Details for Patent: 9,233,077

Title:	Delayed release cysteamine bead formulation, and methods of making and using same
Abstract:	An enteric-coated bead dosage form of cysteamine, and related methods of manufacture and use, are disclosed.
Inventor(s):	Powell; Kathlene (Cary, NC), Muttavarapu; Ramesh (Durham, NC)
Assignee:	RAPTOR PHARMACEUTICALS INC. (Novato, CA)
Filing Date:	Jun 17, 2014
Application Number:	14/306,303
Claims:	1. A pharmaceutical dosage form, comprising delayed-release cysteamine beads, the beads comprising: (i) a core particle comprising cysteamine or a pharmaceutically acceptable salt thereof and a binder, and (ii) an enteric membrane surrounding the core particle, wherein the beads have a distribution of particle sizes in a range of about 0.7 mm to about 2.8 mm; wherein the enteric membrane begins to dissolve within a pH range of about 4.5 to about 6.5; wherein the enteric membrane is present in an amount in a range of about 25% to about 35% by weight, based on the weight of the core particles; and wherein the pharmaceutical dosage form, upon administration in a capsule to fasted healthy normal subjects at 600 mg free cysteamine base, provides: (a) a mean Cmax upon oral dosing in a range of 2.3.+-.0.6 mg/L or in a range of 80% to 125% thereof; and (b) a mean AUC (0-inf_D) upon oral dosing in a range of 0.84.+-.0.19 min*mg/L/mg or in a range of 80% to 125% thereof. 2. The pharmaceutical composition of claim 1, wherein the particle sizes of the beads are in a range of about 0.7 mm to about 2.5 mm. 3. The pharmaceutical dosage form of claim 1, wherein the distribution of bead sizes is characterized by at least 80% by weight of the beads having a particle size in a range of about 850 .mu.m to about 1180 .mu.m. 4. The pharmaceutical composition of claim 1, wherein 5% or less of the beads by weight are retained on a #12 mesh (1.68 mm) screen and 10% or less by weight pass through a #20 mesh (0.84 mm) screen. 5. The pharmaceutical composition of claim 1, wherein the distribution of bead sizes is characterized by less than 5% by weight of the beads being retained on a 1400 .mu.m sieve. 6. The pharmaceutical dosage form of claim 1, wherein the distribution of bead sizes is characterized by less than 30% by weight of the beads being retained on a 1180 .mu.m sieve. 7. The pharmaceutical dosage form of claim 1, wherein the distribution of bead sizes is characterized by less than 70% by weight of the beads being retained on a 1000 .mu.m sieve. 8. The pharmaceutical dosage form of claim 1, wherein the distribution of bead sizes is characterized by less than 20% by weight of the beads being retained on a 850 .mu.m sieve. 9. The pharmaceutical dosage form of claim 1, wherein the distribution of bead sizes is characterized by at least 15% by weight of the beads being retained on a 1180 .mu.m sieve. 10. The pharmaceutical dosage form of claim 1, wherein the distribution of bead sizes is characterized by at least 50% by weight of the beads being retained on a 1000 .mu.m sieve. 11. The pharmaceutical dosage form of claim 1, wherein the distribution of bead sizes is characterized by at least 10% by weight of the beads being retained on a 850 .mu.m sieve. 12. The pharmaceutical dosage form of claim 1, wherein the distribution of bead sizes is characterized by a median particle size in a range of about 850 .mu.m to about 1180 .mu.m. 13. The pharmaceutical dosage form of claim 1, wherein the bead core particle further comprises a filler. 14. The pharmaceutical dosage form of claim 1, wherein the cysteamine (as free base) is present in the bead core particle in an amount of at least 10 wt. %. 15. The pharmaceutical dosage form of claim 1, wherein the cysteamine or pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of cysteamine. 16. The pharmaceutical dosage form of claim 1, wherein 5% or less of the bead core particles by weight are retained on a #12 mesh (1.68 mm) screen and 10% or less by weight pass through a #20 mesh (0.84 mm) screen. 17. The pharmaceutical dosage form of claim 1, wherein the enteric-coated beads are characterized by acid resistance such that not more than 10% of the cysteamine in the beads is dissolved after a period of two hours in a 0.1N HCl solution. 18. The pharmaceutical dosage form of claim 1, wherein the enteric-coated beads are characterized by dissolution such that 80% of the cysteamine or pharmaceutically acceptable salt thereof is released within 20 minutes in a solution buffered at pH 6.8. 19. The pharmaceutical dosage form of claim 1, further comprising a capsule shell enclosing the plurality of beads. 20. The pharmaceutical dosage form of claim 1, wherein the beads provide a mean Cmax and mean AUC (0-inf_D) upon oral dosing, fasted, when administered inside a capsule shell that are bioequivalent to the mean Cmax and mean AUC (0-inf_D) upon oral dosing, fasted, when administered without a capsule shell. 21. The pharmaceutical dosage form of claim 1, wherein the enteric membrane comprises an enteric material that begins to dissolve at pH of about 5.5 in an aqueous solution. 22. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form, upon administration in a capsule to fasted healthy normal subjects at 600 mg free cysteamine base, provides: (a) a mean Cmax upon oral dosing in a range of 2.3.+-.0.6 mg/L; and (b) a mean AUC (0-inf_D) upon oral dosing in a range of 0.84.+-.0.19 min*mg/L/mg. 23. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form, upon administration in a capsule to fasted healthy normal subjects at 600 mg free cysteamine base, provides: (a) a mean Cmax upon oral dosing of 2.3 mg/L or in a range of 80% to 125% thereof; and (b) a mean AUC (0-inf_D) upon oral dosing of 0.84 min*mg/L/mg or in a range of 80% to 125% thereof.