Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Biocides; animal or insect repellents or attractants
Reexamination Certificate
2001-04-16
2004-04-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Biocides; animal or insect repellents or attractants
C424S422000
Reexamination Certificate
active
06719987
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to bioabsorbable materials, which are rendered antimicrobial due to the presence of antimicrobial metals in the form of coatings or powders; processes for their production; and use of same for controlling infection.
BACKGROUND OF THE INVENTION
The risk of acquiring infections from bioabsorbable materials in medical devices is very high. Many medical applications exist for bioabsorbable materials including:
1) Wound Closures: including for example sutures, staples, adhesives;
2) Tissue Repair: including for example meshes for hernia repair;
3) Prosthetic Devices: including for example internal bone fixation, physical barrier for guided bone regeneration;
4) Tissue Engineering: including for example blood vessels, skin, bone, cartilage, and liver; and
5) Controlled Drug Delivery Systems: including for example microcapsules and ion-exchange resins.
The use of bioabsorbable materials in medical applications such as the above have the advantages of reducing tissue or cellular irritation and induction of inflammatory response from prominent retained hardware; eliminating or decreasing the necessity of hardware removal; and in the case of orthopedic implants, permitting a gradual stress transfer to the healing bone and thus allowing more complete remodeling of the bone.
Bioabsorbable materials for medical applications are well known; for example, U.S. Pat. No. 5,423,859 to Koyfman et al., lists exemplary bioabsorbable or biodegradable resins from which bioabsorbable materials for medical devices may be made. In general, bioabsorbable materials extend to synthetic bioabsorbable, naturally derived polymers, or combinations thereof, with examples as below:
1) Synthetic Bioabsorbable Polymers: for example polyesters/polylactones such as polymers of polyglycolic acid, glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc., polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, and copolymers of these and related polymers or monomers; and
2) Naturally Derived Polymers:
a) Proteins: albumin, fibrin, collagen, elastin;
b) Polysaccharides: chitosan, alginates, hyaluronic acid; and
3) Biosynthetic Polyesters: 3-hydroxybutyrate polymers.
Like other biomaterials, bioabsorbable materials are also subjected to bacterial contamination and can be a source of infections which are difficult to control. Those infections quite often lead to the failure of the devices, requiring their removal and costly antimicrobial treatments.
Prior art efforts to render bioabsorbable materials more infection resistant generally have focused on impregnating the materials with antibiotics or salts such as silver salts. However, such efforts usually provide only limited, and instantaneous antimicrobial activity, which is limited by the availability or solubility of the antimicrobial agent over time. It is desirable to have an antimicrobial effect which is sustained over time, such that the antimicrobial effect can be prolonged for the time that the bioabsorbable material is in place. This can range from hours or days, to weeks or even years.
There are suggestions in the prior at to provide metal coatings, such as silver coatings, on medical devices; for example, International Publication No. WO 92/13491 to Vidal and Redmond; Japanese Patent Application Disclosure No. 21912/85 to Mitsubishi Rayon K. K., Tokyo; and U.S. Pat. No. 4,167,045 to Sawyer. None of these references include teachings specific to the use of metal coatings on bioabsorbable materials. In such applications, it is important that the metal coatings do not shed or leave behind large metal particulates in the body, which will induce unwanted immune responses and/or toxic effects.
There is a need for antimicrobial coatings for bioabsorbable materials, which can create an effective and sustainable antimicrobial effect, which do not interfere with the bioabsorption of the bioabsorbable material, and which do not shed or leave behind large metal particulates in the body as the bioabsorbable material disappears.
SUMMARY OF THE INVENTION
This invention provides bioabsorbable materials comprising a bioabsorbable substrate associated with one or more antimicrobial metals being in a crystalline form characterized by sufficient atomic disorder, such that the bioabsorbable material in contact with an alcohol or water based electrolyte, releases atoms, ion, molecules, or clusters of at least one antimicrobial metal at a concentration sufficient to provide an antimicrobial effect. The one or more antimicrobial metals do not interfere with the bioabsorption of the bioabsorbable material, and do not leave behind particulates larger than 2 &mgr;m, as measured 24 hours after the bioabsorbable material has disappeared. Most preferably, the particulate sizing from the coating or powder is sub-micron, that is less than about 1 &mgr;m, as measured 24 hours after the bioabsorbable material has disappeared. Particulates are thus sized to avoid deleterious immune responses or toxic effects. Such antimicrobial metals are in the form of a continuous or discontinuous coating, a powder, or a coating on a bioabsorbable powder.
The antimicrobial coating is thin, preferably less than 900 nm or more preferably less than 500 nm, and very fine grained, with a grain size (crystallite size) of preferably less than 100 nm, more preferably less than 40 nm, and most preferably less than 20 nm. The antimicrobial coating is formed of an antimicrobial metal, which is overall crystalline, but which is created with atomic disorder, and preferably also having either or both of a) a high oxygen content, as evidenced by a rest potential greater than about 225 mV, more preferably greater than about 250 mV, in 0.15 M Na
2
CO
3
against a SCE (standard calomel electrode), or b) discontinuity in the coating.
The antimicrobial metal associated with the bioabsorbable substrate may also be in the form of a powder, having a particle size of less than 100 &mgr;m or preferably less than 40 &mgr;m, and with a grain size (crystallite size) of preferably less than 100 nm, more preferably less than 40 nm, and most preferably less than 20 nm. Such powders may be prepared as a coating preferably of the above thickness, onto powdered biocompatible and bioabsorbable substrates; as a nanocrystalline coating and converted into a powder; or as a powder of the antimicrobial metal which is cold worked to impart atomic disorder.
A method of preparing the above antimicrobial bioabsorbable materials is also provided, with the bioabsorbable substrate being formed from a bioabsorbable polymer, or being a medical device or part of a medical device. The coating or powder of the one of more antimicrobial metals is formed by either physical vapour deposition under specified conditions and/or by forming the antimicrobial material as a composite material; or by cold working the antimicrobial material containing the antimicrobial metal at conditions which retain the atomic disorder, as in the case where the antimicrobial metal is in the form of a powder. Sufficient oxygen is incorporated in the coating or powder such that particulates of the antimicrobial metals during dissociation are sized at preferably less than 2 &mgr;m, or preferably less than 1 &mgr;m, to avoid deleterious immune responses or toxic effects,
As used herein, the terms and phrases set out below have the meanings which follow.
“Alcohol or water-based electrolyte” is meant to include any alcohol or water-based electrolyte that the anti-microbial coatings of the present invention might contact in order to activate (i.e. cause the release of species of the anti-microbial metal) into same. The term is meant to include alcohols, saline, water, gels, fluids, solvents, and tissues containing water, including body fluids (for example blood, urine or saliva), and body tissue (for example skin, muscle or bone).
“Antimicrobial effect” means that atoms, ions, molecules or clusters of the anti-microbial metal (hereinafter “species” of the anti-microbial metal) are released into the alcohol or electrolyte
Burrell Robert Edward
Djokic Stojan
Langford Rita Johanna Mary
Yin Hua Qing
Fish & Richardson P.C.
Howard S.
Nucryst Pharmaceuticals Corp.
Page Thurman K.
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