Process for producing a solid dispersion of an active ingredient

Abstract

A process for producing a solid dispersion of an active ingredient which comprises feeding the active ingredient and a matrix-forming agent to an extruder and forming a uniform extrudate, wherein the extruder comprises at least two rotating shafts ( 2 ), each of the shafts ( 2 ) carrying a plurality of processing elements disposed axially one behind the other, the processing elements defining (i) a feeding and conveying section (R; A), (ii) at least one reverse-flight section (D), and (iii) a discharging section (E), wherein the processing elements defining the reverse-flight section (R; D) comprise at least one reverse-flight element ( 14 ) which is based on a screw-type element having a conveying direction being opposite to the general conveying direction of the extruder.

1 . A process for producing a solid dispersion of an active ingredient which comprises feeding the active ingredient and a matrix-forming agent to an extruder and forming a uniform extrudate, wherein the extruder comprises at least two rotating shafts, each of the shafts carrying a plurality of processing elements disposed axially one behind the other, the processing elements defining
 (i) a feeding and conveying section,   (ii) at least one reverse-flight section, and   (iii) a discharging section,   wherein the processing elements defining the reverse-flight section comprise at least one reverse-flight element which is based on a screw-type element having a conveying direction opposite to the general conveying direction of the extruder.   
   
   
       2 . The process of  claim 1 , wherein the processing elements defining the reverse-flight section comprise at least two reverse-flight elements and at least one positive-flight screw-type element which is arranged between said two reverse-flight elements. 
   
   
       3 . The process of  claim 1 , wherein the processing elements defining the feeding and conveying section comprise positive-flight screw-type elements and wherein the screw pitch of said at least one reverse-flight element is in a range from (−0.5) times to (−1.5) times the screw pitch of screw-type elements of the feeding and conveying section and/or the positive-flight screw-type element(s) arranged between the two reverse-flight elements. 
   
   
       4 . The process of  claim 1 , wherein the processing elements defining the reverse-flight section comprise at least three reverse-flight elements ( 14 - 1  to  14 - 3 ), wherein at least one positive-flight screw-type element is arranged between the respective successive reverse-flight elements. 
   
   
       5 . The process of  claim 4 , wherein the length of the positive-flight screw-type element(s) arranged between the second and third reverse-flight element is in a range from 1 to 15 times the length of the positive-flight screw-type element(s) arranged between the first and second reverse-flight elements. 
   
   
       6 . The process of  claim 1 , wherein the processing elements defining the reverse-flight section comprise at least four reverse-flight elements, wherein at least one positive-flight screw-type element is arranged between the respective successive reverse-flight elements, and wherein the positive-flight screw-type elements arranged between successive reverse-flight elements have the same length. 
   
   
       7 . The process of  claim 1 , wherein the processing elements comprise additionally at least one mixing element that is derived from a screw-type element, wherein the mixing element(s) has/have recesses formed in the screw flight of the screw-type element. 
   
   
       8 . The process of  claim 7 , wherein at least one reverse-flight element is positioned downstream to the mixing element(s). 
   
   
       9 . The process of  claim 7 , wherein at least one mixing element has a plurality of concentric ring portions formed by grooves turned into the screw type element. 
   
   
       10 . The process of  claim 7 , wherein at least one mixing element does not have a plane surface area with a normal that is parallel and opposite to the general conveying direction. 
   
   
       11 . The process of  claim 7 , wherein at least one mixing element does not have a face that is perpendicular to the general conveying direction. 
   
   
       12 . The process of  claim 7 , wherein at least one mixing element does not have abutting faces that are perpendicular to the general conveying direction. 
   
   
       13 . The process of  claim 7 , wherein the processing elements define
 (i) a feeding and conveying section,   (ii) a first mixing section,   (iii) an intermediate conveying section,   (iv) a reverse-flight section, and   (v) a discharging section,   wherein the processing elements defining the first mixing section comprise at least one mixing element and the processing elements defining the reverse-flight section   comprise at least one mixing element and downstream thereto at least one reverse-flight element.   
   
   
       14 . The process of  claim 1 , wherein at least part of the matrix-forming agent is fed to a hopper of the extruder and at least one component selected from
 (i) the remainder of the matrix-forming agent,   (ii) an active ingredient,   (iii) an additive, and   (iv) combinations thereof,   
     is introduced into the extruder through an opening in the extruder barrel at a position upstream of or in a mixing section or reverse-flight section. 
   
   
       15 . The process of  claim 14 , wherein the at least one component is introduced into the extruder at a position at or close to the junction of the feeding and conveying section and a mixing section or reverse-flight section. 
   
   
       16 . The process of  claim 14 , wherein the at least one component is liquid or liquefied. 
   
   
       17 . The process of  claim 14 , wherein the at least one component comprises a pharmaceutically acceptable surfactant. 
   
   
       18 . The process of  claim 1 , wherein the active ingredient is dispersed in a polymer in a state of a solid solution. 
   
   
       19 . The process of  claim 1 , wherein the matrix-forming agent comprises a pharmaceutically acceptable polymer. 
   
   
       20 . The process of  claim 19 , wherein the pharmaceutically acceptable polymer is selected from the group consisting of homopolymers of N-vinyl lactams, copolymers of a N-vinyl lactam and one or more comonomers selected from nitrogen-containing monomers and oxygen-containing monomers, cellulose esters and cellulose ethers, high molecular polyalkylene oxides, polyacrylates and polymethacrylates, oligo- and polysaccharides, poly(hydroxy acids), or mixtures thereof. 
   
   
       21 . The process of  claim 1 , wherein the matrix-forming agent comprises a member selected from polyols, waxes and lipids. 
   
   
       22 . The process of  claim 1 , additionally comprising feeding at least one additive selected from the group consisting of flow regulators; lubricants, fillers, disintegrants, plasticizers, stabilizers or preservatives into the extruder. 
   
   
       23 . The process of  claim 1 , wherein the extrudate is directly shaped into a dosage form. 
   
   
       24 . The process of  claim 23 , wherein shaping is carried out by calendaring, injection moulding or profile extrusion. 
   
   
       25 . The process of  claim 1 , additionally comprising grinding the solidified extrudate. 
   
   
       26 . The process of  claim 25 , additionally comprising compressing said solid dispersion product into a tablet or filling said solid dispersion product into a capsule shell. 
   
   
       27 . The process of  claim 26 , additionally comprising applying a film-coat to the tablet.