Claims
- 1. A soluble crystalline form of cis-itraconazole posaconazole or saperconazole comprising the reaction product of cis-itraconazole, posaconazole or saperconazole and an organic acid or an inorganic acid.
- 2. The soluble crystalline form of claim 1, wherein:
(a) the soluble crystalline form is the reaction product of cis-itraconazole and a dicarboxylic acid; (b) the soluble crystalline form is the reaction product of cis-itraconazole and a carboxylic acid; (c) the soluble crystalline form is the reaction product of cis-itraconazole and an inorganic acid; (d) the soluble crystalline form is the reaction product of cis-itraconazole and an organic acid; (e) the soluble crystalline form is a solvate; (f) the solvate of (e) is formed from an organic solvent; (g) the solvent of (e) is an alcohol; (h) the solvent of (g) is ethanol; (i) the solvent of (e) is dioxane; (j) the soluble crystalline form is a D, L, or D,L-tartaric acid co-crystal, citric acid co-crystal, fumaric acid co-crystal, malonic acid co-crystal, maleic acid co-crystal, adipic acid co-crystal, succinic acid co-crystal, D, L, or D,L-malic acid co-crystal, HCl salt tartaric acid co-crystal, tosylate tartaric acid co-crystal, other co-crystals, or salts, solvates, hydrates and other multicomponent crystal systems comprising a co-crystal thereof; (k) the soluble crystalline form comprises an acid salt selected from di-hydrocholoride, tosylate, phosphate, sulfate, besylate, di-mesylate, other salts or co-crystals, solvates, hydrates and other multicomponent crystal systems comprising a salt thereof; (l) the soluble crystalline form comprises an acid salt formed by the reaction of cis-itraconazole, posaconazole, or saperconazole, and both hydrochloric acid and a compound selected from D, L, or D,L-tartaric acid, fumaric acid, citric acid, malonic acid, D,L or D,L-maleic acid, adipic acid, succinic acid, or malic acid; (m) the soluble crystalline form is a co-crystal; (n) the soluble crystalline form is a salt; (o) the soluble crystalline form is an organic salt; (p) the soluble crystalline form is an inorganic salt; (q) the soluble crystalline form comprises a trimeric congener; (r) the soluble crystalline form of (q) wherein the trimeric congener consists of three different molecules; (s) the soluble crystalline form is an ethanol, hemi-ethanol or dioxane solvate of a di-mesylate salt; (t) the soluble crystalline form is a propylene glycol solvate; (u) the soluble crystalline form is an ether solvate; (v) the soluble crystalline form of (u), wherein the ether is THF, t-butylmethyl ether, or di-isopropyl ether; (w) the soluble crystalline form is an isopropylacetate solvate; (x) the soluble crystalline form is a form of cis-itraconazole characterized by a powder X-ray diffraction pattern comprising peaks expressed in terms of 2 theta angles, wherein:
(i) said form is a DL-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 16.9, 17.3 and 21.0; (ii) said form is a DL-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 6.2, 8.8, 16.0, and 26.2; (iii) said form is a DL-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 6.2, 8.8, 16.0, 16.9, 17.3, 21.0 and 26.2; (iv) said form is a phosphate salt and said X-ray diffraction pattern comprises a peak at 3.2; (v) said form is a phosphate salt and said X-ray diffraction pattern comprises peaks at 3.2, 5.5 and 9.6; (vi) said form is a phosphate salt and said X-ray diffraction pattern comprises peaks at 3.2, 17.4 and 20.5; (vii) said form is a phosphate salt and said X-ray diffraction pattern comprises peaks at 3.2, 5.5 and 23.5; (viii) said form is a phosphate salt and said X-ray diffraction pattern comprises peaks at 3.2, 5.5, 9.6, 17.4, 20.5 and 23.5; (ix) said form is a sulfate salt and said X-ray diffraction pattern comprises a peak at 3.6; (x) said form is a sulfate salt and said X-ray diffraction pattern comprises peaks at 3.6 and 8.2; (xi) said form is a sulfate salt and said X-ray diffraction pattern comprises peaks at 3.6, 8.2 and 13.6; (xii) said form is a fumaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 19.1 and 20.8; (xiii) said form is a fumaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.6, 5.9, 16.2 and 17.0; (xiv) said form is a fumaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.6, 5.9, 16.2, 19.1 and 20.8; (xv) said form is a besylate salt and said X-ray diffraction pattern comprises peaks at 3.4, 20.1 and 25; (xvi) said form is a besylate salt and said X-ray diffraction pattern comprises peaks at 3.4, 18.5, 20.1 and 25; (xvii) said form is a sulfate salt and said X-ray diffraction pattern comprises a peak at 13.5; (xviii) said form is a sulfate salt and said X-ray diffraction pattern comprises peaks at 3.6 and 13.5; (xix) said form is a sulfate salt and said X-ray diffraction pattern comprises peaks at 13.5, 19.4, 22.9, 24.3 and 27.0; (xx) said form is a L-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.1, 6.2, 8.3 and 20.7; (xxi) said form is a L-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.1 and 6.2; (xxii) said form is a L-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 8.3 and 20.7; (xxiii) said form is a L-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.6, 6.2, 8.3, 20.7, 25.6 and 26.3; (xxiv) said form is a D-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 7.2 and 11.8; (xxv) said form is a D-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 7.2, 11.8 and 20.8; (xxvi) said form is a D-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.1, 6.2, 7.2 and 8.3; (xxvii) said form is a D-tartaric and said X-ray diffraction pattern comprises peaks at 4.1, 6.2, 8.3 and 11.8; (xxviii) said form is a D-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.1, 6.2, 7.2, 8.3, 11.8 and 20.8; (xxix) said form is a DL-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 22.6; (xxx) said form is a DL-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 15.9 and 22.6; (xxxi) said form is a DL-tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 6.1, 8.8, 16.9, 17.3, and 21.0; (xxxii) said form is a succinic acid co-crystal and said X-ray diffraction pattern comprises peaks at 17.1; (xxxiii) said form is a succinic acid co-crystal and said X-ray diffraction pattern comprises peaks at 3.0, 17.1 and 24.5; (xxxiv) said form is a L-malic acid co-crystal and said X-ray diffraction pattern comprises peaks at 17.7; (xxxv) said form is a L-malic acid co-crystal and said X-ray diffraction pattern comprises peaks at 5.9 and 17.7; (xxxvi) said form is a L-malic acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.4, 17.7, 20.0 and 22.6; (xxxvii) said form is a L-malic acid co-crystal and said X-ray diffraction pattern comprises peaks at 4.4, 5.9, 17.7, 20.0 21.1 and 22.6; (xxxviii) said form is a L-malic acid co-crystal and said X-ray diffraction pattern comprises peaks at 17.0 and 20.5; (xxxix) said form is a L-malic acid co-crystal and said X-ray diffraction pattern comprises peaks at 6.0, 17.0, 20.5, 21.3 and 22.8; (xl) said form is a HCl salt tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 3.7 and 17.8; (xli) said form is a HCl salt tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 3.7, 11.0, 13.8, 16.5, and 17.8; (xlii) said form is a di-mesylate dioxane solvate and said X-ray diffraction pattern comprises peaks at 16.2 and 19.0; (xliii) said form is a di-mesylate dioxane solvate and said X-ray diffraction pattern comprises peaks at 6.5, 9.1, 19.0, 22.4 and 23.8; (xliv) said form is a di-mesylate dioxane solvate and said X-ray diffraction pattern comprises peaks at 22.4; (xlv) said form is a mesylate ethanolate and said X-ray diffraction pattern comprises peaks at 21.7; (xlvi) said form is a mesylate ethanolate and said X-ray diffraction pattern comprises peaks at 9.0, 16.3 and 19.2; (xlvii) said form is a mesylate ethanolate and said X-ray diffraction pattern comprises peaks at 9.0, 16.3, 19.2 and 21.7; (xlviii) said form is a tosylate and said X-ray diffraction pattern comprises peaks at 3.1, 9.35, 17.8 and 21.2; (xlix) said form is a tosylate tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 6.2; or (l) said form is a tosylate tartaric acid co-crystal and said X-ray diffraction pattern comprises peaks at 3.1, 6.2, 9.3, 17.9, and 21.25; or (x) the soluble crystalline form is a cis-itraconazole HCl salt-tartaric acid co-crystal; (y) the soluble crystalline form has solubility of at least that of the free base; (z) the soluble crystalline form has a solubility at least 5 times great than the free base; (aa) the soluble crystalline form has a dissolution rate that is at least 5 times greater than the free base; (bb) the soluble crystalline form has a dissolution rate that is at least 10 times greater than the free base; (cc) the soluble crystalline form has a dissolution rate that is at least 50 times greater than the free base; (dd) the soluble crystalline form absorbs less than 1% of its weight when cycled between 10 and 75% relative humidity at 25 degrees C. over 24 hours; (ee) the soluble crystalline form absorbs less than 0.5% of its weight when cycled between 10 and 75% relative humidity at 25 degrees C. over 24 hours; (ff) the soluble crystalline form is less hydroscopic than the crystalline or amorphous free base; (gg) the soluble crystalline form is a form of cis-itraconazole characterized by an endothermic transition observed using DSC analysis wherein:
(i) said form is a D,L-tartaric acid co-crystal and said endothermic transition is 174.1+/−1.0 degrees C. (ii) said form is a phosphate salt and said endothermic transition is 142.2+/−1.0 degrees C. (iii) said form is a sulfate salt and said endothermic transition is 222.9+/−2.0 degrees C. (iv) said form is a fumaric acid co-crystal and said endothermic transition is 178.1+/−1.0 degrees C. (v) said form is a L-tartaric acid co-crystal and said endothermic transition is 182.5+/−1.0 degrees C. (vi) said form is a D-tartaric acid co-crystal and said endothermic transition is 181.6+/−1.0 degrees C. (vii) said form is a D,L-tartaric acid co-crystal and said endothermic transition is 174.9+/−1.0 degrees C. (viii) said form is a succinic acid co-crystal and said endothermic transition is 161.0+/−1.0 degrees C. (ix) said form is a L-malic acid co-crystal and said endothermic transition is 156.6+/−1.0 degrees C. (x) said form is a di-HCl salt and said endothermic transition is 113-120+/−1.0 degrees C. (xi) said form is a L-malic acid co-crystal and said endothermic transition is 154.4+/−1.0 degrees C. (xii) said form is a HCl salt-tartaric acid co-crystal and said endothermic transition is 161.0+/−1.0 degrees C. (xiii) said form is a di-mesylate salt dioxane solvate and said endothermic transition is 149.0+/−1.0 degrees C. (xiv) said form is a di-mesylate salt ethanol solvate and said endothermic transition is 135.0+/−1.0 degrees C. (xv) said form is a tosylate salt and said endothermic transition is 119.1+/−1.0 degrees C. (xvi) said form is a tosylate salt-tartaric acid co-crystal and said endothermic transition is 124.7+/−1.0 degrees C.
- 3. A soluble, pharmaceutically acceptable salt, co-crystal, or multicomponent crystal system of the crystalline form of claim 2.
- 4. A pharmaceutically acceptable composition comprising the soluble crystalline form of claim 2.
- 5. A pharmaceutically acceptable salt or co-crystal of the compound of formula (I):
- 6. The pharmaceutically acceptable salt or co-crystal of claim 5, wherein the salt or co-crystal is selected from a di-mesylate salt, a tartaric acid co-crystal, a fumaric acid co-crystal, a malonic acid co-crystal, a maleic acid co-crystal, an adipic acid co-crystal, a malic acid co-crystal, a succinic acid co-crystal, a di-HCl salt or HCl co-crystal, a phosphate salt, a sulfate salt or a benzenesulfonate salt, or a pharmaceutically acceptable hydrate, solvate or polymorph of multicompont crystal system thereof.
- 7. The pharmaceutically acceptable salt or co-crystal of claim 5, wherein the cis-itraconazole is a stereoisomeric form selected from the group consisting of:
(+)-[2R-[2α,4α,4(R)]-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, (+)-[2R-[2α,4α,4(S)]-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, (−)-[2S-[2α,4α,4(R)]-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, and (−)-[2S-[2α,4α,4(S)]-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one (also referred to as the (S,R,S) stereoisomer), and diastereomeric pairs thereof.
- 8. A pharmaceutical composition comprising the reaction product of a conazole and a dicarboxylic acid represented by formula (II):
- 9. A soluble, pharmaceutically acceptable co-crystal of a conazole.
- 10. A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 2.
- 11. The pharmaceutical dosage form of claim 10, wherein:
(a) the dosage form may be administered orally or topically; (b) the dosage form is a prodrug or a controlled release dosage form; or (c) the dosage form wherein at least one pharmaceutically acceptable excipient or diluent is an antioxidant.
- 12. A method of preventing or treating systemic and local fungal, yeast, or dermatophyte infections, comprising administering to a mammal a prophylactically effective amount or a therapeutically effective amount of a pharmaceutical dosage form of claim 10.
- 13. The method of claim 12, wherein the mammal is a human.
- 14. A process of making a soluble crystalline form of a conazole comprising reacting the conazole free base in a reaction medium comprising a solvent and an organic or inorganic acid to form a precipitate of a soluble crystalline form of the conazole, and recovering the precipitate.
- 15. The process of claim 14, wherein:
(a) the conazole is cis-itraconazole, posaconazole, or saperconazole; (b) the soluble crystalline form is a salt; (c) the soluble crystalline form is a co-crystal; (d) the soluble crystalline form has solubility of at least twice that of the free base (e) the soluble crystalline form has a solubility at least 5 times great than the free base; (f) the soluble crystalline form has a dissolution rate that is at least 5 times greater than the free base; (g) the soluble crystalline form has a dissolution rate that is at least 10 times greater than the free base; (h) the soluble crystalline form has a dissolution rate that is at least 50 times greater than the free base; (i) the soluble crystalline form absorbs less than 1% of its weight when cycled between 10 and 75% relative humidity at 25 degrees C. over 24 hours; (j) the soluble crystalline form absorbs less than 0.5% of its weight when cycled between 10 and 75% relative humidity at 25 degrees C. over 24 hours; (k) the soluble crystalline form is less hydroscopic than the crystalline or amorphous free base.
- 16. A soluble crystalline form of claim 2, wherein the form comprises an organic solvent selected from the group consisting of dioxane, 1,2-dichloroethane, dimethoxyethane, diethylene glycol dimethyl ether, tetrahydrofuran, diisopropyl ether, hydrocarbons such as hexane, heptane, cyclohexane, toluene or xylene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, ethylene glycol, methyl ethyl ketone, isobutyl methyl ketone, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and mixtures thereof.
- 17. A composition comprising a co-crystal wherein said co-crystal comprises a conazole and a co-crystal former, and wherein a single congener is a hydrogen-bonded trimer consisting of two molecules of the conazole and one molecule of the co-crystal former.
- 18. The co-crystal of claim 17 wherein:
(a) the co-crystal former is a dicarboxylic acid; (b) the conazole is cis-itraconazole, posaconazole or saperconazole; (c) the conazole molecules are oriented anti-parallel to each other with the co-crystal former filling a void created by a spacer group on the conazole; (d) the co-crystal former is succinic acid; (e) the co-crystal has a greater dissolution rate then the free from; (f) the co-crystal former is hydrogen-bonded to a group between the spacer group and the co-crystal former; (g) the co-crystal former is hydrogen-bonded to a trizole ring.
- 19. The use of a compound of claim 2 for the manufacture of a medicament for the treatment or prevention of a systemic or local fungal, yeast, or dermatophyte infection.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application No. 60/384,152 filed on May 31, 2002; U.S. Provisional Patent Application No. 60/439,282 filed on Jan. 10, 2003; U.S. Provisional Patent Application No. ______ filed on Jan. 31, 2003; and U.S. Provisional Patent Application No. 60/463,962 filed on Apr. 18, 2003, which are all hereby incorporated by reference for all purposes.
Provisional Applications (4)
|
Number |
Date |
Country |
|
60384152 |
May 2002 |
US |
|
60439282 |
Jan 2003 |
US |
|
60444315 |
Jan 2003 |
US |
|
60463962 |
Apr 2003 |
US |