Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – X-ray contrast imaging agent
Reexamination Certificate
2001-12-26
2004-06-29
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
X-ray contrast imaging agent
C424S423000, C424S009400
Reexamination Certificate
active
06756031
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is directed to novel compositions suitable for use in embolizing blood vessels. In particular, this invention is directed to embolizing compositions comprising a biocompatible polymer, a biocompatible solvent and a contrasting agent. The compositions of this invention find particular utility in embolizing blood vessels in, for example, the treatment of aneurysms and in ablating diseased tissues.
References
The following publications are cited in this application as superscript numbers:
Mandai, et al., “Direct Thrombosis of Aneurysms with Cellulose Acetate Polymer”,
J. Neurosurg
., 77:497-500 (1992)
Kinugasa, et al., “Direct Thrombosis of Aneurysms with Cellulose Acetate Polymer”,
J. Neurosurg
., 77:501-507 (1992)
Greff, et al., U.S. Pat. No. 5,580,568 for “Cellulose Diacetate Compositions for Use in Embolizing Blood Vessels.”
Greff, et al., U.S. Pat. No. 5,667,767 for “Novel Compositions for Use in Embolizing Blood Vessels.”
Evans, et al., U.S. Pat. No. 6,103,254 for “Methods for the Reversible Sterilization of Male Mammals.”
Evans, et al., U.S. Pat. No. 5,989,580 for “Methods for the Reversible Sterilization of Female Mammals.”
All of the above references are herein incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated herein by reference in its entirety.
2. State of the Art
It is desirable in many clinical situations to embolize blood vessels to prevent/control bleeding (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm) or to ablate diseased tissue (e.g., tumors, etc.). Embolization of blood vessels has heretofore employed certain polymer compositions and particulates, e.g., silicone, metallic coils, sclerosing materials and the like. Because of their ease in delivery, water insoluble non-biodegradable polymers such as cellulose acetate
1,2,3
or ethylene vinyl alcohol
4
dissolved in, for example, DMSO have been employed to embolize blood vessels. These compositions are delivered to the vascular site to be embolized by, for example, a catheter or a syringe. Typically, these compositions will comprise a contrast agent to facilitate guidance of the catheter or syringe to the vascular site as well as the placement of the polymer precipitate which embolizes the blood vessel. Upon contact with the aqueous blood environment at this vascular site, the DMSO dissipates away from the insoluble polymer which results in polymer precipitation and embolization of the blood vessel.
In addition to use in embolizing blood vessels, these compositions can also be employed in the reversible sterilization of mammalian males and females.
5,6
In the former case, the polymer composition is injected into the vas deferens and upon contact with the aqueous fluid therein, precipitates to block the vas. In the latter case, the polymer composition is injected into the fallopian tubes and upon contact with the aqueous fluid therein, precipitates to block the tube. In either case, sterilization arising from the blockage can be reversed at a latter date by injecting DMSO into the polymer blockage to remove the polymer.
While progress has been made in the development of compositions which can be employed in such methods, only a limited number of polymers suitable for use in such compositions have been identified. While these polymers minimally meet the criteria for use in these environments, the identity of additional polymers is essential to developing versatile methods utilizing the specific characteristics of each polymer. For example, embolization techniques requiring deep vascular penetration will require a composition having a relatively slow polymer precipitation rate. Contrarily, techniques requiring rapid embolization of, for example, a bleeding aneurysm or a high blood flood vascular site will require a composition having a relatively fast polymer precipitation rate.
In either case, polymers suitable for use in such compositions must meet stringent conditions for use in embolizing blood vessels, in reversible sterilization, etc. Specifically, suitable polymers ideally should be soluble in the biocompatible solvent, be easy to deliver (e.g., low viscosity) via a catheter or a syringe, be compatible with a contrast agent, and the resulting precipitate should form a well defined coherent mass which is non-biodegradable. This last requirement is, of course, essential to use in vivo where a coherent mass is critical to either successful embolization or sterilization. Likewise, compatibility with the contrast agent is necessary in order to permit monitoring the in vivo injection of the composition and to confirm its presence after the procedure is complete.
SUMMARY OF THE INVENTION
This invention is directed to the discovery of novel polymers which are suitable in compositions useful in in vivo applications such as in embolizing blood vessels and/or reversibly sterilizing mammalian patients. Specifically, this invention is directed to the discovery that polymers such as polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose and copolymers of urethane/carbonate and copolymers of styrene/maleic acid can be employed in combination with a biocompatible solvent and a contrast agent and the resulting compositions are suitable for use in embolizing blood vessels, in reversible sterilization of mammalian patients, etc.
Accordingly, in one of its composition aspects, this invention is directed to a composition comprising:
(a) from about 2.5 to about 8.0 weight percent of a polymer selected from the group consisting of polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose and copolymers of urethane/carbonate and copolymers of styrene/maleic acid, and mixtures thereof;
(b) from about 10 to about 40 weight percent of a contrast agent;
(c) from about 52 to about 87.5 weight percent of a biocompatible solvent;
wherein the weight percent of the polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition.
In one of its method aspects, this invention is directed to a method for embolizing a blood vessel by injecting into said blood vessel a sufficient amount of a composition comprising:
(a) from about 2.5 to about 8.0 weight percent of a polymer selected from the group consisting of polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose and copolymers of urethane/carbonate and copolymers of styrene/maleic acid, and mixtures thereof;
(b) from about 10 to about 40 weight percent of a contrast agent;
(c) from about 52 to about 87.5 weight percent of a biocompatible solvent
wherein the weight percent of the polymer, contrast agent and biocompatible solvent is based on the total weight of the complete composition
under conditions wherein a precipitate is formed which embolizes the blood vessel.
In a preferred embodiment, the contrast agent is a water insoluble contrast agent. In still a further preferred embodiment, the biocompatible solvent is dimethylsulfoxide (DMSO).
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to novel compositions comprising specific polymers, a contrast agent and a biocompatible solvent.
Prior to discussing this invention in further detail, the following terms will first be defined:
The term “embolizing” as used in conjunction with “embolizing compositions” and “embolizing agents” refers to a process wherein a material is injected into a blood vessel which thereafter fills or plugs the blood vessel and/or encourages clot formation so that blood flow through the vessel ceases. The embolization of the blood vessel is important in preventing/controlling bleeding (e.g., organ bleeding, gastrointestinal bleeding, vascular bleeding, bleeding associated with an aneurysm) or to ablate diseased tissue (e.g., tumors, etc.) by cutting off its blood supply.
The term “contrast agent” refers to a biocompatible (non-toxic) radiopaque material capab
Greff Richard J.
Wright James I.
Foley & Lardner LLP
MicroTherapeutics, Inc.
Webman Edward J.
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