Continuous fluorochemical microdispersions for the delivery of lipophilic pharmaceutical agents

• US 5,667,809 A
• Filed: 06/07/1995
• Issued: 09/16/1997
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Alliance Pharmaceutical Corporation
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Weers, Jeffry G., Dellamary, Luis A., Tarara, Thomas E., Trevino, Leo A., Ranney, Helen M.
• Primary Examiner(s): Azpuru, Carlos A.
• Application Number:
  US08/482,176
• Time in Patent Office: 832 Days
• Field of Search: 424/501, 424/423, 424/427, 424/430, 424/443, 424/435, 424/436, 424/451, 424/464, 514/937
• US Class Current: 424/501
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender

Abstract

A method for preparing a pharmaceutical microdispersion exhibiting enhanced bioavailability, including the steps of providing a thermodynamically stable pharmaceutical composition comprising at least one lipophilic pharmaceutical agent incorporated in a physiologically acceptable liquid carrier, the liquid carrier comprising one or more lipophilic solvents such as fluorochemicals and preferably at least one nonfluorinated co-solvent, and combining the stable pharmaceutical composition with an amount of at least one miscible diluent sufficient to initiate phase separation of the lipophilic pharmaceutical agent from the pharmaceutical composition wherein a microdispersion of the pharmaceutical composition is formed. Also disclosed are microdisperse pharmaceutical compositions and kits for forming such compositions.

Claims

1. A method for preparing a pharmaceutical microdispersion exhibiting enhanced bioavailability, said method comprising the steps of:

providing a thermodynamically stable pharmaceutical composition comprising at least one lipophilic pharmaceutical agent incorporated in a physiologically acceptable liquid carrier, said liquid carrier comprising one or more lipophilic fluorochemicals and at least one nonfluorinated co-solvent; and

combining said stable pharmaceutical composition with an amount of at least one fluorochemical diluent less lipophilic than said one or more lipophilic fluorochemicals, said fluorochemical diluent present in an amount sufficient to initiate phase separation of said at least one lipophilic pharmaceutical agent from said pharmaceutical composition wherein a pharmaceutical microdispersion is formed.

2. The method of claim 1 wherein said pharmaceutical microdispersion is a suspension.

3. The method of claim 1 wherein said pharmaceutical microdispersion is a reverse emulsion.

4. The method of claim 1 wherein said one or more lipophilic fluorchemical is selected from the group consisting of halogenated fluorochemicals, fluorocarbon-hydrocarbon diblock or triblock compounds, halogenated ethers, polyethers, fluorocarbon-hydrocarbon esters, fluorocarbon-hydrocarbon thioesters, fluorocarbon-hydrocarbon amines and fluorocarbon-hydrocarbon amides.

5. The method of claim 1 wherein said one or more lipophilic fluorochemicals are selected from the group consisting of:

C_n F_2n+1 X, XC_n F_2n X, where n=3-8, X=Br, Cl or I;

C_n F_2n+1 --_m H_2m+1, C_n F_2n+1 CH═

CHC_m H_2m+1, where n=2-8 m=2-6;

C_p H_2p+1 --_n F_2n --_m H_2m+1, where p=2-6, m=2-6 and n=2-8;

XC_n F_2n OC_m F_2m X, XCF₂ OC_n F_2n OCF₂ X, where n=1-4, m=1-4, X=Br, Cl or I;

C_n F_2n --O--C_m H_2m+1, where n=2-8;

m=2-6;

C_p H_2p+1 --O--C_n F_2n --O--C_m H_2m+1, where p=2-6, m=2-6 and n=2-8;

1-bromo-F-octane (n-C₈ F₁₇ Br);

1-bromo-F-heptane (n-C₇ F₁₅ Br);

1-bromo-F-hexane (n-C₆ F₁₃ Br) 1-bromo-F-Butane (n-C₄ F₉ Br);

perfluorooctyl chloride (n-C₇ F₁₅ Cl);

1, 6-dichloro-F-hexane (n-ClC₆ F₁₂ Cl);

1, 4-dichloro-F-butane (n-ClC₄ F₈ Cl);

1, 4-dibromo-F-butane and 1,6-dibromo-F-hexane.

6. The method of claim 1 wherein said at least one lipophilic pharmaceutical agent is selected from the group consisting of respiratory drugs, antibiotics, anti-inflammatories, antineoplastics, anesthetics, ophthalmic agents, chemotherapeutic agents, cardiovascular agents, imaging agents and combinations thereof.

7. The method of claim 1 wherein said at least one lipophilic pharmaceutical agent exhibits a log of the Octanol/water partition coefficient (Log Po/w) greater than about 0.5.

8. The method of claim 1 wherein said at least one fluorochemical diluent is selected from the group consisting of bis(F-alkyl) ethenes, cyclic fluorocarbons, perfluorinated amines, brominated perfluorocarbons, perfluorooctyl chloride, perfluorooctyl hydride, perfluoroalkylated ethers perfluoroalkylated polyethers, fluorocarbon-hydrocarbon compounds and combinations thereof.

9. The method of claim 1 wherein said at least one nonfluorinated co-solvent is selected from the group consisting of ethers, alcohols, alkyl sulfoxides, and combinations thereof.

10. The method of claim 1 further comprising the step of introducing a therapeutically beneficial amount of a physiologically acceptable gas into said pharmaceutical microdispersion.

11. The method of claim 1 further comprising the step of adding a fluorinated or nonfluorinated surfactant.

12. The method of claim 1 wherein the concentration of said at least one lipophilic pharmaceutical agent is less than approximately 10% w/v and the concentration of said lipophilic fluorochemical is less than approximately 50% v/v.

13. The method of claim 1 wherein said microdispersion has an average particle diameter less than approximately 3 μ

m.

14. The method of claim 13 wherein said microdispersion has an average particle diameter less than approximately 1 μ

m.

15. A pharmaceutical microdispersion exhibiting enhanced bioavailability prepared according to the method of claim 1.

16. A pharmaceutical microdispersion exhibiting enhanced bioavailability prepared according to the method of claim 2.

17. A pharmaceutical microdispersion exhibiting enhanced bioavailability prepared according to the method of claim 3.

18. A pharmaceutical microdispersion exhibiting enhanced bioavailability prepared according to the method of claim 14.

19. A high bioavailability pharmaceutical formulation comprising:

a substantially homogeneous microdispersion of a pharmaceutically effective amount of at least one lipophilic pharmaceutical agent in a liquid continuous phase, said liquid continuous phase comprising one or more physiologically acceptable lipophilic fluorochemicals, at least one nonfluorinated co-solvent and at least one fluorochemical diluent wherein the fluorochemical diluent is less lipophilic than the lipophilic fluorochemical, said substantially homogeneous microdispersion being formed upon combination of the fluorochemical diluent with the lipophilic fluorochemical.

20. The high bioavailability pharmaceutical formulation of claim 19 wherein said substantially homogeneous microdispersion is a suspension.

21. The high bioavailability pharmaceutical formulation of claim 19 wherein said substantially homogeneous microdispersion is a reverse emulsion.

22. The high bioavailability pharmaceutical formulation of claim 19 wherein said one or more physiologically acceptable lipophilic fluorchemical is selected from the group consisting of halogenated fluorochemicals, fluorocarbon-hydrocarbon diblock or triblock compounds, halogenated ethers, polyethers, fluorocarbon-hydrocarbon esters, fluorocarbon-hydrocarbon thioesters, fluorocarbon-hydrocarbon amines and fluorocarbon-hydrocarbon amides.

23. The high bioavailability pharmaceutical formulation of claim 19 wherein said at least one lipophilic pharmaceutical agent is selected from the group consisting of respiratory drugs, antibiotics, anti-inflammatories, antineoplastics, anesthetics, ophthalmic agents, cardiovascular agents, imaging agents and combinations thereof.

24. The high bioavailability pharmaceutical formulation of claim 19 wherein said at least one lipophilic pharmaceutical agent exhibits an Octanol/water partition log coefficient (Log Po/w) greater than about 0.5.

25. The high bioavailability pharmaceutical formulation of claim 19 wherein said at least one fluorochemical diluent is selected from the group consisting of bis(F-alkyl) ethenes, cyclic fluorocarbons, perfluorinated amines, brominated perfluorocarbons, perfluorooctyl chloride, perfluorooctyl hydride, perfluoroalkylated ethers perfluoroalkylated polyethers, fluorocarbon-hydrocarbon compounds and combinations thereof.

26. The high bioavailability pharmaceutical formulation of claim 19 wherein said at least one nonfluorinated co-solvent is selected from the group consisting of ethers, alcohols, alkyl sulfoxides, and combinations thereof.

27. The high bioavailability pharmaceutical formulation of claim 19 wherein the concentration of said at least one lipophilic pharmaceutical agent is less than approximately 10% w/v and the concentration of said one or more lipophilic fluorochemicals is less than approximately 50% v/v.

28. The high bioavailability pharmaceutical formulation of claim 19 wherein the microdispersion has an average particle diameter less than 1 μ

m.

29. The high bioavailability pharmaceutical formulation of claim 19 wherein a therapeutically beneficial amount of a physiologically acceptable gas is incorporated in said liquid continuous phase.

30. The high bioavailability pharmaceutical formulation of claim 19 further comprising a fluorinated or nonfluorinated surfactant.

52. The high bioavailability pharmaceutical formulation of claim 20 further comprising a fluorinated or nonfluorinated surfactant.

53. The high bioavailability pharmaceutical formulation of claim 20 wherein said suspension has an average particle diameter less than approximately 1 μ

m.

31. A method for delivering one or more lipophilic pharmaceutical agents to a physiologic target site, said method comprising the steps of:

providing a high bioavailability pharmaceutical formulation comprising a substantially homogeneous microdispersion of at least one lipophilic pharmaceutical agent in a liquid continuous phase, said liquid continuous phase comprising one or more lipophilic fluorochemicals, at least one nonfluorinated co-solvent and at least one fluorochemical diluent wherein the fluorochemical diluent is less lipophilic than the lipophilic fluorochemical, said substantially homogeneous microdispersion being formed upon combination of the fluorochemical diluent with the lipophilic fluorochemical; and

introducing a pharmaceutically effective amount of said high bioavailability pharmaceutical formulation to a physiologic target site.

32. The method of claim 31 wherein said pharmaceutical formulation is a suspension.

33. The method of claim 31 wherein said pharmaceutical formulation is a reverse emulsion.

34. The method of claim 31 wherein said one or more lipophilic fluorchemical is selected from the group consisting of halogenated fluorochemicals, fluorocarbon-hydrocarbon diblock or triblock compounds, halogenated ethers, polyethers, fluorocarbon-hydrocarbon esters, fluorocarbon-hydrocarbon thioesters, fluorocarbon-hydrocarbon amines and fluorocarbon-hydrocarbon amides.

35. The method of claim 31 wherein said at least one lipophilic pharmaceutical agent is selected from the group consisting of respiratory drugs, antibiotics, anti-inflammatories, antineoplastics, anesthetics, ophthalmic agents, cardiovascular agents, imaging agents and combinations thereof.

36. The method of claim 31 wherein said at least one lipophilic pharmaceutical agent exhibits a log of the Octanol/water partition coefficient (Log Po/w) greater than about 0.5.

37. The method of claim 31 wherein said at least one fluorochemical diluent is selected from the group consisting of bis(F-alkyl) ethenes, cyclic fluorocarbons, perfluorinated amines, brominated perfluorocarbons, perfluorooctyl chloride, perfluorooctyl hydride, perfluoroalkylated ethers perfluoroalkylated polyethers, fluorocarbon-hydrocarbon compounds and combinations thereof.

38. The method of claim 31 wherein said at least one nonfluorinated co-solvent is selected from the group consisting of ethers, alcohols, alkyl sulfoxides, and combinations thereof.

39. The method of claim 31 wherein the concentration of said at least one lipophilic pharmaceutical agent is less than approximately 10% w/v and the concentration of said one or more lipophilic fluorochemicals is less than approximately 50% v/v.

40. The method of claim 31 wherein said high bioavailability pharmaceutical formulation has an average particle size less than 1 μ

m.

41. The method of claim 31 further comprising the step of introducing a therapeutically beneficial amount of a physiologically acceptable gas into said high bioavailability pharmaceutical formulation.

42. The method of claim 31 wherein the introduction of said pharmaceutical formulation to the physiological target site is accomplished topically, subcutaneously, intramuscularly, intraperitoneally, nasally, pulmonarily, vaginally, rectally, aurally, orally or ocularly.

43. A method for preparing a pharmaceutical material, comprising the steps of:

providing a pharmaceutical composition comprising a lipophilic first fluorochemical liquid, a nonfluorinated co-solvent and a pharmaceutical agent in a single continuous phase; and

adding to said pharmaceutical composition a sufficient amount of a second fluorochemical liquid less lipophilic than said first fluorochemical liquid that is miscible in said first fluorochemical liquid, thereby causing phase separation of said pharmaceutical agent to form a microdisperse discontinuous phase.

44. The method of claim 43, wherein said phase separation results in a reverse emulsion.

45. The method of claim 43, wherein said phase separation results in a suspension.

46. The method of claim 43, wherein said discontinuous phase comprises said nonfluorinated co-solvent and said pharmaceutical agent.

47. The method of claim 43, further comprising the step of storing said pharmaceutical composition for at least one week prior to said adding step.

54. The method of claim 43 wherein said lipophilic first fluorochemical liquid is selected from the group consisting of:

C_n F_2n+1 X, XC_n F_2n X, where n=3-8, X=Br, Cl or I;

C_n F_2n+1 --_m H_2m+1, C_n F_2n+1 CH═

CHC_m H_2m+1, where n=2-8 m=2-6;

C_p H_2p+1 --_n F_2n --_m H_2m+1, where p =2-6, m=2-6 and n=2-8;

XC_n F_2n OC_n F_2m X, XCF₂ OC_n F_2n OCF₂ X, where n=1-4, m=1-4, X=Br, Cl or I;

C_n F_2n --O--C_m H_2m+1, where n=2-8;

m=2-6;

C_p H_2p+1 --O--C_n F_2n --O--C_m H_2m+1, where p=2-6, m=2-6 and n=2-8;

1-bromo-F-octane (n-C₆ F₁₃ Br);

1-bromo-F-heptane (n-C₇ F₁₅ Br);

1-bromo-F-hexane (n-C₆ F₁₃ Br) 1-bromo-F-Butane (n-C₄ F₉ Br);

perfluorooctyl chloride (n-C₇ F₁₅ Cl);

1, 6-dichloro-F-hexane (n-ClC₆ F₁₂ Cl);

1, 4-dichloro-F-butane (n-ClC₄ F₈ Cl);

1, 4 -dibromo-F-butane and 1,6-dibromo-F-hexane.

55. The method of claim 43 wherein said pharmaceutical agent is selected from the group consisting of respiratory drugs, antibiotics, anti-inflammatories, antineoplastics, anesthetics, ophthalmic agents, chemotherapeutic agents, cardiovascular agents, imaging agents and combinations thereof.

56. The method of claim 43 further comprising the step of introducing a therapeutically beneficial amount of a physiologically acceptable gas into said pharmaceutical material.

57. The method of claim 45 further comprising the step of adding a fluorinated or nonfluorinated surfactant.

58. The method of claim 45 wherein said suspension has an average particle diameter less than approximately 1 μ

m.

63. The method of claim 54 wherein said suspension has an average particle diameter less than approximately 1 μ

m.

48. A method for providing a kit for preparing a pharmaceutical preparation, comprising:

placing a first composition comprising a first lipophilic liquid fluorocarbon, a nonfluorinated co-solvent and a pharmaceutical agent in a single continuous phase in a first container; and

adding a second liquid fluorocarbon miscible with said first lipophilic liquid fluorocarbon to a second container, wherein said second liquid fluorocarbon is less lipophilic than said first lipophilic liquid fluorocarbon, such that upon combination of said first composition and said second liquid fluorocarbon, a phase separation of said pharmaceutical agent occurs to form a microdisperse discontinuous phase comprising said pharmaceutical agent.

49. The method of claim 48, wherein said first composition comprises a nonfluorinated co-solvent selected from the group consisting of ethers, alcohols, alkyl sulfoxides, and combinations thereof.

50. The method of claim 48, wherein said discontinuous phase comprises said pharmaceutical agent and said co-solvent.

51. The method of claim 48, wherein said discontinuous phase comprises a suspension of said pharmaceutical agent.

59. The method of claim 48 wherein said first lipophilic fluorochemical liquid is selected from the group consisting of:

C_n F_2n+1 X, XC_n F_2n X, where n=3-8, X=Br, Cl or I;

C_n F_2n +1--_m H_2m+1, C_n F_2n+1 CH═

CHC_m H_2m+1, where n=2-8 m=2-6;

C_p H_2p+1 --_n F_2n --_m H_2m+1, where p =2-6, m=2-6 and n=2-8;

XC_n F_2n OC_m F_2m X, XCF₂ OC_n F_2n OCF₂ X, where n=1-4, m=1-4, X=Br, Cl or I;

C_n F_2n --O--C_m H_2m+1, where n=2-8;

m=2-6;

C_p H_2p+1 --O--C_n F_2n --O--C_m H_2m+1, where p=2-6, m=2-6 and n=2-8;

1-bromo-F-octane (n-C₈ F₁₇ Br);

1-bromo-F-heptane (n-C₇ F₁₅ Br);

1-bromo-F-hexane (n-C₆ F₁₃ Br) 1-bromo-F-Butane (n-C₄ F₉ Br);

perfluorooctyl chloride (n-C₇ F₁₅ Cl);

1, 6-dichloro-F-hexane (n-ClC₆ F₁₂ Cl);

1, 4-dichloro-F-butane (n-ClC₄ F₈ Cl);

1, 4-dibromo-F-butane and 1,6-dibromo-F-hexane.

60. The method of claim 48 wherein said second liquid fluorocarbon is selected from the group consisting of bis(F-alkyl) ethenes, cyclic fluorocarbons, perfluorinated amines, brominated perfluorocarbons, perfluorooctyl chloride, perfluorooctyl hydride, perfluoroalkylated ethers perfluoroalkylated polyethers, fluorocarbon-hydrocarbon compounds and combinations thereof.

61. The method of claim 48 wherein said pharmaceutical agent is selected from the group consisting of respiratory drugs, antibiotics, anti-inflammatories, antineoplastics, anesthetics, ophthalmic agents, chemotherapeutic agents, cardiovascular agents, imaging agents and combinations thereof.

62. The method of claim 51 further comprising the step of adding a fluorinated or nonfluorinated surfactant.