Hydrocarbon oil/fluorochemical preparations and methods of use

• US 5,733,526 A
• Filed: 12/14/1995
• Issued: 03/31/1998
• Est. Priority Date: 12/14/1995
• Status: Expired due to Fees

• Current Assignee: Alliance Pharmaceutical Corporation
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Dellamary, Luis A., Tarara, Thomas E., Trevino, Leo A., Riess, Jean G., Krafft, Marie-Pierre
• Primary Examiner(s): Hollinden, Gary E.
• Assistant Examiner(s): Hartley, Michael G.
• Application Number:
  US08/572,859
• Time in Patent Office: 838 Days
• Field of Search: 424/9.5, 424/9.51, 424/9.52, 424/9.1, 424/455, 424/450, 514/937, 514/938, 514/749, 252/302, 252/350
• US Class Current: 424/9.52
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender
• CPC Class Codes: A61K 9/113 Multiple emulsions, e.g. oil-in-water-in-oil A61K9/0026 takes precedence
• CPC Class Codes: Y10S 977/786 Fluidic host/matrix containing nanomaterials
• CPC Class Codes: Y10S 977/795 Composed of biological material
• CPC Class Codes: Y10S 977/902 Specified use of nanostructure
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/905 Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10S 977/926 Topical chemical, e.g. cosmetic or sunscreen
• CPC Class Codes: Y10S 977/927 Diagnostic contrast agent
• CPC Class Codes: Y10S 977/962 for carrying or transporting

Abstract

Novel hydrocarbon oil/fluorochemical preparations and methods for their use are provided. The preparations, which preferably comprise a fluorophilic dispersing agent, may be in the form of hydrocarbon oil-in-fluorochemical dispersions or in the form of a multiple emulsion comprising a polar liquid continuous phase and are particularly useful for administering bioactive agents. In particular the preparations of the present invention may be used to control the bioavailability and improve the efficacy of lipophilic bioactive agents having limited solubility in an aqueous physiological environment.

Claims

1. A hydrocarbon-based oil-in-fluorochemical preparation comprising:

a disperse phase comprising at least one hydrocarbon-based oil;

a continuous phase comprising at least one fluorochemical; and

an effective dispersing amount of at least one fluorophilic dispersing agent.

2. The preparation of claim 1 wherein said hydrocarbon-based oil comprises at least one bioactive agent.

3. The preparation of claim 2 wherein said at least one bioactive agent is selected from the group consisting of respiratory agents, antibiotics, antivitals, mydriatics, antiglaucomas, anti-inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes, cardiovascular agents, nucleic acids, genetic material, vital vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins, physiological gases and gastrointestinal agents.

4. The preparation of claim 2 wherein said at least one bioactive agent is a lipophilic bioactive agent.

5. The preparation of claim 1 wherein said at least one fluorochemical is selected from the group consisting of perfluoroalkanes, fluorinated cyclic compounds, halogenated fluorochemicals, fluorinated alkenes, fluorinated ethers, fluorinated polyethers, fluorinated amines, fluorinated hydrides and derivatives thereof.

6. The preparation of claim 1 wherein said at least one hydrocarbon-based oil is selected from the group consisting of saturated hydrocarbons, unsaturated hydrocarbons, lipids, triglycerides, natural oils, synthetic oils and derivatives thereof, said natural oils selected from the group consisting of canola oil, soybean oil, olive oil, corn oil, castor oil, sunflower oil, safflower oil and derivatives thereof.

7. The preparation of claim 1 wherein said at least one fluorophilic dispersing agent is selected from the group consisting of fluorinated surfactants, fluorocarbon-hydrocarbon diblock compounds and combinations thereof.

8. The preparation of claim 7 wherein said at least one fluorophilic dispersing agent is a diblock compound, said diblock compound having the formula:

space="preserve" listing-type="equation">R.sub.F -L-R.sub.H -Z

wherein;

R_F is one or more perfluorinated or partially fluorinated group(s);

R_H is one or more hydrocarbon group(s);

L is a linkage unit; and

Z is H or a group more polar or polarizable than the R_H.

9. The preparation of claim 7 wherein said fluorophilic dispersing agent is a diblock compound selected from the group consisting of compounds having the formula C_n F_2n+1 C_m H_2m+1, compounds having the formula C_n F_2n+1 C_m H_2m-1 and combinations thereof, wherein n is an integer from 2 to 12 and m is an integer from 2 to 16.

10. The preparation of claim 7 wherein said fluorophilic dispersing agent is a fluorinated surfactant selected from the group, consisting of compounds having the formula R_F R₁ OP(O) N(CH₂ CH₂)₂ O₂ ! compounds having the formula R_F R_1O!2 P(O) N(CH₂ CH₂)₂ O! and combinations thereof wherein R_F is CF₃ (CF₂)_t, such that t is an integer from 1 to 11 and R₁ is a substituted or unsubstituted, saturated or unsaturated hydrocarbon chain and wherein both R_F and R₁ may contain at least one oxygen and/or sulfur atom.

11. The preparation of claim 1 further comprising at least one bioactive agent.

12. The preparation of claim 11 further comprising one or more additives selected from the group consisting of co-solvents, co-surfactants, co-dispersants, buffers, stabilizers, nutritive agents and combinations thereof.

13. A hydrocarbon-based oil-in-fluorochemical-in-polar liquid multiple emulsion comprising:

an emulsified disperse phase comprising at least one hydrocarbon-based oil, at least one fluorochemical and at least one fluorophilic dispersing agent wherein said emulsified disperse phase comprises a discontinuous hydrocarbon-based oil phase; and

a continuous phase comprising at least one polar liquid having at least one emulsifying agent dispersed therein.

14. The multiple emulsion of claim 13 wherein said hydrocarbon-based oil comprises at least one bioactive agent.

15. The multiple emulsion of claim 14 wherein said at least one bioactive agent is a lipophilic bioactive agent.

16. The multiple emulsion of claim 13 wherein said at least one bioactive agent is selected from the group consisting of respiratory agents, antibiotics, antivirals, mydriatics, antiglaucomas, anti-inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes, cardiovascular agents, nucleic acids, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, promins, physiological gases and gastrointestinal agents.

17. The multiple emulsion of claim 13 further comprising one or more additives selected from the group consisting of co-solvents, co-surfactants, co- dispersants, mineral salts, buffers, stabilizers, oncotic agents, osmotic agents, nutritive agents and combinations thereof.

18. The multiple emulsion of claim 13 wherein said at least one fluorochemical is selected from the group consisting of halogenated fluorochemicals, fluorinated cyclic compounds, perfluoroalkanes, fluorinated alkenes, fluorinated ethers, fluorinated polyethers, fluorinated amines, fluorinated hydrides and combinations thereof.

19. The multiple emulsion of claim 13 wherein said at least one hydrocarbon-based oil is selected from the group consisting of saturated hydrocarbons, unsaturated hydrocarbons, lipids, triglycerides, natural oils, synthetic oils and derivatives thereof, said natural oils selected from the group consisting of canola oil, soybean oil, olive oil, corn oil, castor oil, sunflower oil, safflower oil and derivatives thereof.

20. The multiple emulsion of claim 13 wherein said at least one fluorophilic dispersing agent is selected from the group consisting of fluorinated surfactants, fluorocarbon-hydrocarbon diblock compounds and combinations thereof.

21. The multiple emulsion of claim 20 wherein said at least one fluorophilic dispersing agent is a diblock compound, said diblock compound having the formula:

space="preserve" listing-type="equation">R.sub.F -L-R.sub.H -Z

wherein;

R_F is one or more perfluorinated or partially fluorinated group(s);

R_H is one or more hydrocarbon group(s);

L is a linkage unit; and

Z is H or a group more polar or polarizable than the R_H.

22. The multiple emulsion of claim 21 wherein said fluorophilic dispersing agent is a diblock compound selected from the group consisting of compounds having the formula C_n F_2n+1 C_m H_2m+1, compounds having the formula C_n F_2n+1 C_m H_2m-1 and combinations thereof, wherein n is an integer from 2 to 12 and m is an integer from 2 to 16.

23. The multiple emulsion of claim 20 wherein said fluorophilic dispersing agent is a fluorinated surfactant selected from the group consisting of compounds having the formula R_F R₁ OP(O) N(CH₂ CH₂)₂ O!₂ compounds having the formula R_F R₁ O!₂ P(O) N(CH₂ CH₂)₂ O! and combinations thereof wherein R_f is CF₃ (CF₂)_t, such that t is an integer from 1 to 11 and R₁ is a substituted or unsubstituted, saturated or unsaturated hydrocarbon chain and wherein both R_F and R₁ may contain at least one oxygen and/or sulfur atom.

24. The multiple emulsion of claim 13 further comprising at least one bioactive agent.

25. A method for forming a hydrocarbon-based oil-in-fluorochemical dispersion comprising the steps of:

combining at least one hydrocarbon-based oil with an effective dispersing amount of at least one fluorophilic dispersing agent and at least one fluorochemical to provide a dispersion preparation comprising a discontinuous hydrocarbon-based oil phase; and

admixing said dispersion preparation to produce a hydrocarbon-based oil-in-fluorochemical dispersion.

26. The method of claim 25 wherein said at least one hydrocarbon-based oil comprises a bioactive agent.

27. The method of claim 25 further comprising the step of mixing said hydrocarbon-based oil-in-fluorochemical dispersion with a polar liquid phase comprising at least one polar liquid and at least one emulsifying agent to provide a multiple emulsion.

28. A dispersion prepared according to the method of claim 25.

29. A dispersion prepared according to the method of claim 26.

30. A method for preparing a hydrocarbon-based oil-in-fluorochemical multiple emulsion comprising the steps of:

combining at least one hydrocarbon-based oil with an effective dispersing amount of at least one fluorophilic dispersing agent, at least one fluorochemical, at least one polar liquid and at least one emulsifying agent to provide a multiple emulsion preparation; and

admixing said emulsion preparation to form a multiple emulsion comprising an hydrocarbon-based oil-in-fluorochemical disperse phase and a polar liquid continuous phase.

31. The method of claim 30 comprising the step of incorporating at least one bioactive agent in said emulsion preparation.

32. The method of claim 31 wherein said at least one hydrocarbon-based oil comprises said at least one bioactive agent.

33. A multiple emulsion prepared according to the method of claim 30.

34. A multiple emulsion prepared according to the method of claim 31.

35. A method for delivering a bioactive agent to a patient comprising:

providing a bioactive preparation comprising a hydrocarbon-based oil-in-fluorochemical dispersion and at least one bioactive agent wherein said hydrocarbon-based oil-in-fluorochemical dispersion comprises an effective dispersing amount of at least one fluorophilic dispersing agent; and

administering said bioactive preparation to a patient.

36. The method of claim 35 wherein said at least one bioactive agent is selected from the group consisting of respiratory agents, antibiotics, antivirals, mydriatics, antiglaucomas, anti-inflammatories, antihistaminics, antineoplastics, anesthetics, ophthalmic agents, enzymes, cardiovascular agents, nucleic acids, genetic material, viral vectors, immunoactive agents, imaging agents, immunosuppressive agents, peptides, proteins, physiological gases and gastrointestinal agents.

37. The method of claim 35, wherein said bioactive preparation is administered to a patient using a route of administration selected from the group consisting of topical, subcutaneous, pulmonary, intravenous, intraarterial, sinovial, intramuscular, intraperitoneal, nasal, vaginal, rectal, aural, oral and ocular routes.

38. The method of claim 35 wherein said bioactive preparation comprises a hydrocarbon-based oil-in-fluorochemical dispersion.

39. The method of claim 38 wherein said at least one hydrocarbon-based oil comprises a bioactive agent.

40. The method of claim 35 wherein said bioactive preparation comprises a hydrocarbon-based oil-in-fluorochemical-in-polar liquid multiple emulsion, said multiple emulsion comprising an emulsified hydrocarbon-based oil-in-fluorochemical dispersion comprising at least one hydrocarbon-based oil, at least one fluorochemical and at least one fluorophilic dispersing agent and a continuous phase comprising at least one polar liquid having at least one hydrophilic emulsifying agent dispersed therein.

41. The method of claim 40 wherein said at least one hydrocarbon-based oil comprises a bioactive agent.