Mesoporous calcium silicate compositions and methods for synthesis of mesoporous calcium silicate for controlled release of bioactive agents

• US 9,539,359 B2
• Filed: 11/11/2014
• Issued: 01/10/2017
• Est. Priority Date: 04/25/2006
• Status: Expired due to Fees

• Current Assignee: Washington State University
• Original Assignee: Washington State University
• Inventors: Bose, Susmita, Bandyopadhyay, Amit, Xue, Weichang
• Primary Examiner(s): Tran, Susan
• Assistant Examiner(s): CRAIGO, WILLIAM A
• Application Number:
  US14/538,418
• Publication Number:
  US 20150283294A1
• Time in Patent Office: 791 Days
• Field of Search: None
• US Class Current: 1/1
• 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 biocompatible composition for controlling release of a bioactive agent, comprising:

a plurality of calcium silicate (CaSiO₃) particles each comprising;

(i) a crystalline interior portion having a network of covalently bonded silica (SiO₂) interrupted and modified by a plurality of calcium cations (Ca²⁺); and

(ii) an exterior surface having a layer of silica gel and having a lower calcium cation concentration than the interior portion, wherein the exterior surface is mesoporous;

a bioactive agent deposited onto the exterior surface or incorporated into the interior portion of each of the calcium silicate particles, wherein the bioactive agent is bonded to the calcium silicate particles in vitro; and

a calcium-based ceramic, and wherein the plurality of calcium silicate particles are packed into the calcium-based ceramic.

2. The biocompatible composition of claim 1 wherein the calcium-based ceramic includes at least one of calcium phosphates and calcium sulfates.

3. The biocompatible composition of claim 1 wherein at least one of the calcium silicate particles or 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.

4. The biocompatible composition of claim 3 wherein the dopant includes 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, or CaCO3, present in an amount between 0 wt % and about 10 wt %.

5. The biocompatible composition of claim 1 wherein the bioactive agent is a first bioactive agent, and wherein the composition includes a second bioactive agent adsorbed on the calcium silicate particles.

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

a plurality of calcium silicate (CaSiO₃) particles each comprising;

(i) a crystalline interior portion having a network of covalently bonded silica (SiO₂) interrupted and modified by a plurality of calcium cations (Ca²⁺); and

(ii) an exterior surface having a layer of silica gel and having a lower calcium cation concentration than the interior portion;

a bioactive agent deposited onto the exterior surface or incorporated into the interior portion of each of the calcium silicate particles, wherein the bioactive agent is bonded to the calcium silicate particles in vitro and includes at least one of a protein, a polypeptide, a growth factor, a morphogen, an antibiotic, an antimicrobial agent, an osteoporotic drug, or a vitamin; and

a calcium-based ceramic mixed with the plurality of calcium silicate particles, the calcium-based ceramic containing calcium phosphates or calcium sulfates.

7. The biocompatible composition of claim 6 wherein the exterior surface includes exposed Si—

OH function groups, and wherein the bioactive agent is hydrogen bonded to the exterior surface.

8. The biocompatible composition of claim 6 wherein the plurality of calcium silicate particles do not include calcium cations at the exterior surface.

9. The biocompatible composition of claim 6 wherein a release profile of the bioactive agent includes a burst phase and an extended release phase.

10. The biocompatible composition of claim 9 wherein the extended release phase extends for a plurality of days.

11. The biocompatible composition of claim 6 wherein:

the bioactive agent is a first bioactive agent;

the calcium silicate particles include a first portion of calcium silicate particles having the first bioactive agent adsorbed thereon, the first bioactive agent having a first release profile; and

the calcium silicate particles further include a second portion calcium silicate particles having a second bioactive agent adsorbed thereon, the second bioactive agent having a second release different from the first release profile.

12. The biocompatible composition of claim 6 wherein the calcium silicate particles individually include at least one dopant containing 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, or CaCO3.

13. The biocompatible composition of claim 6 wherein the calcium silicate particles individually include at least one dopant containing 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, or CaCO3, present in an amount between 0 wt % and about 10 wt %.

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

a plurality of calcium silicate (CaSiO₃) particles individually including;

a crystalline interior portion having a network of covalently bonded silica (SiO₂) interrupted and modified by a plurality of calcium cations (Ca²⁺); and

an exterior surface proximate the interior portion, the exterior surface having a layer of hydrated silica gel with a plurality of Si—

OH functional groups;

a bioactive agent deposited onto the exterior surface or incorporated into the interior portion of the individual calcium silicate particles in vitro, wherein the bioactive agent includes at least one of a protein, a polypeptide, a growth factor, a morphogen, an antibiotic, an antimicrobial agent, an osteoporotic drug, or a vitamin; and

a calcium-based ceramic mixed with the plurality of calcium silicate particles, the calcium-based ceramic containing calcium phosphates or calcium sulfates, at least one of the calcium silicate particles or the calcium-based ceramic having a dopant containing 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, or CaCO₃, wherein the dopant in the at least one of the calcium silicate particles or the calcium-based ceramic presents in an amount between 0 wt % and about 10 wt %.

15. The biocompatible composition of claim 14 wherein the exterior surface has a calcium cation concentration lower than that of the crystalline interior portion of the individual calcium silicate particles.

16. The biocompatible composition of claim 14 wherein the exterior surface has a calcium cation concentration lower than that of the crystalline interior portion of the individual calcium silicate particles, and wherein a calcium cation concentration at the exterior surface is generally zero.

17. The biocompatible composition of claim 14 wherein the bioactive agent is hydrogen bonded to the exterior surface of the individual calcium silicate particles.

18. The biocompatible composition of claim 14 wherein:

the crystalline interior portion consists of the network of covalently bonded silica (SiO₂) interrupted and modified by a plurality of calcium cations (Ca²⁺); and

the exterior surface has a calcium cation concentration lower than that of the crystalline interior portion of the individual calcium silicate particles.

19. The biocompatible composition of claim 14 wherein:

the crystalline interior portion consists of the network of covalently bonded silica (SiO₂) interrupted and modified by a plurality of calcium cations (Ca²⁺); and

a calcium cation concentration at the exterior surface is generally zero.