Formulations of pimavanserin

Abstract

Provided herein are capsules containing pimavanserin, processes for manufacturing said capsule, and pharmaceutical compositions containing pimavanserin.

What is claimed is: 
     
         1 . A capsule comprising 5-34 mg pimavanserin, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The capsule according to  claim 1 , wherein the capsule is of size 3 or 4. 
     
     
         3 . The capsule according to  claim 1  or  2 , wherein the capsule is a two-piece capsule. 
     
     
         4 . The capsule according to any one of  claims 1 - 3 , further comprising one or more pharmaceutically acceptable excipient(s) selected from the group consisting of a filler, a binder, and a lubricant. 
     
     
         5 . The capsule according to any one of  claims 1 - 3 , encapsulating a composition consisting of 5-34 mg granulated pimavanserin or a pharmaceutically acceptable salt thereof, a filler and a lubricant. 
     
     
         6 . The capsule according to any one of  claims 1 - 5 , wherein the filler is microcrystalline cellulose, silicified microcrystalline cellulose, hydroxylpropyl cellulose, mixtures thereof or equivalent filters. 
     
     
         7 . The capsule according to any one of  claims 1 - 6 , wherein the capsule contains 20-94% w/w microcrystalline cellulose. 
     
     
         8 . The capsule according to any one of  claims 1 - 7 , comprising at least 20% w/w microcrystalline cellulose, such as 30% w/w microcrystalline cellulose, such as 40% w/w microcrystalline cellulose, such as 50% w/w microcrystalline cellulose, such as 50-94% w/w mg, such as 50-89% w/w microcrystalline cellulose, 57-89% w/w microcrystalline cellulose, such as 57-79% w/w microcrystalline cellulose, such as 57-60% w/w microcrystalline cellulose, such as 57-59.5% w/w microcrystalline cellulose, such as 58.5-59.5% w/w microcrystalline cellulose, such as 59% w/w microcrystalline cellulose. 
     
     
         9 . The capsule according to any one of  claims 6 - 8 , wherein the microcrystalline cellulose is silicified microcrystalline cellulose. 
     
     
         10 . The capsule according to any one of  claims 6 - 8 , wherein the microcrystalline cellulose is selected from the group consisting of is PROSOLV® 90, PROSOLV® 50, AVICEL® PH302, PROSOLV® EASYtab SP, VIVAPUR® 302, EMCOCEL® HD 90, and CELLACTOSE® 80. 
     
     
         11 . The capsule according to any one of  claims 6 - 10 , wherein the microcrystalline cellulose has a particle size distribution (D90) of 180-340 μm and/or a bulk density above 0.40 g/ml, such as AVICEL® PH302 or VIVAPUR® 302. 
     
     
         12 . The capsule according to any one of  claims 1 - 11 , wherein the lubricant is magnesium stearate, sodium stearyl fumarate, mixtures thereof or equivalent lubricants. 
     
     
         13 . The capsule according to any one of  claims 1 - 12 , comprising 0.1-3 mg magnesium stearate. 
     
     
         14 . The capsule according to any one of  claims 1 - 12 , comprising 0.5-2 w/w magnesium stearate, such as 0.5-1.5% w/w magnesium stearate, such as 1% w/w magnesium stearate. 
     
     
         15 . The capsule according to any one of  claims 1 - 14 , wherein the magnesium stearate is vegetable grade. 
     
     
         16 . The capsule according to any one of  claims 1 - 15 , wherein the capsule does not comprise lactose. 
     
     
         17 . The capsule according to any one of  claims 1 - 16 , wherein the capsule is stable upon actual or simulated storage under open conditions at 25° C.±2°/60%±5% relative humidity for at least 1 year, such as at least 1.5 years. 
     
     
         18 . The capsule according to any one of  claims 1 - 17 , comprising 10, 20 or 34 mg pimavanserin. 
     
     
         19 . The capsule according to any one of  claims 1 - 17 , comprising 20 or 34 mg pimavanserin. 
     
     
         20 . The capsule according to any one of  claims 1 - 19 , comprising 59 mg microcrystalline cellulose. 
     
     
         21 . The capsule according to any one of  claims 1 - 20 , comprising 1 mg magnesium stearate. 
     
     
         22 . The capsule according to any one of  claims 1 - 21 , substantially encapsulating 40 mg pimavanserin tartrate (equivalent to 34 mg pimavanserin), 59 mg microcrystalline cellulose selected from microcrystalline cellulose having a particle size distribution (D90) of 180-340 μm and/or a bulk density above 0.40 g/ml, such as AVICEL® PH302 or VIVAPUR® 302, and 1 mg magnesium stearate only, and the total weight of the closed and filled capsule is about 138 mg±10%. 
     
     
         23 . The capsule according to any one of  claims 1 - 22 , wherein the capsule is of size 4. 
     
     
         24 . The capsule according to any one of  claims 1 - 23 , wherein pimavanserin is pimavanserin tartrate, such as pimavanserin tartrate crystalline Form C. 
     
     
         25 . The capsule according to any one of  claims 1 - 24 , wherein the in vitro dissolution is at least Q=80 in 30 min, as obtained according to USP<711>, apparatus 1. 
     
     
         26 . The capsule according to any one of  claims 1 - 25 , wherein the weight of the composition is 75-110 mg, such as 100±7 mg. 
     
     
         27 . The capsule according to any one of  claims 1 - 26 , wherein the bulk density of the composition comprised in the capsule is >0.4 g/ml, such as 0.4-0.6 g/ml, such as about 0.5 g/ml determined according to USP <616>, method 1. 
     
     
         28 . The capsule to any one of  claims 1 - 27 , wherein the particle size distribution (D90) of the composition is 60-380 μm, such as 75-350 μm, such as 100-300 μm obtained using laser light scattering particle size analysis. 
     
     
         29 . The capsule to any one of  claims 1 - 28 , wherein the Specific Energy (SE) of the composition is less than 5 mJ/g, such as less than 4.5 mJ/g, such as less than 4 mJ/g, determined according to ASTM D7891-15. 
     
     
         30 . The capsule to any one of  claims 1 - 29 , wherein the average Flow Rate Index (FRI) of the composition is 0.9-1.2, such as 1.0-1.1, determined according to ASTM D7891-15. 
     
     
         31 . The capsule to any one of  claims 1 - 29 , wherein the conditioned bulk density (CBD) of the composition is >0.45 g/ml, such as 0.45 g/ml-0.6 g/ml, such as 0.47-0.55 g/ml, determined according to ASTM D7891-15. 
     
     
         32 . A process for manufacturing a capsule comprising 5-34 mg pimavanserin, or a pharmaceutically acceptable salt thereof comprising:
 adding water to pimavanserin or a pharmaceutically acceptable salt thereof;   granulating pimavanserin or a pharmaceutically acceptable salt thereof with the water;   controlling the impeller speed and/or amperage;   drying the granulated pimavanserin or a pharmaceutically acceptable salt thereof;   sizing the dried granulated pimavanserin or a pharmaceutically acceptable salt thereof;   blending the dried and granulated pimavanserin or a pharmaceutically acceptable salt thereof and one or more filler; and   encapsulating the blended pimavanserin composition in a capsule of size 3 or 4.   
     
     
         33 . The process according to  claim 32 , wherein the water is sprayed under controlled atomized spray conditions. 
     
     
         34 . The process according to  claim 32  or  33 , wherein the water is sprayed under controlled atomized spray conditions at a pump rate of 1-50 g/min, and an atomization air pressure of 3-20 pounds per square inch (psig). 
     
     
         35 . The process according to any one of  claims 32 - 334 , wherein the water is sprayed under controlled atomized spray conditions at a pump rate of 20-40 g/min, and an atomization air pressure of 3-15 pounds per square inch (psig). 
     
     
         36 . The process according to any one of  claims 32 - 33 , wherein droplet size of the water is 0.05-0.15 mm. 
     
     
         37 . The process according to any one of  claims 32 - 36 , wherein the impeller speed and/or amperage is controlled. 
     
     
         38 . The process according to any one of  claims 32 - 37 , wherein the added water is about 1-10% w/w of pimavanserin or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The process according to  claim 36 , wherein the water is in an amount of about 3-10% w/w, such as about 3-8% w/w of pimavanserin or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The process according to any one of  claims 32 - 39 , further providing one or more excipients selected from the group consisting of binders, and lubricants, or mixtures thereof, post-drying the pimavanserin granulation. 
     
     
         41 . The process according to any one of  claims 32 - 40 , wherein the one or more excipients are added during the sizing step. 
     
     
         42 . The process according to any one of  claims 32 - 42 , wherein the one or more excipients are microcrystalline cellulose and/or magnesium stearate. 
     
     
         43 . The process according to  claim 43 , wherein the microcrystalline cellulose is selected from the group consisting of PROSOLV® 90, PROSOLV® 50, AVICEL® PH302, PROSOLV® EASYtab SP, VIVAPUR® 302, EMCOCEL® HD 90, and CELLACTOSE® 80. 
     
     
         44 . The process according to  claim 43 , wherein the microcrystalline cellulose is selected from microcrystalline cellulose having a particle size distribution (D90) of 180-340 μm and/or a bulk density above >0.40 g/ml, such as AVICEL® PH302 or VIVAPUR® 302. 
     
     
         45 . The process according to any one of  claims 42 - 44 , wherein the amount of microcrystalline cellulose is at least 20% w/w microcrystalline cellulose, such as 30% w/w microcrystalline cellulose, such as 40% w/w microcrystalline cellulose, such as 50% w/w microcrystalline cellulose, such as 50-89% w/w microcrystalline cellulose, such as 20-94% w/w mg, such as 50-94% w/w mg, such as 57-89% w/w microcrystalline cellulose, such as 57-79% w/w microcrystalline cellulose, or 57-60% w/w microcrystalline cellulose, or 57-59.5% w/w microcrystalline cellulose, or 58.5-59.5% w/w microcrystalline cellulose, or 59% w/w microcrystalline cellulose. 
     
     
         46 . The process according to  claim 42 , wherein the magnesium stearate is a vegetable grade. 
     
     
         47 . The process according to any one of  claims 42 - 46 , wherein the amount of magnesium stearate is 0.1-3% w/w, such as 0.5-2% w/w magnesium stearate, or 0.5-1.5% w/w magnesium stearate, or 1% w/w magnesium stearate. 
     
     
         48 . The process according to any one of  claims 32 - 47 , wherein the granulation of pimavanserin is a wet granulation. 
     
     
         49 . The process according to  claim 48 , wherein the wet granulation is high shear granulation, low shear granulation, twin screw granulation, or fluid bed granulation or any combination thereof. 
     
     
         50 . The process according to  claim 48 , wherein the wet granulation is by high shear granulation. 
     
     
         51 . The process according to any one of  claims 32 - 50 , wherein about 40 mg of pimavanserin tartrate, about 59 mg of microcrystalline cellulose is selected from microcrystalline cellulose having a particle size distribution (D90) of 180-340 μm and/or a bulk density above >0.40 g/ml, such as AVICEL® PH302 or VIVAPUR® 302 and about 1 mg magnesium stearate are encapsulated in a size 4 two-piece capsule. 
     
     
         52 . The process according to any one of  claims 32 - 51 , wherein the bulk density of the pimavanserin granulation is >0.4 g/ml, such as 0.4-0.6 g/ml, such as about 0.5 g/ml determined according to USP <616>, method 1. 
     
     
         53 . The process according to any one of  claims 32 - 52 , wherein the maximum holding time of the wet granulation and drying is 120 min, such as 100 min, such as 80 min, such as 60 min. 
     
     
         54 . The process according to any one of  claims 32 - 53 , wherein 20,000 or more capsules are manufactured per hour. 
     
     
         55 . The process according to  claim 54 , wherein 40,000 or more capsules are manufactured per hour. 
     
     
         56 . The process according to any one of  claims 32 - 55 , wherein the composition is not comprising a binder. 
     
     
         57 . The process according to any one of  claims 32 - 56 , wherein the water is added while mixing pimavanserin or pharmaceutically acceptable salt thereof. 
     
     
         58 . A pharmaceutical composition consisting of 5-34 mg pimavanserin or a pharmaceutically acceptable salt thereof, a filler, and a lubricant. 
     
     
         59 . The pharmaceutical composition according to  claim 58  wherein the filler is microcrystalline cellulose. 
     
     
         60 . The pharmaceutical composition according to any one of  claims 58 - 559 , wherein the lubricant is magnesium stearate. 
     
     
         61 . The pharmaceutical composition according to any one of  claims 58 - 60 , wherein the composition is substantially consisting of 5-34 mg pimavanserin; 50-94.1 mg microcrystalline cellulose, such as 57-94.1 mg microcrystalline cellulose; and 0.1-3 mg magnesium stearate. 
     
     
         62 . The pharmaceutical composition of  claim 61  having a total weight of about 100 g. 
     
     
         63 . The pharmaceutical composition according to any one of  claims 58 - 62 , wherein the bulk density of the composition >0.4 g/ml, such as about 0.4-0.6 g/ml, such as about 0.5 g/ml determined according to USP <616>, method 1. 
     
     
         64 . The pharmaceutical composition according to any one of  claims 58 - 63 , wherein the Specific Energy (SE) is less than 5 mJ/g, such as less than 4.5 mJ/g, such as less than 4 mJ/g, determined according to ASTM D7891-15. 
     
     
         65 . The pharmaceutical composition according to any one of  claims 58 - 64 , wherein the average Flow Rate Index (FRI) is 0.9-1.2, such as 1.0-1.1, determined according to ASTM D7891-15. 
     
     
         66 . The pharmaceutical composition according to any one of  claims 58 - 64 , wherein the conditioned bulk density (CBD) is >0.45 g/ml, such as 0.45-0.6 g/ml, such as 0.47-0.55 g/ml, determined according to ASTM D7891-15. 
     
     
         67 . The pharmaceutical composition according to any one of  claims 58 - 66 , encapsulated in a capsule. 
     
     
         68 . The pharmaceutical composition according to any one of  claims 58 - 67 , encapsulated in a size 3 or 4 capsule. 
     
     
         69 . The pharmaceutical composition according to any one of  claims 58 - 68 , encapsulated in a size 4 capsule. 
     
     
         70 . The pharmaceutical composition according to any one of  claims 58 - 69 , wherein the capsule is a two-piece capsule. 
     
     
         71 . The pharmaceutical composition according to any one of  claims 58 - 70 , wherein the in vitro dissolution of pimavanserin is at least Q=80% in 30 min, as obtained according to USP<711>, apparatus 1. 
     
     
         72 . The pharmaceutical composition according to any one of  claims 58 - 71 , manufactured as a tablet.