Copolymers comprising biomolecules

• US 20060148983A1
• Filed: 02/27/2004
• Published: 07/06/2006
• Est. Priority Date: 02/28/2003
• Status: Active Grant

• Current Assignee: EyeSense AG
• Original Assignee: EyeSense AG
• Inventors: Schmieder, Roland, Schmid, Katharina, Muller, Achim
• Granted Patent: US 7,772,286 B2
• Time in Patent Office: Days
• US Class Current: 525/56
• CPC Class Codes: C08F 16/06 Polyvinyl alcohol ; Vinyl alcohol
• CPC Class Codes: C08F 2810/30 leading to the formation or introduction of aliphatic or alicyclic unsaturated groups
• CPC Class Codes: C08F 8/30 Introducing nitrogen atoms or nitrogen-containing groups
• CPC Class Codes: C08F 8/48 Isomerisation; Cyclisation
• CPC Class Codes: C08L 29/04 Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
• CPC Class Codes: G02B 1/043 Contact lenses

Abstract

The present invention relates to a copolymer, which is the reaction product of (a) a first prepolymer, comprising a bioactive moiety and at least one radically polymerizable group, and (b) a second prepolymer which is a polyvinyl alcohol having a weight average molecular weight of at least about 2000 that, based on the number of hydroxy groups of the polyvinyl alcohol, comprises from 0.5 to 80% structural units of formula (I) wherein: R is alkylene having up to 8 carbon atoms, R¹ is hydrogen or alkyl having up to seven carbon atoms, and R² is an olefinically unsaturated, electron-attracting copolymerizable radical.

Claims

1. A copolymer, which is the reaction product of

(a) a first prepolymer, comprising a bioactive moiety and at least one radically polymerizable group, and

(b) a second prepolymer which is a polyvinyl alcohol having a weight average molecular weight of at least about 2000 that, based on the number of hydroxy groups of the polyvinyl alcohol, comprises from 0.5 to 80% structural units of formula

wherein:

R is alkylene having up to 8 carbon atoms, R¹ is hydrogen or alkyl having up to seven carbon atoms, and R² is an olefinically unsaturated, electron-attracting copolymerizable radical.

2. A copolymer according to claim 1, wherein in formula (1), R² is —

[CO—

NH—

(R⁵—

NH—

CO—

O)_q—

R₆—

O—

]_p—

CO—

R⁴,

wherein R⁴ is an olefinically unsaturated copolymerisable radical having from 2 to 8 carbon atoms, and R⁵ and R⁶ are each independently lower alkylene having from 2 to 8 carbon atoms, arylene having from 6 to 12 carbon atoms, a saturated divalent cycloaliphatic group having from 6 to 10 carbon atoms, arylenealkylene or alkylenearylene having from 7 to 14 carbon atoms or arylenealkylenearylene having from 13 to 16 carbon atoms.

3. The copolymer according to claim 1, wherein the first prepolymer is a polyvinyl alcohol having a weight average molecular weight of at least about 500 that, based on the number of hydroxy groups of the polyvinyl alcohol, and comprises

(a) from 0.5 to 80% structural units of formula (1);

and

(b) from 0.1 to 25% structural units of formula

wherein B is the radical of a bioactive organic compound;

X is —

S—

, —

NH—

, —

O—

, or —

OC(O)—

; and

T is linear or branched C₁-C₂₀-alkylene which may be substituted by hydroxy and/or interrupted by one or more —

O—

, —

NHC(O)—

, —

C(O)NH— and

/or —

NR⁷-groups, wherein R⁷ is H or C₁-C₄-alkyl.

4. The copolymer according to claim 3, wherein T is —

CH₂—

O—

CH₂—

CH(OH)—

CH₂—

, X is —

S—

or —

NH—

; and

B is a Concanavalin A radical.

5. The copolymer according to claim 3, wherein T is —

C₁-C₁₀-alkylene-NH—

C(O)—

(CH₂)₃—

X is —

S—

or —

NH—

; and

B is a Concanavalin A radical.

6. The copolymer according to claim 1, wherein the first prepolymer is a polyvinyl alcohol having a weight average molecular weight of at least about 500 that, based on the number of hydroxy groups of the polyvinyl alcohol, and comprises

(a) from 0.5 to 80% structural units of formula (1);

and

(b) from 0.1 to 25%, based on the number of hydroxy groups of the polyvinyl alcohol, structural units of formula

wherein X is —

S—

, —

NH—

, —

O—

, or —

OC(O)—

; and

B is the radical of a bioactive organic compound.

7. The copolymer according to claim 6, wherein X is —

NH—

or —

S— and

B is a Concanavalin A radical.

8. The copolymer according to claim 1, wherein the first prepolymer is of formula

B—

[X-[L¹]_g-(spacer)_n-([L²]_i-Q)_s]_m  

 

(2)

wherein B is a radical derived from a bioactive organic compound, X is —

S—

, —

NH—

, —

O—

, or —

C(O)O—

, L¹ and L² are linking groups, Q is a radically polymerizable group, and (spacer) is linear or branched C₁-C₃₀₀-alkylene which may be substituted by hydroxy;

g, n and i are each 1 or zero, s is an integer from 1 to 20; and

m is an integer from 1 to 50.

9. The copolymer according to claim 8, wherein B is a Concanavalin A radical, X is —

NH—

or —

S—

, g and n are zero, i is 1, L² is —

C(O)—

, Q is —

C(CH₃)═

CH₂ or —

CH₂═

CH₂, s is an integer from 1 to 6, and m is from 1 to 20.

10. The copolymer according to claim 8, wherein B is a Concanavalin A radical, X is —

NH—

or —

S—

, g, n and i are 1, L¹ is —

C(O)—

, (spacer) is the radical of a polyethylene glycol having a weight average molecular weight of up to 20 000, L² is —

OC(O)—

, Q is —

C(CH₃)═

CH₂ or —

CH═

CH₂, and m is from 1 to 20.

11. The copolymer according to claim 1, wherein, in the units of formula (1) of the first prepolymer and/or of the second prepolymer, R is methylene, R¹ is hydrogen and R² is acryloyl.

12. A prepolymer which is a polyvinyl alcohol having a weight average molecular weight of at least about 500 that, based on the number of hydroxy groups of the polyvinyl alcohol, and comprises

from 0.5 to 80% structural units of formula (1)

wherein R is alkylene having up to 8 carbon atoms, R¹ is hydrogen or alkyl having up to seven carbon atoms, and R² is an olefinically unsaturated electron-attracting copolymerizable radical, and

from 0.01 to 40% units of formula (3) and/or formula (15)

wherein

B is the radical of a bioactive organic compound.

X is —

S—

, —

NH—

, —

O—

, or —

OC(O)—

, and

T is linear or branched C₁-C₁₀-alkylene which may be substituted by hydroxy and/or interrupted by one or more —

O—

, —

NHC(O)—

, —

C(O)NH— and

/or —

NR⁷—

groups, wherein R⁷ is H or C₁-C₄-alkyl.

13. A prepolymer of claim 12, wherein the prepolymer comprises from about 0.5% to about 80% structural units of formula (1) and from about 0.01% to about 40% structural units of formula (3).

14. The prepolymer according to claim 12, wherein, in formula (3) or (15), the bioactive compound is a hexokinase, a glucoseoxidase (GOX), or a glucose-galactose-binding protein.

15. The prepolymer according to claim 14, wherein the bioactive compound is a lectin.

16. The prepolymer according to claim 12, wherein, in formula (3), B is —

C₁-C₁₀-alkylene-O—

CH₂—

CH(OH)—

CH₂—

.

17. The prepolymer according to claim 12, wherein, in formula (3), B is —

C₁-C₁₀-alkylene-NH—

C(O)—

(CH₂)_r—

, wherein r is from 3 to 5.

18. The prepolymer according to claim 12, wherein, in the units of formula (1), R is methylene, R¹ is hydrogen and R² is acryloyl.

19. A polymer precursor which is a polyvinyl alcohol having a weight average molecular weight of at least about 500 that, based on the number of hydroxy groups of the polyvinyl alcohol, and comprises

(a) from 0.5 to 80% structural units of formula (1)

wherein R is alkylene having up to 8 carbon atoms, R¹ is hydrogen or alkyl having up to seven carbon atoms, and R² is an olefinically unsaturated, electron-attracting copolymerizable radical, and

(b) from 0.01 to 40% structural units of the formula (14)

wherein,

T³ is T is C₁-C₂₀-alkylene which may be interrupted by one or more —

O—

, —

NHC(O)—

, C(O)NH— and

/or —

NR⁷—

groups, wherein R⁷ is C₁-C₄-alkyl,

X⁴ is

wherein X¹ is —

O—

, —

S—

or —

NH—

,

(ii) —

OH or,

(iii) a leaving group.

20. The polymer precursor according to claim 19, wherein, in the units of formula (14), T³ is methylene and X⁴ is —

OH.

21. The polymer precursor according to claim 19, wherein T³ is C₁-C₁₀-alkylene-NH—

C(O)—

(CH₂)₃—

, and X⁴ is a leaving group.

22. The polymer precursor according to claim 19, wherein T³ is methylene and X⁴ is

23. The polymer precursor according to claim 19, wherein, in formula (1), R is methylene, R¹ is hydrogen and R² is acryloyl.

24. A polymer precursor which is a polyvinyl alcohol having a weight average molecular weight of at least about 500 that, based on the number of hydroxy groups of the polyvinyl alcohol, and comprises

(a) from 0.5 to 80% structural units of formula (1)

wherein R is alkylene having up to 8 carbon atoms, R¹ is hydrogen or alkyl having up to seven carbon atoms, and R² is an olefinically unsaturated, electron-attracting copolymerizable radical, and

(b) from 0.01 to 25% structural units of the formula (16)

wherein R₁₀ is a substituted acyl radical forming an activated ester or an activated amide.

25. The polymer precursor according to claim 24, wherein R¹⁰ is an imidazol-1-carbonyl radical.

26. The polymer precursor according to claim 24, wherein, in units of formula (1), R is methylene, R¹ is hydrogen and R² is acryloyl.

27. A composition comprising

(a) from 0.01% to 40% by weight of a first prepoloymer comprising a bioactive moiety and at least one radically polymerizable group, wherein the bioactive moiety is a bioactive organic compound;

(b) from 20% to 99.99% by weight of a second prepolymer which is a polyvinyl alcohol having a weight-average molecular weight of at least 2000 that, based on the number of hydroxy groups of the polyvinyl alcohol, and-comprises from 0.5% to 80% of units of formula (1)

wherein R is alkylene having up to 8 carbon atoms, R¹ is hydrogen or alkyl having up to seven carbon atoms, and R² is an olefinically unsaturated, electron-attracting copolymerizable radical, and

(c) from 0 to 40% of a vinylic comonomer;

wherein the percentage of each of the components (a), (b) and (c) is based on the total weight of polymerizable and/or crosslinkable material.

28. A composition according to claim 27, wherein the first prepolymer is a polyvinyl alcohol having a weight average molecular weight of at least about 500 that, based on the number of hydroxy groups of the polyvinyl alcohol, and comprises

(a) from 0.5 to 80% structural units of formula (1);

and

(b) from 0.01 to 40% structural units of formula (3) and/or formula (15)

wherein

B is the radical of a bioactive organic compound,

X is —

S—

, —

NH—

, —

O—

or —

OC(O)—

, and

T is linear or branched C₁-C₂₀-alkylene which may be substituted by hydroxy and/or interrupted by one or more —

O—

, —

NHC(O)—

, —

C(O)NH— and

/or —

NR⁷—

groups, wherein R⁷ is H or C₁-C₄-alkyl.

29. A composition according to claim 27, wherein first prepolymer is of formula (2)

B—

[X-[L¹]_g-(spacer)_n-([L²]_i-Q)_s]_m  

 

(2)

wherein B is a radical derived from a bioactive organic compound, X is —

S—

, —

NH—

, —

O—

, or —

C(O)O—

, L¹ and L² are linking groups, Q is a radically polymerizable group, (spacer) is linear or branched C₁-C₃₀₀-alkylene which may be substituted by hydroxyl, g, n and i are each 1 or zero, s is an integer from 1 to 20, and m is an integer from 1 to 50.

30. A process for the manufacture of a copolymer comprising the steps of:

(a) providing a first prepolymer, comprising a bioactive moiety and at least one radically polymerizable group, wherein the bioactive moiety is a bioactive organic compound;

(b) providing a second prepolymer which is a polyvinyl alcohol having a weight average molecular weight of at least about 2000 that, based on the number of hydroxy groups of the polyvinyl alcohol, comprises from 0.5 to 80% structural units of formula (1)

wherein R is alkylene having up to 8 carbon atoms, R¹ is hydrogen or alkyl having up to seven carbon atoms, and R² is an olefinically unsaturated, electron-attracting copolymerizable radical;

(c) mixing the components according to steps (a) and (b); and

(d) photocrosslinking the mixture according to step (c) in the absence or presence of an additional vinylic polymer.

31. The process according to claim 30, wherein the first prepolymer is a polyvinyl alcohol having a weight average molecular weight of at least about 2000 that, based on the number of hydroxy groups of the polyvinyl alcohol, and further comprises from 0.1% to about 25% structural units of formula (3)

32. The process according to claim 30, wherein the first prepolymer is of formula (2)

B—

[—

X-[L¹]_g-(spacer)_n-([L²]_i-Q)_s]_m  

 

(2)

wherein B is a radical derived from a bioactive organic compound, X is —

S—

, —

NH—

, —

O—

, or —

C(O)O—

, L¹ and L² are linking groups, Q is a radically polymerizable group, and (spacer) is linear or branched C₁-C₃₀₀-alkylene which may be substituted by hydroxy;

g, n and i are each 1 or zero, s is an integer from 1 to 20; and

m is an integer from 1 to 50.

33-34. -34. (canceled)