Cyanoacrylates Comprising Inhibitors and an Opacifying Agent as Adhesives

 WORLD INTELLECTUAL PROPERTY ORGANIZATION Intemational Bureau INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 7 1 (11) International Publication Number: WO 00/44287 A61B 17/00, 17/12, A61L 24/04, 31/04 _ _ . (43) International Publication Date: 3 August 2000 (03.08.00) (21) International Application Number: PCT/USO0/02262 (74) Agents‘ WONG: James» J- et 31-9 Ca"‘Pb6“ & Flores LU’: Suite 700, 4370 La Jolla Village Drive, San Diego, CA 92122 (22) International Filing Date: 28 January 2000 (28.01.00) (US)- (30) Priority Data: (81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG, 09/241,368 29 January 1999 (29.01.99) US BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, (63) Related by Continuation (CON) or Continuation-in-Part MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, (CIP) to Earlier Application SD, SE, SG, SI, SK, SL, TJ, TM, TR, "IT, TZ, UA, UG, US 09/241,368 (CIP) US, UZ, VN, YU, ZA, ZW, ARIPO patent (GH, GM, KE, Filed on 29 January 1999 (29.0l.99) LS, MW, SD, SL, SZ, TZ, UG, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, (71) Applicant (for all designated States except US): PROHOLD MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, MEDICAL TECHNOLOGIES, INC. [US/US]; Suite 12, GA, GN, GW, ML, MR, NE, SN, TD, TG). 1444 Pioneer Way, El Cajon, CA 92020 (US). (72) Inventors; and Published (75) Inventors/Applicants (for US only): KRALL, Robert, E. With international search report. [US/US]; 2728 Via Dieguenos, Alpine, CA 91901 (US). Before the expiration of the time limit for amending the KERBER, Charles, W. [US/US]; 4444 Topa Topa Drive, claims and to be republished in the event of the receipt of La Mesa, CA 91941 (US). KNOX, Kimberly [US/US]; 4444 amendments. Topa Topa Drive, La Mesa, CA 91941 (US). (54) Title: CYANOACRYLATES COMPRISING INHIBITORS AND AN OPACIFYING AGENT AS ADHESIVES (57) Abstract A composition comprising of a monomer component comprised of an 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 composition is useful for filling an existing space, e.g., the lumen of a blood vessel, a space created by a transiently placed extemal device, e.g., a catheter or like device, a space created by a procedure, e.g., an excision or implantation of an object, e.g., a stent. 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. FOR THE PURPOSES OF INFORMATION ONLY Codes used to identify States party to the PCT on the front pages of pamphlets publishing intemational applications under the PCT. Albania ES Spain LS Lesotho SI Slovenia Armenia FI Finland LT Lithuania SK Slovakia Austria FR France LU Luxembourg SN Senegal Australia GA Gabon LV Latvia SZ Swaziland Azerbaijan GB United Kingdom MC Monaco TD Chad Bosnia and Herzegovina GE Georgia MD Republic of Moldova TG Togo Barbados GH Ghana MG Madagascar TJ Tajikistan Belgium GN Guinea MK The former Yugoslav TM Turkmenistan Burkina Faso GR Greece Republic of Macedonia TR Turkey Bulgaria I-IU Hungary ML Mali TT Trinidad and Tobago Benin IE Ireland MN Mongolia UA Ukraine Brazil IL Israel MR Mauritania UG Uganda Belarus IS Iceland MW Malawi US United States of America Canada IT Italy MX Mexico UZ Uzbekistan Central African Republic JP Japan NE Niger VN Viet Nam Congo KE Kenya NL Netherlands YU Yugoslavia Switzerland KG Kyrgyzstan N0 Norway ZW Zimbabwe Cote d’Ivoire KP Democratic People’s NZ New Zealand Cameroon Republic of Korea PL Poland China KR Republic of Korea PT Portugal Cuba KZ Kazakstan R0 Romania Czech Republic LC Saint Lucia RU Russian Federation Germany LI Liechtenstein SD Sudan Denmark LK Sri Lanka SE Sweden Estonia LR Liberia SG Singapore WO 00/44287 PCT/US00/02262 CYANOACRYLATES COMPRISING INHIBITORS AND AN OPACIFYING AGENT AS ADHESIVES FIELD OF THE INVENTION This invention relates to cyanoacrylate compositions useful as medical devices. 5 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 10 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 15 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 20 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 25 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 30 embolization of flow-directable distal catheter segment), vascular damage with resultant dissection/occlusion, or WO 00/44287 10 15 20 25 30 PCT/US00/02262 2 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, usefulness. but its histoxicity severely limited its clinical 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 while the methyl homolog remains as a monomer The seconds, for 30 to 55 seconds. ability to wet and spread easily over the surface of an anticoagulated blood film is common to homologs with alkyl chains containing four The ethyl and propyl derivatives or ITIOIE carbon atoms. 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. WO 00/44287 10 15 20 25 30 PCT/US00/02262 3 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 brain tissue. surrounding tissue, for example, Hydrophilic catheter coatings have been developed in the hope of reducingthe risk of inadvertent catheter endovascular fixation during embolization due to reduced bond strength between the hydrophillically 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. permanent intra vascular catheter Fortunately, 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 hydrophilically coated catheters have the potential of decreasing the occurrence of inadvertent endovascular the level of operator proficiency and the actual catheter fixation, experience, and perhaps most importantly, adhesive composition that is used stills play a major role in these events. WO 00/44287 PCT/US00/02262 4 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 5 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. 10 SUMMARY OF THE INVENTION A composition comprising of a monomer component comprised of an alkyl cyanoacrylate and at least one inhibitor, and a second component comprised of a resultant aggregate structure formed from an alkyl 15 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 composition is useful for filling an existing space, e.g., the lumen of 20 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 25 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., 30 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 WO 00/44287 ’ PCT/US00/02262 5 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. BRIEF DESCRIPTION OF THE DRAWINGS 5 No drawing are included. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a composition comprising of a monomer component comprised of an alkyl cyanoacrylate, at least one inhibitor and a second 10 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 15 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, 20 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 25 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 30 object, e.g., a stent or like device, or a space created by the composition. WO 00/44287 10 15 2O 25 30 PCT/US00/02262 6 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 an alkyl cyanoacrylate monomer, and at least two inhibitors, a preferred aspect is where the monomer component is comprised of an alkyl cyanoacrylate and at least three inhibitors, an especially preferred aspect is where the monomer component is comprised of 2—hexyl cyanoacrylate and at least one inhibitor. An especially preferred aspect is where the monomer component is comprised of 2—hexyl cyanoacrylate and at least two inhibitors. A most especially preferred aspect is where the monomer component is comprised of 2—hexyl cyanoacrylate, and three inhibitors, particularly, most especially preferred is the aspect where one of the inhibitors is selected from hydroquinone, p—methoxyphenol or phosphoric acid. A most especially preferred aspect is where the monomer component is comprised of 2—hexyl cyanoacrylate, and three inhibitors, where the three inhibitors are hydroquinone, p-methoxyphenol and phosphoric acid. The quantity of inhibitors used is measured in terms of parts WO 00/44287 10 15 20 25 30 PCT/US00/02262 7 per million of alkyl cyanoacrylate. Preferably, hydroquinone is in the range of about 50 to 150 parts per million (PPM), p—methoxyphenol in the range of about 50 to 150 PPM, and phosphoric acid in the range of about 125 to 375 PPM, more preferred is hydroquinone in the range of about 75 to 125 PPM, p~methoxyphenol in the range of about 75 to 125 PPM, and phosphoric acid in the range of about 187.5 to 312.5 PPM, hydroquinone in the range of about 95 to 105 PPM, and most preferred is p—methoxyphenol in the range of about 95 to lO5 PPM, and phosphoric acid in the range of about 200 to 300 PPM. An especially preferred embodiment of the present invention is a composition comprised of the present monomer component, and a second component comprising of a resultant aggregate structure, i.e., an oligomer or polymer, formed from 2-hexyl cyanoacrylate monomer, an alkyl esterified fatty acid and an opacificant agent, most especially preferred is where the alkyl esterified fatty acid is ethyl myristate, also most especially preferred is where the opacificant agent is gold. Another embodiment of the present invention provides a method for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass. The types of unfilled volumes or spaces within the scope of the present invention includes, but are not limited to the following instances. For example, one aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding an existing space, such as, a lumen of a passageway in the body, e.g., a blood a duct, or a fistula. Examples of vessel, an aneurysm, WO 00/44287 10 15 20 25 3O 35 PCT/US00/02262 8 the types treatments covered by this method of use, include but are not limited to the following. The present invention is useful as a method of treating arteriovenous malformations (AVM) where the blood vessel(s) that feed the AVM are occluded thereby cutting off the blood supply to the AVM. is useful as a method to ablate diseased or undesired The present invention tissue by cutting off the tissue’s blood supply. In particular, the present invention is useful as a method supply, where occluded of treating a tumor having a discrete blood the blood vessel(s) that feed the tumor are thereby cutting off the blood supply to the tumor resulting in diminished growth or death of the tumor. The present invention is useful as a method of preventing or mitigating the development of an aneurysm by creating a partial occlusion at a location in the blood vessel selected to modify the fluid dynamics within the vessel to mitigate the formation or development of an aneurysm. The present invention is useful as a non—surgical method symptomatic uterine leiomyomas by This method has of treating embolizing/occluding the uterine artery. been reported using a non alkyl cyanoacrylate composition in J.Vascular and Intervention Radiology, lO:89l—894, July—August 1999. The present invention is useful as a method of sterilizing a female mammal by occluding the fallopian tubes thereby preventing the passage of the eggs from the ovaries to the uterus. The use of an occluding agent to sterilize a female mammal is disclosed 5,989,580 “Method of Sterilizing in U.S. Patent No. Female Mammals,” herein incorporated by reference. The methods disclosed in this patent can be advantageously applied using the compositions of the present invention, and are within the scope of the present invention. The present invention is useful for obliterating the left atrial appendage. The left atrial appendage is derived WO 00/44287 10 15 20 25 30 PCT/US00/02262 9 from the left wall of the primary atrium. It has been observed that patients with atrial fibrillation have a predilection for thrombus to form in the in the left atrial appendage. A review of this condition and the current status of treatment is disclosed in the article, “Left Atrial Appendage: structure, function, and role in et. al. The present thromboembolism” N.M. Al—Saady, invention provides an advantageous method of obliterating the left atrial appendage. Another aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding a space created by an external device, such as, a catheter balloon. Examples of the types of treatments covered by this method of use include, but are not limited to the following. The present invention is useful as a method of treating an aneurysm by filling the space within the aneurysm with a composition of the present invention, where the composition polymerizes in the space within the aneurysm, thereby preventing the rupture of the aneurysm. This treatment can be effected using the present invention catheter with any number of catheters, catheter coils, wires or catheter balloons commercially available. Examples of such devices are commercially available from For instance, Micro Therapeutics, Inc., 2 California 92618, SOUICGS . markets a line of Goodyear, Irvine, medical devices, such as, the Rebarm Micro Catheter, Equinox“ Occlusion Balloon System and Silverspeedm guidewires. U.S. 5,882,334 “Balloon/delivery Catheter Assembly with Adjustable Similarly, Patent No. Balloon Positioning,” assigned to Target Therapeutics, Inc., and incorporated herein by reference, is directed to a catheter assembly for delivering compositions, such as, those of the present invention. WO 00/44287 10 15 20 25 30 PCT/US00/02262 10 Another aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding a space created or resulting from a procedure, such as with the excision of tissue, or insufflation. Examples of the types of treatments covered by this method of use include, but are not limited to the following. The present invention is useful as a method of treating or mitigating capillary oozing. Another aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding a space created by the placement or implantation of an object, such as, a medical device. Examples of the types of uses covered by this method of use include, The but are not limited to the following. present invention is useful as a method of restoring the normal fluid dynamics at the peripheral edges of a vascular stent by filling the dead spaces between the stent and the lumen wall created by the implantation of the stent. Another aspect of the present embodiment is a method of filling, occluding, partially filling or partially occluding a space created by the composition itself, such as, where the composition is used as a bulking agent. Examples of the types of uses covered by this method of use include, but are not limited to the following. For example, a method of recreating the normal contours to skin following an adverse event, such as, physical trauma. Another embodiment of the present invention provides a method of affixing therapeutics, chemotherapeutics, radiation delivery devices, gene WO 00/44287 10 15 20 25 30 PCT/US00/02262 ll therapy compositions to a desired location where the active agents can be advantageously maintained in proximity to the desired location. The active agent is then release gradually as the resultant aggregate structure from the composition of the present invention is biodegraded. the composition of the Alternatively, present invention can be modified to allow for a specific rate of delivery. This use is particularly beneficial in the treatment of tumors that are ideally treated by localized dosages of chemotherapy or radiation. An advantage of this method is that the patient would not be subjected to as large of a dose of the therapeutic or if the therapeutic or Another radiation as would be necessary, radiation was administered on a systemic basis. advantageous use the present invention is for the delivery of DNA compositions used in gene therapy. A long standing problem in the gene therapy arts has been the inability of practitioners to deliver the DNA therapeutic to the locales in the body most ideally suited for the treatment. The present invention provides a method of affixing the DNA composition at a desired site, where the active agent is then slowly released over a period time as the composition of the present invention biodegrades. Alternatively, a composition of the present invention can be modified to release the active agent in a controlled delivery manner. Another embodiment of the present invention provides a method of utilizing magnetically controlled particles inbedded in a composition of the present invention to deploy the composition to a desired “Magnetic Probe for the Stereotaxic Thrombosis J.F., et. al, 1967 April, location, of Intracranial Aneurysms,” Alksne, Journal of Neurology, Neurosurgery and Psychiatry, 30(2):l59—62; “Magnetically Controlled Focal WO 00/44287 10 15 20 25 30 PCT/US00/02262 12 Intravascular Thrombosis in Dogs” Alksne, J.F., et. al, 1966 Nov, 25(5):5l6—25; “Thrombosis of Intracranial Aneurysms - An experimental Journal of Neurosurgery, approach utilizing magnetically controlled iron particles” Alksne, J.F., et. al, Radiology 1966 Feb. 86(2):342—3 Another embodiment of the present invention provides a method of adhering, joining, connecting or affixing a first section of tissue to a second section of tissue. Examples of the types of uses covered by this method of use include, but are not limited to the following. The present invention is useful as a method of adhering, joining, or connecting two blood vessels, anastimosis, where blood vessels are quickly and e.g., efficiently adhered, under surgical The joined or connected, conditions without the use of sutures or staples. present invention is useful as a method of treating primary wounds or wounds that require immediate intervention, such as, trauma wounds, where the compositions of the present invention are used to temporarily close the wound to minimize the lost of fluids due to evaporation, and to mitigate infection. Another embodiment of the present invention provides a method of adhering, joining, connecting, or affixing tissue to a non—tissue surface, such as a medical device. Examples of the types of uses covered by this method of use include, but are not limited to the following. The present invention is useful as a method of implanting or securing venous valves, replacement heart valves, or stents at their desired location. The aforementioned uses are possible because the compositions of the present invention remain in a WO 00/44287 1O 15 20 25 30 PCT/US00/02262 13 controllable state for a period of time in excess of 1 second after being deployed from an administration device. This property allows the practitioner to incrementally maneuver the deployment of the composition to its most ideal location, even when the composition has been partially deployed distal the the deployment device. For instance, the compositions of the present invention have adequate cohesion to maintain its continuity once it is outside of the deployment device. Without adequate cohesion the composition would break into smaller aggregates dispersing into the blood flow. For instance, the compositions of the present invention have appropriate adhesion properties so that when desired a deployed composition adheres to the immediate location where it is deployed so that the resultant aggregate of the monomer is placed where it is desired. The compositions of the present invention have such that, the practitioner can polymerization rate, effect the desired amount of penetration of the composition into a particular type of space. A composition that polymerizes too quickly would hinder penetration, conversely a composition that polymerizes too slowly would make it difficult to precisely place the polymerized composition resultant aggregate of the monomer . Another embodiment of the present invention provides a method for selectively creating an embolic duct, fistula or blockage in the lumen of a blood vessel, other like body passageways. WO 00/44287 10 15 20 25 30 PCT/US00/02262 14 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 interactions between two materials. Depending on the characteristics of the second material relative to the first material, For a single material, the adhesion may or may not occur. e.g., the composition of the present invention, presence of adhesion is demonstrated by a material sticking to the wall of a lumen of blood vessel, i.e., there is adhesion between the material and the lumen wall. demonstrated for the same material where a micro—catheter Conversely, the absence of adhesion is tip used to deposit the material can be removed from the material, i.e., there is little adhesion between the material and micro—catheter tip. As used herein the term "alkyl" refers to a carbon chain of one to sixteen carbon atoms, where the carbon atoms can be linear or branched. As used herein the term “anionic environment” or “an—ionic environment” refers to an environment that is non—ionic. This an environment that is devoid of charged ions, or where the charged ions are complexed with other molecules which effectively neutralize their For example, a solution of water and a sugar, and blood, charge. is an anionic environment. such as, dextrose, WO 00/44287 PCT/US00/02262 15 As used herein the term "lower—alkyl" refers to a carbon chain of one to eight carbon atoms, where the carbon atoms can be linear or branched. Examples of lower-alkyl moieties include but are not limited to 5 methyl, ethyl, n—butyl, isobutyl, pentyl, n—hexyl, 2—hexyl, n-heptyl, 2-heptyl, n—octyl and 2—octyl. As used herein the term "branched alkyl" refers to a carbon chain of one to sixteen carbon atoms where the carbon chain contains at least one secondary or 10 tertiary substituted carbon atom. As used herein the term "branched lower—alkyl" refers to a carbon chain of one to eight carbon atoms where the carbon chain contains at least one secondary or tertiary substituted carbon atom, for example, 2—hexyl, 15 isobutyl, 2—heptyl and 2—octyl. As used herein the term "cohesion" or "cohesive" means the characteristic or tendency of a material to stick together to itself. For example, this characteristic is demonstrated by a material or 20 composition remaining intact as a single mass when introduced into a stationary fluid, or a fluid stream in motion, such as, blood. Lack of cohesive integrity results in the composition breaking up into multiple smaller subunits. 25 As used herein the term "embolic agent" refers to a non—naturally occurring composition introduced into a body cavity or the lumen of a blood vessel, duct, fistula or other like body passageways for the purpose of forming an embolic block. WO 00/44287 10 15 20 25 30 PCT/US00/02262 16 As used herein the term "embolic block" or "embolic blockage" or occlusion refers to the end result from the administration of a composition useful as an embolic agent. The resulting embolic block mechanically blocks, the lumen of a blood totally or partially, duct, fistula or other like body passageways; or in a like manner forms an occlusion within a cavity, vessel, such as an aneurysm . As used herein the term "alkyl cyanoacrylate monomer" refers to the chemical entity of the general structure H2C=C(CN)—C(O)O—R, where R is an alkyl moiety of one to sixteen carbon atoms, linear or branched, saturated or unsaturated, having the physical characteristic of being able to form the corresponding alkyl cyanoacrylate. As used herein the term "alkyl cyanoacrylate polymer" means an oligomer or polymer resulting from the polymerization of a alkyl cyanoacrylate monomer. As used herein the term "alkyl esterified fatty acid" means a fatty acid derivatized to form an ester functional group with a alkyl moiety, such as ethyl These compounds are formed with an alkyl butyl, and carboxylic acids with alkyl myristate. moiety, such as, methyl, ethyl, propyl, pentyl, hexyl, heptyl, and octyl; side chains ranging from l carbon, i.e., acetic acid, through to and including 17 carbons atoms in length, such as, proprionic, butyric, isobutyric, valeric, isovaleric, pivalic, lauric, myristic, palmitic and stearic acids. As used herein the term "opacificant agent" is compound or composition which selectively absorbs or deflects radiation making the material visible under WO 00/44287 10 15 20 25 30 PCT/US00/02262 l7 x—ray, or any like imaging technique. Typically such agents include, iodinated oils, and brominated oils, as well as commercially available compositions, such as Lipiodol and Ethiodol. These commercially Pantopaque, available compositions acts as opacificant agents, and also dilute the amount of liquid monomer thereby slowing the rate of polymerization. In addition certain metals, such as, gold, platinum, tantalum, titanium, tungsten and barium sulfate and the like, have properties enabling them to act as opacificant agents. As used herein the term "polymerization" refers to the chemical process where identical monomer units react chemically to form larger aggregates of said monomeric units as oligomers or polymers. As used herein the term "polymerization retardant" means an agent that can stop or slow down the rate of polymerization. Examples of such agents are pure phosphoric acid, and 85% phosphoric acid. Certain opacificant agents, such as Pantopaque, Lipiodol and Ethiodol can also function as a polymerization retardant by diluting the amount of liquid monomer and hence slowing polymerization rate. As used herein the term “a space” refers to an unfilled volume or cavity in a mass. Examples of such spaces, include but are not limited by the following, an existing space within a mass, such as, the lumen of a blood vessel, the sac of an aneurysm; a space created by a transiently placed external device, such as, a catheter such as, or like device; a space created by a procedure, an excision or like procedure; a space created by implantation of an object, such as, a stent or like device; or a space created by the composition. WO 00/44287 10 15 20 25 30 PCT/US00/02262 18 As used herein the term "stability" refers to the ability of a monomer component to resist degradation or polymerization after preparation but prior to use. As used herein the term "inhibitor agent" refers to an agent which stabilizes a monomer composition by inhibiting polymerization. Within the context of the current invention, this term refers to agents that stabilize and inhibit polymerization by various mechanisms. By altering the amounts of one or more inhibitor agents, the rate of polymerization can be controlled. Inhibitor agents have different modes of activity, for example, hydroquinone acts primarily to inhibit high energy free radicals; p—methoxyphenol acts primarily to inhibit low energy free radicals; and phosphoric acid influences the rate of anionic polymerization. As use herein the term “Neuracryl M” refers to the composition comprising of a monomer component (“Ml”) comprised of 2—hexyl cyanoacrylate, hydroquinone, p—methoxyphenol and phosphoric acid, and a second component (“M2”) comprising of a resultant aggregate structure formed from 2—hexyl cyanoacrylate monomer, the term "M1" and the ethyl myristate and gold. As noted above, refers to the monomer component of Neuracryl M, term "M2" refers to the second component of Neuracryl M. As used herein the term “deployment device” refers a device used to deploy compositions, such as, those of the present invention. Examples of such devices, include but are not limited to the following. Irvine, California the Rebarm Micro Inc., 2 Goodyear, Micro Therapeutics, 92618, Catheter, markets medical devices, such as, Equinox” Occlusion Balloon System and WO 00/44287 PCT/US00/02262 l 9 Silverspeedm guidewires, that are used in conjunction for treating conditions such as those within the present invention. The devices disclosed in U.S. Patent No. 5,882,334 “Balloon/delivery Catheter Assembly with 5 Adjustable Balloon Positioning,” incorporated herein by reference, directed to a catheter assembly for delivering compositions. Nomenclature The compound 2—hexyl cyanoacetate is depicted 10 as follows, and also as Formula 3 in Schemes A and B. The compound 2—hexyl cyanoacrylate is depicted as follows, and also as Formula 5 in Scheme B. O CH / zfi/“\O CN The present invention is a composition formed from alkyl cyanoacrylate monomeric units, such as, 15 n-butyl, isobutyl, and 2—hexyl cyanoacrylate with at least one inhibitor agent, such as hydroquinone, p—methoxyphenol and phosphoric acid. The composition forms into its resultant aggregate structure, i.e., an WO 00/44287 1O 15 20 25 PCT/US00/02262 20 when it comes in contact with an The oligomer or polymer, anionic environment, such as, blood or tissue. resultant aggregate composition has characteristics which makes it particularly well suited as an embolic agent. The composition of the present invention possess the following properties, which are desirable in an embolization agent. 1) The composition can be prepared and maintained as a monomeric component and second component until needed. 2) The composition has the ability to reliably and predictably change from a liquid state to a solid state, for its introduction and controlled duct, which is essential placement into the lumen of vessel, fistula or other like body passageways. 3) The composition has low viscosity, which is essential for its administration by syringes and micro—catheters or other like devices. 4) The composition has cohesive characteristics such that when the composition in administered into an anionic fluid environment, such as blood, the composition forms a single aggregate structure. 5) The composition has adhesive characteristic such that duct, but not to the degree where it attaches to the lumen of vessel, fistula or other like body passageways, the device depositing the composition will become fixed to it before the practitioner can remove it. 6) The composition causes mild tissue inflammation, sufficient to cause scarring, but not so severe to cause WO 00/44287 l0 15 20 25 30 PCT/US00/02262 21 the formation of pus. Scar formation is necessary to maintain the functionality of the embolic block after the composition has biodegraded, or otherwise eliminated from the lumen. 7) The composition is sufficiently stable to biodegradation to allow for scarring to occur. 8) The composition is radiopaque. Although not necessary for its function as an embolic agent, radiopacity allows the embolic block to be observed with x—ray or other such imaging techniques. 9) The rate of heat released during polymerization of the composition is low enough such that the heat does not adversely effect surrounding tissues that may be heat sensitive, such as brain tissue. 10) The composition and its biodegradation products are sufficiently non—histotoxic and non—cytotoxic so that its presence is well tolerated in the body. The composition of the present invention is used by combining the monomer component and second the invention duct, component. Upon mixing of the components, is administered into the lumen of a blood vessel, fistula or other like body passageways. The characteristics of the present invention permit its accurate placement in the lumen. Contact with an anionic environment, such as blood, or tissue causes the composition to polymerize. The size of the resultant embolic block formed is determined by the amount of composition administered. The characteristics of the composition of the invention can be modified for a specific purpose or WO 00/44287 10 15 20 25 PCT/US00/02262 22 environment for which the embolic agent is intended to be utilized. For example, changes in the length and isomeric configuration of the alkyl side chains can alter the brittleness of the resultant aggregate of cyanoacrylate monomers. Alkyl chains that result in the formation of smaller aggregates tend to be less brittle, while larger aggregates tend to be less flexible. In addition, by combining monomers with different alkyl side chains the characteristics of the resultant polymer can be modified to what is optimal for a desired application. Cyanoacrylates generate heat as they change The amount and rate of from monomeric to polymeric form. heat released, if excessive, can have a detrimental effect on the living tissue proximate to the vessel. Control of the amount and rate at which heat is release during polymerization is critical to the utility of composition. Preparation of the Monomer Component The monomer component of the present invention is prepared by forming the desired precursor ester from the corresponding alkyl alcohol and cyanoacetic acid resulting in the desired alkyl cyanoacetate as depicted in Scheme A. The starting materials for this reaction are commercially available, for example from Aldrich Chemical Company, Sigma Chemical Company or Fluka Chemical Company, or can be prepared following procedures known to those of ordinary skill in the art. WO 00/44287 PCT/US00/02262 23 o 0 cN~)J\oH + R-0” ——> CNAO-R 1 2 3 Sdmnelk The compound of Formula 2 can be any alkyl alcohol, where R is from one to sixteen carbons, including but not limited to alcohols based on alkyl groups, such as, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, 5 heptyl, octyl, nonyl, deca, undeca, dodeca, trideca, tetradeca, pentadeca and hexadeca, where the preceding moieties are linear (e.g., n—propyl, n—butyl, n—pentyl) or variously branched, such as sec—butyl, iso—butyl, tert-butyl, iso—propyl, 2—butyl, 2—pentyl, 2-hexyl, 10 2—heptyl, 2—octyl and the like. Particularly advantageous alcohols are those disclosed in U.S. Patent 3,728,375 entitled "Cyanoacrylate Adhesive Compositions", which is hereby incorporated by reference. Especially preferred are n—butyl, iso—butyl and 2-hexyl alcohols. 15 About 1 molar equivalents of the compounds of Formula 1 and Formula 2 are combined in a solvent like toluene at about 100 ml/molar equivalents. To this mixture is added a catalytic amount (about 1.0 x 10'4 molar equivalents) of p-toluene sulfonic acid. The 20 mixture is stirred and heated to reflux. The preparation ideally yields the desired alkyl cyanoacetate at a purity level of about 95%. The experimental conditions can be readily modified by one of ordinary skill in the art without deviating from the present invention. Aspects WO 00/44287 10 15 20 PCT/US00/02262 24 such as, solvent selection, reaction time, temperature and choice of reagents are well within the skill of one of ordinary skill in the art. If necessary, the material can be further purified using multiple distillations and purification techniques and procedures known to those of such as water extraction, and the like. ordinary skill in the art, vacuum distillation, column chromatography, Preparation of alkyl cyanoacrylate The desired alkyl cyanoacrylate monomer component of the present invention is synthesized from the alkyl cyanoacetate by reacting the it in a Knoevengel type reaction as depicted in Scheme B. O Q 0 + /u\ ____, CNAO-R H H CH2 0"‘ CN 3 4 5 SdrnbB About 1 molar equivalents of formaldehyde (Formula 4), which is prepared from paraformaldehyde, and piperidine (at about 0.33 ml/molar equivalents) are combined in a solvent, such as methanol (at about 166 ml/molar equivalents). To this mixture is added about 1 molar equivalents of previously prepared alkyl cyanoacetate (Formula 3) in a dropwise manner. The reaction mixture is refluxed with stirring yielding the desired alkyl The reaction mixture cyanoacrylate polymer (Formula 5). is further processed with about 0.2 to 0.7 molar WO 00/44287 10 15 20 25 30 PCT/US00/02262 25 equivalents, preferably about 0.2 to 0.6 molar equivalents of phosphorous pentoxide yielding the desired alkyl cyanoacrylate. Care must be taken during purification steps to prevent the compound of Formula 5 from polymerizing; To this end the system is treated with trace amounts of sulfur dioxide, and receiver flasks are treated with hydroquinone and 85% phosphoric acid. After initial purification, the desired alkyl cyanoacrylate is further purified using multiple distillations, or other purification techniques known to such as, and the like. those of ordinary skill in the art, vacuum distillation, spinning band column, Formulation The monomer component of the present invention comprises of at least one alkyl cyanoacrylate and at least one inhibitor agent. Typical inhibitors appropriate for cyanoacrylates are, for example, hydroquinone, p—methoxyphenol, pure phosphoric acid, and alkyl carboxylic acids, where the alkyl moiety ranges from 1 carbon, e.g., acetic acid, through to 15 and 17 carbons atoms in length, palmitic and stearic i.e., acids, respectively; and phosphoric acid at varying percentage solutions. Preferably hydroquinone, p—methoxyphenol, and phosphoric acid are used, individually or in combination. Different inhibitors have different physical characteristics and thereby functions to alter the final hydroquinone properties of the composition. For example, is primarily an inhibitor for high energy free radicals; p—methoxyphenol is primarily an inhibitor for low energy WO 00/44287 10 15 20 25 30 PCT/US00/02262 26 free radicals; and phosphoric acid acts to control or inhibit anionic polymerization and the rate of such polymerization. The quantity of inhibitors used is measured in terms of parts per million of alkyl cyanoacrylate. For for 2—hexyl cyanoacrylate, hydroquinone is in (PPM), example, the range of about 50 to 150 parts per million p-methoxyphenol in the range of about 50 to 150 PPM, and phosphoric acid in the range of about 125 to 375 PPM, more preferred is hydroquinone in the range of about 75 to 125 PPM, p-methoxyphenol in the range of about 75 to 125 PPM, to 312.5 PPM, and phosphoric acid in the range of about 187.5 and most preferred is hydroquinone in the range of about 95 to 105 PPM, p-methoxyphenol in the range of about 95 to 105 PPM, range of about 200 to 300 PPM. and phosphoric acid in the The second component functions as an opacificant agent and a polymerization retardant.‘ To this end, the second component can be an iodinated oil, such as Ethiodol, or a brominated oil. Typically the iodinated oil is mixed as some percent of the total volume of the final composition. The percentage solution of iodinated oil used will influence the polymerization rate and opacity of the composition. Generally advantageous ranges are from about 17% to 66%, preferably about 33%. Alternatively, the second component can be a composition comprising, a opacificant material, such as gold, platinum, tantalum, titanium, tungsten and barium sulfate and the like; an alkyl cyanoacrylate polymer where the. material, and an alkyl esterified fatty acid, for example, alkyl butyrate to 17 fatty acids have 3, wo 00/44237 PCT/US00/02262 27 carbons, for example, alkyl stearate, preferred are, alkyl laurate, alkyl myristate, alkyl palmatate, and alkyl stearate, most preferred is alkyl myristate, and most especially prefereed is ethyl myristate. 5 The opacificant material is used in a fine powder form, typically, with individual particles sized no larger than about 7 microns in diameter, preferably about 5 microns, most preferred about 2 microns and most especially preferred is 1 micron or smaller. 10 The amount of opacificant material used relative to alkyl cyanoacrylate polymer will vary according to the specific materials. Factors that influence the determination of the ratio include the amount and size of the particles that are being coated by 15 the alkyl cyanoacrylate polymer. For example, for 2—hexyl cyanoacrylate and gold, 2 g of 2—hexyl cyanoacrylate is used per 100 g of powdered gold (particle size of about 5 i 2 microns) being coated. The amounts vary accordingly with the opacificant material 20 being coated by the alkyl cyanoacrylate. The alkyl cyanoacrylate and opacificant material are mechanically mixed by processing the alkyl cyanoacrylate into small particulate masses, and mixing with the finely powdered opacificant material. The alkyl cyanoacrylate polymer 25 coated material is then stored in an esterified fatty acid, which serves as a medium where the alkyl cyanoacrylate polymer coated material is maintained prior to use, and as a medium, which when contacted with the monomer component will not interfere with the 30 polymerization of the composition. The unsealed storage containers, preferably appropriately sterilized bottles and caps or the like, with the cyanoacrylate polymer suspension is then treated with ethylene oxide, or WO 00/44287 PCT/US00/02262 2 8 alternatively ketene. This treatment should occur no later than about 48 hours after completion of the coating process, preferably within 24 hours. The treatment process provides sterilization and stabilization of the 5 alkyl cyanoacrylate polymer coated material and follows standard procedures for ethylene oxide use, i.e., positioning the containers so that they are amply exposed to the gas for a sufficient period of time. Polymer M 10 The characteristics of the composition of the invention can be modified for a specific application or environment in which the composition is intended to be utilized. For example, changes in the length and isomeric configuration of the alkyl side chains can alter 15 the brittleness of a polymer formed from a cyanoacrylate monomer. Alkyl chains that result in the formation of smaller aggregates tend to be less brittle, while larger aggregates tend to be less flexible. Another method of modifying the characteristics of a polymer is to use a 20 composition comprising of two or more types of alkyl cyanoacrylate monomers in combination with the appropriate inhibitors. For example, a composition comprised of a monomer component comprising of 2—hexyl cyanoacrylate, 25 hydroquinone, p—methoxyphenol and phosphoric acid; and a second component comprising of 2—hexyl cyanoacrylate polymer, gold, and ethyl myristate results in Polymer M. A qualitative survey of Polymer M is shown in Table A. The physical characteristics disclosed are 30 readily recognized by those of ordinary skill in the art WO 00/44287 PCT/US00/02262 2 9 as being relevant to the applications for which the polymers are used. Table A Characteristics Polymer M 5 polymerization profile polymerizes to semi—solid to soft—solid on contact with tissue or blood 10 Polymer M has excellent cohesion properties. 15 When introduced into a stationary fluid, or a fluid stream in motion, such as, the lumen of a blood vessel or other like passageway, the composition tend to stick together to itself remaining intact as a single mass or aggregate. This permits the composition to be discretely 20 deployed or placed at the desired location without the hazard of having potions of the composition breaking away and depositing at undesired locales. Polymer M has viscosity properties that permit the injection of the liquid composition into a lumen of a blood vessel, duct, 25 fistula or passageway in the body without using excessive pressure. With these properties Polymer M is ideally suited for applications where the composition must penetrate further into anionic environment before WO 00144287 10 15 20 25 30 PCT/US00/02262 30 arriving at the point of final placement. A preferred use is the treatment of arteriovenous malformations, also “AVM”. Polymer M is also ideally suited for the known as treatment of longer type urinary fistulas, this is because preferred treatment requires greater penetration into cavity space by the liquid composition. Additional applications suited for Polymer M are creating a tubal occlusion, For example, a and surgical adhesions. composition of the present invention is applied to raw intraperitoneal tissue to prevent the tissue from adhering to itself or other tissue. Administration The composition of the present invention are administered with any type of commercially available needle, catheter devices, or stereotaxic placement devices, preferably in conjunction with imaging technology that provides the practitioner with guidance as to the placement of the composition. Such devices and methods are readily known to those of ordinary skill in art. For example in U.S. Patent 5,925,683 “Liquid Embolic Agents”, herein incorporated by reference, there is disclosed a method for introducing liquid embolic agents/solutions into the human body to form precipitated embolic occlusion masses, and also how this method is used for treating hepatic tumors using portal vein embolism. In U.S. Patent 5,702,361 “Method for Embolizing Blood Vessels”, herein incorporated by reference, there is disclosed a method of embolizing a vascular site in a patient’s blood vessel comprising of introducing, via a catheter, at the vascular site to be emobolized a non—particulate agent or a plurality of such via a catheter, to said vascular agents, and delivering, site a polymer composition comprising a biocompatible WO 00/44287 10 15 20 25 PCT/US00/02262 3 1 polymer, a biocompatible solvent and contrast agent, wherein the delivery is conducted under conditions where the polymer precipitate forms in situ at the vascular site resulting in the embolizing of the blood vessel and where the non—particulate agent is encapsulated within the precipitate. Additional devices applicable to the present invention are those disclosed in U.S. Patent No. 5,882,334 “Balloon/delivery Catheter Assembly with Adjustable Balloon Positioning,” incorporated herein by reference, directed to a catheter assembly for delivering Further, Inc., Irvine, California 92618, the Rebarm Micro Catheter, compositions. Micro Therapeutics, 2 Goodyear, markets medical devices, such as, Equinox“ Occlusion Balloon System and Silverspeedm guidewires, that are approved by the U.S. Food and Drug Administration for use in treating conditions such as those within the present invention. The compositions of the present invention can be used advantageously in conjunction with any embolization method that employs an embolizing agent, occluding agent, or such composition that creates an embolic block, or occlusion. The compositions of the present are used to particular advantage in conjunction with commercially available stereotaxic devices which facilitate the for precise deposition of the composition, such as, forming an occlusion within a cavity that is to be filled, that is the source of blood supply for a tumor. or for forming an occlusion in a blood vessel WO 00/44287 10 15 20 25 30 PCT/US00/02262 32 Utility The present invention 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, an excision or like e.g., procedure or implantation of an object, a stent or e.g., or a space created by the composition; the like device, 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, a catheter or like device, e.g., a space created by a procedure, an excision or like e.g., procedure or implantation of an object, a stent or e.g., like device, or a space created by the composition. The present invention is useful as an embolic agent that selectively creates an embolic blockage in the duct, fistula or other like body lumen of a blood vessel, passageways. The present invention can be prepared and maintained as a monomeric component and second component until needed. It has the ability to reliably and predictably change from a liquid state to a solid state, which is essential for its introduction and controlled duct, fistula or placement into the lumen of vessel, other like body passageways. The composition has low WO 00/44287 10 15 20 25 PCT/US00/02262 3 3 viscosity, which is essential for its administration by syringes and micro—catheters or other like devices. The cohesive characteristics of the invention are such that when the composition in administered into an anionic fluid environment, such as blood, the composition forms a single aggregate structure. Additionally, the adhesive characteristics are such that the composition attaches to the lumen of vessel, duct, fistula or other like body passageways, but not to the degree where the device depositing the composition will become fixed to it before the practitioner can remove it. The present invention causes mild tissue inflammation, sufficient to cause scarring, but not so severe to cause the formation of pus. Scar formation is desirable as the scar tissue is necessary to maintain the functionality of the embolic block after the composition has biodegraded, or otherwise eliminated from the lumen. The composition is sufficiently stable to biodegradation to allow for scarring to occur. The present invention is radiopaque. Although this characteristic is not necessary for its function as an embolic agent, radiopacity allows the embolic block to be observed with x—ray or other such imaging techniques. The rate of heat released during polymerization of the present invention is low enough such that the heat does not adversely effect surrounding tissues that may be heat sensitive, such as brain tissue. WO 00/44287 10 15 20 25 30 PCT/US00/02262 34 The present invention and its biodegradation products are sufficiently non—histotoxic and non- cytotoxic so that its presence is well tolerated in the body. The composition of the present invention is useful for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass (“a space”). The present invention provides a method for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass. The types of unfilled volumes or spaces within the scope of the present invention includes, but are not limited to the following instances. For example, the present invention is used as a method of filling, occluding, partially filling or partially occluding an existing space, such as, a lumen of a passageway in the body, a blood vessel, a duct, e.g., or a fistula. Examples of the types an aneurysm, treatments covered by this method of use, include but are not limited to the following. The present invention is useful as a method of treating arteriovenous (AVM) the AVM are occluded thereby cutting off the blood supply to the AVM. to ablate diseased or undesired tissue by cutting off the malformations where the blood vessel(s) that feed The present invention is useful as a method In particular, the present tissue’s blood supply. invention is useful as a method of treating a tumor having a discrete blood supply, where the blood vessel(s) that feed the tumor are occluded thereby cutting off the blood supply to the tumor resulting in diminished growth or death of the tumor. The present invention is useful WO 00/44287 10 15 20 25 30 PCT/US00/02262 35 as a method of preventing or mitigating the development of an aneurysm by creating a partial occlusion at a location in the blood vessel selected to modify the fluid dynamics within the vessel to mitigate the formation or development of an aneurysm. The present invention is useful as a non-surgical method of treating symptomatic uterine leiomyomas by embolizing/occluding the uterine artery. This method has been reported using a non alkyl cyanoacrylate composition in the Journal of Vascular and Interventional Radiology, 10:89l—894, July-August 1999. The present invention is useful as a method of sterilizing a female mammal by occluding the fallopian tubes thereby preventing the passage of the eggs from the The use of an occluding agent to Patent No. ovaries to the uterus. sterilize a female mammal is disclosed in U.S. 5,989,580 “Method of Sterilizing Female Mammals,” herein incorporated by reference. The methods disclosed in this patent can be advantageously applied using the compositions of the present invention, and are within the scope of the present invention. The present invention is an embolic agent that provides a method for selectively creating and placing an embolic blockage which mechanically blocks, totally or duct, fistula or partially, the lumen of a blood vessel, other body passageway. In particular, the current invention is particularly useful in blocking, totally or partially, or diverting the flow of blood through the lumen. The present invention can be advantageously used to block blood flow to certain tissues or areas. the present invention can be used to treat (AVM). For example, arteriovenous malformation An AVM is a collection of abnormal blood vessels which are neither arteries or WO 00/44287 10 15 20 25 30 PCT/US00/02262 36 These vessels are packed closely together to form Blood flow into the AVM nidus is veins. the nidus of the AVM. through thinned, enlarged, tortuous vessels and is rapidly shunted into draining veins because the nidus contains no arterioles or capillaries to provide high resistance. Clinical symptoms experienced because of AVMs are bleeding, re—direction of blood from nearby or seizures. normal structures, The primary clinical problem associated with cerebral AVM is the potential for lethal hemorrhage. The current standard of care for treating AVMS is surgical removal, high energy radiation or embolization with particular devices. Further, the present invention can be used for treating cancer by diverting or blocking blood flow to tumors, the present invention is particularly useful for treating tumors in areas that are not easily accessible brain tumors. for surgical intervention, for example, Other advantageous uses of the present invention are for aortopulmonary closure; treatment of artery pseudoaneursym; hepatic artery vascular occlusion and for temporary vascular occlusion during co- treatment of other administration of cytotoxic drugs; types of vessels, for example, the composition can be used for creating tubal occlusions, fallopian tube occlusions, vas deferens occlusions, and urinary occlusions. The present invention provides a method of filling, occluding, partially filling or partially occluding a space created by a transiently placed external device, such as, a catheter balloon. Examples of the types of treatments covered by this method of use include, but are not limited to the following. The WO 00/44287 10 15 20 25 30 PCT/US00/02262 37 present invention is useful as a method of treating an aneurysm by filling the space within the aneurysm with a composition of the present invention, where the composition polymerizes in the space within the aneurysm, thereby preventing the rupture of the aneurysm. This treatment can be effected using the present invention with any number of catheters, catheter coils, catheter wires or catheter balloons commercially available. Examples of such devices are commercially available from For instance, Micro Therapeutics, Inc., 2 California 92618, the Rebar“ Micro Catheter, sources . Goodyear, Irvine, markets a line of medical devices, such as, Equinox“ Occlusion Balloon System and Silverspeedm guidewires. U.S. Patent No. 5,882,334 “Balloon/delivery Catheter Assembly with Adjustable Similarly, Balloon Positioning,” assigned to Target Therapeutics, Inc., and incorporated herein by reference, is directed to a catheter assembly for delivering compositions, such as, those of the present invention. The present invention also provides a method of filling, occluding, partially filling or partially occluding a space created or resulting from a procedure, such as with the excision of tissue, or insufflation. Examples of the types of treatments covered by this method of use include, but are not limited to the following. The present invention is useful as a method of treating oozing capillaries following an excision procedure. The present invention further provides a method of filling, occluding, partially filling or partially occluding a space created by the placement or a medical device. implantation of an object, such as, Examples of the types of uses covered by this method of WO 00/44287 10 15 20 25 30 PCT/US00/02262 38 use include, but are not limited to the following. The present invention is useful as a method of restoring the normal fluid dynamics at the peripheral edges of a vascular stent by filling the dead spaces between the stent and the lumen wall created by the implantation of the stent. Still another advantageous use is the controlling and smoothing the blood flow around stents. A major complication from the balloon angioplasty and the use of stents is disruption of the smooth flow of blood past and around the stent which can lead to the formation of blood clots and their associated complications. The composition of the present invention can be used to modify and make regular the slip streams of blood through and adjacent to the stent to mitigate or alleviate the cause of the turbulence, and such turbulence causing states. The present invention further provides a method of filling, occluding, partially filling or partially occluding a space created by the composition itself, such as, where the composition is used as a bulking agent. Examples of the types of uses covered by this method of For use include, but are not limited to the following. example, a method of recreating normal external contours, such as following physical trauma. Administration The monomer component and second component of the present invention are combined just prior to use. The composition of the present invention is administered using any type of deployment device. The term “deployment device” refers to a device used to deploy WO 00/44287 10 15 20 25 30 35 PCT/US00/02262 39 fluids or compositions similar to those of the present catheter devices, catheter or the like. invention, such as, a needle, balloon, stereotaxic placement devices, Methods for using these devices are readily known to one of ordinary skill in the art, and such devices are commercially available. Such devices and methods are of ordinary skill in art. For 5,925,683 “Liquid Embolic Agents”, readily known to those example in U.S. Patent herein incorporated by reference, there is disclosed a method for introducing liquid embolic agents/solutions into the human body to form precipitated embolic occlusion masses, and also how this method is used for treating hepatic tumors using portal vein embolism. In U.S. Patent 5,702,361 “Method for Embolizing Blood Vessels”, herein incorporated by reference, there is disclosed a method of embolizing a vascular site in a patient’s blood vessel comprising of introducing, via a catheter, at the vascular site to be emobolized a non- particulate agent or a plurality of such agents, and delivering, via a catheter, to said vascular site a polymer composition comprising a biocompatible polymer, a biocompatible solvent and contrast agent, wherein the delivery is conducted under conditions where the polymer precipitate forms in situ at the vascular site resulting in the embolizing of the blood vessel and where the non~ particulate agent is encapsulated within the precipitate. Additional devices applicable to the present invention 5,882,334 “Balloon/delivery Catheter Assembly with Adjustable are those disclosed in U.S. Patent No. Balloon Positioning,” incorporated herein by reference, directed to a catheter assembly for delivering Further, Micro Therapeutics, Inc., Irvine, California 92618, the Rebarm Micro Catheter, compositions. 2 Goodyear, markets medical devices, such as, Equinox“ Occlusion Balloon System and Silverspeedm guidewires, WO 00/44287 10 15 20 25 PCT/US00/02262 40 that are approved by the U.S. Food and Drug Administration for use in treating conditions such as those within the present invention. The composition of the present invention are administered with any type of commercially available catheter devices, or stereotaxic placement needle, devices, preferably in conjunction with imaging technology that provides the practitioner with guidance as to the placement of the composition. The compositions of the present invention can be used advantageously in conjunction with any embolization method that employs an or such composition embolizing agent, occluding agent, that creates an embolic block, or occlusion, or otherwise in effect is used for filling, occluding, partially filling or partially occluding an unfilled volume or space in a mass (“a space"). EXAMPLES The following examples are given to enable those of ordinary skill in the art to more clearly understand and to practice the present invention. The examples should not be considered as limiting the scope of the invention, but merely as illustrative and representative thereof. EXAMPLE 1 PREPARATION OF 2-HEXYL CYANOACETATE A 5 liter, 24/40 ground glass jointed flask was configured with a reflux condenser, Dean—Stark trap, and The reaction vessel was (Aldrich football magnetic stirring bar. charged with the 1,275.0 g of cyanoacetic acid WO 00144287 10 15 20 25 30 PCT/US00/02262 41 1,581.5 g of 2-hexanol (Aldrich Chemical and 3.0 g of p-toluenesulfonic acid (Aldrich and 1,500 of toluene (Aldrich Chemical Chemical Co.), Co.) Chemical Co.), Co.). The reaction mixture was stirred and heated to Water was formed as a byproduct of the reaction The reflux. and was collected during the course of the reaction. reaction was continued until there was a period of over 30 minutes where no water was produced. The amount of water collected was 230 ml and indicated that the reaction had completed with a 85.2% theoretical yield. The reaction mixture was allowed to cool to room temperature. The reaction mixture was stirred and 500 ml of a saturated baking soda (sodium bicarbonate) solution was The reaction mixture was The gradually added to the mixture. stirred vigorously until the frothing stopped. reaction mixture was poured into a six liter separatory funnel, to which an additional 500 ml of water was added. The aqueous phase The pH of the The funnel was vigorously agitated. was separated and saved as Reaction Water. aqueous layer was measured to insure that the pH was Another 500 ml of water was added to the organic The over 8. phase reaction mixture in the separatory funnel. contents of the funnel were again agitated, the aqueous and organic phases were allowed to settle, and the aqueous phase separated and also saved as Reaction Water. This washing procedure was repeated two additional times. The organic phase was moved to a 5—liter flask. The flask was configured with a distillation condenser. The and the remaining The reaction mixture was heated to reflux, water was separated from the mixture and discarded. apparatus was reconfigured for vacuum fractional the toluene and 2-hexanol in distillation. Initially, the mixture were removed by reducing the pressure of the WO 00/44287 10 15 20 25 30 PCT/US00/02262 42 apparatus to about 5 Torr, and then by heating the mixture to 60° with stirring. After the solvents were removed, the pressure was further reduced to less than 1 Torr and gradually increased heat until the desired 2—hexyl cyanoacetate began to distill off. The heat was adjusted so that the product was recovered at a rate of 2 (70.76% and was halted when drops/sec. The recovery collected 1921.1 g yield) no more material came out of the distillation unit. of the 2—hexyl cyanoacetate, Gas chromatographic analysis of the purity of the 2—hexyl cyanoacetate indicated that the product was 98.3% pure, which was well above 95% purity requirement for proceeding to the next procedure. If the purity of the 2—hexyl cyanoacetate had been below 95%, the material could have be purified by vacuum distillation, or using any like technique for purification known to those of ordinary skill in the art. EXAMPLE 2 PREPARATION OF 2-HEXYL CYANOACRYLATE A 5—liter three—necked flask was configured with a reflux condenser, Dean-Stark trap, an addition funnel and a mechanical stirrer with a glass paddle in a Paraformaldehyde 272.4 g and The 5—liter heating mantle. methanol 1,500 ml were combined in the flask. reaction mixture was heated to reflux and stirred for a 3 ml period of 1 hr until the solution began to cleared. of piperidine was washed into the reaction mixture with followed by 1521.9 g of The methanol, 2—hexyl cyanoacetate added in a dropwise fashion. resulting reaction was exothermic, and the heat was adjusted to maintain the reaction mixture at reflux temperature. The reaction WO 00/44287 10 15 20 25 30 PCT/US00/02262 43 mixture was refluxed for an additional 30 minutes after the conclusion of the addition. Methanol was distilled from the reaction mixture and collected through the Dean- (98%) The reaction Stark trap until 1420 ml of the original methanol was recovered (compensating for spillage). mixture was halted overnight at this point. The reaction vessel was configured with a and placed under The vacuum apparatus to collect residues, high vacuum to remove remaining volatile materials. vacuum was gradually increased until less than 10 Torr was reached. The apparatus was heated until all the solvent had been removed. Once the solvent was removed, 75 g of phosphorous pentoxide was added to the mixture taking care to minimize its exposure to air. The heat was discontinued, and the mixture was stirred for one hour. The apparatus was then flooded with sulfur dioxide. The pressure was reduced to less than 10 Torr and heated slowly, the flow of sulfur dioxide was adjusted for a constant low—level flow of gas into the apparatus. A 1 liter flask was washed with concentrated sulfuric acid, three times with water, and once with ultra pure water. The flask was oven dried for one hour at 110°C and was allowed to cool to room temperature. 10 drops of 85% phosphoric acid and approximately 25-50 mg of hydroquinone was added to the 1 liter flask. The flask was fitted as the receiver flask to the distillation apparatus. The pressure of the distillation was reduced to less than 10 Torr. The reaction mixture was heated and stirred until the distillation began. 418 g of 2—hexyl cyanoacrylate was collected at a 25% yield. The distillation was halted when the temperature rose above 110°C. WO 00/44287 PCT/US00/02262 44 EXAMPLE 3 Purification of 2—Hexyl Cyanoacrylate The 2—hexyl cyanoacrylate was purified in a two step process. The compound was first by vacuum 5 distillation, and then further purified by spinning band column. Vacuum Distillation A vacuum distillation apparatus was configured with a 2 L flask, magnetic stirrer, fraction cutter, a 10 10" Vigreux column a clasien head, condenser, thermometer and a 100 ml forecut receiving flask. 10 drops of 85% phosphoric acid and 10 mg of hydroquinone was added to the forecut flask. The unpurified 2—hexyl cyanoacrylate was place into the distillation flask and the pressure of 15 the unit was reduced to just under 1 Torr. The material was stirred and gradually heated until product was being distilled and collected at a rate of one drop per minute. After 35 ml of distillate was collected, a second 2 L receiving flask that had been prepared by acid washing, 20 followed by the addition of 25 drops of 85% phosphoric acid and 20 mg hydroquinone was placed to receive the distillate. The distillation rate was gradually increase till the product was being collected at a rate of 2-3 drops per second. When the distillation head temperature 25 rose 2°C above that used to collect the main fraction, the distillation was completed. Heat was discontinued, and the material was allow to cool under dry air by air filtered through a drying tube. WO 00/44287 1O 15 20 25 30 PCT/US00/02262 45 Spinning Band Column Purification The spinning band column (B/R Instrument Corp., 9119 Centreville Road, Easton, Maryland 21601, Model 9600) is a long jacketed silvered column fitted with a 30/50 socket joint at the bottom. A magnetic stirring bar was added to the 5 L socket joint flask, which was then filled with the product to be purified. A heating mantle is supported on a magnetic stirrer that is raised and lowered with a laboratory jack to fit to the column. On the upper right hand side of the column there was another 30/50 male socket joint for a 100 ml All flasks and joints were greased with When receiving flask. high vacuum grease to assure a good vacuum seal. assembled, a glass temperature probe was inserted into the 10/15 joint of the flask, and a metal Tempora probe was inserted inside the glass probe. The 29/42 joint containing the stopcock was greased and placed into the flask and connected to a sulfur dioxide gas line. The pressure of the system was gradually reduced down to just under 1 Torr of pressure. Operation of the spinning band column was controlled by a microprocessor. The column was programmed to operate under the following conditions, the water cooling temperature was set to 15°C, the column’s motor turns on at 24°C, equilibration time was 2 min, open temperature 28°C, close temperature 90°C, mantle rate 24°C, 90°C. flow of sulfur dioxide was leaked into the system. reflux ratio 20 to 1 and pot temperature to end run Just prior to beginning the distillation a small The temperature of the flask was monitored during the distillation to ensure that the temperature at no time rose above lOO°C. The distillate was collected in the receiver flask at the end of the distillation. WO 00/44287 l0 15 20 25 30 PCT/US00/02262 46 The contents in the flask of the spinning band column were allowed to cool for 30 min. A second high vacuum distillation apparatus configured identically to the vacuum distillation apparatus first used in this procedure was setup using a 2 L round bottom flask. To 0.0275 g The this flask was added 0.0269 g of hydroquinone, of p—methoxyphenol, and 0.0794 g of phosphoric acid. residue for pot of the spinning band column was added to the 2 L round bottom flask of the vacuum distillation apparatus. The contents of the flask was stirred and the pressure of the unit was reduced to just less than 1 Torr. A small stream of sulfur dioxide was leaked into the apparatus as the distillation continued. A receiver flask was prepared by adding 10 mg hydroquinone and 15 drops of 85% phosphoric acid. A forecut fraction of 86.3 g was collected at the rate of 2-6 drops per minute. The main fraction was collected in a receiver similarly prepared as the forecut fraction flask. 1620.1 g of main fraction product was collected at a rate of 20-25 drops per minute. The material was then re—distilled by the spinning band column under the previous conditions. The purity of the 2—hexyl cyanoacrylate was determined by gas chromatography. The gas chromatograph was configured as follows, HP 5890 Gas Chromatograph with HP Chemstation Software. Column Description: Supelco Nukol (60 meter, I.D.—O.32 mm, film thickness—l micron). Instrument Parameters: Method 1 Injector Temperature: 220°C Detector Temperature: 280°C Head Pressure: 15 PSI Air Pressure: 35 PS1 WO 00/44287 PCT/US00/02262 47 Hydrogen Pressure: 20 PSI Aux: 60 PSI Initial Oven Temperature: 140°C for 20 min. Ramp: 5°C/min. 5 Final Oven Temperature: 200°C for 50 min. A Splitless System. Injection Volume: 1.0 micro liter 1.0069 g of the 2—hexyl cyanoacrylate was mixed thoroughly with 2 drops of 1-hexanol (0.0044 g), was 10 analyzed and impurities were found to be at an acceptable for use. The 2—hexyl cyanoacrylate was sufficiently pure to use for product. EXAMPLE 4 FORMULATION OF THE MONOMER COMPONENT 15 The monomer component was formulated with the following materials 2—hexyl cyanoacrylate 1249.9 g, hydroguinone 0.0764 g, p—methoxyphenol 0.0874 g and phosphoric acid 0.1693 g. The hydroquinone and p—methoxyphenol were kept under reduced pressure in a 20 dessicator over a drying agent. The pure phosphoric acid was particularly deliquescent and care was taken not permit water contamination. The calculated molar quantities and PPM of each material were as follows, Material Moles ggm 25 2—hexyl cyanoacrylate 6.8964 999,547 hydroquinone 0.000694 100 p—methoxyphenol 0.000704 102 phosphoric acid 0.001726 250 WO 00/44287 PCT/US00/02262 4 8 Overall purity of the formulation was determined by gas chromatograph to be less than 1%, using 1—hexanol as an internal standard. Instrument Description: HP589O Gas 5 Chromatograph with HP chemstation software. Column Description: Supelco Nukol (60 meters- length,'I.D., 0.32 mm, Film Thickness 1 micron) 10 Instrument Parameters: Method 1 Injector Temperature: 220°C Detector Temperature: 280°C Head Pressure: 15 PSI Air Pressure: 35 PSI 15 Hydrogen Pressure: 40 PSI Aux.: 60 PSI Initial Oven Temperature: 140°C for 20 min. Ramp: 5°C/min. Final Oven Temperature: 200°C for 50 min. 20 A Splitless System: Injection Volume: 1.0 microliter W0 00/44237 PCT/US00/02262 49 EXAMPLE 5 PREPARATION OF THE 2-HEXYL CYANOACRYLATE POLYMER COMPONENT (“the Second Component”) 5 Ethyl myristate was obtained commercially from 1O 15 20 25 30 Aldrich Chemical Company at 97% purity. Prior to use, the ethyl myristate was further purified by vacuum distillation to 99.8% purity following standard routine chemical procedures. Six 3 ml syringes were fill with purified 2—hexyl cyanoacrylate. 500 mg of sodium bicarbonate and 250 ml of ultra pure water were placed into a Waring blender. The lid of the blender was adjusted so that the contents of the syringes could be emptied dropwise into the center of blender while the blender was stirring. With the speed of the blender set to high, each of the syringes were emptied in a dropwise fashion into the stirring blender. When the addition was completed, the lid of the blender was closed and the mixture was stirred for another minute. The solution was decanted from the blender leaving just solid material in the blender. Residual solid material that was inadvertently removed with the decanted solution was recovered by filtration, washed with ultra pure water and placed back into the blender. of the blender was rinsed with ultra pure water back with An additional 250 Solid material adhering to the inside portion the rest of the solids in the blender. ml of ultra pure water was added into the blender, and the water and solid mixture was blended for 1 minute. Following the last procedure, water solution was decanted large coarse fritted glass funnel filter that The solid through a recovered solid material in the solution. WO 00/44287 10 15 20 25 30 PCT/US00/02262 50 methanol prior to be added back to the rest of the solid material. The walls of the methanol to collect all the the blender. 250 ml of Methanol material was washed with blender were rinsed with solid material back into was added to the blender. The solids were blended for one minute. The solid material is filtered from the methanol. Any residual solid material in the blender is washed with methanol and combined with the solid material filtered from the methanol. The solid material on the filter was placed under a low vacuum to remove the rest of the methanol. The solid material was moved quantitatively to a lOO ml round bottom standard tapered flask. remove the remaining methanol. The flask was placed under reduced pressure to 2 g of the solid material was combined with 100 g of powdered gold. The mixture was placed into a standard laboratory blender and blended for one minute. The blender was agitated constantly during the blending to ensure that the gold did not settle during the blending. 1.020 g portions of the blended material were placed into previously cleaned and To each bottle was added 500 mg of The filled bottles were prepared bottles. ethyl myristate at 99.8% purity. kept under a Laminar flow hood. The unsealed bottles were arranged in trays for immediate ethylene oxide sterilization by Sharp Coronado Hospital, Sterile Processing Department under standard conditions. EXAMPLE 6 COMPARISON OF CATHETHER ADHESION FORCE FOR 2-HEXYL CYANOACRYLATE (NEURACRYL M) AND n-BUTYL CYANOACRYLATE (HISTOACRYL) COMPOSITIONS The present invention is also known by the name of Neuracryl M, where Neuracryl Ml corresponds to the WO 00/44287 10 15 20 25 30 PCT/US00/02262 51 monomer component, and Neuracryl M2 corresponds to the second component comprising of the gold coated 2—hexyl acrylate. This example demonstrates differences in adhesion between the two cyanoacrylates by measuring the amount of force required to remove a catheter from various compositions of Neuracryl and Histoacryl. Histoacryl is commercially available from Braun GmbH. It is similar to Neuracryl M in that it is a polymer composition also based on a cyanoacrylate structure, i.e., n—butyl cyanoacrylate. However, the force required to withdraw a catheter from Histoacryl is greater than that required for Neuracryl M, and in this key aspect, Neuracryl M possesses a surprising and unexpected advantage over Histoacryl. The force resulting from catheter adhesion was determined for Neuracryl M1 and M2 (mixed), pure Neuracryl Ml, Neuracryl Ml mixed with 33% Ethiodol, Neuracryl Ml mixed with 50% Ethiodol, pure Histoacryl, Histoacryl mixed with 33% Ethiodol, and Histoacryl mixed with 50% Ethiodol were measured and compared. All the mixtures were injected through a TurboTracker micro catheter device (Medi—tech/Boston MA). immediately prior to use to prevent separation of the Scientific, Watertown, All mixtures were prepared components or contamination. The catheter tips were placed at the bottom of 10 mm deep by 5 mm diameter wells filled with 0.2 mL of heparinized human whole blood. Through the micro catheter, 0.15 mL of each embolic mixture was injected into each well, surrounding the tip of the micro catheter. Mixtures containing Histoacryl were allowed to polymerize for 1 minute, and those containing Neuracryl for 3 minutes. The microcatheters WO 00/44287 10 15 20 25 30 PCT/US00/02262 52 were then extracted from the polymerized cyanoacrylates (Model 1000 Materials MA) at a constant speed of 8.3 mm/sec Testing System; Instron, Canton, and the forces required for extraction were measured and recorded 25-lb capacity; Interface Scottsdale, AZ). (Minibeam Force Transducer, Advanced Force Measurement, Five samples of each mixture were tested. Comparison of the results was performed using the Student t test. Successful mesurements of the peak forces required for the extraction of the catheters from the polymerized cyanoacrylates were obtained for six of the seven mixtures tested. A wide range of peak forces were required to extract the microcatheters from the various mixtures. The force of extraction for the Neuracryl M1 and 50% Ethiodol mixture was less than 0.05 Newtons and beyond the ability of the apparatus to obtain precise measurements. The peak forces required to extract the microcatheters from either Histoacryl mixed with 33% Ethiodol (1.44 N i 0.33) (P