Controlled release carvedilol compositions

Abstract

A controlled release pharmaceutical composition for oral use comprising carvedilol. The composition releases carvedilol after oral administration to a mammal, Including a human, in such a manner that a prolonged residence of carvedilol is obtained In the circulatory system compared with the known compositions of carvedilol. Furthermore, a composition according to the present invention makes available to the body a suitable plasma concentration of one or both of the enantiomeric species, namely R(+) and/or S(−) carvedilol for obtaining the desired therapeutic effect.

1 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in R(+) form, wherein the release of carvedilol from the composition after administration to a human results in a t max  of R(+) carvedilol of from about 1.5 hour to about 8 hours such as, e.g. from about 2 to about 7 hours, from about 2.5 to about 6.5 hours, from about 2.5 to about 6 hours, from about 2.5 to about 5 hours, from about 2.5 to about 4.5 hours, from about 2.5 to about 4 hours, from about 2.5 to about 3.5 or from about 2.8 to about 3.5, the t max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         2 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in R(+) form, wherein the release of carvedilol from the composition after administration to a human results in a ratio of (t max  of R(+) carvedilol from the controlled release composition)/(t max  of R(+) carvedilol from a Dimitone®) composition) is from about 1.0 to about 5 such as, e.g., from about 1.3 to about 4.51 from about 1.5 to about 4, from about 1.5 to about 3.5, from about 1.5 to about 3.0, from about 1.5 to about 3, the t max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         3 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in S(−) form, wherein the release of carvedilol from the composition after administration to a human results in a t max  of S(−) carvedilol of from about 1.5 hour to about 8 hours such as, e.g. from about 2 to about 7 hours, from about 2.5 to about 6.5 hours, from about 2.8 to about 6 hours, from about 3 to about 5 hours, from about 3 to about 4.5 hours or from about 3 to about 4 hours, the t max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         4 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in S(−) form, wherein the release of carvedilol from the composition after administration to a human results in a ratio of (t max  of S(−) carvedilol from the controlled release composition)/(t max  of S(−) carvedilol from a Dimitone® composition) is from about 1.5 to about 5 such as. e.g., from about 1.7 to about 4.5, from about 1.8 to about 4, from about 1.9 to about 3.5, from about 2 to about 3.3, from about 2 to about 3, the t max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         5 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in R(+) form, wherein the release of carvedilol from the composition after administration to a human results in a MRT of R(+) carvedilol which is at least about 6.5 hours such as, e.g. at least about 7 hours or is between from about 6.5 to about 20 hours such as, e.g. from about 7 to about 18 hours, from about 7 to about 17 hours, from about 7 to about 15 hours, from about 7 to about 13 hours, or from about 7 to about 11 hours, the MRT being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         6 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in R(+) form, wherein the release of carvedilol from the composition after administration to a human results in a ratio of (MRT of R(+) carvedilol from the controlled release composition)/(MRT of R(+) carvedilol from a Dimitone® composition) is from about is from about 0.5 to about 5 such as, e.g., from about 0.7 to about 4.5, from about 0.8 to about 4, from about 0.9 to about 3.5, from about 1 to about 3.3, from about 1 to about 3, the MRT being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         7 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in S(−) form, wherein the release of carvedilol from the composition after administration to a human results in a MRT of S(−) carvedilol which is at least about 7 hours such as, e.g. at least about 8 hours or is between from about 7 to about 22 hours such as, e.g. from about 7.5 to about 20 hours, from about 8 to about 19 hours, from about 9 to about 18 hours, from about 9 to about 16 hours from about 9 to about 15 hours, from about 10 to about 16 hours or from about 11 to about 14 hours, the MRT being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         8 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in S(−) form, wherein the release of carvedilol from the composition after administration to a human results in a ratio of (MRT of S(−) carvedilol from the controlled release composition)/(MRT of S(−) carvedilol from a Dimitone® composition) is from about is from about 1.0 to about 5 such as, e.g., from about 1.2 to about 4.5, from about 1.3 to about 4, from about 1.4 to about 3.5, from about 1.5 to about 3.3, from about 1.5 to about 3, the t max being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         9 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in R(+) form, wherein the release of carvedilol from the composition after administration to a human results in a C max which—compared to the results after administration of a Dimitone® composition—is at the most about 90% of the value obtained from a Dimitone® composition such as, e.g. at the most about 85%, at the most about 80%, at the most about 75%, at the most about 70%, at the most about 65%, at the most about 60%, at the most about 55%, at the most about 50% or at the most about 45%, the C max being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         10 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in R(+) form, wherein the release of carvedilol from the composition after administration to a human results in a C max  of R(+) carvedilol which—when calculated as a dosage correlated C max ,C calc , (C max in ng/ml)/mg carvedilol in the composition—corresponds to a C calc  from about 14 to about 0.1 such as, e.g. from about 1.3 to about 0.2, from about 1.3 to about 0.3, from about 1.2 to about 0.35, from about 1.1 to about 0.4, from about 1.0 to about 0.45, from about 0.9 to about 0.4, from about 0.9 to about 0.5, from about 0.8 to about 0.4, or from about 0.8 to about 0.5, the C max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         11 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in S(−) form, wherein the release of carvedilol from the composition after administration to a human results in a C max  which—compared to the results after administration of a Dimitone® composition—is at the most about 90% of the value obtained from a Dimitone® composition such as, e.g. at the most about 85%, at the most about 80%, at the most about 75%, at the most about 70%, at the most about 65%, at the most about 60%, at the most about 55%, at the most about 50%, at the most about 45% or at the most about 40%, the C max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         12 . A controlled release pharmaceutical composition for oral use comprising carvedilol at least partly in S(−) form, wherein the release of carvedilol from the composition after administration to a human results in a C max  of S(−) carvedilol which—when calculated as a dosage correlated C max , C calc , (C max  in ng/ml)/mg carvedilol in the composition—corresponds to a C calc  from about 0.6 to about 0.05 such as, e.g. from about 0.55 to about 0.1, from about 0.5 to about 0.15, from about 0.45 to about 0.15, from about 0.4 to about 0.15, or from about 0.35 to about 0.2, the C max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         13 . A composition according to any of claims  1 ,  2 ,  5 , or  6 , wherein the carvedilol is in the form of the R(+) carvedilol.  
     
     
         14 . A composition according to any of claims  3 ,  4 ,  7 , or  8 , wherein the carvedilol is in the form of the S(−) carvedilol.  
     
     
         15 . A composition according to any of the preceding claims comprising a solid dispersion of 
 i) carvedilol, which at least partially is in an amorphous or crystalline form,    ii) a polyethylene glycol and/or a polyethylene oxide having a molecular weight of at least about 20,000 in crystalline and/or amorphous form or a mixture such polymers, and    iii) optionally, a stabilizing agent,    the at least one therapeutically, prophylactically and/or diagnostically active substance having a water solubility of at the most 3 mg/ml at 25° C. such as, e.g. at the most about 2 mg/ml, at the most about 1 mg/ml, and the composition being designed to release the active substance with a substantially zero order release.    
     
     
         16 . A composition according to  claim 15 , wherein the composition is coated with a coating a coating having at least one opening exposing at the one surface of said matrix, the coating comprising 
 i) a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in the aqueous medium in which the composition is to be used,    and at least one of    ii) a second cellulose derivative which is soluble or dispersible in water,    iii) a plasticizer, and    iv) a filler.    
     
     
         17 . A composition according to claims  15  or  16  for controlled release of the active substance into an aqueous medium by erosion of at least one surface of the composition.  
     
     
         18 . A composition according to any of the preceding claims, wherein the active substance is selected from the group consisting of the racemate: (RS)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol, the two individual enantiomers: (S)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol and (S)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol, metabolites of carvedilol including desmethylcarvedilol, pharmaceutically acceptable salts, complexes, solvates and anhydrate thereof, and mixtures thereof.  
     
     
         19 . A composition according to any of the preceding claims, wherein the active substance is present In any of its crystalline, polymorphous or amorphous forms or mixtures thereof.  
     
     
         20 . A composition according to any of the preceding claims, wherein the active substance at least partially is present in solid form in the dispersion.  
     
     
         21 . A composition according to any of the preceding claims, wherein the active substance at least partially is present in a molecular dispersion such as, e.g., in the form of a solid or semi-solid solution.  
     
     
         22 . A composition according to  claim 21 , wherein the active substance at least partially is present in a colloidal dispersion.  
     
     
         23 . A composition according to  claim 21 , wherein the active substance at least partially is present in a crystalline form.  
     
     
         24 . A composition according to  claim 20 , wherein carvedilol at least partially is present In amorphous form with a mean particle size of from about 0.01 μm to about 500 μm such as, e.g., from about 0.05 μm to about 500 μm, from about 0.1 μm to about 500 μm, typically from about 0.5 μm to about 300 μm, more typically from about 1 μm to about 200 μm, especially from about 1 μm to about 100 μm.  
     
     
         25 . A controlled release pharmaceutical composition for oral use comprising carvedilol, wherein the release of carvedilol from the composition after administration to a human results in a t max  of carvedilol of from about 1.5 hour to about 8 hours such as, e.g. from about 2 to about 7 hours, from about 2.5 to about 6.5 hours, from about 2.5 to about 6 hours, from about 2.5 to about 5 hours, from about 25 to about 4.5 hours, from about 2.5 to about 4 hours, or from about 2.8 to about 3.5, the t max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         26 . A controlled release pharmaceutical composition for oral use comprising carvedilol, wherein the release of carvedilol from the composition after administration to a human results in a ratio of (t max  of carvedilol from the controlled release composition)/(t max  of carvedilol from a Dimitone® composition) is from about 1.0 to about 5 such as, e.g., from about 1.2 to about 4.5, from about 1.3 to about 4, from about 1.4 to about 3.5, from about 1.5 to about 3.5, from about 1.5 to about 3.5, or from about 1.5 to about 30, the t max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         27 . A controlled release pharmaceutical composition for oral use comprising carvedilol, wherein the release of carvedilol from the composition after administration to a human results in a MRT which is at least about 5.5 hours such as, e.g. at least about 6 hours or is between from about 5.5 to about 20 hours such as, e.g. from about 6 to about 18 hours, from about 7 to about 17 hours, from about 8 to about 17 hours, from about 8 to about 16 hours, from about 8 to about 15 hours, from about 8 to about 13 hours, or from about 8 to about 12 hours, the MRT being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         28 . A controlled release pharmaceutical composition for oral use comprising carvedilol, wherein the release of carvedilol from the composition after administration to a human results in a ratio of (MRT of carvedilol from the controlled release composition)/(MRT of carvedilol from a Dimitone® composition) is from about 0.7 to about 5 such as, e.g., from about 0.8 to about 4.5, from about 0.9 to about 4, from about 1.0 to about 3.5, from about 1.0 to about 3.3, from about 1.0 to about 3, the MRT being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         29 . A controlled release pharmaceutical composition for oral use comprising carvedilol, wherein the release of carvedilol from the composition after administration to a human results in a C max  which—compared to the results after administration of a Dimitone® composition—is at the most about 90% of the value obtained from a Dimitone® composition such as, e.g. at the most about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50% or about 45%, the C max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         30 . A controlled release pharmaceutical composition for oral use comprising carvedilol, wherein the release of carvedilol from the composition after administration to a human results in a C max  of carvedilol which—when calculated as a dosage correlated C max , C calc , (C max in ng/ml)/mg carvedilol in the composition—corresponds to a C calc  from about 2.0 to about 0.1 such as, e.g. from about 1.9 to about 0.2, from about 1.9 to about 0.3, from about 1.8 to about 0.35, from about 1.7 to about 0.4, from about 1.6 to about 0.45, from about 1.6 to about 0.4, or from about 1.5 to about 0.5, the C max  being determined as described herein as a mean value of results from at least six healthy adults.  
     
     
         31 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol, wherein between 10% and 90% of the total carvedilol absorbed is absorbed within 2 hours from administration, such as between 20% and 80%, preferable between 30% and 70%, such as between 40% and 60%  
     
     
         32 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol wherein between 30% and 95% of the total carvedilol absorbed is absorbed within 3 hours from administration, such as between 20% and 95%, preferable between 40% and 90%, such as between 50% and 85%, and more preferred between 60% and 80%.  
     
     
         33 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol wherein between 40% and 98% of the total carvedilol absorbed is absorbed within 4 hours from administration, such as between 30% and 95%, preferable between 50% and 90%, such as between 60% and 85%, and more preferred between 70% and 80%.  
     
     
         34 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol wherein between 50% and 100% of the total carvedilol absorbed is absorbed within 5 hours from administration, such as between 60% and 98%, preferable between 70% and 95%, such as between 75% and 90%, and more preferred between 80% and 90%.  
     
     
         35 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol wherein between 60% and 100% of the total carvedilol absorbed is absorbed within 6 hours from administration, such as between 70% and 98%, preferable between 80% and 95%, such as between 85% and 95%, and more preferred between 80% and 90%.  
     
     
         36 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol wherein between 60% and 100% of the total carvedilol absorbed is absorbed within 7 hours from administration, such as between 70% and 98%, preferable between 80% and 95%, such as between 85% and 95%, and more preferred between 85% and 95%.  
     
     
         37 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol wherein at the most 60% of the total carvedilol absorbed is absorbed within 1 hour from administration and at least 40% is absorbed within 3 hours, preferable at the most 60% absorbed within 2 hours and at least 50 absorbed within 3 hours.  
     
     
         38 . A controlled release composition according to any of the preceding claims wherein release of carv dilol from the composition after oral administration to a human results in an absorption of the carvedilol wherein at least 30% and at the most 70% of total carvedilol absorbed is absorbed within 2 hours from administration and at least 60% is absorbed within 4 hours, and at least 80% is absorbed within 5 hours.  
     
     
         39 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the R(+) carvedilol wherein between 10% and 90% of the total R(+) carvedilol absorbed is absorbed within 2 hours from administration, such as between 20% and 80%, preferable between 30% and 70%, such as between 40% and 60%  
     
     
         40 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the R(+) carvedilol wherein between 30% and 95% of the total R(+) carvedilol absorbed is absorbed within 3 hours from administration, such as between 20% and 95%, preferable between 40% and 90%, such as between 50% and 85%, and more preferred between 60% and 80%.  
     
     
         41 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the R(+) carvedilol wherein between 40% and 98% of the total R(+) carvedilol absorbed is absorbed within 4 hours from administration, such as between 30% and 95%, preferable between 50% and 90%, such as between 60% and 85%, and more preferred between 70% and 80%.  
     
     
         42 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the R(+) carvedilol wherein between 50% and 100% of the total carvedliol absorbed is absorbed within 5 hours from administration, such as between 60% and 98%, preferable between 70% and 95%, such as between 75% and 90%, and more preferred between 80% and 90%.  
     
     
         43 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the R(+) carvedilol wherein between 60% and 100% of the total R(+) carvedilol absorbed is absorbed within 6 hours from administration, such as between 70% and 98%, preferable between 80% and 95%, such as between 85% and 95%, and more preferred between 80% and 90%.  
     
     
         44 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the R(+) carvedilol wherein between 60% and 100% of the total R(+) carvedilol absorbed is absorbed within 7 hours from administration, such as between 70% and 98%, preferable between 80% and 95%, such as between 85% and 95%, and more preferred between 85% and 95%.  
     
     
         45 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the R(+) carvedilol wherein at the most 60% of the total R(+) carvedilol absorbed is absorbed within 1 hour from administration and at least 40% is absorbed within 3 hours, preferable at the most 60% absorbed within 2 hours and at least 50 absorbed within 3 hours.  
     
     
         46 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the R(+) carvedilol wherein at least 30% and at the most 70% of total R(+) carvedilol absorbed is absorbed within 2 hours from administration and at least 60% is absorbed within 4 hours, and at least 80% is absorbed within 5 hours.  
     
     
         47 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the S(−)carvedilol wherein between 10% and 90% of the total S(−)-carvedilol absorbed is absorbed within 2 hours from administration, such as between 20% and 80%, preferable between 30% and 70%, such as between 40% and 60%  
     
     
         48 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the S(−)carvedilol wherein between 30% and 95% of the total S(−)-carvedilol absorbed is absorbed within 3 hours from administration, such as between 20% and 95%, preferable between 40% and 90%, such as between 50% and 85%, and more preferred between 60% and 80%.  
     
     
         49 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the S(−)carvedilol wherein between 40% and 98% of the total S(−)-carvedilol absorbed is absorbed within 4 hours from administration, such as between 30% and 95%, preferable between 50% and 90%, such as between 60% and 85%, and more preferred between 70% and 80%.  
     
     
         50 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the S(−)carvedilol wherein between 50% and 100% of the total carvedilol absorbed is absorbed within 5 hours from administration, such as between 60% and 98%, preferable between 70% and 95%, such as between 75% and 90%, and more preferred between 80% and 90%.  
     
     
         51 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the S(−)carvedilol wherein between 60% and 100% of the total S(−)-carvedilol absorbed is absorbed within 6 hours from administration, such as between 70% and 98%, preferable between 80% and 95%, such as between 85% and 95%, and more preferred between 80% and 90%.  
     
     
         52 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the S(−)carvedilol wherein between 60% and 100% of the total S(−)-carvedilol absorbed is absorbed within 7 hours from administration, such as between 70% and 98%, preferable between 80% and 95%, such as between 85% and 95%, and more preferred between 85% and 95%.  
     
     
         53 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the S(−)carvedilol wherein at the most 60% of the total S(−)carvedilol absorbed is absorbed within 1 hour from administration and at least 40% is absorbed within 3 hours, preferable at the most 60% absorbed within 2 hours and at least 50 absorbed within 3 hours.  
     
     
         54 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the S(−)carvedllol wherein at least 30% and at the most 70% of total S(−)-carvedilol absorbed is absorbed within 2 hours from administration and at least 60% is absorbed within 4 hours, and at least 80% is absorbed within 5 hours.  
     
     
         55 . A controlled release composition according to any of the preceding claims wherein release of carvedlol from the composition after oral administration to a human results In an absorption of the carvedilol and/or any or both of the enatiomers S(−)carvedilol and R(+)carvedilol which is delayed at least 100%, such as at least 200%, such as at least 300%, preferable at least 400% such as at least 500% in time compared with an immediate release formulation at the time where 40% is absorbed.  
     
     
         56 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol and/or any or both of the enatiomers S(−)carvedilol and R(+)carvedilol which is delayed at least 100%, such as at least 200%, such as at least 300%, preferable at least 400% such as at least 500% in time compared with an immediate release formulation at the time where 50% is absorbed.  
     
     
         57 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol and/or any or both of the enatiomers S(−)carvedilol and R(+)carvedilol which is delayed at least 100%, such as at least 200%, such as at least 300%, preferable at least 400% such as at least 500% in time compared with an immediate release formulation at the time where 80% is absorbed.  
     
     
         58 . A controlled release composition according to any of the preceding claims wherein release of carvedilol from the composition after oral administration to a human results in an absorption of the carvedilol and/or any or both of the enantiomers S(−)carvedilol and R(+)carvedilol which is delayed at least 100%, such as at least 200%, such as at least 300%, preferable at least 400% such as at least 500% in time compared with an immediate release formulation at the time where 90% is absorbed.  
     
     
         59 . A controlled release composition according to any of the preceding claims, wherein he release of carvedilol from the composition is a zero order release and the total in vitro dissolution time of carvedilol is in a range of from about 3 to about 10 hours such as, e.g., from about 4 to about 10 hours, from about 4 to about 9 hours, from about 4.5 to about 8 hours, from about 4.5 to about 7 hours, from about 4.5 to about 6 hours, or from about 5 to about 6 hours.