1-22. (canceled)
23. A solid pharmaceutical composition for oral administration comprising
a 5-HT4 partial agonist in base or salt form in an amount of up to 10% by weight,
a diluent in an amount of 70 to 90% by weight,
a disintegrant in an amount of less than 15% by weight, and
wherein the amounts by weight are based on the total weight of the composition.
24. A pharmaceutical composition as claimed in claim 23 optionally, further comprising a glidant.
25. A pharmaceutical composition as claimed in claim 24 wherein the glidant is colloidal silica dioxide.
26. A pharmaceutical composition as claimed in claim 24 optionally, further comprising a lubricant.
27. A pharmaceutical composition as claimed in claim 26 wherein the lubricant is present in an amount of 3 to 7% based on the total weight of the composition.
28. A pharmaceutical composition as claimed in claim 26 wherein the lubricant is glycerol monostearate or glycerol behenate.
29. A pharmaceutical composition as claimed in claim 26 optionally, further comprising a binder.
30. A pharmaceutical composition as claimed in claim 29 wherein the binder is hydroxy propylmethyl cellulose.
31. A pharmaceutical composition as claimed in claim 29 wherein the 5-HT4 partial agonist is tegaserod.
32. A pharmaceutical composition as claimed in claim 31 wherein tegaserod is in the form of the maleate salt.
33. A pharmaceutical composition as claimed in claim 29 wherein the diluent is selected from the group consisting of lactose, mannitol, sucrose, calcium phosphate or microcrystalline cellulose.
34. A pharmaceutical composition as claimed in claim 33 wherein the diluent is lactose.
35. A pharmaceutical composition as claimed in claim 29 wherein the disintegrant is present in an amount of 12% or less by weight based on the total weight of the composition.
36. A composition as claimed in claim 29 wherein the disintegrant is crospovidone.
37. A process for the production of a composition as claimed in claim 29 which process is carried out under substantially dry conditions using granulation.
38. A process for the production of a composition as claimed in claim 29 which process comprises:
(i) preparing a mixture of 5-HT4 partial agonist, e.g. tegaserod, diluent and lubricant,
(ii) sieving the mixture,
(iii) adding the disintegrant, glidant and optionally binder and blending the sieved mixture of step (ii), and
(iv) forming tablets by direct compression.
39. A process for the production of a composition as claimed in claim 38 wherein the components are mixed with tegaserod, sieved and mixed again before tabletting.
40. A process for the production of a composition as claimed in claim 29 which process comprises:
(i) preparing a mixture of 5-HT4 partial agonist, e.g. tegaserod, and diluent
(ii) sieving the mixture
(iii) adding the disintegrant, glidant and optionally binder and blending the sieved mixture of step (ii)
(iv) adding the lubricant by spray lubrication when forming tablets by direct compression.
41. A process for the production of a composition as claimed in claim 40 wherein all the components are mixed with tegaserod, sieved through and mixed again before tabletting.
42. A process for the production of a composition as claimed in claim 29 which process comprises:
(i) preparing a mixture of 5-HT 4 partial agonist e.g. tegaserod, diluent, disintegrant, glidant and optionally binder
(ii) compacting the premix of step (i) by roller compaction
(iii) milling the mixture of step (ii) and
(iv) forming tablets by compression.
43. A solid pharmaceutical composition for oral administration consisting of or consisting essentially of
tegaserod in base or salt form in an amount of up to 10% by weight,
a diluent in an amount of 70 to 90% by weight,
a disintegrant in an amount of less than 15% by weight,
a glidant and a lubricant,
wherein the amounts are by weight based on the total weight of the composition.
44. A solid pharmaceutical composition for oral administration consisting of or consisting essentially of
tegaserod in base or salt form in an amount of up to 10% by weight,
a diluent in an amount of 70 to 90% by weight,
a disintegrant in an amount of less than 15% by weight,
a binder, glidant and a lubricant,
wherein the amounts are by weight based on the total weight of the composition.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A copolymer, comprising:
a predominantly alternating monomer structure, comprising:
at least one monomer unit derived from a radically (co)polymerizable monomer having electron-donor properties; and
at least one monomer unit derived from a radically (co)polymerizable monomer having electron-acceptor properties;
a terminal functional group selected from a radically transferable atom or group, a halogen, Cl, Br, I, OR10, SR14, SeR14, OC(\u2550O)R14, OP(\u2550O)R14, OP(\u2550O)(OR14)2, O\u2014N(R14)2, S\u2014C(\u2550S)N(R14)2, CN, NC, SCN, CNS, OCN, CNO, N3, OH, C1-C6-alkoxy, (SO4), PO4, HPO4, H2PO4, triflate, hexafluorophosphate, methanesulfonate, arylsulfonate, carboxylic acid halide, R15CO2, NH2, COOH, or CONH2, where R14 is aryl or a straight or branched C1-C20 alkyl group or where an N(R14)2 group is present, the two R14 groups may be joined to form a 5-, 6- or 7-member heterocyclic ring, R15 is H or a straight or branched C1-C6 alkyl group, aryl or aryl substituted 1 to 5 times with a halogen, and R10 is an alkyl of from 1 to 20 carbon atoms or an alkyl of from 1 to 20 carbon atoms in which each of the hydrogen atoms may be replaced by a halide, alkenyl of from 2 to 20 carbon atoms, alkynyl of from 2 to 10 carbon atoms, phenyl, phenyl substituted with from 1 to 5 halogen atoms or alkyl groups with from 1 to 4 carbon atoms, aralkyl, aryl substituted alkyl, in which the aryl group is phenyl or substituted phenyl and the alkyl group is from 1 to 6 carbon atoms;
a residue of initiator, wherein the residue is of the formula:
R11R12R13C;
R11C(\u2550O);
R11R12R13Si;
R11R12N;
R11N;
(R11)nP(O)m; or
(R11)(R12O)P(O)m
where:
R11, R12 and R13 are each independently selected from the group consisting of H, halogen, C1-C20 alkyl, C3-C8 cycloalkyl, R83Si, C(\u2550Y)R5, C(\u2550Y)NR6R7, COCl, OH, CN, C2-C20 alkenyl or alkynyl, oxiranyl, glycidyl, C2-C6 alkylene or alkenylene substituted with oxiranyl or glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, aryl-substituted alkenyl, and alkenyl is vinyl which may be substituted with one or two C1-C6 alkyl groups andor halogen atoms, C1-C6 alkyl in which from 1 to all of the hydrogen atoms are replaced with halogen and C1-C6 alkyl substituted with from 1 to 3 substituents selected from the group consisting of C1-C4 alkoxy, aryl, heterocyclyl, C(\u2550Y)R5, C(\u2550Y)NR6R7, oxiranyl and glycidyl, with the provisio that no more than 2 of R11, R12 and R13 are H;
R5 is C1-20 alkyl, C1-20 alkylthio, OR24, C1-20 alkoxy, aryloxy or heterocyclyloxy, where R24 is H or an alkali metal;
Y is NR8, S, or O; and
R6 and R7 are independently H or C1-20 alkyl, or R6 and R7 may be joined together to form a C2-7 alkylene group, thus forming a 3- to 8-membered ring, and R8 is H, straight or branched C1-C20 alkyl or aryl;
m is 0 or 1; and n is 0, 1 or 2;
at least one of an average degree of polymerization of at least 3 and a number average molecular weight of at least 250 gmol; and
a molecular weight distribution less than 2, wherein the copolymer is an alternating copolymer or the predominantly alternating monomer structure is a block in a block copolymer, star copolymer, graft copolymer, comb copolymer or hyperbranched copolymer.
2. The copolymer of claim 1, wherein the radically (co)polymerizable monomer having electron-donor properties is selected from unsaturated hydrocarbons, vinyl ethers, C2-C20 unsaturated hydrocarbons, C2-C20 unsaturated hydrocarbons having one or more alky, alkenyl, alkynyl, alkoxy, alkylthio, dialkylamino, aryl or trialkyl silyl, or tri aryl silyl, isobutene, or vinyl C3-C10 ethers and the monomer having electron-acceptor properties is at least one of acrylates, methacrylates, unsaturated nitrites, unstaturated ketones, (meth)acrylic acid, methacrylic acid salts, C1-C20(meth)acrylate, esters, C3-C20 unsaturated nitrites, C3-C20 \u03b1-\u03b2 unsaturated aldehydes, ketones, sulfones, phosphates, or sulfonates.
3. The copolymer of claim 1, wherein the radically (co)polymerizable monomer having electron-acceptor properties is methyl acrylate and the radically polymerizable monomer having electron-donor properties is isobutylene.
4. The copolymer of claim 1, wherein the radically (co)polymerizable monomer having electron-acceptor properties is an acrylate and the radically polymerizable monomer having electron-donor properties is a vinyl ether.
5. The copolymer of claim 1, wherein the radically (co)polymerizable monomer having electron-acceptor properties is an methyl acrylate and the radically polymerizable monomer having electron-donor properties is isobutyl vinyl ether.
6. The copolymer of claim 1, wherein the radically (co)polymerizable monomer having electron-acceptor properties is an acrylate and the radically polymerizable monomer having electron-donor properties is an alkene.
7. The copolymer of claim 1, comprising:
at least one monomer unit derived from a monomer having bulky substituents selected from 1,1-diarylethylene, didehydromalonate C1-C20 diesters, C1-C20 diesters of maleic or fumaric acid, maleic anhydride, maleic diimides, C1-C8 alkyl maleimides, or 1,1-diphenylethylene; and
at least one monomer unit derived from a monomer selected from styrene, acrylonitrile, or C1-C8 esters of (meth)acrylic acid.
8. A copolymer, comprising:
a predominantly alternating monomer structure, comprising:
at least one monomer unit derived from a radically (co)polymerizable monomer having electron-donor properties; and
at least one monomer unit derived from a radically (co)polymerizable monomer having electron-acceptor properties;
a terminal functional group selected from a radically transferable atom or group, a halogen, Cl, Br, I, OR10, SR14, SeR14, OC(\u2550O)R14, OP(\u2550O)R14, OP(\u2550O)(OR14)2, O\u2014N(R14)2, S\u2014C(\u2550S)N(R14)2, CN, NC, SCN, CNS, OCN, CNO, N3, OH, C1-C6-alkoxy, (SO4), PO4, HPO4, H2PO4, triflate, hexafluorophosphate, methanesulfonate, arylsulfonate, carboxylic acid halide, R15CO2, NH2, COOH, or CONH2, where R14 is aryl or a straight or branched C1-C20 alkyl group or where an N(R14)2 group is present, the two R14 groups may be joined to form a 5-, 6- or 7-member heterocyclic ring, R15 is H or a straight or branched C1-C6 alkyl group, aryl or aryl substituted 1 to 5 times with a halogen, and R10 is an alkyl of from 1 to 20 carbon atoms or an alkyl of from 1 to 20 carbon atoms in which each of the hydrogen atoms may be replaced by a halide, alkenyl of from 2 to 20 carbon atoms, alkynyl of from 2 to 10 carbon atoms, phenyl, phenyl substituted with from 1 to 5 halogen atoms or alkyl groups with from 1 to 4 carbon atoms, aralkyl, aryl substituted alkyl, in which the aryl group is phenyl or substituted phenyl and the alkyl group is from 1 to 6 carbon atoms;
a residue of initiator, wherein the residue is of the formula:
R11R12R13C;
R11C(\u2550O);
R11R12R13Si;
R11R12N;
R11N;
(R11)nP(O)m; or
(R11)(R12O)P(O)m
where:
R11, R12 and R13 are each independently selected from the group consisting of H, halogen C1-C20 alkyl, C3-C8 cycloalkyl, R83Si, C(\u2550Y)R5, C(\u2550Y)NR6R7, COCl, OH, CN, C2-C20 alkenyl or alkynyl, oxiranyl, glycidyl, C2-C6 alkylene or alkenylene substituted with oxiranyl or glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, aryl-substituted alkenyl, and alkenyl is vinyl which may be substituted with one or two C1-C6 alkyl groups andor halogen atoms, C1-C6 alkyl in which from 1 to all of the hydrogen atoms are replaced with halogen and C1-C6 alkyl substituted with from 1 to 3 substituents selected from the group consisting of C1-C4 alkoxy, aryl, heterocyclyl, C(\u2550Y)R5, C(\u2550Y)NR6R7, oxiranyl and glycidyl, with the provisio that no more than 2 of R11, R12 and R13 are H;
R5 is C1-20 alkyl, C1-20 alkylthio, OR24, C1-20 alkoxy, aryloxy or heterocyclyloxy, where R24 is H or an alkali metal;
Y is NR8, S, or O; and
R6 and R7 are independently H or C1-20 alkyl, or R6 and R7 may be joined together to form a C2-7, alkylene group, thus forming a 3- to 8-membered ring, and R8 is H straight or branched C1-C20 alkyl or aryl;
m is 0 or 1; and n is 0, 1 or 2;
at least one of an average degree of polymerization of at least 3 and a number average molecular weight of at least 250 gmol; and
a molecular weight distribution less than 2.
9. The copolymer of claim 8, wherein the radically (co)polymerizable monomer having electron-donor properties is selected from unsaturated hydrocarbons, vinyl ethers, C2-C20 unsaturated hydrocarbons, C2-C20 unsaturated hydrocarbons having one or more alkyl, alkenyl, alkynyl, alkoxy, alkylthio, dialkylamino, aryl or trialkyl silyl, or tri aryl silyl, isobutene, or vinyl C3-C10 ethers and the monomer having electron-acceptor properties is at least one of acrylates, methacrylates, unsaturated nitriles, unstaturated ketones, (meth)acrylic acid, methacrylic acid salts, C1-C20(meth)acrylate esters, C3-C20 unsaturated nitriles, C3-C20 \u03b1-\u03b2unsaturated aldehydes, ketones, sulfones, phosphates, or sulfonates.
10. The copolymer of claim 8, wherein the radically (co)polymerizable monomer having electron-acceptor properties is methyl acrylate and the radically polymerizable monomer having electron-donor properties is isobutylene.
11. The copolymer of claim 8, wherein the radically (co)polymerizable monomer having electron-acceptor properties is an acrylate and the radically polymerizable monomer having electron-donor properties is a vinyl ether.
12. The copolymer of claim 8, wherein the radically (co)polymerizable monomer having electron-acceptor properties is a methyl acrylate and the radically polymerizable monomer having electron-donor properties is isobutyl vinyl ether.
13. The copolymer of claim 8, wherein the radically (co)polymerizable monomer having electron-acceptor properties is an acrylate and the radically polymerizable monomer having electron-donor properties is an alkene.
14. A copolymer, comprising:
a predominantly alternating monomer structure, comprising:
at least one monomer unit derived from a radically (co)polymerizable monomer having electron-donor properties; and
at least one monomer unit derived from a radically (co)polymerizable monomer having electron-acceptor properties;
a residue of initiator, wherein the residue is of the formula:
R11R12R13C;
R11C(\u2550O);
R11R12R13Si;
R11R12N;
R11N;
(R11)nP(O)m; or
(R11)(R12O)P(O)m
where:
R11, R12 and R13 are each independently selected from the group consisting of H, halogen, C1-C20 alkyl, C3-C8 cycloalkyl, R83Si, C(\u2550Y)R5, C(\u2550Y)NR6N7, COCl, OH, CN, C2-C20 alkenyl or alkynyl, oxiranyl, glycidyl, C2-C6 alkylene or alkenylene substituted with oxiranyl or glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, aryl-substituted alkenyl, and alkenyl is vinyl which may be substituted with one or two C1-C6 alkyl groups andor halogen atoms, C1-C6 alkyl in which from 1 to all of the hydrogen atoms are replaced with halogen and C1-C6 alkyl substituted with from 1 to 3 substituents selected from the group consisting of C1-C4 alkoxy, aryl, heterocyclyl, C(\u2550Y)R5, C(\u2550Y)NR6R7, oxiranyl and glycidyl, with the provisio that no more than 2 of R11, R12 and R13 are H;
R5 is C1-20 alkyl, C1-20 alkylthio, OR24, C1-20 alkoxy, aryloxy or heterocyclyloxy, where R24 is H or an alkali metal;
Y is NR8, S , or O; and
R6 and R7 are independently H or C1-20 alkyl, or R6 and R7 may be joined together to form a C2-7 alkylene group, thus forming a 3- to 8-membered ring, and R8 is H, straight or branched C1-C20 alkyl or aryl;
m is 0 or 1; and
n is 0, 1 or 2;
at least one of an average degree of polymerization of at least 3 and a number average molecular weight of at least 250 gmol; and
a molecular weight distribution less than 2.
15. A copolymer, comprising:
a predominantly alternating monomer structure, comprising:
at least one monomer unit derived from a radically (co)polymerizable monomer having electron-donor properties; and
at least one monomer unit derived from a radically (co)polymerizable monomer having electron-acceptor properties;
a residue of initiator, wherein the residue is of the formula:
R11R12R13C;
R11C(\u2550O);
R11R12R13Si;
R11R12N;
R11N;
(R11)nP(O)m; or
(R11)(R12O)P(O)m
where:
R11, R12 and R13 are each independently selected from the group consisting of H, halogen, C1-C20 alkyl, C3-C8 cycloalkyl, R83Si, C(\u2550Y)R5, C(\u2550Y)NR6R7, COCl, OH, CN, C2-C20 alkenyl or alkynyl, oxiranyl, glycidyl, C2-C6 alkylene or alkenylene substituted with oxiranyl or glycidyl, aryl, heterocyclyl, aralkyl, aralkenyl, aryl-substituted alkenyl, and alkenyl is vinyl which may be substituted with one or two C1-C6 alkyl groups andor halogen atoms, C1-C6 alkyl in which from 1 to all of the hydrogen atoms are replaced with halogen and C1-C6 alkyl substituted with from 1 to 3 substituents selected from the group consisting of C1-C4 alkoxy, aryl, heterocyclyl, C(\u2550Y)R5, C(\u2550Y)NR6R7, oxiranyl and glycidyl, with the provisio that no more than 2 of R11, R12 and R13 are H;
R5 is C1-20 alkyl, C1-20 alkylthio, OR24, C1-20 alkoxy, aryloxy or heterocyclyloxy, where R24 is H or an alkali metal;
Y is NR8, S, or O; and
R6 and R7 are independently H or C1-20 alkyl, or R6 and R7 may be joined together to form a C2-7 alkylene group, thus forming a 3- to 8-membered ring, and R8 is H, straight or branched C1-C20 alkyl or aryl;
m is 0 or 1; and n is 0, 1 or 2;
at least one of an average degree of polymerization of at least 3 and a number average molecular weight of at least 250 gmol; and
a molecular weight distribution less than 2,
wherein the radically (co)polymerizable monomer having electron-donor properties is selected from unsaturated hydrocarbons, vinyl ethers, C2-C20 unsaturated hydrocarbons, C2-C20 unsaturated hydrocarbons having one or more alkyl, alkenyl, alkynyl, alkoxy, alkylthio, dialkylamino, aryl or trialkyl silyl, or tri aryl silyl, isobutene, or vinyl C3-C10 ethers and the monomer having electron-acceptor properties is at least one of acrylates, methacrylates, unsaturated nitriles, unstaturated ketones, (meth)acrylic acid, methacrylic acid salts, C1-C20(meth)acrylate esters, C3-C20 unsaturated nitriles, C3-C20 \u03b1-\u03b2 unsaturated aldehydes, ketones, sulfones, phosphates, or sulfonates.