Particle-forming compositions containing fused pyrrolocarbazoles
AssigneeCephalon, Inc.
InventorsDavid A. Dickason, Piyush R. Patel, Vincent Corvari, Efraim Shek, Joseph L. Herman, Jeffry M. Skell
Life of this patent
Estimating the term…
Abstract
A non-aqueous, particle-forming, fused pyrrolocarbazole-containing composition is disclosed. Upon contact with an aqueous medium, the particle-forming composition spontaneously disperses into suspended particles, thereby forming a stable suspension that provides greatly improved bioavailability of orally administered fused pyrrolocarbazole compounds.
Claims39
A composition comprising a fused pyrrolocarbazole with the formula:
- wherein
- R3 and R4 are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(═O)NHCH2CH3, N(CH3)2, CH═NNH, CH2N(CH3)2, and CH2OCH2CH3;
- R7 is selected from H and alkyl;
- and
- R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl;
- or a stereoisomer or pharmaceutically acceptable salt form thereof;
- a surfactant is present at least about 20% (w/w) and is selected from a polyoxyethylene sorbitan fatty acid ester, a polyethylene glycol ether, a saturated polyglycolized glyceride, a fatty acid ester of polyethylene glycol, a hydroxylated lecithin, a medium chain monoglyceride, a medium chain fatty acid ester, a polyethylene/propylene glycol copolymer, a poloxyl stearate, a poloxyl castor oil, a polyethylene glycol hydroxystearate, and a d-α-tocopheryl polyethylene glycol succinate;
- and an organic solvent selected from propylene glycol, propylene carbonate, dimethyl isosorbide, and polyethylene glycol.
A stable suspension of fused pyrrolocarbazole-containing particles in an aqueous medium, wherein the fused pyrrolocarbazole has the formula:
- wherein
- R3 and R4 are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(═O)NHCH2CH3, N(CH3)2, CH═NNH, CH2N(CH3)2, and CH2OCH2CH3;
- R7 is selected from H and alkyl;
- and R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl;
- or a stereoisomer or pharmaceutically acceptable salt form thereof.
A method of forming a stable suspension of fused pyrrolocarbazole-containing, suspended particles, comprising contacting a fused pyrrolocarbazole in a non-aqueous liquid containing a surfactant in an amount from about 20% to greater than about 99% with an aqueous medium, wherein the fused pyrrolocarbazole has the formula:
- wherein
- R3 and R4 are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(═O)NHCH2CH3, N(CH3)2, CH═NNH, CH2N(CH3)2, and CH2OCH2CH3;
- R7 is selected from H and alkyl;
- and R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl;
- or a stereoisomer or pharmaceutically acceptable salt form thereof.
A method of forming a stable suspension of fused pyrrolocarbazole-containing, suspended particles, comprising:
- (a) dissolving a fused pyrrolocarbazole in a non-aqueous liquid containing a surfactant in an amount from about 20% to greater than 99%, to form a particle-forming composition;
- and
- (b) contacting the particle-forming composition with an aqueous medium to form a stable suspension;
- wherein the fused pyrrolocarbazole has the formula:
- wherein
- R3 and R4 are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(═O)NHCH2CH3, N(CH3)2, CH═NNH, CH2N(CH3)2, and CH2OCH2CH3;
- R7 is selected from H and alkyl;
- and R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl;
- or a stereoisomer or pharmaceutically acceptable salt form thereof.
A method of treating a pathological or neurological disorder associated with the aberrant activity of target receptors in a mammal in need thereof, comprising administering a therapeutically effective amount of a fused pyrrolocarbazole in a non-aqueous, particle-forming composition comprising a surfactant in an amount of at least 20% (w/w) to the mammal;
- wherein the fused pyrrolocarbazole has the formula:
- wherein
- R3 and R4 are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(═O)NHCH2CH3, N(CH3)2, CH═NNH, CH2N(CH3)2, and CH2OCH2CH3;
- R7 is selected from H and alkyl;
- and R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl;
- or a pharmaceutically acceptable salt thereof.
A method of treating a pathological or neurological disorder associated with the aberrant activity of target receptors in a mammal in need thereof, comprising:
- (a) contacting a fused pyrrolocarbazole in a non-aqueous, particle-forming a composition comprising a surfactant in an amount of at least 20% (w/w) with an aqueous medium, thereby forming a stable suspension comprising suspended particles;
- and
- (b) administering a therapeutically effective amount of the stable suspension to the mammal;
- wherein the fused pyrrolocarbazole has the formula:
- wherein
- R3 and R4 are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(═O)NHCH2CH3, N(CH3)2, CH═NNH, CH2N(CH3)2, and CH2OCH2CH3;
- R7 is selected from H and alkyl;
- and R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl;
- or a pharmaceutically acceptable salt thereof.
A composition comprising a fused pyrrolocarbazole with the formula:
- wherein
- R3 and R4are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(═O)NHCH2CH3, N(CH3)2, CH═NNH, CH2N(CH3)2, and CH2OCH2CH3;
- R7 is selected from H and alkyl;
- and R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl;
- or a stereoisomer or pharmaceutically acceptable salt thereof;
- polyethylene glycol 1450;
- Pluronic® F68;
- hydroxypropyl-β-cyclodextrin and water.
A method of treating a pathological or neurological disorder associated with the aberrant activity of target receptors in a mammal in need thereof, comprising administering a therapeutically effective amount of a fused pyrrolocarbazole in a composition comprising polyethylene glycol 1450, Pluronic® F68, hydroxypropyl-β-cyclodextrin and water to the mammal, wherein the fused pyrrolocarbazole has the formula:
- wherein
- R3 and R4 are selected from H, alkyl, Cl, Br, CH2OH, CH2SOCH2CH3, CH2SO2CH2CH3, NHCONHC6H5, CH2SCH2CH3, CH2SC6H5, NHCO2CH3, CH2OC(═O)NHCH2CH3, N(CH3)2, CH═NNH, CH2N(CH3)2, and CH2OCH2CH3;
- R7 is selected from H and alkyl;
- and R15 and R16 are independently selected from H, alkyl, OH, CH2OH, alkoxy, and CO2alkyl;
- or a stereoisomer or pharmaceutically acceptable salt thereof.
A composition comprising a compound of the formula:
- or a stereoisomer or pharmaceutically acceptable salt thereof, a polyethylene/propylene glycol copolymer, and a medium chain monoglyceride.
Dependencies are inferred from the claim text.