Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-03-15
2002-11-19
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C523S114000, C523S115000
Reexamination Certificate
active
06482427
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compositions and methods useful for the repair of osseous defects and the accelerated healing of wounds and burns, for example, in various parts of the body of a human or animal. More particularly, the invention relates to compositions including, and methods using such compositions, bioactive, biocompatible glass particles having defined chemical make-ups and particle size distributions, which provide substantial benefits in cost and in the treatment of osseous defects, wounds and burns.
Glass particles have previously been suggested for repairing osseous defects. For example, Low et al U.S. Pat. No. 4,851,046 discloses using glass particles having a broad size distribution of 90 to 710 microns to repair periodontal osseous defects. This patent discloses that a mixture of glass particles having a larger or wider particle size range, including particles having a size range of 500 to 710 microns, might produce a clinically more desirable product. This patent discloses glass particle compositions having a wide overall size distribution and including particles of 500 to 710 microns in size.
Schepers et al U.S. Pat. No. 5,204,106 discloses compositions of glass particles at least 95% by weight of which have sizes between 280 and 425 microns for use in a process for filling an osseous defect or deficiency. This narrow particle size distribution adversely impacts the cost of the product. Moreover, this patent make clear that if the particles are too small, that is smaller than 280 microns, the particles have a tendency to break, and if these particles are present in excessive amounts, that is 5% or more by weight, the desired performance is not achieved. Thus, although the narrow particle size composition is more costly, this patent concludes that such narrow size distribution provides enhanced performance benefits.
Ducheyne et al U.S. Pat. No. 5,658,332 discloses methods for forming osseous tissue in defect sites in the appendicular skeleton or in sites exhibiting reduced metabolic state using glass particles having a size from 200 to 300 microns. This narrow particle size distribution, which is even more narrow than disclosed in the above-noted Schepers et al patent, disadvantageously increases the cost of the product.
It would be advantageous to provide a product, which is effective in repairing osseous defects, meaning to include osseous deficiencies as well, and which is cost effective to produce and use.
Adverse reactions of repairing osseous defect are frequently related to infections associated with biomaterials, which often lead to revision surgery. At present, systemically administered antibiotics, or prophylaxis, is the main defense against bacterial infection following implant surgery. However, antibiotic efficacy is often reduced if the bacteria strains are firmly adherent to the implant materials. In addition, parenteral and oral administration of antibiotics may lead to undesirable side effects by depleting benign microbial flora normally present in the body. Accordingly it would be advantageous to provide a product which is effective in repairing osseous defects, resisting microbial infections and capable of restoring the deficiency or defect site to its original load bearing state.
Particulate bioactive glass is designed to serve as a scaffolding material to encourage cellular growth after implantation. Bioactive glass particles do not show inhibitory actions against bacteria growth under normal physiological conditions.
Since ancient times, silver ion, Ag
+
, has been used as an antimicrobial agent in treating wounds and broken bones. Silver ion possesses a broad spectrum of antimicrobial action which is suitable for the treatment of infections resulting from polymicrobial colonization on the biomaterials.
The antimicrobial effect of silver-containing ceramics including hydroxyapatite (HA), and bioactive glass have been studied and demonstrated in vitro. For example, Bellantone et al J Biomed Mater Res (51) 484, 2000 disclose a sol-gel derived bioactive glass SiO2-CaO-P205-Ag2O that exhibits a marked bacteriostatic effect on
E. coli
MG1655 without significantly affecting its ability to transform the surface layer of bioactive glass into hydroxy carbonate apatite in vitro. Kim et al J Mater Sci: Mater Med (9) 129, 1998 report that ionic silver in hydroxyapatite possesses antimicrobial effect, while ionic copper and zinc in hydroxyapatite do not exhibit significant antibacterial effect. Cartmell et al J Mater Sci: Mater Med (9) 773, 1998 study the soft tissue response to controlled release glass particulate Na2O-CaO-P205-Ag2O having particle size less than 53 microns and reports that the degrading glass causes tissue necrosis. These studies show that silver ions released from bioceramic exert toxicity toward microbials and might potentially be toxic to tissue as well. The effect of silver ions on the biocompatability of ceramic materials has not been fully studied and/or reported. Silver may form complexes with electron donor groups such as amines, phosphates and thiols by chelation. It has been postulated that silver exerts it toxicity at multiple cellular sites, disrupting the respiratory chain and cell wall synthesis. None of the prior studies address the questions of whether the silver-containing bioceramic is suitable for long-term implantation, and more particularly load bearing function after long term implantation. Silver ion released from bioactive glass may inhibit cellular growth onto and/or into the bioactive glass implant, compromising biocompatability, osseous integration and resulting in implant failure. It is also possible that the implant may exhibit an initial success and later, due to long term accumulation of silver ions, result in implant failure or adverse reactions. Possibly, the long-term failure may not reveal itself until under extreme load bearing conditions.
Glass particles have also been suggested to treat wounds and burns. For example, Greenspan et al U.S. Pat. No. 5,834,008 discloses composition for the accelerated healing of wounds and burns using a mixture of a topical antibiotic and particulate of bioactive glass. This prior art, however, disadvantageously requires that the antibiotic and the particulate bioactive glass be mixed just prior to application in order to minimize reactions between the two components. It would be advantageous to provide a product which is effective in the treatment of wounds and burns without the need to mix a topical antibiotic with the particulate of bioactive glass prior to application.
SUMMARY OF THE INVENTION
New compositions and methods useful to repair osseous defects, and heal wounds and burns, have been discovered. Such compositions provide performance benefits, for example, in terms of effectiveness in repairing osseous defects, in resisting microbial infections and/or in being able to be easily and effectively handled or manipulated prior to such use relative to many of the prior art compositions. In addition, since the present compositions have a relatively broad particle size distribution range, the present compositions are cost effective to produce and use, often more cost effective to produce and use relative to prior art compositions. Moreover, the present compositions can be easily produced and used, for example, employing conventional techniques which are well known in the art.
In one broad aspect of the present invention, compositions useful to repair osseous defects, and heal wounds and burns are provided and comprise particulate bioactive and biocompatible glass. In one embodiment, the present glass particles have the following chemical make-up:
Silica
about 40% to about 58% by weight
Calcia
about 10% to about 32% by weight
Soda
about 10% to about 32% by weight
Phosphorus pentoxide
about 2% to about 10% by weight
Antimicrobial agent
about 0% or about
0.001% to about 8% by weight
The antimicrobial agent is present, if at all, in an amount that is in a range of about 0.001%-8%. Preferably, the antimicrobial agent is pres
Azpuru Carlos
Stout, Uxa Buyan & Mullins, LLP
Unicare Biomedical, Inc.
Uxa Frank J.
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