Nonaqueous fluorinated drug delivery vehicle suspensions

• US 5,518,731 A
• Filed: 06/14/1994
• Issued: 05/21/1996
• Est. Priority Date: 09/27/1990
• Status: Expired due to Fees

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: Meadows, David L.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/260,482
• Time in Patent Office: 707 Days
• Field of Search: 424/427, 424/423, 424/426, 424/428, 424/434, 424/435, 424/499, 424/501, 424/78.03, 424/78.04, 424/78.33, 514/912, 514/963, 514/965, 523/122
• US Class Current: 424/427
• CPC Class Codes: A61K 31/02 Halogenated hydrocarbons
• CPC Class Codes: A61K 31/025 carbocyclic
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61P 27/02 Ophthalmic agents

Abstract

Nonaqueous pharmaceutical compositions for use in aqueous physiological systems are disclosed comprising drug delivery vehicles suspended in nonaqueous perfluorocarbon or fluorinated silicone liquid carriers. The suspended drug delivery vehicles may be water labile or water stable and incorporate therapeutic or diagnostic compounds which remain stable and pharmaceutically effective for extended periods. The pharmaceutical compositions have improved bioavailability, are capable of low dose volume delivery, and do not leach the incorporated therapeutic or diagnostic compounds into the liquid carriers making them well suited for multi-dose packaging and administration.

Claims

1. A low delivery volume nonaqueous pharmaceutical composition displaying the property of enhanced drug bioavailability at a physiological target site and reduced side effects, said composition comprising:

a drop instillable mixture of a nonaqueous, physiologically acceptable perfluorocarbon liquid carrier and a pharmaceutically effective amount of a therapeutic or diagnostic compound incorporated in a particulate polymer drug delivery vehicle, said mixture having a delivery volume on the order of 10 μ

l.

2. The low delivery volume pharmaceutical composition of claim 1 wherein said delivery volume is greater than about 1 μ

l and less than about 10 μ

l.

3. The low delivery volume pharmaceutical composition of claim 1 wherein said delivery volume is about 4 μ

l to about 8 μ

l.

4. The low delivery volume pharmaceutical composition of claim 1 wherein said mixture includes a surfactant.

5. The low delivery volume pharmaceutical composition of claim 1 wherein said nonaqueous physiologically acceptable perfluorocarbon liquid carrier is selected from the group consisting of perfluoro (decahydronaphthalene), perfluoro(decahydro-1-methylnaphthalene), perfluoro (decahydrodimethylnaphthalene), perfluoroperhydrophenanthrene, perfluoromethylcyclohexane, perfluoro(1,3-dimethylcyclohexane), perfluorotrimethylcyclohexane, perfluoroisopropylcyclohexane, perfluoro-1-methyl-4-isopropylcyclohexane, perfluoro-n-butylcyclohexane, perfluoroendotetrahydrodicyclopentadiene, perfluoromethyladamantane, perfluorodimethylbicyclo (3.3.1.) nonane, and perfluorotrimethylbicyclo(3.31.) nonane.

6. The low delivery volume pharmaceutical composition of claim 1 wherein said nonaqueous physiologically acceptable perfluorocarbon liquid carrier is selected from the group consisting of perfluorotributylamine and perfluorotriisopropylamine.

7. The low delivery volume pharmaceutical composition of claim 1 wherein said nonaqueous physiologically acceptable perfluorocarbon liquid carrier is selected from the group consisting of perfluorotetrahydrofuran and perfluoroether.

8. The low delivery volume pharmaceutical composition of claim 1 wherein said therapeutic or diagnostic compound is selected from the group consisting of oligopeptides, antibacterials, antihistaminics, anti-inflammatories, miotics, mydriatics, antiglaucomals, antivirals, carbonic anhydrase inhibitors, antifungals, anesthetics, diagnostics, immunosupporessive agents, and mixtures thereof.

9. The low delivery volume pharmaceutical composition of claim 1 wherein said polymeric drug delivery vehicle is a hydrolytically labile polymer selected from the group consisting of poly(methylvinylether/maleic anhydride), polyfumaric acid/sebacic acid, collagen, gelatin, polyvinyl alcohol, methylcelluloses, polyorthoesters, polyglycolic acid, polylactic acid, polyvinylpyrrolidone, polysebacic acid anhydride, polycarboxyphenoxypropane anhydride, polyterephthalic acid anhydride, and polyphosphazine.

10. The low delivery volume pharmaceutical composition of claim 1 wherein said polymeric drug delivery vehicle comprises a plurality of microparticulates, each of said microparticulates being formed of a polymeric matrix incorporating said therapeutic or diagnostic compound.

11. The low delivery volume pharmaceutical composition of claim 10 wherein each of said microparticulates is sized from approximately 2 microns to 200 microns.

12. The low delivery volume pharmaceutical composition of claim 10 wherein said microparticulates are microcapsules, each of said microcapsules being formed of an erodible polymer encapsulating said therapeutic or diagnostic compound.

13. The low delivery volume pharmaceutical composition of claim 10 wherein said polymeric matrix is a hydrolytically labile polymer selected from the group consisting of poly(methylvinylether/maleic anhydride), polyfumaric acid/sebacic acid, collagen, gelatin, polyvinyl alcohol, methylcelluloses, polyorthoesters, polyglycolic acid, polylactic acid, polyvinylpyrrolidone, polysebacic acid anhydride, polycarboxyphenoxypropane anhydride, polyterephthalic acid anhydride, and polyphosphazine.

14. The low delivery volume pharmaceutical composition of claim 1 wherein said therapeutic or diagnostic compound is selected from the group consisting of protein growth factors, anticholinergics and antiparasitics.

15. An enhanced drug bioavailability nonaqueous pharmaceutical composition exhibiting a drop delivery volume on the order of 10 μ

l, said composition comprising a mixture of a nonaqueous physiologically acceptable perfluorocarbon liquid carrier and a therapeutic or diagnostic compound incorporated in a particulate polymeric drug delivery vehicle.

16. The enhanced drug bioavailability pharmaceutical composition of claim 15 wherein said mixture is a suspension in said nonaqueous physiologically acceptable perfluorocarbon liquid carrier of said therapeutic or diagnostic compound incorporated in said polymeric dug delivery vehicle.

17. The enhanced drug bioavailability pharmaceutical composition of claim 16 wherein said suspension includes a surfactant.

18. The enhanced drug bioavailability pharmaceutical composition of claim 15 wherein said nonaqueous physiologically acceptable perfluorocarbon liquid carrier is selected from the group consisting of perfluoro (decahydronaphthalene), perfluoro (decahydro-1-methylnaphthalene), perfluoro (decahydrodimethylnaphthalene), perfluoroperhydrophenanthrene, perfluoromethylcyclohexane, perfluoro(1,3-dimethylcyclohexane), perfluorotrimethylcyclohexane, perfluoroisopropylcyclohexane, perfluoro-1-methyl-4-isopropylcyclohexane, perfluoro-n-butylcyclohexane, perfluoroendotetrahydrodicyclopentadiene, perfluoromethyladamantane, perfluorodimethylbicyclo(3.3.1.) nonane, and perfluorotrimethylbicyclo(3.3.1) nonane.

19. The enhanced drug bioavailability pharmaceutical composition of claim 15 wherein said nonaqueous physiologically acceptable perfluorocarbon liquid carrier is selected from the group consisting of perfluorotributylamine and perfluorotriisopropylamine.

20. The enhanced drug bioavailability pharmaceutical composition of claim 15 wherein said nonaqueous physiologically acceptable perfluorocarbon liquid carrier is selected from the group consisting of perfluorotetrahydrofuran and perfluoroether.

21. The enhanced drug bioavailability pharmaceutical composition of claim 15 wherein said therapeutic or diagnostic compound is selected from the group consisting of oligopeptides, antibacterials, antihistaminics, anti-inflammatories, miotics, mydriatics, antiglaucomals, antivirals, carbonic anhydrase inhibitors, antifungals, anesthetics, diagnostics, immunosupporessive agents, and mixtures thereof.

22. The enhanced drug bioavailability pharmaceutical composition of claim 15 wherein said polymeric drug delivery vehicle comprises a plurality of microparticulates, each of said microparticulates being formed of a polymeric matrix incorporating said at least one therapeutic or diagnostic compound.

23. The enhanced drug bioavailability pharmaceutical composition of claim 15 wherein said polymeric drug delivery vehicle is a hydrolytically labile polymer selected from the group consisting of poly(methylvinylether/maleic anhydride), polyfumaric acid/sebacic acid, collagen, gelatin, polyvinyl alcohol, methylcelluloses, polyorthoesters, polyglycolic acid, polylactic acid, polyvinylpyrrolidone, polysebacic acid anhydride, polycarboxyphenoxypropane anhydride, polyterephthalic acid anhydride, and polyphosphazine.

24. The enhanced drug bioavailability pharmaceutical composition of claim 15 wherein said therapeutic or diagnostic compound is selected from the group consisting of protein growth factors, anticholinergics and antiparasitics.