Radiopaque Cyanoacrylate Compositions

 US007862800Bl (12) Ulllted States Patent (10) Patent No.: US 7,862,800 B1 Broadley et al. (45) Date of Patent: Jan. 4, 2011 (54) RADIOPAQUE CYANOACRYLATE 4,713,235 A 12/1987 Krall ........................... .. 424/5 COMPOSITIONS 5,342,716 A * 8/1994 Kato et al. . . . . . . . . .. 430/91 5,530,037 A 6/1996 McDonnell ................ .. 522/79 (75) Inventors; Kenneth N, Broadleys Naas (IE); 5,695,480 A 12/1997 Evans ....................... .. 604/264 Neeleen B_ swords, Dublin (llg); Clare 5,874,044 A 2/1999 Kotzev 422/40 1)_ G1-ealis, Dublin (IE) 6,040,408 A 3;2000 Koole 526/29/2.1 6,136,236 A 10 2000 Boccar 264 40 (73) Assignee: Henkel AG & Co. KGaA, Duesseldorf 5310455 B1 10;2001 Hickey ----- -- 525/3:183 DE 6,428,800 B2 8 2002 Greenspan .. 424 405 ( ) 6,562,317 B2 5/2003 Greff ....................... .. 424/1.25 ( >x< ) Notice: Subject to any disclaimer, the term Ofthis 6,579,916 B1 6/2003 Askill ...................... .. 522/152 patent is extended or adjusted under 35 6,759,028 B2 7/2004 Wallace ................... .. 424/1.25 U.S.C. 154(b) by 1396 days. FOREIGN PATENT DOCUMENTS (21) Appl.No.: 11/328,109 EP 0684222 10/1998 (22) Filed: Jan. 10, 2006 EP 0559441 3/2002 W0 W0 2005.053578 6/2005 Related U.S. Application Data (60) Provisional application No. 60/643,604, filed on Jan. OTHER PUBLICATIONS 14’ 2005 ‘ Artola et al., “A Radiopaque Polymeric Matrix for Acrylic Bone Cement”, J. Biomaterial Res. Part B; Appl. Biomaterial, 64B, 44-55 (51) Int. C1. (2002). A61K 49/04 (200501) Kruft et a1., “Studies on Two New Radiopaque Polymeric Biomateri- A61K 31/74 (2006.01) als”, J. Biomed. Mat’1s Res., 28, 1259-66 (1994). A61K 31/785 (2006.01) * . . A61K 31/765 (2006.01) “ted by exammer AWN 41/02 (200601) Primary Examiner—Michael G Hartley A61M 31/00 (200001) Assistant Examiner—Leah Schlientz (52) U.S. Cl. .................. .. 424/9.455; 424/9.4; 424/9.45; (74) Attorney Agent] or F,'rm__lanies E. pinnnwski; Steven 424/78.31; 424/78.35; 424/78.37; 514/527; C. Bannian 604/48 (58) Field of Classification Search ................ .. 424/9.4, (57) ABSTRACT 424/9.45, 9.455, 78.31, 78.35, 78.37; 514/527; S 1. . fil f 1 h h. 604/48 This invention relates to sterilized cyanoacrylate adhesive 00 app lcanon 0 or Comp ete Seam lstory‘ compositions with x-ray imagining capabilities, methods of (56) References Cited making such compositions, and methods of using such com- positions. U.S. PATENT DOCUMENTS 4,359,454 A * 11/1982 Hoffman ............... .. 424/9.451 8 Claims, N0 Drawings US 7,862,800 B1 1 RADIOPAQUE CYANOACRYLATE COMPOSITIONS This application claims the benefit of an earlier filing date from U.S. Provisional Application No. 60/643,604, filed Jan. 5 14, 2005. BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to sterilized cyanoacrylate adhesive compositions with x-ray imaging capabilities, methods of making such compositions, and methods of using such com- positions. 2. Brief Description of Related Technology In recent years, the use of cyanoacrylate-based biomedical adhesives and sealants has increased dramatically. Once seen as a triage type of treatment, cyanoacrylate-based biomedical adhesives and sealants have found their way into more main- stream use, for instance, as topical wound closure treatments. More recently, internal applications of cyanoacrylate-based biomedical adhesives and sealants have been and are cur- rently being explored. In such applications, it is desirable for the cyanoacrylate- based biomedical adhesives and sealants to be sterilized against bacterial growth. One commercially successful way to achieve that sterilizing is described and claimed inU.S. Pat. No. 5,530,037 (McDonnell). The ’037 patent, under which a product manufactured by Henkel Loctite (Ireland) Ltd. and distributed in the U.S. by Tyco Healthcare under the regis- tered trade mark INDERMIL, provides a curable cyanoacry- late adhesive composition for use inbonding tissue, where the composition has been sterilized in liquid form by gamma irradiation and is the irradiation product of a composition comprising a cyanoacrylate monomer; and a combination of an anionic stabilizer and a free-radical stabilizer in amounts effective to stabilize the composition during irradiation and to stabilize the sterilized composition during storage prior to cure. Particularly for internal use applications in patients, it would be desirable to observe the location of the cyanoacry- late-based biomedical adhesive and sealant after dispensing onto or into the desired area of the patient. With certain cyanoacrylate-based biomedical adhesives and sealants designed and developed for topical use, a dye has been intro- duced into the adhesive or sealant composition to assist in visualization on the skin once applied. See for instance HIS- TOACRYL BLUE from B. Braun Melsungen AG. However, with internal applications, a simple dye carmot be visualized. Instead, a radiopaque material should be employed. Radiopaque materials have been proposed for use with cyanoacrylates in the past. For instance, U.S. Pat. No. 4,713, 235 (Krall) describes and claims radiopaque polymerizable cyanoacrylate compositions that are mixtures of an ester of 2-cyanoacrylic acid and a radiopaque additive stable to and not substantially decreasing the storage life of the cyanoacry- late ester. This additive the ’235 patent reports is selected from triiodophenol, iodoform and tetraiodoethylene. The so- formed radiopaque polymerizable cyanoacrylate composi- tions have between 0.5 and 11 mole percent iodine atoms. These iodo additives have poor solubility in cyanoacrylates generally, however, and thus require heating in order to dis- solve them. Other contrast agents have been used in cyanoacrylates as well. For instance, U.S. Pat. No. 6,562,317 (Greff) describes and claims a composition suitable for treating a solid mass tumor in a mammal. This composition includes a biocompat- 10 15 20 25 30 35 40 45 50 55 60 65 2 ible prepolymer; an optional biocompatible solvent; and from about 0.1 to about 25 weight percent of a water insoluble radioisotope having from a radioactive content of from about 0.5 microcurie to about 100 millicurie. The biocompatible prepolymer may be cyanoacrylate. Optionally, the composi- tion may include a non-radioactive contrast agent, which may be water soluble or water insoluble. The water-soluble con- trast agents are selected from metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and meglumine; the water-insoluble contrast agents are selected from tantalum, tantalum oxide, barium sulfate, tungsten, gold and platinum. And U.S. Pat. No. 6,759,028 (Wallace) describes and claims a method for treating an arteriovenous malformation (“AVM”) in a mammal. This method includes the steps of selecting a fluidic composition comprising a biocompatible prepolymer, a water insoluble radioisotope and optionally a biocompatible solvent; and injecting a sufiicient amount of the composition into one of more vascular sites leading to or within the AVM under conditions, where a solid mass is formed thereby ablating at least part of the then AVM, where the radioisotope is employed in an amount effective to further ablate the AVM and to inhibit regrowth of the AVM. Like the ’317 patent above, the composition may be a cyanoacrylate with a contrast agent selected from those recited in the pre- ceding paragraph. U.S. Pat. No. 5,695,480 (Evans) speaks more generally about specific compositions embraced by those used in the methods of the ’3 17 and ’028 patents. Water insoluble contrast agents are undesirable because they tend to destabilize cyanoacrylates (causing the cyanoacrylates to prematurely cure) and sediment from the cyanoacrylate com- position. Once sedimented, at least with silver contrast agents in thickened cyanoacrylate compositions, the silver contrast agents are difficult to re-disperse. Also, in the context of treating AVMs, butyl cyanoacrylate has been combined with Lipiodol (iodinized ethyl esters of poppy seed oil fatty acids) and tantalum. However, Liopodol destabilizes the butyl cyanoacrylate, and as such the compo- nents must be mixed immediately prior to use. Thus, such Lipiodol/tantulum-containing cyanoacrylate compositions do not have a shelf life, and cannot reasonably be made to be a practical commercial product in a one part composition. In A. Artola et al., “A Radiopaque Polymeric Matrix for Acrylic Bone Cement”, J. Biomazerial Res. Part B; App]. Biomaterial 64B, 44-55 (2002), the authors refer to the use of a radiopaque agent, 4-iodophenol methacrylate, in a bone cement for implants that consisted of methyl methacrylate as the resin matrix. In their conclusions, the authors note that cements containing 15% 4-iodophenol methacrylate per- formed better as a bone cement than conventional cements containing barium sulfate as an x-ray contrast agent. Despite the state of the technology, there has been no disclosure, teaching, suggestion or motivation to date to use 4-iodophenol methacrylate (or any iodophenol-substituted methacrylate) in a matrix other than methacrylates for use as anything other than bone cements. Thus, because of the state of the technology, there was no disclosure, teaching, sugges- tion or motivation to date to use iodophenol-substituted meth- acrylates in a cyanoacrylate composition, let alone one that has been sterilized and whose end use is suitable for use as adhesives and sealants with soft tissue. SUMMARY OF THE INVENTION The present invention thus provides a shelf stable, one-part cyanoacrylate adhesive composition having as a radiopaque agent, iodo-substituted phenol (meth)acrylates. The compo- sition should be sterilized, and when sterilized is in liquid US 7,862,800 B1 3 form prior to exposure to sterilization conditions and remains flowable at room temperature even after sterilization. The iodo-substituted phenol (meth)acrylates may be embraced by H2C:CO()—COOY, where X is hydrogen or alkyl andY is Zm—Ar—In; Z is alkyl, halogen (other than iodine), hydroxyl and carboxyl, m is 0 or 1, and n is 1-5, provided that when m is 0, n is 1-5 and when m is l, n is 1-4. The invention also provides a method of making such a cyanoacrylate adhesive composition; and methods of using such a cyanoacrylate adhesive composition, such as to bond soft tissue or adheringly seal a vascular cavity. DETAILED DESCRIPTION OF THE INVENTION As noted above, the invention provides a shelf stable, one- part cyanoacrylate adhesive composition having in addition to a cyanoacrylate component, iodo-substituted phenol meth- acrylates as a radiopaque agent. The iodo-substituted phenol methacrylates may be embraced by H2C:CO()—COOY, where X is hydrogen or alkyl andY is Zm—Ar—In; Z is alkyl, halogen (other than iodine), hydroxyl and carboxyl, m is 0 or 1, and n is 1-5, provided that when m is 0, n is 1-5 and when m is l, n is 1-4. The iodophenol methacrylate in a more particular embodi- ment may be embraced by H2C:C(X):C00 In wherein X is hydrogen or methyl and n is 1-5. For instance, a particularly desirable iodophenol methacrylate is H2c=c(cH3)—co0 1 Di or tri-iodo substituted phenol methacrylates are also desir- able, as less of the radiopaque agent can be used in the composition to achieve a comparable visualization effect under x-ray exposure. Other desirable iodophenol methacrylates include Me 10 15 20 25 30 35 40 45 50 55 60 65 -continued B Me O O C O; :0 I Me O (0 O O In addition, iodonized-phenol derivatives of polymethyl methacrylates may also be used. When used, these materials are capable of serving a dual function—one as a radiopaque agent and the other as a thickener. The radiopaque agent should be included in an amount in the range of 0.5 to 75 percent by weight, desirably 5-50 percent by weight, such as 7 to 20 percent by weight. The radiopaque agent should be added to the cyanoacrylate before sterilization, and the composition should not require further additives once it is to be sterilized. The cyanoacrylate component includes cyanoacrylate monomers which may be chosen with a raft of substituents, such as those represented by H2C:C(CN)—COOR, where R is selected from C1_ 1 5 alkyl, alkoxyalkyl, cycloalkyl, alk- enyl, aralkyl, aryl, allyl and haloalkyl groups. Desirably, the cyanoacrylate monomer is selected from methyl cyanoacry- late, ethyl-2-cyanoacrylate, propyl cyanoacrylates, butyl cyanoacrylates, octyl cyanoacrylates, allyl-2-cyanoacrylate, 8-methoxyethyl-2-cyanoacrylate and combinations thereof. A particularly desirable cyanoacrylate monomer for use herein is n-butyl cyanoacrylate. As is known in the art of manufacturing cyanoacrylates, stabilizers are included to decrease the potential of premature polymerization and hence enhance shelf life stability. To that end, since basic materials react quickly with cyanoacrylates at even trace levels, an acidic material is added to neutralize any such basic contaminants. In addition, free radical stabi- lizers in the form of anti-oxidants are included as are anionic US 7,862,800 B1 5 stabilizers. Such acidic, free radical and anionic stabilizers are well known in the cyanoacrylate art and may be found described in the ’037 patent. In the context of irradiated cyanoacrylate compositions, the ’037 patent teaches a combination of anionic and free radical stabilizers to maintain a flowable cyanoacrylate even after exposure to sterilizing doses of gamma irradiation. The technology of the ’037 patent may also be employed herein, and as such is expressly incorporated herein by reference. See also U.S. Pat. No. 6,310,166. In addition or altematively, other sterilization methods may be used. For instance, U.S. Pat. No. 5,874,044 (Kotzev) speaks to a method of sterilizing a 2-cyanoacrylate prepara- tion that consists of only a 2-cyanoacrylate compound and one or more anionic or free-radical polymerization inhibitors that prevent premature polymerization. The method includes the step of heating the preparation in a suitable container that is hermetically closed to a temperature of at least 160° C. without causing polymerization of the 2-cyanoacrylate preparation. Related U.S. Pat. No. 6,136,236 speaks to pack- age comprising a sealed aluminum container and a composi- tion so sterilized the above method heat treatment disposed therein. Also, E-beam sterilization may be used in the practice of the present invention. For instance, U.S. Pat. No. 6,248,800 speaks to a method for preparing a polymerizable, sterile, cyanoacrylate ester composition in a shipping element com- prising multiple individual package cyanoacrylate composi- tions. The method includes the steps of (a) selecting a pack- aging element; (b) adding a cyanoacrylate ester composition comprising a polymerizable cyanoacrylate ester to an indi- vidual packaging element selected in (a) above; and (c) com- bining multiple individual package elements into a shipping element; (d) exposing the shipping element formed in (c) above to a sufficient dosage of E-beam irradiation maintained at an initial fluence of at least 2 p.Curie/cm2 to sterilize both the packaging elements and the cyanoacrylate ester compo- sition without gelling the composition. Significantly, the average bulk density of the materials comprising the shipping element is less than about 0.2 gm/cm3. In U.S. Pat. No. 6,579,916 a method is disclosed for pre- paring a polymerizable, sterile, cyanoacrylate ester composi- tion through the exposure to a predetermined dosage of vis- ible light irradiation having wavelengths of from 390 to 780 nanometers which predetermined dosage is sufiicient to ster- ilize the polymerizable cyanoacrylate ester composition without gelling the polymerizable cyanoacrylate ester com- position and is from about 0.01 to 50 J/cmz. And ultrafiltration sterilization may be used too. In order to sterilize by way of exposure to gamma-irradia- tion, the inventive cyanoacrylate compositions are packed into a suitable container, such as a bottle, tube, or vial. The filled bottles are then sealed in metal foil (e.g., aluminium foil) pouches and subjected to gamma irradiation, such as with a dose of 25 kGy under ambient conditions. Irradiation doses of less than 25 kGy should sufiice as well, such as doses as low as 10 kGy. Free radical stabilizers and anionic stabilizers are fre- quently added to cyanoacrylates either during or after manu- facture to assist in providing a meaningful commercial shelf life. Free radical stabilizers or anti-oxidants which may be used include methyl hydroquinone, catechol, tert-butyl hydro- quinone, 4-tert-butoxyphenol, 4-ethoxyphenol, 3-methox- yphenol, 2-tert-butyl-4-methoxyphenol, 2,2-methylene-bis- 10 15 20 25 30 35 40 45 50 55 60 65 6 (4-methyl-6-tert-butylphenol), butyl hydroxy toluenes (such as BHT, or 4-methyl-2,6-di-tert-butylphenol) and butylated hydroxy anisole (BHA). Concentrations of the free radical stabilizer may vary in the range of 500 to 10,000 ppm. However, the appropriate con- centration can be determined by testing along the lines described in the ’037 patent. Known anionic (or acid) stabilizers for cyanoacrylate adhesives include sulphur dioxide (S02), sulphonic acids, sulphuric acid, sulphur trioxide, phosphorous acids, carboxy- lic acids, picric acid, boron trifluoride (BF3), BF3-ether com- plexes, BF3.2H20, citric acid, hydrofluoric acid, tin (IV) chloride, iron (III) chloride, and combinations thereof. S02 is particularly well known as a satisfactory stabilizer for cyanoacrylate adhesives under normal conditions of stor- age and use, and during sterilization, such as gamma irradia- tion treatment. Concentrations of anionic stabilizers in cyanoacrylate compositions ordinarily vary in the range of 25 to 500 ppm. From an S02 standpoint, sterilization of cyanoacrylate compositions of this invention can be achieved using this anionic stabilizer in the range 20 to 150 ppm. In the invention compositions, initial results of stabiliza- tion with BF 3 .2H20 have shown at least as promising stability data as with S02. Conventional additives such as thickeners, dyes and thixo- tropic agents may be included in the compositions as required. However, for medical or veterinary use care must be taken as noted in the ’037 patent to ensure that additives do not introduce toxic contaminants which survive or are pro- duced by irradiation. Sterilization by way of irradiation may itself cause some thickening of the composition. For medical or veterinary use a maximum composition viscosity after sterilization of about 200 mPas is desirable, preferably less than 50 mPas, especially less than 25 mPas, unless of course a thickened version is desired. The invention will be more fully appreciated by a reading of the following examples. EXAMPLES Example 1 Adapted from M. Kruft et al ., “Studies On Two New Radio- paque Polymeric Biomaterials”, J. Biomed. Mafls Res., Vol. 28, 1259-1266 (1994), 4-iodophenol methacrylate was pre- pared as follows: 1. 15.05 grams of 4-iodophenol and 13.85 grams of dry triethylamine were added to 200 ml dry dichloromethane in a round bottom flask and cooled with a cooling bath of ethanol and liquid nitrogen to a temperature of —5° C. 2. 8.55 g of methacryoyl chloride in 75 ml of dry dichlo- romethane was added dropwise at a temperature of —5° C. with constant stirring to the solution of iodophenol/triethy- lamine. This addition was carried out over a period of 60 minutes. After completion of the addition, the cooling bath was removed and the mixture was allowed to stir for 4 to 6 hours. After 6 hours of stirring the mixture was cooled to —5° C., and then 250 ml of distilled H20 was added. 3. The organic phase was separated and washed with satu- rated NaHC03 (200 ml>69 >43 5% 4-iodophenol 27-28 7-8 >69 >43 10% 4-iodophenol 27-28 7-8 >69 >43 15% 4-iodophenol 23-24 7-8 >69 >43 20% 4-iodophenol 23-24 7-8 53-54 39-40 1% 2,4,6— 21-22 7-8 >69 >43 triiodophenol 2.5% 2,4,6— 2-4 1-2 17-19 14-15 triiodophenol 5% 2,4,6— -1.5