Azole pharmaceutical formulations for parenteral administration and methods for preparing and using the same as treatment of diseases sensitive to azole compounds
A parenteral azole composition comprises a first solvent, made of benzyl alcohol and/or an acidified alcohol such as ethanol, and a lipophilic component such as PEG400, and the azole, or triazole, such as itraconazole or posaconazole dissolved in this first composite solvent vehicle that is essentially free of surfactants, particularly non-ionic surfactants, and has low levels of water, preferably less than 5% water. The composition may be further diluted with an infusion fluid, such as normal saline or 5% or 10% dextrose in water, before infusion into an immunocompromized mammal, preferably a human. The composition is useful for the treatment and suppression of infections caused by microbes such as yeast and molds that are sensitive to azoles, but it may be extended to dissolve other pharmaceutically active agents that can be used to treat other types of infectious diseases or other ailments, such as malignant and autoimmune diseases.
1. A clinically acceptable infusion fluid comprising a composition diluted with an infusion fluid selected from the group consisting of normal saline, dextrose in water, and a lipid-based infusion emulsion fluid, wherein the composition is a pharmaceutical composition suitable for parenteral administration comprising an azole antifungal pharmaceutical agent and a first solvent, said first solvent comprising a) an alcohol component selected from benzyl alcohol and/or acidified ethanol, and b) a polyethylene glycol solvent (PEG), wherein the azole agent is dissolved in said first solvent, wherein the composition is essentially free of non-ionic surfactants and particulates and comprises less than 5% water (v/v).
2. The clinically acceptable infusion fluid of claim 1 , wherein said infusion fluid is dextrose in water.
3. The clinically acceptable infusion fluid of claim 1 , wherein said fluid comprises between 1 mg/ml and 5 mg/ml of the azole agent after dilution in said infusion fluid.
4. The clinically acceptable infusion fluid of claim 1 wherein said azole pharmaceutical agent is stable for at least 12 hours at room temperature.
5. The clinically acceptable infusion fluid of claim 1 , wherein the composition is further defined as comprising less than 3% water (v/v).
6. The clinically acceptable infusion fluid of claim 5 , wherein the composition is further defined as comprising less than 1% water (v/v).
7. The clinically acceptable infusion fluid of claim 6 , wherein the composition is further defined as essentially free of water.
8. The clinically acceptable infusion fluid of claim 1 , wherein said first solvent of the composition comprises both acidified ethanol and benzyl alcohol.
9. The clinically acceptable infusion fluid of claim 1 , wherein the first solvent of the composition comprises acidified ethanol.
10. The clinically acceptable infusion fluid of claim 9 , wherein the acidified ethanol of the composition is further defined as a combination of ethanol and an acid, and the first solvent has a pH of from about 1 to about 5.
11. The clinically acceptable infusion fluid of claim 10 , wherein the first solvent of the composition has a pH of from about 3 to about 4.
12. The clinically acceptable infusion fluid of claim 10 , wherein the acid of the composition is HCl, citric acid, acetic acid or glutamic acid.
13. The clinically acceptable infusion fluid of claim 1 , wherein the ratio of PEG to alcohol in the composition is from 27 to 2 (v/v).
14. The clinically acceptable infusion fluid of claim 13 , wherein the ratio of PEG to alcohol in the composition is from 12 to 8 (v/v).
15. The clinically acceptable infusion fluid of claim 1 , wherein said PEG of the composition is selected from the group consisting of PEG-100, PEG-200, PEG-300, PEG-400 and PEG-800.
16. The clinically acceptable infusion fluid of claim 15 , wherein the polyethylene glycol of the composition is PEG-400.
17. The clinically acceptable infusion fluid of claim 1 , wherein the first solvent of the composition comprises from 10% to 90% (v/v) PEG.
18. The clinically acceptable infusion fluid of claim 17 , wherein the first solvent of the composition comprises from 30% to 90% (v/v) PEG.
19. The clinically acceptable infusion fluid of claim 1 , wherein the first solvent of the composition comprises from 40% to 80% (v/v) PEG.
20. The clinically acceptable infusion fluid of claim 1 , wherein the alcohol component of the composition is from 1% to 99% of the first solvent (v/v).
21. The clinically acceptable infusion fluid of claim 20 , wherein the alcohol component of the composition is from 5% to 60% of the first solvent (v/v).
22. The clinically acceptable infusion fluid of claim 21 , wherein the alcohol component of the composition is from 10% to 40% of the first solvent (v/v).
23. The clinically acceptable infusion fluid of claim 1 , wherein the azole pharmaceutical agent of the composition is an imidazole, triazole or thiazole.
24. The clinically acceptable infusion fluid of claim 23 , wherein the azole pharmaceutical agent of the composition is miconazole, ketoconazole, clotrimazole, econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole or abafungin.
25. The clinically acceptable infusion fluid of claim 24 , wherein the azole agent of the composition is itraconazole.
26. The clinically acceptable infusion fluid of claim 24 , wherein the azole agent of the composition is posconazole.
27. The clinically acceptable infusion fluid of claim 1 , wherein said composition comprises between 3 mg/ml to 25 mg/ml of the azole pharmaceutical agent.