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US 2006/0235083 A1Published application
PEG-poly(ortho ester) graft copolymers and pharmaceutical compositions
AssigneeA.P. Pharma, Inc.
InventorJorge Heller
Life of this patent
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Abstract
This invention relates to graft copolymer delivery vehicles comprising a polyethyleneglycol-poly(ortho ester), and to controlled release pharmaceutical compositions comprising the delivery vehicle and an active agent. The graft copolymer delivery vehicles may be thermogels graft copolymers. The pharmaceutical compositions may be in the form of a topical, syringable, or injectable formulation for local controlled delivery of the active agent.
Claims91
A graft copolymer of Formula L1 or Formula L2:
- wherein:
- L′ is linker comprising a backbone chain of 2-10 atoms comprising C, N, O, S, or P optionally interrupted with one or more —C(O)O—, —OC(O)—, —COS—, —SC(O)—, —C(S)O—, —CON—, —CONH—, —CONR′—, —NCO—, —NHCO—, —R′NCO—, —OCO2—, —OCON—, —OCONH—, —NCO2—, —NHCO2—, —OCONR′—, —R′NCO2—, —NCONH—, —NHCON—, —NHCONH—, NR′CONH—, NR′CON—, —NHCONR′—, —NCONR′—, —NR′CONR′—, —CO—, optionally substituted C2-C4 alkenes, or optionally substituted C2-C4 alkynes, where each R′ is independently alkyl, substituted alkyl, aryl or substituted aryl groups;
- n is an integer from 2 to 500;
- p and q are independently integers from 5 to 100;
- R1 is C1-C4 alkyl;
- R and R3 are each independently H or C1-C4 alkyl;
- and
- each A is independently selected from R4, R5, R6, and R7;
- where:
- R4 is
- in which:
- x is an integer from 0 to 10;
- R8 is H or C1-C6 alkyl;
- and
- R9 is selected from
- where m′ is an integer from 1 to 6,
- s is an integer from 0 to 30,
- t is an integer from 1 to 200, and
- R10 and R11 are independently H or C1-C4 alkyl;
- R5 is selected from:
- where m′ is an integer from 1 to 6;
- R6 is selected from:
- where:
- x is an integer from 0 to 30;
- y is an integer from 1 to 200;
- R10 and R11 are independently H or C1-C4 alkyl;
- R12 and R13 are independently C1-C12 alkylene;
- R14 is H or C1-C6 alkyl;
- and R15 is C1-C6 alkyl;
- or R14 and R15 together are C3-C10 alkylene;
- and
- R7 is (i) the residue of a diol containing at least one amine functionality incorporated therein, or
- (ii) the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups.
30 more elements
A graft copolymer of Formula I, Formula II, Formula III, or Formula IV:
- wherein:
- n is an integer from 2 to 500;
- p and q are independently integers from 5 to 100;
- R1 is C1-C4 alkyl;
- R, R2 and R3 are each independently H or C1-C4 alkyl;
- and
- each A is independently selected from R4, R5, R6, and R7;
- where:
- R4 is
- in which:
- x is an integer from 0 to 10;
- R8 is H or C1-C6 alkyl;
- and
- R9 is selected from
- where m′ is an integer from 1 to 6,
- s is an integer from 0 to 30,
- t is an integer from 1 to 200, and
- R10 and R11 are independently H or C1-C4 alkyl;
- R5 is selected from:
- where m′ is an integer from 1 to 6;
- R6 is selected from:
- where:
- x is an integer from 0 to 30;
- y is an integer from 1 to 200;
- R10 and R11 are independently H or C1-C4 alkyl;
- R12 and R13 are independently C1-C12 alkylene;
- R14 is H or C1-C6 alkyl;
- and R15 is C1-C6 alkyl;
- or R14 and R15 together are C3-C10 alkylene;
- and
- R7 is (i) the residue of a diol containing at least one amine functionality incorporated therein, or
- (ii) the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups.
29 more elements
A process for preparing a copolymer of Formula I, Formula II, Formula III, or Formula IV:
- wherein:
- n is an integer from 2 to 500;
- p and q are independently integers from 5 to 100;
- R1 is C1-C4 alkyl;
- R, R2 and R3 are each independently H or C1-C4 alkyl;
- and
- each A is independently selected from R4, R5, R6, and R7;
- where:
- R4 is
- in which:
- x is an integer from 0 to 10;
- R8 is H or C1-C6 alkyl;
- and
- R9 is selected from
- where m′ is an integer from 1 to 6,
- s is an integer from 0 to 30,
- t is an integer from 1 to 200, and
- R10 and R11 are independently H or C1-C4 alkyl;
- R5 is selected from:
- where m′ is an integer from 1 to 6;
- R6 is selected from:
- where:
- x is an integer from 0 to 30;
- y is an integer from 1 to 200;
- R10 and R11 are independently H or C1-C4 alkyl;
- R12 and R13 are independently C1-C12 alkylene;
- R14 is H or C1-C6 alkyl;
- and R15 is C1-C6 alkyl;
- or R14 and R15 together are C3-C10 alkylene;
- and
- R7 is (i) the residue of a diol containing at least one amine functionality incorporated therein, or
- (ii) the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups;
- the process comprising reacting together a di(ketene acetal), the diol HO-A-OH, and a compound of the Formula Ia, Formula IIa, Formula IIIa, or Formula IVa:
- where L is hydrogen or a C1-3 alkyl;
- R, R2 and R3 are each independently H or C1-C4 alkyl;
- with a diol of the formula HO-A-OH that is defined as HO—R4—OH, HO—R5—OH, HO—R6—OH, or HO—R7—OH, or a mixture thereof.
33 more elements
A copolymer that is the product of a reaction between:
- (a) a di(ketene acetal) of formula:
- where:
- L is hydrogen or a C1-C3 alkyl, and
- (b) at least two polyols or mixture of polyols.
1 more element
A graft copolymer of Formulae L3 or L4:
- wherein:
- L′ is linker comprising a backbone chain of 2-10 atoms comprising C, N, O, S, or P optionally interrupted with one or more —C(O)O—, —OC(O)—, —COS—, —SC(O)—, —C(S)O—, —CON—, —CONH—, —CONR′—, —NCO—, —NHCO—, —R′NCO—, —OCO2—, —OCON—, —OCONH—, —NCO2—, —NHCO2—, —OCONR′—, —R′NCO2—, —NCONH—, —NHCON—, —NHCONH—, NR′CONH—, NR′CON—, —NHCONR′—, —NCONR′—, —NR′CONR′—, —CO—, optionally substituted C2-C4 alkenes, or optionally substituted C2-C4 alkynes, where each R′ is independently alkyl, substituted alkyl, aryl or substituted aryl groups;
- n is an integer from 2 to 500;
- p and q are independently integers from 5 to 100;
- R1 is C1-C4 alkyl;
- R and R3 are each independently H or C1-C4 alkyl;
- and
- each A is independently selected from R4, R5, R6, and R7;
- where:
- R4 is
- in which:
- x is an integer from 0 to 10;
- R8 is H or C1-C6 alkyl;
- and
- R9 is selected from
- where m′ is an integer from 1 to 6,
- s is an integer from 0 to 30,
- t is an integer from 1 to 200, and
- R10 and R11 are independently H or C1-C4 alkyl;
- R5 is selected from:
- where m′ is an integer from 1 to 6;
- R6 is selected from:
- where:
- x is an integer from 0 to 30;
- y is an integer from 1 to 200;
- R10 and R11 are independently H or C1-C4 alkyl;
- R12 and R13 are independently C1-C12 alkylene;
- R14 is H or C1-C6 alkyl;
- and R15 is C1-C6 alkyl;
- or R14 and R15 together are C3-C10 alkylene;
- and
- R7 is (i) the residue of a diol containing at least one amine functionality incorporated therein, or
- (ii) the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups.
30 more elements
A graft copolymer of Formula IV, Formula V, Formula VI or Formula VII:
- where:
- n is an integer from 2 to 500;
- p and q are independently an integer from 5 to 100;
- R′ is a bond, —(CH2)a—, or —(CH2)b—O—(CH2)c—;
- where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
- R1 is C1-C4 alkyl;
- R, R2 and R3 are each independently H or C1-C4 alkyl;
- and
- each B is independently selected from R4, R5, R6, and R7;
- where:
- R4 is
- in which:
- x is an integer from 0 to 10;
- R8 is H or C1-C6 alkyl;
- and
- R9 is selected from
- where m is an integer from 1 to 6,
- s is an integer from 0 to 30,
- t is an integer from 1 to 200, and
- R10 and R11 are independently H or C1-C4 alkyl;
- R5 is selected from:
- where m′ is an integer from 1 to 6;
- R6 is selected from:
- where:
- x is an integer from 0 to 30;
- y is an integer from 1 to 200;
- R10 and R11 are independently H or C1-C4 alkyl;
- R12 and R13 are independently C1-C12 alkylene;
- R14 is H or C1-C6 alkyl;
- and R5 is C1-C6 alkyl;
- or R14 and R15 together are C3-C10 alkylene;
- and
- R7 is (i) the residue of a diol containing at least one amine functionality incorporated therein, or
- (ii) the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups.
31 more elements
A process for preparing a copolymer of Formula IV, Formula V, Formula VI, or Formula VII:
- where:
- n is an integer from 2 to 500;
- p and q are independently an integer from 5 to 100;
- R′ is a bond, —(CH2)a—, or —(CH2)b—O—(CH2)c—;
- where a is an integer of 1 to 10, and b and c are independently an integers of 1 to 5;
- R1 is C1-C4 alkyl;
- and
- R, R2 and R3 are each independently H or C1-C4 alkyl;
- and
- each B is independently selected from R4, R5, R6, and R7;
- where:
- R4 is
- in which:
- x is an integer from 0 to 10;
- R8 is H or C1-C6 alkyl;
- and
- R9 is selected from
- where m′ is an integer from 1 to 6,
- s is an integer from 0 to 30,
- t is an integer from 1 to 200, and
- R10 and R11 are independently H or C1-C4 alkyl;
- R5 is selected from:
- where m′ is an integer from 1 to 6;
- R6 is selected from:
- where:
- x is an integer from 0 to 30;
- y is an integer from 1 to 200;
- R10 and R11 are independently H or C1-C4 alkyl;
- R12 and R13 are independently C1-C12 alkylene;
- R14 is H or C1-C6 alkyl;
- and R15 is C1-C6 alkyl;
- or R14 and R15 together are C3-C10 alkylene;
- and
- R7 is (i) the residue of a diol containing at least one amine functionality incorporated therein, or
- (ii) the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups;
- the process comprising reacting together a di(ketene acetal), the diol HO—B—OH, and a compound of the Formula IVa, Formula Va, Formula VIa, or Formula VIIa:
- where L is hydrogen or a C1-3 alkyl;
- R, R2 and R3 are each independently H or C1-C4 alkyl;
- with a diol of the formula HO—B—OH that is defined as HO—R4—OH, HO—R5—OH, HO—R6—OH, or HO—R7—OH, or a mixture thereof.
36 more elements
Dependencies are inferred from the claim text.