Highly loaded metal oxide materials by self-assembly for extended biologically active molecule release in medical and dental applications

Patent metadata

Field	Value
Publication number	US-11129774-B2
Application number	US-201716301773-A
Country	US
Kind code	B2
Filing date	May 16, 2017
Priority date	May 16, 2016
Publication date	Sep 28, 2021
Grant date	Sep 28, 2021

Abstract

A biocompatible composite material for controlled release is disclosed, comprising a biocompatible metal oxide structure with a loaded network of pores. The pore network of the biocompatible composite material is filled with a uniformly distributed biologically active micellizing amphiphilic molecule, the size of these pores ranging from about 0.5 to about 100 nanometers. The material is characterized in that when exposed to phosphate-buffered saline (PBS), the controlled release of the active amphiphilic molecule is predominantly diffusion-driven over time.

First claim

What is claimed is:

1. A biocompatible composite material for controlled release, comprising:
a biocompatible metal oxide structure containing an unaligned network of interconnected pores, said pores being filled with a micellizing, amphiphilic, biologically active agent distributed substantially uniformly throughout said network of pores in said metal oxide structure in self-assembled form, said composite material characterized in that:
the unaligned network of pores in said metal oxide structure is characterized by x-ray diffraction data wherein only one resolvable peak indicative of pore structure is present between about 1.1 and about 6 degrees (two theta); and
the amphiphilic molecule of the biologically active agent serves a dual role of (i) providing a template for the formation of the metal oxide structure comprising the network of pores, and (ii) substantially loading the porous network as the biologically active agent of the composite material; and
when exposed to phosphate-buffered saline (PBS) the rate of controlled release of the amphiphilic biologically active agent is predominantly diffusion-driven over the rate of degradation of the metal oxide structure due to the unaligned network of interconnected pores so that the rate of release is a sustained rate of controlled release as compared to the release rate obtained from an ordered and aligned network of interconnected pores.

2. The composite material according to claim 1 , wherein said amphiphilic, biologically active agent is an antimicrobial agent.

3. The composite material according to claim 2 , wherein said amphiphilic, biologically active agent is any one of octenidine dihydrochloride, polyhexamethylene biguanide, cetylpyridinium chloride or lauric arginate.

4. The composite material according to claim 1 , characterized in that the controlled release of amphiphilic biologically active agent is not dependent on degradation of the biocompatible metal oxide structure.

5. The composite material according to claim 1 , characterized in that during the course of the controlled release of the amphiphilic biologically active agent, the metal oxide structure maintains structural integrity.

6. The composite material according to claim 1 , wherein said biocompatible metal oxide is comprised of any of the following metal oxides: silicon dioxide, organosilicates, aluminosilicate, aluminum oxide, calcium phosphate, titanium dioxide, and zinc oxide.

7. The composite material according to claim 1 , wherein the biocompatible metal oxide is obtained with a species that react, condense, or assemble to form a biocompatible metal oxide.

8. The composite material of claim 1 , for use as any one or combination of, or as a component of, a coating for orthopedic implants, resin tooth bonding agent, cavity liner, cavity varnish, dental cement, resin coating or bulk of dentures, coating material or bulk of resin fillings, coating material for endosseous dental implant abutment or component, coating material for endosseous dental implant, resin composite tooth restorative material, denture relining, repairing, or rebasing resin, pit and fissure sealant and conditioner, temporary/interim/provisional crown and bridge resin, root canal (endodontic) filling resin sealer or endodontic core material, bone grafting material, coating material for total temporomandibular joint prosthesis, coating material for glenoid fossa prosthesis, coating material for mandibular condyle prosthesis, coating material for interarticular disc prosthesis, coating material for orthodontic appliance, resin bonding agent/cement for orthodontic brackets, coating material or bulk of orthodontic plastic bracket, oral cavity abrasive polishing agent, dentifrice, dental floss, and massaging pick or tip for oral hygiene.

9. The composite material of claim 1 , for use in preventing or inhibiting bacterial growth or bacterial proliferation, or in increasing resistance of a material to enzymatic degradation.

10. The composite material of claim 9 , wherein the said micellizing amphiphilic biologically active agent is released from the composite material into a patient's body or a patient's oral cavity when the composite material is place in the patient's body or oral cavity.

11. A process for synthesizing a biocompatible composite material for controlled release as defined in claim 1 , comprising:
a) mixing a biocompatible metal oxide and a micellizing, amphiphilic, biologically active agent, with a solvent to form a synthesis solution; and
b) at one point as the synthesis proceeds, said active agent self-assembles into a micellar system in the synthesis solution for self-assembly said metal oxide source to assemble around the solution-facing micelle walls wherein the micellizing, amphiphilic, biologically active agent serves a dual role of providing a template for formation of a metal oxide structure comprising an unaligned network of pores characterized by x-ray diffraction data wherein only one resolvable peak indicative of pore structure is present between about 1.1 and about 6 degrees (two theta), and substantially loading said porous network with the amphiphilic molecules as a final payload, and form the composite material comprising the metal oxide structure condensed around loaded, self-assembled and unaligned network of interconnected pores containing said active agent, the composite material being characterized by a sustained rate of controlled release of said active agent as compared to the release rate obtained from an ordered and aligned network of interconnected pores.

12. The process according to claim 11 , wherein said amphiphilic, biologically active agent is an antimicrobial agent.

13. The process according to claim 11 , wherein said composite material is synthesized in a coating form by spreading a solution of solvent, said micellizing, amphiphilic, biologically active agent and biocompatible metal oxide source over a surface as a coating, where the evaporation of solvent forces an ordered co-assembly of the biologically active agent and metal oxide, with a subsequent increase in solution concentration by solvent evaporation causing the condensation of metal oxide around templating micelles into a porous solid coating.

14. The process according to claim 11 , wherein said composite material is synthesized in a particulate form by aerosolizing or spraying a solution of solvent, said micellizing, amphiphilic, biologically active agent and biocompatible metal oxide source, where the evaporation of solvent from solution aerosol droplets forces an ordered co-assembly of the biologically active agent and metal oxide, with a subsequent increase in solution concentration by solvent evaporation causing the condensation of metal oxide around templating micelles into a porous solid coating.

15. The process according to claim 11 , characterized in that the controlled release of biologically active agent is not dependent on degradation of the biocompatible metal oxide structure.

16. The process according to claim 11 , characterized in that during the course of the controlled release of the biologically active agent, the metal oxide structure maintains structural integrity.

Assignees

• Governing Council Univ Toronto

Inventors

• Stewart Cameron Alexander
• Hatton Benjamin David
• Finer Yoav

Classifications

• A61K6/802

  comprising ceramics · CPC title

• A61K6/71

  Fillers · CPC title

• A61K9/0063

  Periodont · CPC title

• A61K6/853

  Silicates · CPC title

• A61L27/425

  of phosphorus containing material, e.g. apatite · CPC title