Pediatric dosage forms, methods of making and using
Pediatric and modified release dosage forms of vitamin D compounds, and methods of making and using the dosage forms, are disclosed.
1. A solid extended release oral dosage form, the dosage form comprising a 25-hydroxyvitamin D compound in a solid hydrophilic matrix comprising
about 30 wt. % to about 50 wt. % microcrystalline cellulose;
about 1 wt. % to about 20 wt. % ethylcellulose;
about 5 wt. % to about 25 wt. % glyceryl behenate;
about 5 wt. % to about 25 wt. % glyceryl distearate/palmitostearate;
about 1 wt. % to about 20 wt. % polyglycolized glycerides; and
about 1 wt. % to about 15 wt. % methylcellulose.
2. The oral dosage form of claim 1 , in the form of a plurality of particles having a particle size characterized by a diameter in a range of about 0.2 mm to about 2.8 mm.
3. The oral dosage form of claim 2 , wherein the particles have a particle size characterized by a diameter in a range of about 0.20 mm to about 2.0 mm.
4. The oral dosage form of claim 3 , wherein the particles have a particle size characterized by a diameter of less than 1.0 mm.
5. The oral dosage form of claim 1 , wherein the microcrystalline cellulose is characterized by a crystallinity in a range of about 60% to about 80%.
6. The oral dosage form of claim 1 , wherein the microcrystalline cellulose is characterized by a mean particle size in a range of about 10 microns to about 200 microns.
7. The oral dosage form of claim 1 , wherein the microcrystalline cellulose is in present in an amount of at least 35 wt. %.
8. The oral dosage form of claim 1 , wherein the ethylcellulose is characterized by a viscosity in a range of 9 to 11 cP.
9. The oral dosage form of claim 1 , wherein the ethylcellulose is characterized by an ethoxyl content of in a range of about 48% to 49.5%.
10. The oral dosage form of claim 1 , wherein the glyceryl behenate is present in an amount of at least 15 wt. %.
11. The oral dosage form of claim 1 , wherein the polyglycolized glycerides component is selected from a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides, or a carpylocaproyl macrogol-8-glyceride.
12. The oral dosage form of claim 1 , wherein the polyglycolized glycerides component comprises PEG-32 mono and diesters of stearic and palmitic acid.
13. The oral dosage form of claim 1 , wherein the methylcellulose is further hydroxypropyl substituted.
14. The oral dosage form of claim 13 , wherein the methylcellulose has a methoxyl content in a range of about 19% to about 30%.
15. The oral dosage form of claim 13 , wherein the methylcellulose has a hydroxypropyl content in a range of about 5% to about 15%.
16. The oral dosage form of claim 13 , wherein the methylcellulose has a 2% aqueous viscosity at 20° C. in a range of about 2 to about 6 cP.
17. The oral dosage form of claim 1 , wherein the matrix is an extruded matrix.
18. The oral dosage form of claim 17 , wherein the matrix is an extruded, spheronized matrix.
19. The oral dosage form of claim 1 , wherein the matrix further comprises medium chain triglycerides.
20. The oral dosage form of claim 19 , wherein the medium chain triglycerides are present in an amount in a range of about 1 wt. % to about 20 wt. %.
21. The oral dosage form of claim 1 , wherein the matrix is a heat-cured matrix.
22. The oral dosage form of claim 21 , wherein the heat-cured matrix has been cured at a temperature below 65° C.
23. The oral dosage form of claim 21 , wherein the heat-cured matrix has been cured for at least 2 hours.
24. The oral dosage form of claim 1 , wherein the dosage form is characterized by an in vitro dissolution release profile as measured by USP Apparatus II (Paddle with Sinker) at 75 RPM, with a medium of 0.5% SDS in 5 mM sodium dihydrogenphosphate monohydrate, pH 6.8, 37±0.5° C., with a volume of 500 mL) of:
less than 20% at 2 hours;
35% to 45% at 4 hours;
55% to 80% at 6 hours;
65% to 85% at 8 hours;
at least 85% at 10 hours; and
at least 90% at 12 hours.
25. The oral dosage form of claim 1 , wherein the 25-hydroxyvitamin D compound is 25-hydroxyvitamin D2 and/or 25-hydroxyvitamin D 3 .
26. The oral dosage form of claim 1 , wherein the 25-hydroxyvitamin D compound is 25-hydroxyvitamin D 3 .
27. The oral dosage form of claim 1 , wherein the formulation is free of hydrocarbon waxes, including paraffin.
28. The oral dosage form of claim 1 , wherein the matrix is devoid of a coating thereon.
29. The oral dosage form of claim 1 , wherein the matrix is disposed in a capsule shell.
30. The oral dosage form of claim 29 , wherein the capsule shell is a hydroxypropyl methylcellulose (HPMC) shell.