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US 2006/0235084 A1Published application
PEG-polyacetal diblock and triblock copolymers and pharmaceutical compositions
OwnerJorge Heller, Etienne Schacht +1inventors
InventorsJorge Heller, Etienne Schacht, Veska Toncheva
Life of this patent
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Abstract
This invention relates to block copolymer delivery vehicles comprising a polyethyleneglycol-polyacetal, and to controlled release pharmaceutical compositions comprising the delivery vehicle and an active agent. The block copolymers of the invention may be thermogel block copolymers. The pharmaceutical compositions may be in the form of a topical, syringable, or injectable formulation for local controlled delivery of the active agent.
Claims64
A triblock copolymer of Formula I or Formula II:
- wherein:
- m is an integer from 2 to 500;
- u is an integer from 3 to 100;
- R0 is H or C1-C3 alkyl;
- R1 is C1-C4 alkyl;
- R and R3 are each independently H or C1-C4 alkyl;
- and
- D and D′ are each 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 process for preparing a copolymer of Formula I:
- wherein:
- m is an integer from 2 to 500;
- u is an integer from 3 to 100;
- R1 is C1-C4 alkyl;
- R and R3 are each independently H or C1-C4 alkyl;
- and
- D and D′ are each 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 divinyl ether of the Formula Ia:
- R0CH═CH—O—D—O—CH═CHR0 Formula Ia
- where R0 is H or C1-C3 alkyl;
- and D is as defined above;
- with a diol of the formula HO—D′—OH that is defined as HO—R4—OH, HO—R5—OH, HO—R6—OH, or HO—R7—OH, or a mixture thereof;
- to form a compound of the Formula Ib:
- where D, D′, R1 and u are as defined above;
- and the compound of the Formula Ib is reacted with a compound of Formula Ic:
- where R and R3 are each independently H or C1-C4 alkyl;
- and
- m is an integer from 2 to 500.
40 more elements
A copolymer that is the product of a reaction between:
- (a) a divinyl ether of Formula Ia:
- R0CH═CH—O—D—O—CH═CHR0 Formula Ia
- where:
- R0 is H or C1-C3 alkyl;
- D and D′ are each 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;
- with
- (b) a polyol of the Formula HO—D′—OH or a mixture of polyols, where D′ is as defined above;
- and with
- (c) a compound of Formula Ic:
- where R, and R3 are each independently H or C1-C4 alkyl;
- and
- m is an integer from 2 to 500.
34 more elements
A process for preparing a copolymer of Formula II:
- wherein:
- m is an integer from 2 to 500;
- u is an integer from 3 to 100;
- R0 is H or C1-C3 alkyl;
- R1 is C1-C4 alkyl;
- each R is independently H or C1-C4 alkyl;
- and
- D and D′ are each 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 divinyl ether of the Formula IIa:
- R0CH═CH—O—D—O—CH═CHR0 Formula IIa
- where R0 is H or C1-C3 alkyl;
- and D is as defined above;
- with a diol of the formula HO—(CH2—CHR)m-OH, where R is H or C1-C4 alkyl;
- to form a compound of the Formula IIb:
- where D, R, R0, R1 and m are as defined above;
- followed by the reaction with a divinyl ether of the Formula Ia:
- R0CH═CH—O—D—O—CH═CHR0 Formula Ia
- where R0 is H or C1-C3 alkyl;
- and D is as defined above;
- and with a compound of Formula IIc:
- HO—D′—OH Formula IIc
- where D′ is as defined above.
44 more elements
A copolymer that is the product of a reaction between:
- a divinyl ether of the Formula Ia:
- R0CH═CH—O—D—O—CH═CHR0 Formula Ia
- where R0 is H or C1-C3 alkyl;
- and
- D and D′ are each independently selected from R4, R5, R6, and R7;
- wherein the divinyl ether is derived from a polyol or mixtures of polyols in which at least 0.1 mole percent of the total polyol content is a diol of the formula HO—D—OH, 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;
- with a diol of the formula HO—(CH2—(CH2)z-CHR)m-OH, where z is o, 1, 2, 3 or 4, R is H or C1-C4 alkyl;
- and
- a compound of Formula IIc:
- HO—D′—OH Formula IIc
- wherein Formula IIc is diol, a polyol or mixtures of polyols in which at least 0.1 mole percent of the total polyol content is a diol of the Formula IIc, and where D′ is as defined above.
32 more elements
A diblock copolymer of Formula III:
- wherein:
- m is an integer from 2 to 500;
- u is an integer from 3 to 100;
- R0 is H or C1-C3 alkyl;
- R1 is C1-C4 alkyl;
- R and R3 are each independently H or C1-C4 alkyl;
- and
- D and D′ are each 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
- R7is (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 III:
- wherein:
- m is an integer from 2 to 500;
- u is an integer from 3 to 100;
- R′ is C1-C4 alkyl;
- R and R3 are each independently H or C1-C4 alkyl;
- and
- D and D′ are each 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 divinyl ether of the Formula Ia:
- R0CH═CH—O—D—O—CH═CHR0 Formula Ia
- where R0 is H or C1-C3 alkyl;
- and D is as defined above;
- with a diol of the formula HO—D′—OH that is defined as HO—R4—OH, HO—R5—OH, HO—R6—OH, or HO—R7—OH, or a mixture thereof;
- to form a compound of the Formula IIIb:
- where D, D′, R0, R1 and u are as defined above;
- and the compound of the Formula IIIb is reacted with a compound of Formula IIIc:
- where R and R3 are each independently H or C1-C4 alkyl;
- and
- m is an integer from 2 to 500.
40 more elements
A copolymer that is the product of a reaction between:
- (a) a divinyl ether of Formula Ia:
- R0CH═CH—O—D—O—CH═CHR0 Formula Ia
- where:
- R0 is H or C1-C3 alkyl;
- D and D′ are each 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;
- with
- (b) a polyol of the Formula HO—D′—OH or a mixture of polyols, where D′ is as defined above;
- and with
- (c) a compound of Formula IIIc:
- where R, and R3 are each independently H or C1-C4 alkyl;
- and
- m is an integer from 2 to 500.
34 more elements
Dependencies are inferred from the claim text.