Solid formulation
(wherein R 1 , R 2 and R 3 may be the same or different and each represents a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl; and R 4 represents cycloalkyl, —(CH 2 ) n —R 5 or the above formula (II)) The present invention provides a solid formulation comprising a xanthine derivative represented by the above formula (I) or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, which possesses excellent pharmaceutical properties, for example, in hardness, disintegration property, dissolution property, stability or the like.
1 . A solid formulation comprising microcrystalline derivative represented by formula (I)
wherein R 1 , R 2 and R 3 dependently represent a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl; and
R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R 5 represents substituted or unsubstituted aryl or a substituted heterocyclic group; and n represents an integer of 0 to 4 ) or formula (II)
(in which Y 1 and Y 2 may be the same or different and each represents a hydrogen atom, halogen or lower alkyl; and Z represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group)
or a pharmaceutically acceptable salt thereof.
2 . The solid formulation according to claim 1 , wherein R 4 is formula (II).
3 . The solid formulation according to claim 2 , wherein Y 1 and Y 2 each are a hydrogen atom.
4 . The solid formulation according to claim 2 or 3 , wherein Z is substituted or unsubstituted aryl or formula (III)
in which R 6 represents a hydrogen atom, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino; and m represents an integer of 1 to 3.
5 . A solid formulation comprising (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione represented by formula (1A)
or a pharmaceutically acceptable salt thereof, and
microcrystalline cellulose.
6 . The solid formulation according to any one of claims 1 to 3 , which contains a sugar.
7 . The solid formulation according to claim 6 , wherein the sugar content is 1.0 to 9.0 parts by weight per 1.0 part by weight of microcrystalline cellulose.
8 . The solid formulation according to claim 6 , wherein the sugar content is 1.0 to 5.0 parts by weight per 1.0 part by weight of microcrystalline cellulose.
9 . The solid formulation according to claim 6 , wherein the sugar content is 1.5 to 3.0 parts by weight per 1.0 part by weight of microcrystalline cellulose.
10 . The solid formulation according to claim 25 , wherein the sugar is lactose, sucrose, glucose, cyclodextrin or mannitol.
11 . The solid formulation according to claim 25 , wherein the sugar is lactose.
12 . The solid formulation according to claim 10 , which contains a binder.
13 . The solid formulation according to claim 12 , wherein the binder is hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or polyvinyl alcohol.
14 . The solid formulation according to claim 12 , wherein the binder is polyvinyl alcohol.
15 . The solid formulation according to claim 13 , wherein the binder content is 0.1 to 10.0% of the total weight of the solid formulation.
16 . The solid formulation according to claim 12 , which contains a disintegrator.
17 . The solid formulation according to claim 16 , wherein the disintegrator is crospovidone, croscarmellose sodium, low substituted hydroxypropylcellulose, carmellose calcium or sodium starch glycolate.
18 . The solid formulation according to claim 16 , wherein the disintegrator is crospovidone.
19 . The solid formulation according to claim 17 , wherein the disintegrator content is 0.5 to 20.0% of the total weight of the solid formulation.
20 . The solid formulation according to claim 12 , wherein a dosage form of the solid formulation is a tablet.
21 . The solid formulation according to claim 20 , which is a film-coated solid formulation.
22 . A method for stabilizing a xanthine derivative comprising the steps of admixing a compound represented by formula (I)
wherein R 1 , R 2 and R 3 independently represent a hydrogen atom, lower alkyl, lower alkenyl or lower alkynyl; and
R 4 represents cycloalkyl, —(CH 2 ) n —R 5 (in which R represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group; and n represents an integer of 0 to 4) or formula (II)
(in which Y 1 and Y 2 may be the same or different and each represents a hydrogen atom, halogen or lower alkyl; and Z represents substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group) or a pharmaceutically acceptable salt thereof with microcrystalline cellulose to prepare a solid formulation.
23 . The solid formulation according to claim 4 , which contains a sugar.
24 . The solid formulation according to claim 5 , which contains a sugar.
25 . The solid formulation according to claim 23 , wherein the sugar content is 1.5 to 3.0 parts by weight per 1.0 part by weight of microcrystalline cellulose.
26 . The solid formulation according to claim 24 , wherein the sugar content is 1.5 to 3.0 parts by weight per 1.0 part by weight of microcrystalline cellulose.
27 . (canceled)