Formulations of deferasirox and methods of making the same
The disclosure provides for improved pharmaceutical compositions containing deferasirox (DFX) and methods of manufacturing the same. In particular, the compositions are prepared using thermokinetic compounding and provide improved properties as well as more efficient methods of manufacture.
1. A method of making a pharmaceutical composition comprising:
(a) providing crystalline deferasirox (DFX) and one or more pharmaceutically acceptable excipients;
(b) compounding the materials of step (a) in a thermokinetic mixer at about 100° C. to 200° C. for 5 to about 300 seconds,
wherein the thermokinetic compounding of DFX and the one or more pharmaceutically acceptable excipients forms a melt blended pharmaceutical composite, and wherein said melt blended composite is an amorphous solid dispersion that comprises about 30%-60% DFX and remains amorphous per x-ray diffraction analysis following storage in an open container at about 40° C., relative humidity of about 75%, at five weeks.
2. The method of claim 1 , wherein said pharmaceutical composition comprises a second active pharmaceutical ingredient in addition to DFX.
3. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a pharmaceutical polymer.
4. The method of claim 3 , wherein the pharmaceutical polymer comprises an agent selected from the group consisting of poly(vinyl acetate)-co-poly(vinylpyrrolidone) copolymer, ethylcellulose, hydroxypropylcellulose, cellulose acetate butyrate, poly(vinylpyrrolidone), poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), hydroxypropy I methylcellulose, hydroxyethylcellulose, sodium carboxymethy I-cellulose, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, ethylacrylate methylmethacrylate copolymer, cellulose acetate phthalate, cellulose acetate trimelletate, poly(vinyl acetate) phthalate, hydroxypropylmethylcellulose phthalate, poly(methacrylate ethylacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:2) copolymer, hydroxypropylmethylcellulose acetate succinate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
5. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a surfactant.
6. The method of claim 5 , wherein the one or more surfactants comprises an agent selected from the group consisting of sodium dodecyl sulfate, dioctyl sodium sulphosuccinate, polyoxyethylene (20) sorbitan monooleate, glycerol polyethylene glycol oxystearate-fatty acid glycerol polyglycol esters-polyethylene glycols-glycerol ethoxylate, glycerol-polyethylene glycol ricinoleate-fatty acid esters of polyethyleneglycol-polyethylene glycols-ethoxylated glycerol, vitamin E TPGS and sorbitan laurate.
7. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises one or more surfactants and one or more polymer carriers.
8. The method of claim 7 , wherein the surfactant comprises an agent selected from the group consisting of sodium dodecyl sulfate, dioctyl sodium sulphosuccinate, polyoxyethylene (20) sorbitan monooleate, glycerol polyethylene glycol oxystearate-fatty acid glycerol polyglycol esters-polyethylene glycols-glycerol ethoxylate, glycerol polyethylene glycol ricinoleate-fatty acid esters of polyethyleneglycol-polyethylene glycols-ethoxylated glycerol, vitamin E TPGS, and sorbitan laurate, and the pharmaceutical polymer comprises an agent selected from a group consisting of poly(vinylacetate)-co-poly(vinylpyrrolidone) copolymer, ethylcellulose, hydroxypropylcellulose, cellulose acetate butyrate, poly(vinylpyrrolidone), poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethy I-cellulose, dimethylaminoethy I methacrylate-methacrylic acid ester copolymer, ethylacrylate-methylmethacrylate copolymer, cellulose acetate phthalate, cellulose acetate trimelletate, poly(vinyl acetate) phthalate, hydroxypropyl lmethylcellulose phthalate, poly(methacry late ethylacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:2) copolymer, hydroxypropylmethylcellulose acetate succinate and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
9. The method of claim 1 , wherein the composite comprises about 40%-60% DFX, about 30% DFX, 35% DFX, 40% DFX, 45% DFX, 50% DFX, 55% DFX, or 60% DFX.
10. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a processing agent.
11. The method of claim 10 , wherein the processing agent is a plasticizer.
12. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a water soluble pharmaceutical polymer.
13. The method of claim 12 , wherein the water soluble pharmaceutical polymer comprises a polymer selected from a group consisting of poly(vinyl acetate)-co poly(vinylpyrrolidone) copolymer, poly(vinylpyrrolidone), cellulose acetate phthalate, poly(vinyl acetate) phthalate, hydroxypropylmethylcellulose phthalate, poly(methacrylate ethylacrylate) (1:1) copolymer, poly(methacrylate methylmethacrylate) (1:1) copolymer, poly(methacry late methylmethacry late) (I:2) copolymer, hydroxypropy I methylcellulose, hydroxypropylmethylcellulose acetate succinate, poly(vinyl alcohol), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.
14. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a cross-linked pharmaceutical polymer.
15. The method of claim 14 , wherein the cross-linked pharmaceutical polymer is, carbomer, crospovidone, or croscarmellose sodium.
16. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a pharmaceutical polymer of high melt viscosity.
17. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises a thermally labile pharmaceutical polymer.
18. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises poly(methacrylate ethylacrylate) (1:1) copolymer or poly(vinyl acetate)-co-poly(vinylpyrrolidone).
19. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises poly(methacrylate ethylacrylate) (1:1) copolymer and poly(vinyl acetate)-co-poly(vinylpyrrolidone).
20. The method of claim 1 , wherein the one or more pharmaceutically acceptable excipients comprises poly(vinyl acetate)-co-poly(vinylpyrrolidone) and hydroxypropylmethylcellulose acetate succinate.
21. The method of claim 1 , wherein said composite has a single glass transition temperature.
22. The method of claim 1 , wherein the purity of DFX in said composition is about 95%, is about 99%, is about 99.5%, or is about 95% to about 100%.
23. The method of claim 1 , wherein the DFX to pharmaceutical polymer weight:weight ratio is about 2:8 to about 7:3.