Sustained-release formulation

Abstract

A sustained-release formulation is provided comprising a solid dispersion composition comprising a tricyclic compound or a pharmaceutically acceptable salt thereof in a mixture comprising a water-soluble polymer and a water-insoluble polymer, and an excipient.

1 - 26 . (canceled)  
     
     
         27 . A sustained-release formulation comprising a solid dispersion composition, wherein the solid dispersion composition comprises a tricyclic compound represented by the general formula I or a pharmaceutically acceptable salt thereof  
       
         
           
           
               
               
           
         
         wherein each of adjacent pairs of R 1  and R 2 , R 3  and R 4 , and R 5  and R 6  independently 
 (a) is two adjacent hydrogen atoms, but R 2  may also be an alkyl group or  
 (b) may form another bond formed between the carbon atoms to which they are attached;  
 
         R 7  is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with R 1 ;  
         R 8  and R 9  are independently a hydrogen atom or a hydroxy group;  
         R 10  is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group;  
         X is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula —CH 2 O—;  
         Y is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula N—NR 11 R 12  or N—OR 13 ;  
         R 11  and R 12  are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;  
         R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 22  and R 23  are independently a hydrogen atom or an alkyl group;  
         R 24  is an optionally substituted ring system which may contain one or more heteroatoms;  
         n is an integer of 1 or 2; and  
         in addition to the above definitions, Y, R 10  and R 23 , together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a benzyl, a group of the formula —CH 2 Se(C 6 H 5 ), and an alkyl substituted by one or more hydroxy groups in a mixture comprising a water-soluble polymer and a water-insoluble polymer, and an excipient.  
       
     
     
         28 . The sustained-release formulation of  claim 27 , wherein the solid dispersion composition has a particle size equal to or smaller than 250 μm.  
     
     
         29 . The sustained-release formulation of  claim 27 , wherein the weight ratio of the water-soluble polymer to the tricyclic compound is 0.2-0.4:1, and the weight ratio of the water-insoluble polymer to the tricyclic compound is 0.1-5:1.  
     
     
         30 . The sustained-release formulation of  claim 29 , wherein the weight ratio of the water-insoluble polymer to the tricyclic compound is 0.1-1:1.  
     
     
         31 . The sustained-release formulation of  claim 27 , wherein the water-insoluble polymer is ethylcellulose.  
     
     
         32 . The sustained-release formulation of  claim 27 , wherein the water-soluble polymer is hydroxypropylmethyl cellulose.  
     
     
         33 . The sustained-release formulation of  claim 27 , wherein the excipient is lactose.  
     
     
         34 . The sustained-release formulation of  claim 33 , wherein the weight ratio of lactose to the tricyclic compound is 2, 3 or 5:1.  
     
     
         35 . The sustained-release formulation of  claim 27 , wherein the solid dispersion composition does not substantially contain any disintegrators.  
     
     
         36 . The sustained-release formulation of  claim 27 , wherein the tricyclic compound or the pharmaceutically acceptable salt thereof is present as an amorphous state.  
     
     
         37 . The sustained-release formulation of  claim 28 , wherein the weight ratio of the water-soluble polymer to the tricyclic compound is 0.2-0.4:1, and the weight ratio of the water-insoluble polymer to the tricyclic compound is 0.1-5:1.  
     
     
         38 . The sustained-release formulation of  claim 37 , wherein the weight ratio of the water-insoluble polymer to the tricyclic compound is 0.1-1:1.  
     
     
         39 . The sustained-release formulation of  claim 32 , wherein the water-insoluble polymer is ethylcellulose.  
     
     
         40 . The sustained-release formulation of  claim 39 , wherein the excipient is lactose.  
     
     
         41 . The sustained-release formulation of  claim 27 , wherein the tricyclic compound or the pharmaceutically acceptable salt thereof is present as an amorphous state in a mixture of ethylcellulose and hydroxypropylmethyl cellulose.  
     
     
         42 . The sustained-release formulation of  claim 41 , wherein the weight ratio of the ethylcellulose to the tricyclic compound is 0.3:1, and the weight ratio of the hydroxypropylmethyl cellulose to the tricyclic compound is 0.3:1.  
     
     
         43 . The sustained-release formulation of  claim 42 , wherein the excipient is lactose.  
     
     
         44 . The sustained-release formulation of  claim 43 , wherein the weight ratio of lactose to the tricyclic compound is 2:1.  
     
     
         45 . The sustained-release formulation of  claim 44 , wherein the solid dispersion composition has a particle size equal to or smaller than 212 μm.  
     
     
         46 . The sustained-release formulation of  claim 29 , wherein the water-insoluble polymer is ethylcellulose and the water soluble polymer is hydroxypropylmethyl cellulose.  
     
     
         47 . The sustained-release formulation of  claim 27 , in a form of a powder, granule, tablet or capsule.  
     
     
         48 . The sustained-release formulation of  claim 27 , wherein R 24  is selected from the group consisting of 
 (a) a 3,4-di-oxo-cyclohexyl group;    (b) a 3-R 20 -4-R 21 -cyclohexyl group, 
 in which R 20  is hydroxy, an alkoxy group, an oxo group, or a —OCH 2 OCH 2 CH 2 OCH 3  group, and 
 R 21  is hydroxy, —OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, a —OCH 2 OCH 2 CH 2 OCH 3  group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy, or R 25 R 26 CHCOO—, 
 in which R 25  is optionally protected hydroxy or protected amino, and R 26  is hydrogen or methyl, or  
 
 R 20  and R 21  together form an oxygen atom in an epoxide ring; and  
 
   (c) cyclopentyl group substituted by methoxymethyl, optionally protected hydroxymethyl, acyloxymethyl, one or more amino and/or hydroxy groups which may be protected, or aminooxalyloxymethyl.    
     
     
         49 . The sustained-release formulation of  claim 27 , wherein each of adjacent pairs of R 3  and R 4  or R 5  and R 6  independently form another bond formed between the carbon atoms to which they are attached; 
 each of R 8  and R 23  is independently a hydrogen atom;    R 9  is a hydroxy group;    R 10  is a methyl group, an ethyl group, a propyl group or an allyl group;    X is (a hydrogen atom and a hydrogen atom) or an oxo group;    Y is an oxo group;    each of R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 22  is a methyl group;    R 24  is a 3-R 20 -4-R 21 -cyclohexyl group, 
 in which R 20  is hydroxy, an alkoxy group, an oxo group, or a —OCH 2 OCH 2 CH 2 OCH 3  group, and 
 R 21  is hydroxy, —OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, a —OCH 2 OCH 2 CH 2 OCH 3  group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy, or R 25 R 26  CHCOO—, 
 in which R 25  is optionally protected hydroxy or protected amino, and R 26  is hydrogen or methyl, or  
 
 R 20  and R 21  together form an oxygen atom in an epoxide ring; and  
 
   n is an integer of 1 or 2.