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.

What is claimed is: 
     
         1 . A pharmaceutical dosage form, comprising a plurality of cysteamine beads, the beads comprising a core particle comprising cysteamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and an enteric membrane surrounding the core, wherein the plurality of beads is characterized by a distribution of particle sizes. 
     
     
         2 . A pharmaceutical dosage form comprising a plurality of cysteamine beads, the beads comprising a core particle including cysteamine or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and an enteric membrane surrounding the core, wherein the plurality of beads is characterized by a distribution of enteric membrane thicknesses and optionally the plurality of beads is characterized by a distribution of particle sizes. 
     
     
         3 . The pharmaceutical composition of any one of the preceding claims, wherein the particle sizes of the beads are in a range of about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm. 
     
     
         4 . The pharmaceutical dosage form of any one of the preceding claims, 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 μm to about 1180 μm. 
     
     
         5 . The pharmaceutical composition of any one of the preceding claims, 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. 
     
     
         6 . The pharmaceutical composition of any one of the preceding claims, wherein the distribution of bead sizes is characterized by less than 5% by weight of the beads being retained on a 1400 μm sieve. 
     
     
         7 . The pharmaceutical dosage form of any one of the preceding claims, wherein the distribution of bead sizes is characterized by less than 30% by weight of the beads being retained on a 1180 μm sieve. 
     
     
         8 . The pharmaceutical dosage form of any one of the preceding claims, wherein the distribution of bead sizes is characterized by less than 70% by weight of the beads being retained on a 1000 μm sieve. 
     
     
         9 . The pharmaceutical dosage form of any one of the preceding claims, wherein the distribution of bead sizes is characterized by less than 20% by weight of the beads being retained on a 850 μm sieve. 
     
     
         10 . The pharmaceutical dosage form of any one of the preceding claims, wherein the distribution of bead sizes is characterized by at least 15% by weight of the beads being retained on a 1180 μm sieve. 
     
     
         11 . The pharmaceutical dosage form of any one of the preceding claims, wherein the distribution of bead sizes is characterized by at least 50% by weight of the beads being retained on a 1000 μm sieve. 
     
     
         12 . The pharmaceutical dosage form of any one of the preceding claims, wherein the distribution of bead sizes is characterized by at least 10% by weight of the beads being retained on a 850 μm sieve. 
     
     
         13 . The pharmaceutical dosage form of any one of the preceding claims, wherein the distribution of bead sizes is characterized by a median particle size in a range of about 850 μm to about 1180 μm. 
     
     
         14 . The pharmaceutical dosage form of any one of the preceding claims, wherein the distribution of enteric membrane thicknesses, expressed in terms of weight gain of enteric membrane material, is in a range of about 2% to about 14% based on the weight of the coated beads. 
     
     
         15 . The pharmaceutical dosage form of any one of the preceding claims, wherein the bead core particle excipient comprises a filler and a binder. 
     
     
         16 . The pharmaceutical dosage form of any one of the preceding claims, wherein the cysteamine (as free base) is present in the bead core particle in an amount of at least 10 wt. %, or at least 15 wt. % or at least 20 wt. %. 
     
     
         17 . The pharmaceutical dosage form of any one of the preceding claims, wherein the cysteamine as the bitartrate salt is present in the bead core particle in an amount of at least 50 wt. %, or greater than 50 wt. %, or at least 55 wt. %, or at least 60 wt. %, or at least 65 wt. %, or at least 70 wt. %, or at least 75 wt. %, or at least 80 wt. %. 
     
     
         18 . The pharmaceutical dosage form of any one of the preceding claims, wherein the cysteamine or pharmaceutically acceptable salt thereof is cysteamine bitartrate. 
     
     
         19 . The pharmaceutical dosage form of any one of the preceding claims, wherein the enteric membrane is present in an amount in a range of about 20% to about 40%, or about 25% to about 35% weight gain, or in a range of about 25% to about 31% weight gain, based on the weight of the bead core particles. 
     
     
         20 . The pharmaceutical dosage form of any one of the preceding claims, 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. 
     
     
         21 . The pharmaceutical dosage form of any one of the preceding claims, 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. 
     
     
         22 . The pharmaceutical dosage form of any one of the preceding claims, wherein the enteric-coated beads are characterized 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. 
     
     
         23 . The pharmaceutical dosage form of any one of the preceding claims, further comprising a capsule shell enclosing the beads. 
     
     
         24 . The pharmaceutical dosage form of any one of the preceding claims, characterized by a mean Tmax upon oral dosing of greater than 75 minutes, or at least 110 minutes, or at least 2 hours, or in a range of about 2.2 hours to about 3.48 hours, or about 2.22 hours to about 3.34 hours, or about 2.78 hours 
     
     
         25 . The pharmaceutical dosage form of any one of the preceding claims, characterized by a mean Cmax upon oral dosing in a range of about 22.16 μmol/L to about 34.63 μmol/L, or about 22.16 μmol/L to about 33.24 μmol/L, or about 22.7 μmol/L, normalized to a 450 mg dose. 
     
     
         26 . The pharmaceutical dosage form of any one of the preceding claims, characterized by a mean AUC (0-6 hours) upon oral dosing in a range of about 60.74 μmol·h/L to about 94.91 μmol·h/L, or about 60.74 μmol·h/L to about 91.12 μmol·h/L, or about 75.93 μmol·h/L, normalized to a 450 mg dose. 
     
     
         27 . The pharmaceutical dosage form of any one of the preceding claims, characterized by a mean AUC (0-12 hours) upon oral dosing in a range of about 79.41 μmol·h/L to about 124.08 μmol·h/L, or about 79.41 μmol·h/L to about 119.11 μmol·h/L, or about 99.26 μmol·h/L, normalized to a 450 mg dose. 
     
     
         28 . The pharmaceutical dosage form of any one of the preceding claims, characterized by the dosage form when administered orally in a hard capsule shell being bioequivalent to the beads administered orally without a capsule shell. 
     
     
         29 . The pharmaceutical dosage form of any one of the preceding claims, characterized by the dosage form when administered orally in a hard capsule shell exhibiting a Cmax in a range of 80% to 125%, or 80% to 120%, of Cmax exhibited by the beads administered orally without a capsule shell. 
     
     
         30 . The pharmaceutical dosage form of any one of the preceding claims, characterized by the dosage form when administered orally in a hard capsule shell exhibiting an AUC (0-12 h) or AUC (0-inf) in a range of 80% to 125%, or 80% to 120%, of that exhibited by the beads administered orally without a capsule shell. 
     
     
         31 . A pharmaceutical dosage form, comprising a plurality of cysteamine beads, the beads comprising a core particle comprising cysteamine bitartrate, and an enteric membrane surrounding the core, the dosage form characterized by providing mean pharmacokinetic parameters upon oral dosing, fasted, of: Tmax 194±38 minutes, Cmax 2.3±0.6 mg/L, and/or AUC (0-inf_D) 0.84±0.19 min*mg/L/mg, or a bioequivalent Tmax, Cmax or AUC in a range of 80% to 125%, or 80% to 120% of such reference parameter. 
     
     
         32 . The pharmaceutical dosage form of any one of the preceding claims, wherein said Tmax, Cmax, and AUC are evaluated in humans. 
     
     
         33 . The pharmaceutical dosage form of any one of the preceding claims, characterized by having less than 5 wt. % cystamine, based on the amount of cysteamine, following storage at 25° C. and 40% relative humidity for 12 months, or 18 months, or 24 months, or 30 months, as determined by reverse phase HPLC with UV detection at 210 nm. 
     
     
         34 . The pharmaceutical dosage form of any one of the preceding claims, characterized by having less than 5 wt. % cystamine, based on the amount of cysteamine, following storage at 25° C. and 60% relative humidity for 6 months, or 12 months, or 18 months, or 24 months, as determined by reverse phase HPLC with UV detection at 210 nm. 
     
     
         35 . The pharmaceutical dosage form of any one of the preceding claims, characterized by having less than 5 wt. % cystamine, based on the amount of cysteamine, following storage at 40° C. and 75% relative humidity for 3 months, or 6 months, as determined by reverse phase HPLC with UV detection at 210 nm. 
     
     
         36 . The pharmaceutical dosage form of any one of the preceding claims, further characterized by having less than 8 wt. % total related substances (impurities) based on the amount of cysteamine, under the described storage conditions and times, as determined by reverse phase HPLC with UV detection at 210 nm. 
     
     
         37 . A pharmaceutical dosage form, comprising a plurality of cysteamine beads, the beads comprising a core particle comprising cysteamine bitartrate, a filler (optionally microcrystalline cellulose), a binder (optionally hypromellose), and an enteric membrane (optionally Eudragit L30 D-55) surrounding the core,
 wherein the plurality of beads is characterized by a distribution of particle sizes in a range of about 0.7 mm to about 2.5 mm;   wherein the enteric membrane is present in an amount in a range of about 20% to about 40% based on the weight of the bead core particles;   and wherein the beads are disposed in a capsule shell.   
     
     
         38 . A method of treating a patient in need of cysteamine comprising administering to the patient a dosage form according to any one of the preceding claims. 
     
     
         39 . A method for the preparation of the dosage form of any one of the preceding claims, comprising coating a core particle comprising cysteamine or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form the enteric membrane. 
     
     
         40 . The method according to  claim 39 , comprising forming the core particle comprising cysteamine or a pharmaceutically acceptable salt thereof by granulating a mixture of cysteamine or a pharmaceutically acceptable salt thereof with an excipient and milling, and/or by extrusion and spheronization of a mixture of cysteamine or a pharmaceutically acceptable salt thereof with an excipient. 
     
     
         41 . The method according to  claim 40 , wherein the excipient comprises microcrystalline cellulose. 
     
     
         42 . The method according to any one of  claims 39  to  41 , wherein the forming comprises extrusion and spheronization of a mixture of cysteamine or a pharmaceutically acceptable salt thereof with an excipient. 
     
     
         43 . The method according to any one of  claims 40  to  42 , wherein the moisture content of the granulation mixture, prior to drying, is in a range of about 25 wt. % to about 35 wt. %, or about 28 wt. % to about 32 wt. %, or at least about 28 wt. %, or at least about 28.5 wt. %. 
     
     
         44 . The method according to any one of  claims 39  to  43 , further comprising sorting the core particles prior to enteric coating to retain particles in a predetermined size range, or sizes in a range of about 0.7 mm to about 2.8 mm, or about 0.7 mm to about 2.5 mm, or about 0.8 mm to about 1.7 mm. 
     
     
         45 . The method of any one of  claims 39  to  44 , further comprising sorting the enteric-coated core particles to retain particles in a predetermined size range, or sizes in a range of about 0.7 mm to about 2.8 mm, or about 0.7 mm to about 2.5 mm, or about 0.8 mm to about 1.7 mm. 
     
     
         46 . The method of any one of  claims 39  to  45 , further comprising encapsulating the enteric-coated beads in a capsule shell. 
     
     
         47 . A method for the preparation of a pharmaceutical dosage form comprising cysteamine beads, comprising forming a wet mass comprising cysteamine bitartrate and an excipient, optionally microcrystalline cellulose, with a moisture content in a range of in a range of about 20 wt. % to about 40 wt. %, extruding and spheronizing the wet mass comprising cysteamine bitartrate and excipient to make core particles, sorting the core particles to a target particle size range, optionally 0.7 mm to 2.5 mm, coating the sorted core particles with an enteric polymer to form cysteamine beads comprising a core particle and an enteric membrane, and sorting the bead particles to a target particle size range, optionally 0.7 mm to 2.5 mm. 
     
     
         48 . A dosage form and/or method of treatment as substantially herein described.