Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-05-23
2003-03-25
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C424S009400, C424S078310, C424S078350, C424S078370, C424S422000, C424S423000, C514S519000, C514S526000, C514S772300, C514S772400, C514S772600, C514S785000, C604S500000, C604S507000, C604S508000, C604S509000
Reexamination Certificate
active
06538026
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to cyanoacrylate 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 homeostasis 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 reducing the risk of inadvertent endovascular catheter fixation during embolization due to reduced bond strength between the hydrophilicly coated catheter and the adhesive. However, micro catheter 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 intra vascular catheter fixation is usually well tolerated, nonetheless this remains a highly undesirable event. An in vitro study has shown that recently available hydrophilic micro catheter coatings decrease catheter adhesion of both pure normal butyl cyanoacrylate and mixtures of normal butyl cyanoacrylate and ethiodized oil. Although hydrophilicly 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 comprising of a monomer component comprised of at least one alkyl cyanoacrylate and at least one inhibitor, and a second component comprised of a resultant aggregate structure formed from an alkyl cyanoacrylate monomer, an alkyl esterified fatty acid and an opacificant agent where said composition forms a resultant aggregate structure when said composition contacts an anionic environment. The compositions are useful for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass in an anionic environment. The composition are also useful for ablating diseased or undesired tissue by cutting off the blood supply to the tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
No drawings are included.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition comprising of a monomer component comprised of at least one alkyl cyanoacrylate, at least one inhibitor and a second component that functions as a opacificant agent and polymerization retardant. The composition is useful for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass (“a space”). In particular, the composition is useful for filling an existing space, e.g., the lumen of a blood vessel, or the sac of an aneurysm, a space created by a transiently placed external device, e.g., a catheter or like device, a space created by a procedure, e.g., an excision or like procedure or implantation of an object, e.g., a stent or like device, or a space created by the composition; the composition is also useful for adhering tissue to tissue, or adhering tissue to a device. The composition has the property of polymerizing when it comes in contact with an anionic environment, or when it is deployed in situ in an existing space, e.g., the lumen of a blood vessel, or the sac of an aneurysm, a space created by a transiently placed external device, e.g., a catheter or like device, a space created by a procedure, e.g., an excision or like procedure or implantation of an object, e.g., a stent or like device, or a space created by the composition;
Another aspect of the present embodiment is where the second component is comprised of a halogenated oil. Preferred are iodinated and brominated oils, such as Ethiodol, Lipiodol and Pantopaque. Most preferred is Ethiodol.
One embodiment of the present invention is where the second component is Ethiodol.
Another aspect of the present embodiment is where the second component is comprised of a resultant aggregate structure, i.e., an oligomer or polymer, formed from a composition of alkyl cyanoacrylate monomer, an alkyl esterified fatty acid and an opacificant agent.
Another aspect of the present embodiment is where the monomer component is comprised of one alkyl
Kerber Charles W.
Knox Kimberly
Krall Robert E.
Choi Frank
Gray Cary Ware & Freidenrich LLP
Haile Lisa A.
Hartley Michael G.
Provasis Therapeutics Inc.
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