Membranes with controlled permeability to polar and apolar molecules in solution and methods of making same

• US 7,871,456 B2
• Filed: 08/10/2006
• Issued: 01/18/2011
• Est. Priority Date: 08/10/2006
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Lim, Drahoslav, Gough, David A., Tsay, Hwai-Min, Lucisano, Joseph Y., Lin, Joe T.
• Primary Examiner(s): Greene; Jason M
• Application Number:
  US11/503,461
• Publication Number:
  US 20080034972A1
• Time in Patent Office: 1,622 Days
• Field of Search: 96/4, 96/11, 96/12, 96/13, 96/14, 95/45, 95/46, 95/51, 95/54, 210/640, 210/500.21, 210/500.27, 210/500.28, 210/500.33, 210/500.35, 600/345, 600/347, 600/365, 204/403.5, 204/403.6, 204/415, 204/418, 204/403.05, 204/403.06
• US Class Current: 95/45
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: B01D 2323/30 Cross-linking
• CPC Class Codes: B01D 2325/36 Hydrophilic membranes
• CPC Class Codes: B01D 2325/38 Hydrophobic membranes
• CPC Class Codes: B01D 69/02 characterised by their properties
• CPC Class Codes: B01D 69/125 In situ manufacturing by polymerisation, polycondensation, cross-linking or chemical reaction
• CPC Class Codes: B01D 69/141 Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
• CPC Class Codes: B01D 69/1411 containing dispersed material in a continuous matrix
• CPC Class Codes: B01D 71/76 Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74 rubbers in general B01D71/24
• CPC Class Codes: C12Q 1/006 for glucose

Abstract

A membrane for use in an implantable glucose sensor including at least one crosslinked substantially hydrophobic polymer and at least one crosslinked substantially hydrophilic polymer; wherein the first and second polymers are different polymers and substantially form an interpenetrating polymer network, semi-interpenetrating polymer network, polymer blend, or copolymer. The membranes are generally characterized by providing a permeability ratio of oxygen to glucose of about 1 to about 1000 in units of (mg/dl glucose) per (mmHg oxygen). Three methods of making membranes from hydrophobic and hydrophilic monomers formed into polymer networks are provided, wherein according to at least two of the methods, the monomers may be substantially immiscible with one another.

Claims

1. A membrane having controlled permeability to polar and non-polar solutes, for use in an implantable sensor, comprising different first and second polymers, the first polymer comprising at least one crosslinked substantially hydrophobic polymer and the second polymer comprising at least one crosslinked substantially hydrophilic polymer;

wherein the hydrophobic and hydrophilic polymers are present in a mass ratio from between about 50;

50 to 5;

95 of the total mass of the hydrophobic and hydrophilic polymers, and form an interpenetrating polymer network, semi-interpenetrating polymer network or polymer blend; and

wherein further the membrane is characterized by a permeability ratio of oxygen to glucose of about 1 to about 1000 in units of (mg/dl glucose) per (mmHg oxygen).

2. The membrane of claim 1, wherein the hydrophobic and hydrophilic polymers are present in a ratio of 12.5:

87.5.

3. The membrane of claim 1, wherein the permeability ratio of oxygen to glucose is about 1 to about 100.

4. The membrane of claim 3, wherein the permeability ratio of oxygen to glucose is about 10 to about 60.

5. The membrane of claim 1, wherein the membrane has a water uptake of about 1 wt. % to about 20 wt. %.

6. The membrane of claim 1, wherein the membrane has a water uptake of about 5 wt. % to about 20 wt. %.

7. The membrane of claim 1, wherein the membrane has a water uptake of about 10 wt. % to about 20 wt. %.

8. The membrane of claim 1, wherein the first polymer comprises a silicone-containing polymer.

9. The membrane of claim 1, wherein the second polymer comprises an acrylate or methacrylate polymer.

10. The membrane of claim 1, wherein the first polymer and the second polymer are not mutually soluble.

11. The membrane of claim 1, wherein the first polymer is prepared from a first monomer, and the second polymer is prepared from a second monomer, and the first and second monomers are not miscible.

12. The membrane of claim 1, wherein the first polymer comprises a silicone-containing polymer, the second polymer comprises an acrylate or methacrylate polymer, and the permeability ratio of oxygen to glucose is about 10 to about 60 in units of (mg/dl glucose) per (mmHg oxygen).

13. The membrane of claim 1, wherein the first polymer comprises a silicone-containing polymer, the second polymer comprises an acrylate or methacrylate polymer, the membrane has a water uptake of about 10 wt. % to about 20 wt. %;

and the first polymer and the second polymer are not mutually soluble.

14. The membrane of claim 1, wherein the first polymer is present in units of % wt. of the overall wt. of polymer present in the membrane in a range from 2% wt. to 50% wt.

15. The membrane of claim 14, wherein the first polymer is present in a range from 5% wt to 30% wt.

16. The membrane of claim 15, wherein the first polymer is present in a range from 7% wt to 20% wt.

17. The membrane of claim 1, wherein the second polymer is present in units of % wt. of the overall wt. of polymer present in the membrane in a range from 25% wt to 95% wt.

18. The membrane of claim 17, wherein the second polymer is present in a range from 70% wt to 95% wt.

19. The membrane of claim 18, wherein the second polymer is present in a range from 80% wt to 93% wt.

20. The membrane according to claim 1, wherein the first polymer is selected from the group of polymers consisting of siloxanes, polyphosphazene, and hydrophobically modified celluloses.

21. The membrane according to claim 1, wherein the first polymer includes siloxane linkages in the polymer backbone.

22. The membrane according to claim 21, wherein the first polymer comprises a polyorganosiloxane, poly(dimethyl siloxane), silicone rubber or a silicone elastomer.

23. The membrane according to claim 21, wherein the first polymer is produced from a monomer selected from the group consisting of MPPMDS, MPTTMS, TFEMA and PDMS.

24. The membrane according to claim 1, wherein the second polymer comprises a de-silylated polymer derived from a silylated polymer selected from the group of polymers consisting of silylated vinyl polymers, polyethers, polyesters, polyamides, polyvinyl pyrrolidone, polyvinyl alcohol, glutaraldehyde crosslinked proteins, collagen, albumin, alginates, hydrophilically-modified siloxanes and hydrophilically-modified polypohosphazene.

25. The membrane according to claim 24, wherein the second polymer includes acrylate linkages in the polymer backbone.

26. The membrane according to claim 25, wherein the second polymer is produced from a silylated monomer comprising silylated HEMA or silylated HPMA.

27. The membrane according to claim 1, claim 21 or claim 24 further comprising a cross-linking agent in 0.1 mass % to about 10 mass %, based on grams of cross-linking agent to total grams of polymer.

28. An implantable glucose sensor

comprising:

(A) a glucose sensor body; and

(B) a membrane according to claim 1.

39. A method for making an implantable glucose sensor comprising mounting at least one membrane according to claim 1, claim 21 or claim 24 on a biocompatible sensor body.

29. An implantable glucose sensor comprising:

(A) a glucose sensor body;

(B) at least one membrane disposed on the glucose sensor body comprising a solvent swellable polymeric material comprising hydrophilic polymer component and hydrophobic polymer component;

wherein the hydrophobic and hydrophilic polymers are present in a mass ratio from between about 50;

50 to 5;

95 of the total mass of the hydrophobic and hydrophilic polymers; and

wherein the membrane is characterized by a permeability ratio of oxygen to glucose of about 1 to about 1000 in units of (mg/dl glucose) per (mmHg oxygen).

30. The sensor of claim 29, wherein the hydrophobic and hydrophilic polymers are present in a ratio of 12.5:

87.5.

31. An implantable glucose sensor comprising:

(A) a glucose sensor body;

(B) at least one membrane disposed on the glucose sensor body comprising a solvent soluble polymeric material comprising hydrophilic polymer component and hydrophobic polymer component;

wherein the hydrophobic and hydrophilic polymers are present in a mass ratio from between about 50;

50 to 5;

95 of the total mass of the hydrophobic and hydrophilic polymers; and

wherein the membrane is characterized by a permeability ratio of oxygen to glucose of about 1 to about 1000 in units of (mg/dl glucose) per (mmHg oxygen).

32. The sensor according to claim 31, wherein the permeability ratio of oxygen to glucose is about 10 to about 40.

33. A method of making membranes having controlled permeability to oxygen and glucose,

comprising:

(a) providing a hydrophobic polymer membrane, a hydrophobic monomer, and at least one silylated hydrophilic monomer;

(b) combining the hydrophobic and hydrophilic monomers to form a mixture;

(c) impregnating the hydrophobic polymer membrane with the monomer mixture;

(d) polymerizing the monomers; and

(e) desilylating the polymerized hydrophilic monomer,

wherein at least one cross-linking agent is provided separately to each of the monomers in step (a), or to the mixture of monomers in step (b), to form an interpenetrating or semi-interpenetrating polymer network, or polymer blend.

34. The method according to claim 33, wherein the hydrophobic and hydrophilic monomers are immiscible with one another.

35. The method according to claim 33, further comprising disposing the membrane on an implantable sensor body.

40. A membrane with controlled permeability to apolar and polar solutes produced by the method of claim 33.

36. A method of making membranes having controlled permeability to oxygen and glucose, comprising:

(a) providing a mixture of at least one hydrophobic monomer and at least one silylated hydrophilic monomer;

(b) placing the mixture into a cavity of a membrane mold;

(c) polymerizing the monomers in the mixture; and

(d) desilylating the polymerized hydrophilic monomer,

wherein at least one cross-linking agent is provided to the mixture of monomers in step (a) to form an interpenetrating or semi-interpenetrating polymer network of the monomers, or a polymer blend, or a copolymer.

37. The method according to claim 36, wherein the hydrophobic and hydrophilic monomers are immiscible with one another.

41. A membrane with controlled permeability to apolar and polar solutes produced by the method of claim 36.

38. A method of making membranes having controlled permeability to oxygen and glucose, comprising:

(a) providing a solution of at least one non-silylated hydrophobic monomer including siloxane linkages in the polymer backbone, at least one non-silylated hydrophilic monomer including acrylate linkages in the polymer backbone, at least one polymerization initiator and a solvent compatible with the hydrophobic and hydrophilic monomers, wherein none of the monomers present in the solution is silylated, and wherein further, the hydrophobic monomer and the hydrophilic monomer are present in a mass ratio from between about 50;

50 to 5;

95 of the total mass of the hydrophobic and hydrophilic monomers;

(b) allowing the monomers in the solution to polymerize; and

(c) allowing the solvent to evaporate.

42. A membrane with controlled permeability to apolar and polar solutes produced by the method of claim 38.