Dosage forms with improved bioavailability

Abstract

A solid dispersion product comprising an effective amount of one or more active ingredients and an effective amount of one or more hydroxypropyl methylcellulose(s), which satisfies the Formula 0.35>ΔH tr (1) (wherein ΔH tr represents the endotherm (J/g) accompanying a transition at about 240° C.). The solid dispersion product is used for the manufacture of a dosage form having improved bioavailability of said one or more active ingredients by oral administration to a patient in need thereof.

1 . A solid dispersion product comprising
 (i) an effective amount of one active ingredient or a mixture of two or more active ingredients and   (ii) an effective amount of a hydroxypropyl methylcellulose or a mixture of two or more hydroxypropyl methylcelluloses, wherein said solid dispersion product satisfies the formula
   0.35>ΔH tr    
   
     wherein ΔH tr  represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C. 
   
   
       2 . The solid dispersion product of  claim 1 , which satisfies the formula
   0.20>ΔH tr      
     wherein ΔH tr  represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C. 
   
   
       3 . The solid dispersion product of  claim 1 , which satisfies the formula
   0.15>ΔH tr      
     wherein ΔH tr  represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C. 
   
   
       4 . The solid dispersion product of  claim 1 , wherein the endothermic peak temperature is in the range of from about 240° C. to about 250° C. 
   
   
       5 . The solid dispersion product of  claim 1 , having a weight-average particle size of less than 600 m. 
   
   
       6 . The solid dispersion product of  claim 1 , wherein the total content of methoxy and hydroxypropyl groups in the hydroxypropyl methylcellulose is in the range of 23 to 42% by weight. 
   
   
       7 . The solid dispersion product of  claim 6 , wherein the methoxy group content is in the range of 19 to 30 wt % and the hydroxypropyl group content is in the range of 4 to 12% by weight. 
   
   
       8 . The solid dispersion product of  claim 7 , wherein the hydroxypropyl methylcellulose has an apparent viscosity of from about 3 to about 15 mPa·s, as determined as an 2 wt. % aqueous solution at 20° C. 
   
   
       9 . The solid dispersion product of  claim 1 , wherein the weight ratio of active ingredient hydroxypropyl methylcellulose is in the range of 1:1 to 1:17. 
   
   
       10 . A pharmaceutical dosage form comprising particles of the solid dispersion product of  claim 1  and at least one additive selected from the group consisting of a diluent and a disintegrant. 
   
   
       11 . A method for preparing a solid dispersion product, which comprises:
 a) blending (i) an effective amount of one active ingredient or a mixture of two or more active ingredients and (ii) an effective amount of a hydroxypropyl methylcellulose or a mixture of two or more hydroxypropyl methylcelluloses;   b) heating the blend, under preset conditions of temperature, shear and throughput rate, to obtain a homogeneous melt;   c) forcing the thus obtained melt through one or more nozzles;   d) allowing the melt to solidify to obtain a solid dispersion product;   e) subjecting a representative sample of the obtained solid dispersion product to differential scanning calorimetry measurement; and, if necessary, e) adjusting the conditions of temperature, shear and throughput rate used in step b) such that the solid dispersion product satisfies the formula
   0.35>ΔH tr , 
   preferably 0.20>ΔH tr ,   more preferably 0.15>ΔH tr ,   
     wherein ΔH tr  represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C. 
   
   
       12 . The method of  claim 11 , wherein step b) is carried out in an extruder and the blend is subjected to a kneading action in a kneading section of the extruder. 
   
   
       13 . The method of  claim 11 , wherein step b) is carried out in an extruder, the extruder operating temperature and the nozzle temperature being in the range of from about 195° C. to about 300° C. 
   
   
       14 . The method of  claim 11 , wherein the total content of methoxy and hydroxypropyl groups in the hydroxypropyl methylcellulose is in the range of 23 to 42% by weight. 
   
   
       15 . The method of  claim 14 , wherein the methoxy group content is in the range of 19 to 30 wt % and the hydroxypropyl group content is in the range of 4 to 12% by weight. 
   
   
       16 . The method of  claim 15 , wherein the hydroxypropyl methylcellulose has an apparent viscosity of from about 3 to about 15 mPa·s, as determined as an 2 wt. % aqueous solution at 20° C. 
   
   
       17 . The method of  claim 11 , wherein the weight ratio of active ingredient:hydroxypropyl methylcellulose is in the range of 1:1 to 1:17. 
   
   
       18 . The method of  claim 11 , additionally comprising grinding the solid dispersion product. 
   
   
       19 . The method of  claim 18 , additionally comprising sieving the ground solid dispersion product. 
   
   
       20 . The method of  claim 18 , additionally comprising compressing the ground solid dispersion product into a tablet. 
   
   
       21 . The use of a solid dispersion product comprising
 (i) an effective amount of one active ingredient or a mixture of two or more active ingredients and   (ii) an effective amount of a hydroxypropyl methylcellulose or a mixture of two or more hydroxypropyl methylcelluloses, for the manufacture of a dosage form having improved bioavailability of said one or more active ingredients by oral administration to a patient in need thereof, wherein said solid dispersion product satisfies the formula
   0.35>ΔH tr    
   
     wherein ΔH tr  represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C. 
   
   
       22 . The use of  claim 21 , wherein said solid dispersion product satisfies the formula
   0.20>ΔH tr      
     wherein ΔH tr  represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C. 
   
   
       23 . The use of  claim 21 , wherein said solid dispersion product satisfies the formula
   0.15>ΔH tr      
     wherein ΔH tr  represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C. 
   
   
       24 . The use  claim 21 , wherein the endothermic peak temperature is in the range of from about 240° C. to about 250° C. 
   
   
       25 . The use  claim 21 , wherein the solid dispersion product is comprised of particles having a weight-average particle size of less than 600 μm. 
   
   
       26 . The use  claim 21 , wherein the total content of methoxy and hydroxypropyl groups in the hydroxypropyl methylcellulose is in the range of 23 to 42% by weight. 
   
   
       27 . The use of  claim 26 , wherein the methoxy group content is in the range of 19 to 30 wt % and the hydroxypropyl group content is in the range of 4 to 12% by weight. 
   
   
       28 . The use of  claim 27 , wherein the hydroxypropyl methylcellulose has apparent viscosity of from about 3 to about 15 mPa·s, as determined as an 2 wt. % aqueous solution at 20° C. 
   
   
       29 . The use  claim 21 , wherein the weight ratio of active ingredient: hydroxypropyl methylcellulose is in the range of 1:1 to 1:17.