Stable dosage forms of spiro and dispiro 1,2,4-trioxolane antimalarials

Abstract

The field of the invention relates to stable dosage forms comprising spiro or dispiro 1,2,4-trioxolane antimalarials, or their pharmaceutically acceptable salts, prodrugs and analogues, and processes for their preparation. The water content of the dosage form is not more than 6.5% w/w.

1 . A stable oral solid dosage form comprising:
 (a) a therapeutically effective amount of a compound having the structure of Formula I,   
     
       
         
         
             
             
         
       
     
     and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates, wherein:
 R 1  and R 2  are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl ring attaching R 1  and R 2  are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms; and 
 (b) one or more pharmaceutically acceptable excipients, 
 wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 6 months. 
 
   
   
       2 . The stable solid dosage form according to  claim 1 , wherein the compound has the structure of Formula II. 
     
       
         
         
             
             
         
       
     
   
   
       3 . The stable solid dosage form according to  claim 1 , wherein the dosage form further comprises one or more of other antimalarial drugs selected from quinine, mefloquine, lumefantrine, sulfadoxine-pyrimethamine, dihydroartimisinin, piperaquine, chloroquine, amodiaquine, proguanil, atovaquone, chloroproguanil, dapsone, fosmidomycin, tetracycline, clindamycin, and DB 289. 
   
   
       4 . A stable oral solid dosage form comprising:
 (a) a therapeutically effective amount of a compound having the structure of Formula II,   
     
       
         
         
             
             
         
       
     
     and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates;
 (b) piperaquine; and 
 (c) one or more pharmaceutically acceptable excipients. 
 
   
   
       5 . The stable solid dosage form according to  claim 4 , wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 3 months. 
   
   
       6 . The stable solid dosage form according to  claim 1  or  4 , wherein the pharmaceutically acceptable excipients comprises one or more of binders, diluents, glidants/lubricants, disintegrants, surfactants and coloring agents. 
   
   
       7 . The stable solid dosage form according to  claim 7 , wherein the diluent is microcrystalline cellulose. 
   
   
       8 . The stable solid dosage form according to  claim 7 , wherein water content of the excipients is not more than 6.5% w/w. 
   
   
       9 . The stable solid dosage form according to  claim 1  or  4 , wherein the dosage form comprises a tablet, capsule, pill, granule and powder. 
   
   
       10 . The stable solid dosage form according to  claim 9 , wherein the tablet is coated with one or more functional and/or non-functional coating layers comprising film-forming polymers and coating additives. 
   
   
       11 . The stable solid dosage form according to  claim 10 , wherein the coating additives comprises one or more of plasticizers, glidants or flow regulators, opacifiers and lubricants. 
   
   
       12 . The stable solid dosage form according to  claim 1  or  4 , wherein the dosage form provides immediate release profile or modified release profile. 
   
   
       13 . The stable oral solid dosage form according to  claim 1  or  4 , wherein the dosage form is prepared using a dry or non-aqueous process. 
   
   
       14 . The stable solid dosage form according to  claim 1 , wherein the dosage form is prepared by a process comprising the steps of:
 (a) blending a compound of Formula I and, optionally, one or more other antimalarial drugs, and one or more intragranular excipients;   (b) granulating the blend by roller compaction;   (c) blending the granules with one or more extragranular excipients; and   (d) compressing the blend into tablets or filling into capsules.   
   
   
       15 . The stable solid dosage form according to  claim 1 , wherein the dosage form is prepared by a process comprising the steps of:
 (a) blending a compound of Formula I and, optionally, one or more other antimalarial drugs, and one or more intragranular excipients;   (b) granulating the blend by slugging;   (c) blending the granules with one or more extragranular excipients; and   (d) compressing the blend into tablets or filling into capsules.   
   
   
       16 . The stable solid dosage form according to  claims 1 , wherein the dosage form is prepared by a process comprising the steps of:
 (a) blending a compound of Formula I and, optionally, one or more other antimalarial drugs, and one or more pharmaceutically acceptable excipients; and   (b) directly compressing the blend into tablets or filling into capsules.   
   
   
       17 . The stable solid dosage form according to  claim 1 , wherein the dosage form is prepared by a process comprising the steps of:
 (a) blending a compound of Formula I and, optionally, one or more other antimalarial drugs, and one or more intragranular excipients;   (b) wet granulating the blend with a non-aqueous granulating fluid;   (c) drying and reducing the granules to a suitable size;   (d) blending the granules with one or more extragranular excipients; and   (e) compressing into tablets or filling into capsules.   
   
   
       18 . The stable solid dosage form according to  claim 1 , wherein the dosage form is prepared by a process comprising the steps of:
 (a) granulating a blend of one or more excipients;   (b) drying the excipient granules;   (c) blending excipient granules with a compound of Formula I and, optionally, one or more other antimalarial drugs; and   (d) compressing the blend into tablets or filling into capsules.   
   
   
       19 . A method of prophylaxis or treatment of malaria, the method comprising administering a stable oral solid dosage form comprising:
 (a) a therapeutically effective amount of a compound having the structure of Formula I,   
     
       
         
         
             
             
         
       
     
     and its enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts and pharmaceutically acceptable solvates, wherein:
 R 1  and R 2  are same or different and are selected from hydrogen, substituted or unsubstituted linear or branched alkyl, aryl, and alkaryl groups and substituted or unsubstituted alicyclic groups that are optionally interrupted by one or more oxygen, sulfur or nitrogen atoms, substituted or unsubstituted aromatic or heterocyclic groups that may be interrupted by one or more oxygen, sulfur or nitrogen atoms, a hydroxy group, and a halogen, and further providing that the spirocyclohexyl ring attaching R 1  and R 2  are optionally interrupted by one or more oxygen, sulfur, or nitrogen atoms; and 
 (b) one or more pharmaceutically acceptable excipients, 
 wherein not more than 5% w/w total related substances are formed on storage at 40±2° C. and 75±5% relative humidity over a period of 6 months. 
 
   
   
       20 . The method of prophylaxis or treatment of malaria according to  claim 19 , wherein the dosage form further comprises one or more of other antimalarial drugs.