Incorporation of biological molecules into bioactive glasses

• US 5,874,109 A
• Filed: 09/04/1997
• Issued: 02/23/1999
• Est. Priority Date: 07/27/1994
• Status: Expired due to Term

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Ducheyne, Paul, Radin, Shulamith, Santos, Erick Manuel
• Primary Examiner(s): Harrison, Robert H.
• Application Number:
  US08/923,324
• Time in Patent Office: 537 Days
• Field of Search: 424/422, 424/423, 424/424, 424/425, 424/426, 424/484, 424/486, 424/601, 424/602, 424/724, 501/11, 501/12, 501/17, 501/32, 501/53, 501/55, 501/63, 501/72, 514/953
• US Class Current: 424/486
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/30767 Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
• CPC Class Codes: A61F 2002/30677 Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61K 38/14 Peptides containing saccharide radicals; Derivatives thereof , e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/57 from animals; from humans A61K38/553, A61K38/556 take precedence
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/402 Anaestetics, analgesics, e.g. lidocaine
• CPC Class Codes: A61L 2300/406 Antibiotics
• CPC Class Codes: A61L 2300/41 Anti-inflammatory agents, e.g. NSAIDs
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/306 Other specific inorganic materials not covered by A61L27/303 - A61L27/32
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C03C 4/0007 for biologically-compatible glass

Abstract

Carriers comprising silica-based glass providing for the controlled release of biologically active molecules, their methods of preparation, and methods of use are disclosed. The carriers are prepared using a sol-gel-derived process. Biologically active molecules are incorporated within the matrix of the glass during production.

Claims

1. A controlled-release carrier comprising bioactive silica-based glass having a porous matrix and biologically active molecules incorporated throughout said matrix of said glass, wherein said carrier is prepared using a sol-gel derived process, and said biologically active molecules are incorporated during the liquid phase of the sol, at a temperature of about 40°

C. or below.

2. A controlled-release carrier as claimed in claim 1 comprising bioactive silica-based glass having a porous matrix and biologically active molecules incorporated throughout said matrix of said glass wherein said glass comprises:

from about 60 to about 100% SiO₂ ;

up to about 40% CaO; and

up to about 10% P₂ O₅, and from about 0.0001 to about 10% biologically active molecules by weight.

3. A controlled-release carrier as claimed in claim 1 comprising bioactive silica-based glass having a porous matrix and biologically active molecules incorporated throughout said matrix of said glass wherein said glass comprises:

from about 60 to about 80% SiO₂ ;

up to about 40% CaO; and

up to about 10% P₂ O₅, by weight, said carrier being produced by a process utilizing conditions which preserve the biological activity of said molecules.

4. The carrier of claim 1 wherein said conditions comprise processing temperatures less than about 40°

C. and a pH from about 1 to about 4.5.

5. The carrier of claim 1 wherein said glass comprises from about 60 to about 100% SiO₂ by weight.

6. The carrier of claim 1 wherein said biologically active molecules comprise from about 0.0001 to about 10% of said carrier by weight.

7. The carrier of claim 6 wherein said biologically active molecules comprise a drug.

8. The carrier of claim 7 wherein said drug comprises an antibiotic.

9. The carrier of claim 8 wherein said antibiotic is vancomycin.

10. The carrier of claim 1 wherein said glass is in granular form.

11. The carrier of claim 10 wherein said granules are less than about 2 mm in diameter.

12. The carrier of claim 1 wherein said glass is in disc form.

13. The carrier of claim 12 wherein said discs are about 11 millimeters in diameter and 4 millimeters in height.

14. The carrier of claim 12 wherein said discs are about 5.5 millimeters in diameter and 8 millimeters in height.

15. A controlled-release carrier as claimed in claim 1 comprising bioactive silica-based glass having a porous matrix and biologically active molecules incorporated throughout said matrix of said glass wherein said glass comprises from about 60 to about 100% SiO₂, by weight, and said carrier is produced by a process utilizing a silicon alkoxide precursor and water under conditions which preserve the biological activity of said molecules and promote the sustained release of said biologically active molecules upon immersion in solution.

16. The carrier of claim 15 wherein said conditions comprise processing temperatures less than about 40°

C., a pH of from about 1 to about 4.5, and a water to silicon alkoxide precursor molar ratio of from about 6;

1 to about 20;

1.

17. The carrier of claim 7 wherein said drug is a growth factor.

18. The carrier of claim 7 wherein said growth factor is TGF-β

.

19. The carrier of claim 7 wherein said drug is an anti-inflammatory agent.

20. The carrier of claim 7 wherein said drug is an analgesic.

21. The carrier of claim 1 wherein said carrier is in the form of a coating on an implant for filling a bony defect.

22. The carrier of claim 21 wherein said implant is in granular form.

23. The carrier of claim 21 wherein said implant is a prosthetic device.

24. A composition comprising granules of controlled-release carriers as claimed in claim 1 comprising silica-based glass having a porous matrix and biologically active molecules incorporated throughout said matrix of said glass wherein said composition comprises granules in the size range of from about 500 μ

m to about 700 μ

m.

25. A composition comprising granules of controlled-release carriers as claimed in claim 1 comprising silica-based glass having a porous matrix and biologically active molecules incorporated throughout said matrix of said glass wherein said composition comprises granules in the size range of from about 500 μ

m to about 5 mm in diameter.

26. A composition comprising granules of controlled-release carriers as claimed in claim 1 comprising silica-based glass having a porous matrix and biologically active molecules incorporated throughout said matrix of said glass wherein said composition comprises at least two populations of granules, each of said populations having a different type of biologically active molecules incorporated therein.

27. The composition of claim 25 further wherein at least one of said populations comprises granules of a different size range than said other populations.

28. A controlled-release carrier as claimed in claim 1 comprising silica-based glass having a porous matrix and at least two different types of biologically active molecules incorporated throughout said matrix of said glass.

29. The carrier of claim 28 wherein said carrier is a compound carrier comprising granules and a coating, said granules containing a first type of biologically active molecules incorporated therein, and said coating containing a second type of biologically active molecules incorporated therein.

30. A compound controlled-release carrier as claimed in claim 1 comprising silica-based glass having a porous matrix, said carrier comprising granules and a coating, said granules containing biologically active molecules at a first concentration incorporated therein, and said coating containing said biologically active molecules at a second concentration incorporated therein.

31. The carrier of claim 3 wherein said process comprises the steps of:

a) combining a silicon alkoxide precursor and a calcium alkoxide or a phosphorous alkoxide, or both, to form a first mixture;

b) adding said biologically active molecules in an acid solution to said first mixture to form a second mixture having a pH in the range of from about 1 to about 4.5;

c) allowing the second mixture to form a gel at a temperature of from about 0°

C. to about 40°

C.;

d) aging the gel at a temperature of from about 0°

C. to about 40°

C. for from about one day to about four weeks; and

e) drying the aged gel at a temperature of from about 15°

C. to about 40°

C. until a weight loss of from about 50% to about 80% is observed in said gel.

32. The carrier of claim 15 wherein said process comprises the steps of:

a) combining a silicon alkoxide precursor with deionized water to form a first mixture;

b) adding acid to form a second mixture having a pH in the range of from about 1 to about 4.5;

c) adding said biologically active molecules to said second mixture while maintaining the pH within the range of from about 1 to about 4.5 to form a third mixture, said third mixture having a water/precursor molar ratio of from about 6;

1 to about 20;

1;

d) allowing the third mixture to form a gel at a temperature of from about 0°

C. to about 40°

C.;

e) aging the gel at a temperature of from about 0°

C. to about 40°

C. for from about one day to about four weeks; and

f) drying the aged gel at a temperature of from about 15°

C. to about 40°

C. until a weight loss of from about 50% to about 80% is observed in said gel.

33. A controlled-release carrier comprising bioactive silica-based glass having a porous matrix and biologically active molecules incorporated throughout said matrix, said carrier having been immersed in a solution with an ion content similar to interstitial fluid for a period of up to about seven days.