Delayed release cysteamine bead formulation, and methods of making and using same
An enteric-coated bead dosage form of cysteamine, and related methods of manufacture and use, are disclosed.
1. A method of preparing a pharmaceutical dosage form comprising delayed-release cysteamine beads, the beads comprising:
(i) a core particle comprising a mixture of cysteamine bitartrate 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,
wherein the method comprises coating the beads of cysteamine bitartrate and the binder with the enteric membrane.
2. The method of claim 1 , wherein the cysteamine as free base comprises at least 10 wt. % of the core particle.
3. The method of claim 1 , wherein the cysteamine bitartrate comprises at least 50 wt. % of the core particle.
4. The method 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.
5. The method 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.
6. The method 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.
7. The method 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.