Solid dispersions comprising tacrolimus
A pharmaceutical composition comprising tacrolimus (FK-506) dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature have improved bioavailability.
1. A method of suppressing rejection of a transplanted organ in a patient comprising administering an effective amount of a pharmaceutical composition comprising a solid dispersion consisting essentially of tacrolimus as the sole active ingredient dispersed or dissolved in a mixture of two or more hydrophilic or water-miscible vehicles, wherein the melting point of the vehicle is at least 20° C. and the active ingredient is present therein in a concentration of between about 0.01 w/w % and about 15 w/w %.
2. The method of claim 1 , wherein the active ingredient is partly dissolved in the vehicle to form a mixture of solid dispersion and solid solution at ambient temperature.
3. The method of claim 1 , wherein the active ingredient is fully dissolved in the vehicle to form a solid solution at ambient temperature.
4. The method of claim 1 , wherein the hydrophilic or water-miscible vehicle has a melting point of at least 30° C.
5. The method of claim 1 , wherein the concentration of the active ingredient in the hydrophilic or water-miscible vehicle is at the most 10 w/w %.
6. The method of claim 1 , wherein the concentration of the active ingredient in the hydrophilic or water-miscible vehicle is at least about 0.05w/w %.
7. The method of claim 1 , wherein each hydrophilic or water-miscible vehicle is selected from the group consisting of polyethylene glycols, polyoxyethylene oxides, poloxamers, polyoxyethylene stearates, poly-epsilon caprolactone, polyglycolized glycerides, and mixtures thereof.
8. The method of claim 1 , wherein each hydrophilic or water-miscible vehicle is selected from the group consisting of polyvinylpyrrolidones, polyvinyl-polyvinylacetate copolymers (PVP-PVA), polyvinyl alcohol (PVA), polymethacrylic polymers, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, pectins, cyclodextrins, galactomannans, alginates, carragenates, xanthan gums and mixtures thereof.
9. The method of claim 1 , wherein the vehicle comprises polyethylene glycol (PEG).
10. The method of claim 9 , wherein the polyethylene glycol has an average molecular weight of at least 1500.
11. The method of claim 1 , wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
12. The method of claim 1 , wherein the pharmaceutically acceptable excipients are selected from the group consisting of fillers, disintegrants, binders and lubricants.
13. The method of claim 1 , wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives selected from the group consisting of flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents, absorption enhancing agents and release modifying agents.
14. The method of claim 11 , wherein at least one pharmaceutically acceptable excipient is selected from the group consisting of silica acid, silicates, silicon dioxide and polymers thereof, magnesium aluminosilicate and/or magnesium aluminometasilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite.
15. The method of claim 11 , wherein at least one pharmaceutically acceptable excipient is silicon dioxide or a polymer thereof.
16. The method of claim 1 , wherein each hydrophilic or water-miscible vehicle is selected from the group consisting of polyethylene glycols, polyoxyethylene oxides, poloxamers, polyoxyethylene stearates, poly-epsilon caprolactone, polyglycolized glycerides, and mixtures thereof.