Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-01-29
2002-11-05
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C424S009400, C424S009420, C424S078310, C424S078350, C424S078370, C424S422000, C424S601000, C424S605000, C424S649000, C424S667000, C424S723000, C514S526000, C514S546000, C514S558000, C514S560000, C514S718000, C514S731000, C514S970000, C604S048000, C604S500000, C604S507000, C604S514000, C604S518000
Reexamination Certificate
active
06476069
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to cyanoacrylate polymer compositions useful as medical devices.
BACKGROUND OF THE INVENTION
Cyanoacrylate tissue adhesives have been in clinical endovascular use since the 1970's. Liquid acrylics are extremely useful as endovascular embolic agents because of their ability to create permanent vascular occlusion. They may, however, be difficult to use technically as they have a variable and sometime unpredictable polymerization time based on the operator selection of an acrylic mix with either iodinated oil or glacial acetic acid. The appropriate choice of polymerization time depends on a number of variables, including the transit time between arterial and venous elements in the embolic target, the target volume, the architecture of the target, for example, a fistula versus nidus, which affects the relative endovascular turbulence, and the method of injection (bolus, full column, or wedge-flow arrest). Typical complications associated with the use of liquid acrylics for embolization occur when there is occlusion of normal arterial branches or acrylic penetration into critical venous outflow channels. Additionally, reflux of acrylic around the delivery catheter tip can result in permanent endovascular catheter adhesion, which may require permanent catheter implantation. Overzealous attempts at withdrawal can produce catheter fracture (and resultant embolization of flow-directable distal catheter segment), vascular damage with resultant dissection/occlusion, or avulsion of the involved vascular pedicle (with resultant subarachnoid hemorrhage).
Alkyl alpha cyanoacrylates are a homologous series of organic molecules which polymerize and can adhere to moist living tissues. The methyl homolog has been used in hemostasis and non-suture closure since 1960, but its histoxicity severely limited its clinical usefulness. The synthesis of longer alkyl chain homologs and the evaluation of these in various animal species have shown that the histoxicity of cyanoacrylates could be diminished without sacrificing their hemostatic and tissue bonding properties. Extensive animal studies have been completed using n-butyl and isobutyl homologs, and preliminary human trials have been undertaken.
Polymerization speed is another function of chain length. It has been reported that homologs with six or more carbon atoms on the alkyl chain polymerize almost immediately upon contact with moist tissues. The n-butyl and isobutyl monomers require from four to 15 seconds, while the methyl homolog remains as a monomer for 30 to 55 seconds. The ability to wet and spread easily over the surface of an anticoagulated blood film is common to homologs with alkyl chains containing four or more carbon atoms. The ethyl and propyl derivatives wet and spread poorly, and the methyl not at all.
Since the advent of NBCA (n-butyl-2-cyanoacrylate), there has been very little advancement in the science of “superglue” embolization of vascular structures, primarily arteriovenous malformations (AVMs). Certain properties of superglue are advantageous for embolization, such as adhesion, the ability transform from a liquid or solid state and rapid polymerization. However, these properties can be detrimental when present to an excessive degree, in particular, adhesion which can result in permanent catheter fixation. Rapid polymerization allows the material to set in flowing blood without passing through small channels into venous structures. However, rapid polymerization may also release amounts of heat that can cause damage to the surrounding tissue, for example, brain tissue.
Hydrophilic catheter coatings have been developed in the hope of which reduce the risk of inadvertent endovascular catheter fixation during embolization due to reduced bond strength between the hydrophililically coated catheter and the adhesive. However, microcatheter cyanoacrylate adhesion remains a problem during intravascular embolization. Inadvertent gluing of the catheter tip onto the artery is a well recognized and distressing complication. Vessel rupture or occlusive embolization of a detached catheter tip may occur if excessive force is used to attempt to retrieve the catheter. Fortunately, permanent intravascular catheter fixation is usually well tolerated, nonetheless this remains a highly undesirable event. An in vitro study has shown that recently available hydrophilic microcatheter coatings decrease catheter adhesion of both pure normal butyl cyanoacrylate and mixtures of normal butyl cyanoacrylate and ethiodized oil. Although hydrophilically coated catheters have the potential of decreasing the occurrence of inadvertent endovascular catheter fixation, the level of operator proficiency and experience, and perhaps most importantly, the actual adhesive composition that is used stills play a major role in these events.
There exists a continuing unmet need for a composition that has the correct amount of cohesiveness, produces a robust rubbery casting, is tolerated by the body, can trigger the appropriate amount of tissue inflammation response and is radiopaque.
It has now been surprisingly found that such a composition exists that has the requisite combination of properties in cohesion, stability, body tolerance, low catheter adhesion and radiopacity.
SUMMARY OF THE INVENTION
A composition useful as an embolic agent that selectively creates an embolic blockage in the lumen of a blood vessel, duct, fistula or other like body passageways by combining a monomer component and a second component wherein, said monomer component comprises of a alkyl cyanoacrylate monomer and at least one inhibitor agent; and said second component that functions as an opacificant agent and a polymerization retardant.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition useful as an embolic agent that selectively creates an embolic blockage in the lumen, either totally or partially, of a blood vessel, duct, fistula or other body passageways by combining a monomer component and a second component where the monomer component comprises of a alkyl cyanoacrylate monomer and at least one inhibitor agent; and the second component functions as an opacificant agent and a polymerization retardant.
One embodiment of the present invention is where the second component is Ethiodol.
Another embodiment of the present invention is a composition useful as an embolic agent that selectively creates an embolic blockage in the lumen of a blood vessel, duct, fistula or other like body passageways by combining a monomer component and a second component where the monomer component comprises of a alkyl cyanoacrylate monomer and at least one inhibitor agent; and the second component comprises, a polymer resulting from the alkyl cyanoacrylate monomer, a alkyl esterified fatty acid and an opacificant agent. In particular, where the monomer component comprises of 2-hexyl cyanoacrylate monomer, hydroquinone, p-methylphenol and phosphoric acid; and the polymer component comprises of 2-hexyl cyanoacrylate polymer, gold, and ethyl myristate.
Ethyl myristate, other fatty acid esters, subbicates, and other plasticizers, are useful for fastening the polymers of the cyanoacrylates. See U.S. Pat. No. 6,037,366 (which has been incorporated herein in its entirety), Column 3, lines 45-52, Column 4, lines 1, 2.
Another embodiment of the present invention provides a method for selectively creating an embolic blockage in the lumen of a blood vessel, duct, fistula or other like body passageways.
Another embodiment of the present invention provides a method of treating arteriovenous malformation (AVM).
Definitions
As used herein the terms “adhesion” or “adhesive” means the characteristic or tendency of a material to be attracted to the surface of a second material. Adhesion occurs as the result of interacts between two materials. Depending on the characteristics of the second material relative to the first material, adhesion may or may not occur. For a single material, e.g., the composition of the present invention, the presence of adhesion i
Kerber Charles W.
Knox Kimberly
Krall Robert E.
Choi Frank
Dees Jose′ G.
Gray Cary Ware & Freidenrich LLP
Haile Lisa A.
Provasis Therapeutics Inc.
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