Nonaqueous fluorinated drug delivery suspensions

• US 6,458,376 B1
• Filed: 12/30/1993
• Issued: 10/01/2002
• 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 Louis
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/179,508
• Time in Patent Office: 3,197 Days
• Field of Search: 424/427, 514/912-914
• 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 suspension of nonaqueous perfluorocarbon or fluorinated silicone liquid carriers. The suspended drug may be water labile or water stable and therapeutic or diagnostic compounds which will remain stable and pharmaceutically effective for extended periods. The pharmaceutical compositions have improved bioavailability, are capable of low dose volume delivery, and do not degrade the incorporated therapeutic or diagnostic compounds making them well suited for multi-dose packaging and administration.

Claims

1. A nonaqueous multi or unit dose pharmaceutical composition comprising:

a drop instillable suspension of a pharmaceutically effective amount of a therapeutic or diagnostic compound in a nonaqueous physiologically acceptable perfluorocarbon liquid carrier, said suspension including a surfactant and forming a dose volume of greater than 1 microliter and less than 20 microliters.

2. The multi or unit dose pharmaceutical composition of claim 1 wherein said dose volume is 6 microliters to 12 microliters.

3. The multi or unit dose pharmaceutical composition of claim 1 wherein said nonaqueous physiologically acceptable perfluorocarbon liquid carrier is selected from the group consisting of perfluorocyclocarbons, nitrogen containing perfluorocyclocarbon derivatives, oxygen containing perfluorocyclocarbon derivatives, acyclic perfluorocarbons, nitrogen containing acyclic perfluorocarbon derivatives, and oxygen containing acyclic perfluorocarbon derivatives.

4. The multi or unit dose pharmalceutical 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(3.3.1.)nonane.

5. The multi or unit dose pharmaceutical composition of claim 1 wherein said nonaqueous physiologically acceptable perfluorocarbon liquid carrier is selected from the group consisting of perfluoro(decahydronaphthalene) and perfluoroperhydrophenanthrene.

6. The multi or unit dose 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 multi or unit dose 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 multi or unit dose pharmaceutical composition of claim 1 wherein said therapeutic or diagnostic compound is selected from the group consisting of oligopeptides, antihistaminics, anti-inflammatories, miotics, anticholinergics, antiglaucomals, antiparasitics, carbonic anhydrase inhibitors, anesthetics, diagnostics, and immunosuppressive agents, and mixtures thereof.

9. The multi or unit dose pharmaceutical composition of claim 1 wherein said therapeutic or diagnostic compound is selected from the group consisting of epithelial growth factor, dipivefrin, levo-bunolol hydrochloride, pilocarpine, sodium fluorescein, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, tobramycin, ciprofloxacin, norfloxacin, penicillin, erythromycin, cefazolin, ceftazadime, imipenem, idoxuridine, hydrocortisone, dexamethasone dexamethasone-21-phosphate, fluocinolone, medrysone, prednisolone acetate, fluormetholone, betamethasone, phenylephrine, eserine salicylate, carbachol, echothiophate iodide, demecarium bromide, cyclopentolate, homatropine, scopolamine, epinephrine, ibuprofen, aceclidine, teretinoin, and pirenoxine.

14. The multi or unit dose pharmaceutical composition of claim 1 wherein said dose volume is greater than 1 microliter and less than 10 microliters.

16. The multi or unit dose pharmaceutical composition of claim 1 wherein said therapeutic or diagnostic compound is selected from the group consisting of protein growth factors, antibacterials, antivirals, antifungals, mydriatics, and mixtures thereof.

10. A method for delivering pharmaceutical compounds to a physiologic target site, said method comprising the steps of:

providing a nonaqueous drop instillable pharmaceutical composition comprising a suspension of a therapeutic or diagnostic compound in a nonaqueous physiologically acceptable perfluorocarbon liquid carrier, said suspension including a surfactant; and

administering a pharmaceutically effective amount of said drop instillable pharmaceutical composition to said target site in a dose volume greater than 1 microliter and less than 20 microliters.

11. The method of claim 10 wherein said nonaqueous perfluorocarbon liquid carrier is selected from the group consisting of perfluorocyclocarbons, nitrogen containing perfluorocyclocarbon derivatives, oxygen containing perfluorocyclocarbon derivatives, acyclic perfluorocarbons, nitrogen containing acyclic perfluorocarbon derivatives, and oxygen containing acyclic perfluorocarbon derivatives.

12. The method of claim 10 wherein said dose by, volumes 6 microliters to 12 microliters.

13. The method of claim 10 wherein said target site is the eye.

15. The method of claim 10 wherein said dose volume is greater than 1 microliter and less than 10 microliters.