Adhesive bonding and miscellaneous chemical manufacture – Methods – Surface bonding and/or assembly therefor
Reexamination Certificate
2000-06-07
2001-10-23
Gallagher, John J. (Department: 1733)
Adhesive bonding and miscellaneous chemical manufacture
Methods
Surface bonding and/or assembly therefor
C424S078060, C424S078310, C427S002100, C523S118000, C523S202000, C523S205000, C523S210000, C526S298000
Reexamination Certificate
active
06306243
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to improved compositions useful as biomedical adhesives, sealants, implants and bioactive agent release matrices. This invention also relates to medical, surgical and other in vivo applications in which body tissue surfaces are joined or reinforced with biocompatible compositions.
BACKGROUND
The products in primary use for wound closure are surgical sutures and staples. Sutures are recognized to provide adequate wound support. However, sutures cause additional trauma to the wound site (by reason of the need for the needle and suture to pass through tissue) and are time-consuming to place, and, at skin level, can cause unattractive wound closure marks. Surgical staples have been developed to speed wound apposition. However, surgical staples also impose additional wound trauma and require the use of ancillary and often expensive devices for positioning and applying the staples.
To overcome these drawbacks, fast-acting surgical adhesives have been proposed. One group of such adhesives is the monomeric forms of alpha-cyanoacrylates.
Reference is made, for example, to U.S. Pat. No. 3,527,841 (Wicker et al.); U.S. Pat. No. 3,722,599 (Robertson et al.); U.S. Pat. No. 3,995,641 (Kronenthal et al.); and U.S. Pat. No. 3,940,362 (Over-hults), which disclose that alpha-cyanoacrylates are useful as surgical adhesives. All of the foregoing references are hereby incorporated by reference herein.
Typically, when used as adhesives and sealants, cyanoacrylates are applied in monomeric form to the surfaces to be joined or sealed, where, typically, in situ anionic polymerization of the monomer occurs, giving rise to the desired adhesive bond or seal. Implants, such as rods, meshes, screws, and plates, may also be formed of cyanoacrylate polymers, formed typically by radical-initiated polymerization.
However, a drawback to the in vivo biomedical use of alpha-cyanoacrylate monomers and polymers has been their potential for causing adverse tissue response. For example, methyl alpha-cyanoacrylate has been reported to cause tissue inflammation at the site of application.
The adverse tissue response to alpha-cyanoacrylates appears to be caused by the products released during in vivo biodegradation of the polymerized alpha-cyanoacrylates. It is believed that formaldehyde is the biodegradation product most responsible for the adverse tissue response and, specifically, the high concentration of formaldehyde produced during rapid polymer biodegradation. Reference is made, for example, to F. Leonard et al.,
Journal of Applied Polymer Science
, Vol. 10, pp. 259-272 (1966); F. Leonard,
Annals New York Academy of Sciences
, Vol. 146, pp. 203-213 (1968); Tseng, Yin-Chao, et al.,
Journal of Applied Biomaterials
, Vol. 1, pp. 111-119 (1990), and to Tseng, Yin-Chao, et al.,
Journal of Biomedical Materials Research
, Vol. 24, pp. 1355-1367 (1990).
For these reasons, cyanoacrylates have not come into widespread use for biomedical purposes.
Efforts to increase the tissue compatibility of alpha-cyanoacrylates have included modifying the alkyl ester group. For example, increasing the alkyl ester chain length to form the higher cyanoacrylate analogues, e.g., butyl-2-cyanoacrylates and octyl-2-cyanoacrylates, has been found to improve biocompatibility but the higher analogues biodegrade at slower rates than the lower alkyl cyanoacrylates.
Other examples of modified alpha-cyanoacrylates used in biomedical applications include carbalkoxyalkyl alpha-cyanoacrylates (see, for example, U.S. Pat. No. 3,995,641 to Kronenthal et al.), fluorocyanoacrylates (see, for example, U.S. Pat. No. 3,722,599 to Robertson et al.), and alkoxyalkyl 2-cyanoacrylates (see, for example, U.S. Pat. No. 3,559,652 to Banitt et al.). Other efforts have included mixing alpha-cyanoacrylates with dimethyl methylenemalonate and higher esters of 2-cyanoacrylic acid (see, for example, U.S. Pat. No. 3,591,676 to Hawkins et al.).
In other efforts to increase the usefulness of alpha-cyanoacrylate adhesive compositions for surgical applications, certain viscosity modifiers have been used in combination with alkyl alpha-cyanoacrylate monomers, such as methyl alpha-cyanoacrylate. See, for example, U.S. Pat. No. 3,564,078 (wherein the viscosity modifier is poly(ethyl 2-cyanoacrylate)) and U.S. Pat. No. 3,527,841 (wherein the viscosity modifier is poly(lactic acid)), both patents being to Wicker et al.
In a related application, U.S. Ser. No. 08/040,618, filed Mar. 31, 1993 (U.S. Pat. No. 5,328,687), the entire contents of which are hereby incorporated by reference, the use of formaldehyde scavengers has been proposed to improve biocompatibility of alpha-cyanoacrylate polymers, whose biodegradation produces formaldehyde, for use in in vivo applications. It is known that various compounds can affect polymerization of alpha-cyanoacrylate monomers, including acids to inhibit or slow polymerization (e.g., Leonard et al., U.S. Pat. No. 3,896,077), and bases to accelerate polymerization (e.g., Coover et al., U.S. Pat. No. 3,759,264 and Dombroski et al., U.S. Pat. No. 4,042,442).
SUMMARY OF THE INVENTION
It has not been known to regulate polymer biodegradation by regulating the pH of an immediate in vivo environment of a biocompatible composition. Such regulation would improve, for instance, the biocompatibility of 1,1-disubstituted ethylene polymers for in vivo applications, by controlling the rate of release of harmful byproducts (e.g., formaldehyde) and controlling the rate of degradation of the polymer in situ.
Combining the monomer composition with a biocompatible pH modifier effective to regulate the pH of an immediate environment of the in situ polymer will substantially improve the usefulness of polymers formed from such monomers, particularly in combination with use of formaldehyde scavengers.
The present invention is also directed to methods of using the above-described monomers, copolymers and polymers made therefrom for biomedical purposes.
The monomer compositions of this invention and polymers formed therefrom are useful as tissue adhesives, sealants for preventing bleeding or for covering open wounds, systems for delivery of therapeutic or other bioactive agents, and in other biomedical applications. They find uses in, for example, apposing surgically incised or traumatically lacerated tissues; setting fractured bone structures; retarding blood flow from wounds; aiding repair and regrowth of living tissue; and serving as matrices for delivering bioactive agents and as implants.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Embodiments of the present invention provide a biocompatible monomer composition, comprising an effective amount of at least one biocompatible pH modifier effective to regulate the pH of an immediate in vivo environment of the polymer to a pH range at which the polymer's in vivo biodegradation proceeds at a different rate than it does at physiologic pH.
In a further embodiment, the present invention is directed to a biocompatible composition comprising a polymer whose in vivo biodegradation may produce formaldehyde, and a pH modifier as described previously, and optionally including a formaldehyde scavenger.
The monomers used in this invention are polymerizable, e.g. anionically polymerizable or free radical polymerizable, to form polymers which biodegrade. In some embodiments, they form active formaldehyde upon biodegradation.
Monomer compositions of this invention may be applied to a surface to be sealed or joined together with a second surface in vivo, where, typically, in situ anionic polymerization of the monomer occurs, giving rise to the desired adhesive bond or seal.
Useful 1,1-disubstituted ethylene monomers include, but are not limited to, monomers of the formula:
CHR═CXY (I)
wherein X and Y are each strong electron withdrawing groups, and R is H, —CH═CH
2
or, provided that X and Y are both cyano groups, a C
1
-C
4
alkyl group.
Examples of monomers within the scope of formula (I) include alpha-cyanoacrylates, vinylidene cyanides, C
1
-C
4
alkyl homolo
Clark Jeffrey G.
Leung Jeffrey C.
Closure Medical Corporation
Gallagher John J.
Oliff & Berridg,e PLC
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