MESOPOROUS CALCIUM SILICATE COMPOSITIONS AND METHODS FOR SYNTHESIS OF MESOPOROUS CALCIUM SILICATE FOR CONTROLLED RELEASE OF BIOACTIVE AGENTS

• US 20090068272A1
• Filed: 09/15/2008
• Published: 03/12/2009
• Est. Priority Date: 04/25/2006
• Status: Active Grant

• Current Assignee: Washington State University
• Original Assignee: Washington State University
• Inventors: Xue, Weichang, Bose, Susmita, Bandyopadhyay, Amit
• Granted Patent: US 8,916,198 B2
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 47/6923 the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
• CPC Class Codes: A61K 9/5115 Inorganic compounds
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/428 Vitamins, e.g. tocopherol, riboflavin
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• 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 27/025 Other specific inorganic materials not covered by A61L27/04 - A61L27/12
• CPC Class Codes: A61L 27/10 Ceramics or glasses
• 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: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Mesoporous calcium silicate compositions for controlled release of bioactive agents and methods for producing such compositions are disclosed herein. In one embodiment, mesoporous calcium silicate is synthesized by acid modification of wollastonite particles using hydrochloric acid. A hydrated silica gel layer having abundant Si—OH functional groups can be formed on the surface of wollastonite after acid modification. Bruhauer-Emmett-Teller (BET) surface area increased significantly due to acid modification and, in one arrangement, reached over 350 m²/g. Acid modified mesoporous calcium silicate compositions show a higher ability to adsorb protein compared to unmodified particles and demonstrate controlled release kinetics of these proteins.

Claims

1. A mesoporous calcium silicate composition for controlling release of a bioactive agent, comprising:

acid-modified calcium silicate particles, the calcium silicate particles having a mesoporous structure; and

a bioactive agent.

2. The composition of claim 1 wherein the mesoporous structure includes exposed Si—

OH function groups, and wherein the bioactive agent is hydrogen bonded to the mesoporous structure.

3. The composition of claim 1 wherein the mesoporous structure includes a hydrated silica gel layer formed on a surface of the mesoporous structure.

4. The composition of claim 1 wherein the bioactive agent includes a protein.

5. The composition of claim 1 wherein the bioactive agent includes at least one of a growth factor, a pharmaceutical agent, and a vitamin.

6. The composition of claim 1 wherein the bioactive agent includes an osteoporotic drug.

7. The composition of claim 1 wherein a release profile of the bioactive agent includes a burst phase and an extended release phase.

8. The composition of claim 7 wherein the extended release phase is a slow release phase extending for a plurality of days.

9. The composition of claim 7 wherein:

the acid-modified calcium silicate particles includes a first portion of acid-modified calcium silicate particles having a first bioactive agent adsorbed thereon, the first bioactive agent having a first release profile; and

the composition further includes a second portion of acid-modified calcium silicate particles having a second bioactive agent adsorbed thereon, the second bioactive agent having a second release different from the first release profile.

10. The composition of claim 1 wherein the bioactive agent is a first bioactive agent, and wherein the composition includes a second bioactive agent.

11. The composition of claim 1 wherein the composition is biocompatible and bioresorbable, and wherein biocompatible comprises biocompatibility with respect to at least one of eukaryotic cells, mammalian cells, bone forming cells, osteoblast cells, cartilage cells, muscle cells, stem cells, differentiated stem cells, bone marrow stem cells and nerve cells.

12. The composition of claim 1 wherein the composition is used for regenerating tissue, and wherein the tissue includes at least one of bone, cartilage, muscle and musculoskeletal tissue.

13. The composition of claim 1 wherein the acid-modified calcium silicate particles includes at least one dopant, and wherein the dopant includes one or more of a metal salt with metal ions and a metal oxide.

14. A biocompatible composition for controlling release of a bioactive agent, comprising:

mesoporous calcium silicate particles;

a bioactive agent, wherein the bioactive agent is adsorbed on the particles; and

a calcium-based ceramic.

15. The composition of claim 14 wherein the calcium-based ceramic includes at least one of calcium phosphates and calcium sulfates.

16. The composition of claim 14 wherein at least one of the mesoporous calcium silicate and the calcium-based ceramic includes at least one dopant, and wherein the dopant includes one or more of a metal salt with metal ions and a metal oxide.

17. The composition of claim 16 wherein the dopant can include one or more of Zn²⁺, Mg²⁺, Si²⁺, Na⁺, K⁺, Sr²⁺, Cu²⁺, Fe³⁺/Fe²⁺, Ag⁺, Ti⁴⁺, CO₃²⁻

, F⁻

, MgO, ZnO, NaF, KF, FeO/Fe₂O₃, SrO, CuO, SiO₂, TiO₂, Ag₂O and CaCO₃, present in an amount between 0 and about 10 wt %.

18. The composition of claim 14 wherein the bioactive agent is a first bioactive agent, and wherein the composition includes a second bioactive agent adsorbed on the particles.

19. A method for synthesizing a mesoporous calcium silicate composition for controlling release of a bioactive agent, comprising:

preparing a calcium silicate slurry from calcium silicate particles; and

treating the calcium silicate slurry with an acid to produce a mesoporous structure on the calcium silicate particles to form the mesoporous calcium silicate composition, whereby the mesoporous calcium silicate composition controls release of a bioactive agent.

20. The method of claim 19 wherein treating the calcium silicate slurry with an acid includes treating the calcium silicate slurry with a hydrochloric acid solution.

21. The method of claim 19 wherein treating the precipitate slurry with an acid includes adding an acid to adjust a slurry pH to approximately pH 0.5 to approximately pH 7.0.

22. The method of claim 19 wherein the acid is added continuously to maintain a constant slurry pH.

23. The method of claim 19, further comprising adsorbing a bioactive agent by the mesoporous calcium silicate composition from a bioactive agent solution.

24. The method of claim 23 wherein the bioactive agent solution includes two or more types of bioactive agents, and wherein adsorbing a bioactive agent by the mesoporous calcium silicate composition includes adsorbing the two or more types of bioactive agents.

25. The method of claim 23 wherein the mesoporous calcium silicate composition is a first mesoporous calcium silicate composition and the bioactive agent is a first bioactive agent, and wherein the method further comprises combining the first mesoporous calcium silicate composition having the first bioactive agent with a second mesoporous calcium silicate composition having a second bioactive agent, wherein the second bioactive agent is different the first bioactive agent.

26. The method of claim 23 wherein adsorbing a bioactive agent includes adsorbing a protein molecule.

27. The method of claim 23 wherein adsorbing a bioactive agent includes adsorbing at least one of a drug, a growth factor, a vitamin, and a morphogen.

28. The method of claim 19, further comprising placing the mesoporous calcium silicate composition under body, body fluid or simulated body fluid conditions.

29. The method of claim 19, further comprising precipitating calcium silicate particles from a mixture of Ca(NO₃)₂.4H₂O and Na₂SiO₃ 9H₂O.

30. The method of claim 19 wherein the mesoporous structure includes pores having a pore size of approximately 4 nm to approximately 10 nm.

31. A bone graft material for musculoskeletal tissue regeneration, comprising:

a mesoporous calcium silicate composition including a bioactive agent adsorbed therein, the bioactive agent having an extended release profile from a mesoporous structure on a surface of the composition when placed under body fluid conditions.