowering the temperature of said therapeutic mixture during said step of homogenizing said therapeutic mixture.

39. The method of claim 38 wherein said step of homogenizing said therapeutic mixture is carried out using a lower energy mixer, a microfluidizer or both a lower energy mixer and microfluidizer.

40. The method of claim 32 wherein the fluorinated therapeutic compound is 5% to 30% of the volume of said therapeutic formulation;

wherein the stabilizing additive is a perhalogenated fluorocarbon stabilizing additive and is 1% to 20% of the volume of said therapeutic formulation; and

wherein the semi-fluorinated block copolymers have a concentration selected over the range of 1 mg ml<sup>−

1</sup> to 45 mg ml<sup>−

1</sup>.

41. The method of claim 32 wherein said fluorinated therapeutic compound is greater than 5% by volume of said therapeutic emulsion.

42. The method of claim 32 wherein said therapeutic emulsion comprises a nanoemulsion.

43. The method of claim 32 wherein said fluorinated therapeutic compound is selected from the group consisting of sevoflurane, isoflurane, desflurane, enflurane and methoxyflurane.

44. A method of making a therapeutic emulsion containing a fluorinated therapeutic compound, said method comprising the steps of:

providing a therapeutic formulation comprising;

an aqueous solution;

semi-fluorinated block copolymers having a hydrophilic block and a fluorophilic block;

a fluorinated therapeutic compound; and

a perhalogenated fluorocarbon stabilizing additive; and

emulsifying said therapeutic formulation, thereby making said therapeutic emulsion.

45. The method of claim 44 wherein said step of emulsifying said therapeutic formulation comprises the steps of:

adding said fluorinated therapeutic compound and said perhalogenated fluorocarbon stabilizing additive to said aqueous solution having said semi-fluorinated block copolymers therein, thereby generating a therapeutic mixture; and

homogenizing said therapeutic mixture, thereby generating said therapeutic emulsion.

46. The method of claim 44 further comprising the step of lowering the temperature of said therapeutic mixture during said step of homogenizing said therapeutic mixture.

47. The method of claim 44 wherein said step of homogenizing said therapeutic mixture is carried out using a lower energy mixer, a microfluidizer or both a lower energy mixer and microfluidizer.

48. A method of stabilizing a therapeutic emulsion containing a fluorinated therapeutic compound, said method comprising the steps of:

providing a therapeutic formulation comprising;

an aqueous solution;

semi-fluorinated block copolymers having a hydrophilic block and a fluorophilic block; and

a fluorinated therapeutic compound;

adding a perhalogenated fluorocarbon stabilizing additive to said therapeutic formulation; and

emulsifying said therapeutic formulation, thereby stabilizing said therapeutic emulsion.