Ansamycin formulations and methods of use thereof
Provided herein, inter alia, are solid forms of geldanamycin analogs, pharmaceutical compositions comprising a geldanamycin analog and a crystallization inhibitor, methods of making and using such compositions. Additionally, provided are methods for the treatment of cancer, a neoplastic disease state and/or a hyperproliferative disorder, and methods of inhibiting Heat Shock Protein 90 (“Hsp90”).
1. A pharmaceutical composition comprising a substantially amorphous benzoquinone ansamycin compound formulated for oral administration as a molecular dispersion with a crystallization inhibitor to provide an area under the curve (AUC) circulatory bioavailability of at least 1000 ng·hr/ml wherein the compound is 17-amino-geldanamycin (17-AG).
2. A composition comprising substantially amorphous 17-amino-geldanamycin (17-AG) formulated for oral delivery to a subject to provide an area under the curve (AUC) circulatory bioavailability of at least 1000 ng·hr/ml.
3. The composition according to claim 2 wherein the 17-amino-geldanamycin (17-AG) is formulated for oral delivery at a dose of at least 5 mg.
4. The composition according to claim 2 wherein the 17-amino-geldanamycin (17-AG) is formulated for oral delivery at a dose of at least 25 mg.
5. The composition according to claim 2 wherein the 17-amino-geldanamycin (17-AG) is formulated for oral delivery at a dose of at least 50 mg.
6. The composition according to claim 2 wherein the 17-amino-geldanamycin (17-AG) is formulated for oral delivery at a dose of at least 125 mg.
7. The composition according to claim 2 wherein the 17-amino-geldanamycin (17-AG) is formulated for oral delivery at a dose of at least 250 mg.
8. A composition comprising substantially amorphous 17-amino-geldanamycin (17-AG) and at least about 10% by weight of a crystallization inhibitor.
9. The composition according to claim 8 , wherein the composition contains at least about 25% by weight of the crystallization inhibitor.
10. The composition according to claim 8 , wherein the composition contains at least about 50% by weight of the crystallization inhibitor.
11. The composition according to claim 8 , wherein the composition contains at least about 75% by weight of the crystallization inhibitor.
12. The composition according to claim 8 , wherein the crystallization inhibitor is polyvinylpyrrolidone (PVP).
13. A pharmaceutical composition comprising substantially amorphous 17-amino-geldanamycin (17-AG)
or a pharmaceutically acceptable salt thereof, wherein the composition is present as a molecular dispersion.
14. The composition according to claim 1 wherein the crystallization inhibitor is selected from polyvinylpyrrolidone; crospovidone; gums; a cellulose derivative which is selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, ethyl cellulose, hydroxyethylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and sodium carboxymethyl cellulose; dextran; acacia; homo- and copolymers of vinyllactam, and mixtures thereof; cyclodextrins; gelatins; hypromellose phthalate; sugars; polyhydric alcohols; polyethylene glycol; polyethylene glycol-hydroxystearate; polyethylene oxides; polyoxyethylene; polyvinyl alcohol; propylene glycol; sodium lauryl sulfate (SLS); Tween; and combinations thereof.
15. A pharmaceutical composition comprising substantially amorphous 17-amino-geldanamycin (17-AG)
or a pharmaceutically acceptable salt thereof wherein the composition further comprises a polyvinylpyrrolidone.
16. The composition according to claim 15 , wherein the polyvinylpyrrolidone is selected from homo- and co-polymers of polyvinylpyrrolidone; and homo- and co-polymers of N-vinylpyrrolidone.
17. The composition according to claim 1 , wherein a crystallization inhibitor is present in an amount of at least about 5%, 10%, 15%, or 25% (w/w), based on the total weight of the composition.
18. The composition according to claim 17 , wherein the amount is at least about 10% (w/w), based on the total weight of the composition.
19. The composition according to claim 17 , wherein the amount is at least about 15% (w/w), based on the total weight of the composition.
20. The composition according to claim 17 , wherein the amount is at least about 25% (w/w), based on the total weight of the composition.
21. The composition according to claim 13 , wherein the molecular dispersion results from: (a) milling; (b) extrusion; (c) melt processes; (d) solvent modified fusion; (e) solvent processes; or (f) non-solvent precipitation.
22. The composition according to claim 21 , wherein the solvent processes are selected from lyophilization, rotary evaporation, spray coating and spray-drying.