Fluorochemical solutions for the delivery of lipophilic pharmaceutical agents

• US 5,874,481 A
• Filed: 06/07/1995
• Issued: 02/23/1999
• Est. Priority Date: 06/07/1995
• Status: Expired due to Fees

• Current Assignee: Alliance Pharmaceutical Corporation
• Original Assignee: Alliance Pharmaceutical Corporation
• Inventors: Ranney, Helen M., Weers, Jeffry G., Dellamary, Luis A., Tarara, Thomas E., Trevino, Leo A.
• Primary Examiner(s): Jarvis, William R. A.
• Application Number:
  US08/483,468
• Time in Patent Office: 1,357 Days
• Field of Search: 514/757, 514/761, 514/724
• US Class Current: 514/761
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender

Abstract

A thermodynamically stable molecular solution providing enhanced bioavailability for lipophilic pharmaceutical agents, comprising a liquid carrier comprising one or more physiologically acceptable lipophilic fluorochemicals, and a pharmaceutically effective amount of at least one lipophilic pharmaceutical agent in said liquid carrier to form a thermodynamically stable molecular solution, optionally also including a co-solvent for facilitating solubilization of the pharmaceutical agent. Methods of making and using the molecular solution are also disclosed.

Claims

1. A thermodynamically stable molecular solution providing enhanced bioavailability for lipophilic pharmaceutical agents, said molecular solution comprising:

a liquid carrier comprising one or more physiologically acceptable lipophilic fluorochemicals comprising four or more carbon atoms and at least one nonfluorinated co-solvent; and

a pharmaceutically effective amount of at least one lipophilic pharmaceutical agent in said liquid carrier.

2. The thermodynamically stable molecular solution of claim 1, wherein said one or more physiologically acceptable lipophilic perfluorochemicals are 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.

3. The thermodynamically stable molecular solution of claim 1 wherein said one or more physiologically acceptable lipophilic fluorochemicals are selected from the group consisting of:

C_n F_2n+1 X, XC_n F_2n X, where n=4-8, X=Br, Cl or I;

C_n F_2n+1 --C_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 --C_n F_2n --C_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-pentane (n-C₅ F₁₁ Br);

1-bromo-F-butane (n-C₄ F₉ Br);

perfluorooctyl chloride (n-C7F₁₅ 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.

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

5. The thermodynamically stable molecular solution 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.

6. The thermodynamically stable molecular solution of claim 1 wherein a therapeutically beneficial amount of a physiologically acceptable gas is incorporated in said liquid carrier.

7. The thermodynamically stable molecular solution 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.

8. The thermodynamically stable molecular solution of claim 7 wherein said one or more physiologically acceptable lipophilic perfluorochemicals 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.

9. The thermodynamically stable molecular solution of claim 7 wherein said at least one lipophilic pharmaceutical agent is selected from the group consisting of respiratory agents, antibiotics, anti-inflammatories, antineoplastics, chemotherapeutic agents, anesthetics, ophthalmic agents, cardiovascular agents, imaging agents and combinations thereof.

10. The thermodynamically stable molecular solution of claim 7 wherein the concentration of said at least one incorporated pharmaceutical agent is less than approximately 10% w/v and the concentration of said at least one co-solvent is less that approximately 50% v/v.

11. The thermodynamically stable molecular solution of claim 7 wherein said at least one co-solvent is ethanol, the physiologically acceptable lipophilic fluorochemical is 1,4 -dibromo-F-butane and the concentration of said at least one incorporated lipophilic pharmaceutical agent is less than approximately 10% w/v.

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

12. A method for preparing a thermodynamically stable molecular solution exhibiting enhanced bioavailability, said method comprising the steps of:

providing a liquid carrier comprising one or more physiologically acceptable lipophilic fluorochemicals comprising four or more carbon atoms and at least one nonfluorinated co-solvent; and

combining a pharmaceutically effective amount of at least one lipophilic pharmaceutical agent with said liquid carrier to form said thermodynamically stable molecular solution.

13. The method of claim 12 wherein said one or more physiologically acceptable lipophilic perfluorochemicals 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.

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

16. The method of claim 12 wherein said lipophilic pharmaceutical agent exhibits a log of the octanol/water partition coefficient (Log Po/w) greater than about 0.5.

17. The method of claim 12 further comprising the step of introducing a therapeutically beneficial amount of a physiologically acceptable gas into said liquid carrier.

18. The method of claim 12 wherein said at least one nonfluorinated co-solvent is selected from the group consisting of ethers, alcohols, alkyl sulfoxides and combinations thereof.

19. The method of claim 18 wherein said at least one lipophilic pharmaceutical agent is selected from the group consisting of respiratory agents, antibiotics, anti-inflammatories, antineoplastics, chemotherapeutic agents, anesthetics, ophthalmic agents, cardiovascular agents, imaging agents and combinations thereof.

20. The method of claim 18 wherein the concentration of said at least one lipophilic pharmaceutical agent is less than approximately 10% w/v and the concentration of said at least one co-solvent is less than approximately 50% v/v.

21. A molecular solution prepared according to the method of claim 12.

22. A molecular solution prepared according to the method of claim 18.

23. A molecular solution prepared according to the method of claim 20.

24. A method for delivering at least one lipophilic pharmaceutical agent to a physiologic target site, said method comprising the steps of:

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

introducing a pharmaceutically effective amount of said thermodynamically stable molecular solution to a physiologic target site.

25. The method of claim 24 wherein said one or more lipophilic perfluorochemicals are 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.

26. The method of claim 24 wherein said at least one lipophilic pharmaceutical agent is selected from the group consisting of respiratory agents, antibiotics, anti-inflammatories, antineoplastics, chemotherapeutic agents, anesthetics, ophthalmic agents, cardiovascular agents, imaging agents and combinations thereof.

27. The method of claim 24 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.

28. The method of claim 24 further comprising the step of introducing a therapeutically beneficial amount of a physiologically acceptable gas into said liquid carrier.

29. The method of claim 24 wherein said at least one nonfluorinated co-solvent is selected from the group consisting of ethers, alcohols, alkyl sulfoxides, and combinations thereof.

30. The method of claim 29 wherein said one or more physiologically acceptable lipophilic perfluorochemicals 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.

31. The method of claim 29 wherein said at least one lipophilic pharmaceutical agent is selected from the group consisting of respiratory agents, antibiotics, anti-inflammatories, antineoplastics, chemotherapeutic agents, anesthetics, ophthalmic agents, card vascular agents, imaging agents and combinations thereof.

32. The method of claim 24 wherein the introduction of said molecular solution to the physiological target site is accomplished topically, subcutaneously, intramuscularly, intraperitoneally, nasally, pulmonarily, vaginally, rectally, aurally, orally or ocularly.

33. The method of claim 24 wherein said physiological target site comprises the lung.

34. The method of claim 24 wherein said physiological target site comprises the eye.

35. The method of claim 24 wherein said physiological target site comprises the gastrointestinal tract.