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Claims for Patent: 9,358,297

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Claims for Patent: 9,358,297

Title:Posaconazole intravenous solution formulations stabilized by substituted .beta.-cyclodextrin
Abstract: The present invention relates to aqueous solutions useful as pharmaceutical compositions of posaconazole for intravenous administration. These compositions include a solubilizing agent, such as a modified .beta.-cyclodextrin in an acidified solution, which can also include a chelating agent such as disodium edetate (EDTA). In clinical trials, a 200 mg posaconazole dose of the selected composition was found to achieve acceptable pharmacokinetic properties.
Inventor(s): Heimbecher; Susan K. (Morris Plains, NJ), Monteith; David (Pittstown, NJ), Pipkin; James D. (Lawrence, KS)
Assignee: Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:14/668,683
Patent Claims: 1. A pharmaceutical composition for intravenous administration comprising: 100 mg to 400 mg of posaconazole, or a pharmaceutically acceptable salt thereof; and a modified .beta.-cyclodextrin which comprises sulfobutylether-.beta.-cyclodextrin having a degree of substitution of 6.5 and a molecular weight of 2163 g/mole; in aqueous solution, wherein the pH of said composition is between about 2.0 and about 3.5, wherein the concentration of said posaconazole, or pharmaceutically acceptable salt thereof, is between about 14 and about 22 mg/mL, and the concentration of said modified .beta.-cyclodextrin is between about 350 and about 450 mg/mL.

2. A pharmaceutical composition comprising: 100 mg to 400 mg of posaconazole free base, and a modified .beta.-cyclodextrin which comprises sulfobutylether-.beta.-cyclodextrin having a degree of substitution of 6.5 and a molecular weight of 2163 g/mole, in aqueous solution, wherein the pH of said composition is between 2.0 and 3.5, wherein the concentration of said posaconazole free base is between 14 and 22 mg/mL, and the concentration of said modified .beta.-cyclodextrin is between 350 and 450 mg/mL.

3. The pharmaceutical composition according to claim 2, further comprising a chelating agent.

4. The pharmaceutical composition according to claim 3, wherein said chelating agent is EDTA, and wherein said pH is between 2.3 and 3.0.

5. The pharmaceutical composition according to claim 4, wherein the concentration of said EDTA is between 0.1 and 0.3 mg/mL.

6. The pharmaceutical composition according to claim 4, wherein the concentration of said posaconazole free base is 18 mg/mL, the concentration of said sulfobutylether-.beta.-cyclodextrin is 400 mg/mL, and the concentration of said EDTA is 0.2 mg/mL.

7. The pharmaceutical composition according to claim 6 further comprising hydrochloric acid and/or sodium hydroxide in an amount sufficient to adjust the pH to 2.6 TABLE-US-00014 Components Quantity Posaconazole about 18 mg/mL sulfobutyl ether-.beta.-cyclodextrin, about 400 mg/mL (185 mM) sodium salt, molecular weight 2163 g/ mole (degree of substitution = 6.5), solubility >800 mg/mL in water Disodium Edetate (EDTA) about 0.2 mg/mL 1N Hydrochloric Acid sufficient quantity to adjust to pH of about 2.6 1N Sodium Hydroxide sufficient quantity to adjust to pH of about 2.6 Water q.s. ad 1 mL

8. A method of treating or prophylaxis of an infection in a human in need thereof which comprises administering to said human an effective amount of the pharmaceutical composition of claim 2.

9. The method of claim 8 where said infection is caused by a fungus or a parasite.

10. The method of claim 8 wherein said infection is one or more selected from the group consisting of: invasive aspergillosis, candidiasis, fusarriosis, scedosporiosis, infections due to dimorphic fungi, zygomycosis, and invasive infections due to rare molds and yeasts; invasive mycoses in patients who are refractory to, or intolerant of, other therapies; Candidiasis, invasive mold infections in patients who have undergone intensive chemotherapy and/or radiation therapy for hematologic malignancies, bone marrow or peripheral stem cell transplant conditioning regimes, and patients receiving combination immunosuppressive therapy for the treatment of acute or chronic graft-versus-host disease or solid organ transplantation; Chagas disease; and Leishmaniasis.

11. The pharmaceutical composition according to claim 2, wherein after said composition has been injected into an infusion bag, the composition and an infusate have been admixed, and the resulting admixture has been allowed to stand for up to 24 hours, no posaconazole free base precipitate is visible.

12. The method of claim 8 for prophylaxis of invasive Aspergillus and Candida infection.

13. The method according to claim 8 wherein administration of said pharmaceutical composition occurs once per day.

14. The method according to claim 8 wherein administration of said pharmaceutical composition occurs twice per day.

15. The method of claim 8 further comprising administering a second active ingredient selected from one or more of the group consisting of antifungals, antibacterials, antivirals, steroids, nonsteroidal anti-inflammatory drugs, chemotherapeutics and anti-emetics.

16. The method of claim 15 wherein said antifungals are selected from the group consisting of azoles, echinocandin, allylamine, polyene, flucytosine, benzoic acid, ciclopirox, 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborate, tolnaftate, undecyclenic acid, griseofulvin and haloprogin.

17. A pharmaceutical composition made by adding diluent to the composition of claim 2.

18. The pharmaceutical composition of claim 17 wherein the diluent is selected from normal saline solution and 5% dextrose solution.

19. A method of treating or prophylaxis of an infection in a human in need thereof which comprises administering the composition of claim 17 in an amount sufficient to deliver a dose of from 100 mg to 400 mg of posaconazole free base to said human.

20. The method of claim 19 wherein administration of said dose occurs once per day.

21. The method of claim 19 wherein administration of said dose occurs twice per day.

22. The method of claim 19 where said infection is caused by a fungus or a parasite.

23. The method of claim 19 wherein said infection is one or more selected from the group consisting of: invasive aspergillosis, candidiasis, fusarriosis, scedosporiosis, infections due to dimorphic fungi, zygomycosis, and invasive infections due to rare molds and yeasts; invasive mycoses in patients who are refractory to, or intolerant of, other therapies; Candidiasis, invasive mold infections in patients who have undergone intensive chemotherapy and/or radiation therapy for hematologic malignancies, bone marrow or peripheral stem cell transplant conditioning regimes, and patients receiving combination immunosuppressive therapy for the treatment of acute or chronic graft-versus-host disease or solid organ transplantation; Chagas disease; and Leishmaniasis.

24. The method of claim 19 for prophylaxis of invasive Aspergillus or Candida infection.

25. The method of claim 19 further comprising administering a second active ingredient selected from one or more of the group consisting of antifungals, antibacterials, antivirals, steroids, nonsteroidal anti-inflammatory drugs, chemotherapeutics and anti-emetics.

26. The method of claim 25 wherein said antifungals are selected from the group consisting of azoles, echinocandin, allylamine, polyene, flucytosine, benzoic acid, ciclopirox, 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborate, tolnaftate, undecyclenic acid, griseofulvin and haloprogin.

27. A method of treating or prophylaxis of an infection in a human in need thereof which comprises administering the composition of claim 18 in an amount sufficient to deliver a dose of from 100 mg to 400 mg of posaconazole to said human.

28. The method according to claim 27 wherein said administration occurs once per day.

29. The method according to claim 27 wherein said administration occurs twice per day.

30. The method of claim 27 where said infection is caused by a fungus or a parasite.

31. The method of claim 27 wherein said infection is one or more selected from the group consisting of: invasive aspergillosis, candidiasis, fusarriosis, scedosporiosis, infections due to dimorphic fungi, zygomycosis, and invasive infections due to rare molds and yeasts; invasive mycoses in patients who are refractory to, or intolerant of, other therapies; Candidiasis, invasive mold infections in patients who have undergone intensive chemotherapy and/or radiation therapy for hematologic malignancies, bone marrow or peripheral stem cell transplant conditioning regimes, and patients receiving combination immunosuppressive therapy for the treatment of acute or chronic graft-versus-host disease or solid organ transplantation; Chagas disease; and Leishmaniasis.

32. The method of claim 27 for prophylaxis of invasive Aspergillus or Candida infection.

33. The method of claim 27 further comprising administering a second active ingredient selected from one or more of the group consisting of antifungals, antibacterials, antivirals, steroids, nonsteroidal anti-inflammatory drugs, chemotherapeutics and anti-emetics.

34. The method of claim 33 wherein said antifungals are selected from the group consisting of azoles, echinocandin, allylamine, polyene, flucytosine, benzoic acid, ciclopirox, 1,3-dihydro-5-fluoro-1-hydroxy-2,1-benzoxaborate, tolnaftate, undecyclenic acid, griseofulvin and haloprogin.
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