Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-08-02
2003-09-16
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C424S451000, C514S642000, C514S644000
Reexamination Certificate
active
06620846
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to monomer and polymer adhesive and sealant compositions, and to their production and use for industrial and medical applications.
2. State of the Art
Monomer and polymer adhesives are used in both industrial (including household) and medical applications. Included among these adhesives are the 1,1 -disubstituted ethylene monomers and polymers, such as the &agr;-cyanoacrylates. Since the discovery of the adhesive properties of such monomers and polymers, they have found wide use due to the speed with which they cure, the strength of the resulting bond formed, and their relative ease of use. These characteristics have made &agr;-cyanoacrylate adhesives the primary choice for numerous applications such as bonding plastics, rubbers, glass, metals, wood, and, more recently, biological tissues.
Medical applications of 1,1-disubstituted ethylene adhesive compositions include use as an alternate or an adjunct to surgical sutures and staples in wound closure as well as for covering and protecting surface wounds such as lacerations, abrasions, burns, stomatitis, sores, and other surface wounds. When an adhesive is applied, it is usually applied in its monomeric form, and the resultant polymerization gives rise to the desired adhesive bond.
For example, polymerizable 1,1 -disubstituted ethylene monomers, and adhesive compositions comprising such monomers, are disclosed in U.S. Pat. No. 5,328,687 to Leung et al. Suitable methods for applying such compositions to substrates, and particularly in medical applications, are described in, for example, U.S. Pat. Nos. 5,928,611; 5,582,834; 5,575,997; and 5,624,669, all to Leung et al.
Some monomeric &agr;-cyanoacrylates are extremely reactive, polymerizing rapidly in the presence of even minute amounts of an initiator, including moisture present in the air or on moist surfaces such as animal tissue. Monomers of &agr;-cyanoacrylates are anionically polymerizable or free radical polymerizable, or polymerizable by zwitterions or ion pairs to form polymers. Once polymerization has been initiated, the cure rate can be very rapid to very slow, depending on the choice of monomer.
However, not all cyanoacrylates polymerize at the same rate; and therefore, various initiators have been added to cyanoacrylates to induce polymerization. For example, each of U.S. Pat. Nos. 5,928,611 to Leung; 5,902,443 to Kanakubo et al.; 4,460,759 to Robins; 4,378,213 to Severy; 5,066,743 and 4,979,993 to Okamoto et al.; 5,262,200 to Puder et al.; 4,012,402 and 3,903,055 to Buck; and 3,940,362 to Overhults discloses cyanoacrylate monomers polymerized by the addition of various initiators. The compositions are however directed to catalyzing reactions which only require minor stimulation or initiation to occur. U.S. Pat. No. 5,079,098 to Liu also addresses the addition of initiators to cyanoacrylates, but only for the purpose of promoting increased bonding.
U.S. Pat. No. 5,928,611 to Leung broadly discloses 1,1-disubstituted ethylene monomers having a large number of possible substituent groups. The disclosure focuses on alpha cyanoacrylates, with alternative representation of ester cyanoacrylates having an organic radical substituent. However, the disclosure does not specify particular properties, such as absorbability, possessed by particular cyanoacrylates. The disclosure does not indicate which initiators work well with which cyanoacrylates. Not all cyanoacrylates work well with all initiators, because cyanoacrylates and initiators are specific in their polymerization interaction. The disclosure also does not disclose absorption rates, or the effect of the selection of initiators on the properties possessed by cyanoacrylates or polymerization products thereof.
U.S. Pat. No. 3,995,641 to Kronenthal et al. discloses absorbable carbalkoxyalkyl 2-cyanoacrylates. The disclosure does not discuss the use of initiators, but rather indicates that blood and other body fluids polymerize the monomers. The disclosure also does not address the effect of the selection of initiators on the properties possessed by cyanoacrylates or polymerization products thereof.
Absorbable adhesives have additional benefits over non-absorbable adhesives under some circumstances, particularly for some medical applications. However, some absorbable cyanoacrylate adhesive compositions have particularly slow reaction kinetics which reduce their practical value as surgical adhesives. Therefore, there is still a need for an adhesive composition that combines absorbability and a rapid cure rate sufficient for medical applications.
SUMMARY OF THE INVENTION
The present invention is based on a subclass of cyanoacrylates, alkyl ester cyanoacrylates, that possess exceptional adhesive characteristics and additionally are minimally toxic to non-toxic as well as absorbable by living organisms. Benefits of biocompatible adhesives of the invention include ease and rapidity of application, which may be accompanied by inhibition of microbial growth, and lower cost than sutures or staples. The present invention provides a method of treating living tissue, comprising applying to living tissue a biocompatible adhesive composition comprising at least one alkyl ester cyanoacrylate monomer and a polymerization initiator or accelerator, wherein the polymerization initiator or accelerator is a quaternary amine. The combination of an alkyl ester cyanoacrylate and a quaternary amine provides desirable reaction kinetics coupled with absorbability.
The present invention also provides a kit, comprising a saleable package comprising a first container that contains at least one alkyl ester cyanoacrylate monomer; and a polymerization initiator or accelerator, wherein the polymerization initiator or accelerator is a quaternary amine.
The present invention also provides a method of treating living tissue, comprising applying to living tissue a biocompatible adhesive composition comprising a polymerization initiator or accelerator and at least one member selected from the group consisting of butyl lactoyl cyanoacrylate monomer and butyl glycoloyl cyanoacrylate monomer.
The present invention also provides a method of treating living tissue, comprising determining a desired rate at which an adhesive polymer is absorbed; selecting a suitable combination of monomer and polymerization initiator or accelerator to provide the desired absorption rate; and applying to living tissue the polymerization initiator or accelerator and monomer to form an absorbable adhesive polymer.
Absorbable cyanoacrylates have broad application for closure and hemostatic sealing of wounds and the like in various living tissue, including but not limited to internal organs and blood vessels. Due to their biodegradability, these absorbable formulations can be applied on the interior or exterior of blood vessels and various organs and other tissue.
Adhesives of the present invention are biocompatible with living tissue, may be applied in vivo to living tissue, and may be applied internally or externally in or on living tissue.
In embodiments, the present invention provides at least one alkyl ester cyanoacrylate monomer having the formula
wherein R
1
and R
2
are independently H, a straight, branched or cyclic alkyl group, or are combined together in a cyclic alkyl group, and R
3
is a straight, branched or cyclic alkyl group.
The present invention also provides for the use with the monomers of quaternary amine polymerization initiators or accelerators such as quaternary amines having the formula
wherein R
4
, R
5
, R
6
and R
7
are each independently H or a substituted or unsubstituted straight, branched or cyclic alkyl group; a substituted or unsubstituted aromatic ring; a substituted or unsubstituted aralkyl group; or a substituted or unsubstituted alkyl or aromatic group which may include one or more hetero atom functionalities such as oxygen, sulfur, nitrogen, etc.; and X
−
is an anion such as a halide, for example chloride, bromide, or fluoride, or hydroxyl; suitable quaternary amin
Bobo John
Jonn Jerry Y.
Moseley Jon P.
Quintero Julian
Closure Medical Corporation
Dees Jose′ G.
George Konata M.
Oliff & Berridg,e PLC
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