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(12) Patent Application Publication (10) Pub. No.: US 2007/0082870 A1 Buchanan Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0082870 A1 Buchanan Et Al US 20070082870A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0082870 A1 Buchanan et al. (43) Pub. Date: Apr. 12, 2007 (54) PHARMACEUTICAL FORMULATIONS OF Related U.S. Application Data CYCLODEXTRINS AND ANTIFUNGAL AZOLE COMPOUNDS (60) Provisional application No. 60/724,792, filed on Oct. 11, 2005. (76) Inventors: Charles Michael Buchanan, Kingsport, TN (US); Norma Lindsey Buchanan, Publication Classification Kingsport, TN (US); Juanelle Little Lambert, Gray, TN (US) (51) Int. Cl. A6II 3L/724 (2006.01) Correspondence Address: A6II 3L/496 (2006.01) FINNEGAN, HENDERSON, FARABOW, (52) U.S. Cl. ......................................... 514/58: 514/254.07 GARRETT & DUNNER LLP (57) ABSTRACT 901 NEW YORK AVENUE, NW WASHINGTON, DC 20001-4413 (US) This invention relates to methods of increasing the aqueous solubility of an antifungal azole using hydroxybutenyl (21) Appl. No.: 111545,516 cyclodextrins. This invention also relates to method of increasing the bioavailability of an antifungal azole com (22) Filed: Oct. 11, 2006 pounds administered to Subjects. Patent Application Publication Apr. 12, 2007 Sheet 1 of 8 US 2007/0082870 A1 Figure 1 ONone OHBenBCD HPBCD SBEBCD 4.5 0. 3 0. 2 Patent Application Publication Apr. 12, 2007 Sheet 2 of 8 US 2007/0082870 A1 Figure 2 HBenBCD (water) HBenBCD (pH 3 buffer) HPBCD (pH 3 buffer) a . SBEBCD (pH 3 buffer) o 25 50 75 100 125 150 175 200 225 250 275 CD (g/L) Patent Application Publication Apr. 12, 2007 Sheet 3 of 8 US 2007/0082870 A1 Figure 3 HBenBCD 2O 14 Patent Application Publication Apr. 12, 2007 Sheet 4 of 8 US 2007/0082870 A1 Figure 4 1 2 D None HBenBCD 1 O 3. 8 Patent Application Publication Apr. 12, 2007 Sheet 5 of 8 US 2007/0082870 A1 Figure 5 s O HBenBCD A SBEBCD O 50 100 150 200 250 300 350 400 450 CD (g/L) Patent Application Publication Apr. 12, 2007 Sheet 6 of 8 US 2007/0082870 A1 Figure 6 2.50 2.OO A HPBCD 1.75 1.50 1.25 1.OO O.75 0.50 O.25 O.OO O 25 50 75 100 125 150 175 200 225 250 275 CD (g/L) Patent Application Publication Apr. 12, 2007 Sheet 7 of 8 US 2007/0082870 A1 Figure 7 120 110 CS 100 6 O O 2 3 4. 5 6 7 Time (h) itz:HBenBCD pH 1.2 itz:HBenBCD pH 4.5 itz:HBenBCD:chitosan pH 1.2 itz:HBenBCD:chitosan pH 4.5 Sporanox pH 1.2 Sporanox pH 4.5 Patent Application Publication Apr. 12, 2007 Sheet 8 of 8 US 2007/0082870 A1 Figure 8 700 600 40O 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Time (h) US 2007/0O82870 A1 Apr. 12, 2007 PHARMACEUTICAL FORMULATIONS OF 0006. One treatment of cutaneous and systemic fungal CYCLODEXTRINS AND ANTIFUNGALAZOLE infections has been by the administration of antifungal azole COMPOUNDS compounds. Antifungal azole compounds are structurally diverse and are characterized by having imidazole or a 0001. This application claims the benefit of priority of triazole functionalities. This class includes such drugs as U.S. Provisional Patent Application Ser. No. 60/724,792, itraconazole, ketoconazole, fluconazole, Saperconazole, filed Oct. 11, 2005. miconazole, ravunconazole, posaconazole, Voriconazole and several others. Many compounds in this class, although FIELD OF THE INVENTION highly effective antifungal agents, are not widely used 0002 This invention relates to methods of increasing the clinically because of their poor water solubility and, as a aqueous solubility of an antifungal azole using hydroxy result, poor bioavailability. butenyl cyclodextrins. This invention also relates to method of increasing the bioavailability of an antifungal azole SUMMARY OF THE INVENTION compounds administered to Subjects. 0007. Applicants have developed methods of increasing BACKGROUND OF THE INVENTION the aqueous solubility of an antifungal azole compound comprising forming a complex or mixture of at least one 0003 Cyclodextrins (CDs) are cyclic oligomers of glu antifungal azole compound with a hydroxybutenyl cyclo cose joined by C-1.4 linkages. The most common cyclodex dextrin. trins contain 6, 7, or 8 glucose monomers and are commonly called C-CD, B-CD, and Y-CD, respectively. Higher oligo 0008. In certain embodiments, the hydroxybutenyl cyclo mers containing up to 12 glucose monomers are also known. dextrin is hydroxybutenyl-C. B. or Y-cyclodextrin. In other Topologically, CD can be represented as a toroid in which embodiments, the hydroxybutenyl cyclodextrin is hydroxy the primary hydroxyls are located on the smaller circumfer butenyl-f-cyclodextrin. ence, and the secondary hydroxyls are located on the larger 0009. In some embodiments, the hydroxybutenyl cyclo circumference. Because of this arrangement, the interior of dextrin has a molar substitution of about 1 to about 12, or the torus is hydrophobic while the exterior is sufficiently from about 3 to about 10, or from about 4 to about 7. In other hydrophilic to allow the CD to be dissolved in water. This embodiments, the hydroxybutenyl cyclodextrin Is water difference between the interior and exterior faces allows the soluble. CD to act as a host molecule and to form inclusion com plexes with guest molecules, provided the guest molecule is 0010. In certain embodiments, the hydroxybutenyl cyclo of the proper size to fit in the cavity. The CD inclusion dextrin derivative is sulfonated hydroxybutenyl cyclodex complex can then be dissolved in water thereby providing trin; in others, Sulfonated hydroxybutenyl-C, B, or Y-cyclo for the introduction of guest molecules that have little or no dextrin hydroxybutenyl; and in others, sulfonated aqueous solubility into an aqueous environment. Reviews of hydroxybutenyl-B-cyclodextrin. CD complexes can be found in Chem. Rev., 1997, 97,1325 0011. In some embodiments, the sulfonated hydroxybute 1357 and in Supramolecular Chemistry, 1995, 6, 217-223. nyl cyclodextrin has a molar substitution-of sulfonate of 0004 Unmodified cyclodextrins, especially B-cyclodex about 0.02 to about 12, and in other embodiments, from trin, have limited aqueous solubility, and can crystallize about 0.1 to about 2. from Solution, particularly after renal concentration. This 0012. In certain embodiments, the antifungal azole com means that the ability of unmodified cyclodextrins to solu pound is an imidazole or triazole compound. In other bilize and stabilize guest molecules in an aqueous environ embodiments, the antifungal azole compound is albacona ment is limited. Furthermore, unmodified cyclodextrins, e.g. Zole, becliconazole, bifonazole, bilastine, butoconazole, car B-cyclodextrin, have been shown to cause renal and liver bendazim, clotrimazole, doconazole, eberconazole, econa damage after parenteral administration. These issues have Zole, fenticonazole, fluconazole, flutrimazole, led to exploration of the use of chemically modified or fosfluconazole, genaconazole, imiquimod, itraconazole, derivatized cyclodextrins that avoid these problems. Two ketoconazole, lanoconazole, liaroZole, luliconazole, metron examples of derivatized cyclodextrins are hydroxybutenyl idazole, miconazole, mycoprex, omoconazole, parconazole, cyclodextrins (HBenCD), which are disclosed in U.S. Pat. posaconazole, ravunconazole, residuimod, rifaximin, Sami No. 6,479,467 (2002) and in Carbohydrate Research, 2002, dazole, Saperconazole, seraconazole, terconazole, or Vori 327(6), 493-507, and sulfonated hydroxybutenyl cyclodex conazole or structural analogs or metabolites thereof. In trins (SulfoHBenCD), which are disclosed in U.S. Pat. No. alternative embodiments, the antifungal azole compound is 6.479,467. These CD derivatives solve many of the issues noted for the parent unmodified CDs. itraconazole, Voriconazole, ravunconazole, or posaconazole. 0013 In alternative embodiments, the aqueous solubility 0005 Unmodified cyclodextrins and cyclodextrin deriva of the antifungal azole compound as a complex or mixture tives have been used to increase the solubility, dissolution with the hydroxybutenyl cyclodextrin is from about 1.1 to rate, and/or stability of many different types of compounds. about 1000 times greater, from about 2 to about 100 times It has also been found that for many compounds, complex greater, from about 2 to about 50 times greater, from about ation with cyclodextrins either is not possible or yields no 2 to about 25 times greater, or from about 2 to about 5 times advantage. Structurally different cyclodextrin derivatives greater than the aqueous solubility of the antifungal azole can also provide dramatically different solubilization rates, compound without the hydroxybutenyl cyclodextrin. dissolution rates, and stabilization of drugs under otherwise similar conditions (cf. Cyclodextrins in Drug Formulations: 0014) Another aspect of the invention is a method of Part II, Pharmaceutical Technology, 1991, 24-38). increasing the aqueous solubility of an antifungal azole US 2007/0O82870 A1 Apr. 12, 2007 compound comprising forming a complex or mixture of an 0024 FIG. 5 shows the equilibrium solubility of vori antifungal azole compound with a hydroxybutenyl cyclo conazole in pH 3 succinate buffer from 0 to ca. 40 wt % dextrin in the presence of a chiral compound or salt. In cyclodextrin concentrations. Abbreviations: HBenBCD, certain embodiments, the method further comprises match hydroxybutenyl-B-cyclodextrin; SBEBCD, sulfobutyl-3-cy ing the Stereochemical configuration of the antifungal azole clodextrin. compound, the hydroxybutenyl cyclodextrin and the chiral compound. 0025 FIG. 6 shows equilibrium solubility of clotrimazole in water from 0 to ca. 25 wt % cyclodextrin concentrations. 0015. In alternative embodiments of the invention, the Abbreviations: HBenBCD, hydroxybutenyl-3-cyclodextrin; chiral compound is citric acid or a salt thereof, tartaric acid HPBCD, hydroxypropyl-3-cyclodextrin. or a salt thereof, D-tartaric acid or a salt thereof, or L-tartaric 0026 FIG. 7 shows the dissolution profiles of itracona acid or a salt thereof. Zole:HBenBCD complexes. 0016. Another aspect of the invention is a method of increasing the bioavailability of an antifungal azole com 0027 FIG. 8 shows a time versus concentration plot from pound comprising administering a complex or mixture of an a study involving IV and oral administration of itracona antifungal azole compound with a hydroxybutenyl cyclo Zole:HBenBCD complexes to Sprague-Dawley rats.
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