Sterilized Cyanoacrylate Adhesive Composition, and a Method of Making such a Composition

Sterilized Cyanoacrylate Adhesive Composition, and a Method of Making such a Composition

US5530037
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A curable cyanoacrylate adhesive composition intended for medical and/or veterinary uses is sterilized in liquid form by gamma irradiation. The composition comprises

a) a cyanoacrylate monomer

b) a combination of an anionic stabilizer in amounts effective to stabilize the composition during storage prior to cure, wherein the free radical stabilizer is a selected phenolic antioxidant (but not including hydroquinone).

The preferred free radical stabilizer is butylated hydroxyanisole. After irradiation the cyanoacrylate monomer is substantially ungelled.

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United States Patent [19] McDonnell et al. H||||||l|||l||l|l||||||||l|||||||||l|llIll||||||||||||||llllllllllllllllll US005530037A [11] Patent Number: "[45] Date of Patent: 5,530,037 Jun. 25, 1996 [54] STERILIZED CYANOACRYLATE ADHESIVE COMPOSITION, AND A METHOD OF MAKING SUCH A COMPOSITION [75] Inventors: Patrick F. McDonnell, Dublin; Robert J. Lambert, County Dublin, both of Ireland [73] Assignee: Loctite (Ireland) Limited, Tallaght, Ireland [21] Appl. No.: 360,511 [22] Filed: Dec. 21, 1994 [30] Foreign Application Priority Data Dec. 23, 1993 [IE] Ireland ................................... .. 931009 [51] Int. Cl.“ ................................ .. C08J 3/28; C09] 4/04; C08K 5/13 [52] U.S. Cl. ............................... .. 522/79; 522/74; 522/76; 522/173; 523/111; 514/527 [58] Field of Search ................................ .. 522/75, 79, 74, 522/152, 76, 81, 173; 252/404; 523/111; 574/527 [56] References Cited U.S. PATENT DOCUMENTS 3,527,224 9/1970 Rabinowitz ........................... .. 128/334 3,699,127 10/1972 0’Sul1ivanetal. . 260/33.2 4,100,141 7/1978 0’Su11ivan 522/79 4,820,755 4/1989 Webster ...... .. 522/79 5,403,591 4/1995 Tighe et a1. ........................... .. 424/445 FOREIGN PATENT DOCUMENTS 1281457 7/1972 United Kingdom .......... .. C07C 67/06 W081/00701 3/1981 WIPO .......................... .. B65D 39/00 OTHER PUBLICATIONS Yves Hemon, “Gamma Processing: The State of the Art,” Medical Device Technology, Jun./Jul. 1992, Publication No. 0010, pp. 30-37. K. L. Shantha et a1., “Developments and applications of cyanoacrylate adhesives,” J. Adhesion Sci. Technol., vol. 3, No. 4, pp. 237-260 (1989). E. M. Al-Khawam et al., Adhesion 7, Applied Science Publishers, 1983, Chapter 6, “Cyanoacrylate Adhesives of Potential Medical Use,” pp. 109-133, odd numbered pages only. Chemical Abstract CA84(13):88097e, Mutsuo Ishizaki et al., “Degradation of food additives by irradiation,” Khoku— hin Eisenigaku Zasshi, 16(4), 1975, pp. 230-233. Chemical Abstract CA98(14):108587j, East Ger. Patent No. DD 156365 18 Aug. 1982—Population Research, Inc., “Adhesive from 2—cyanacrylic acid methyl ester”. Chemical Abstract CA79(7):348511m, K. F. Lindenau et al., “Animal experimental review of new tissue adhesives of fimomed potassium chloride,” Dent. Gesundheitsw., 28(5), 1973, pp. 218-220. Chemical Abstract CA79(2):9856x, Kalman Somogyvari, “Alloplastics,” Acta Vet., 22(3), 1972, pp. 307-314. Primary Examiner—Susan W. Berrnan Attorney, Agent, or Firm—Vidas, Arrett & Steinkraus [57] ABSTRACT A curable cyanoacrylate adhesive composition intended for medical and/or veterinary uses is sterilized in liquid form by gamma irradiation. The composition comprises a) a cyanoacrylate monomer b) a combination of an anionic stabilizer and a free-radical stabilizer in amounts effective to stabilize the compo- sition during irradiation and to stabilize the sterilized composition during storage prior to cure, wherein the free radical stabilizer is a selected phenolic antioxidant (but not including hydroquinone). The preferred free radical stabilizer is butylated hydroxya- nisole. After irradiation the cyanoacrylate monomer is sub- stantially ungelled. 18 Claims, No Drawings 5,530,037 1 STERILIZED CYANOACRYLATE ADHESIVE COMPOSITION, AND A METHOD OF MAKING SUCH A COMPOSITION BACKGROUND OF THE INVENTION 1) Field of the Invention This invention relates to a sterilized cyanoacrylate adhe- sive composition, and to a method of making such a com- position. The composition is suitable for bonding a wide range of substrates but is especially intended for medical and/or veterinary uses such as wound closure and general surgical applications. 2) Description of the Related Art There is considerable experience in the use of cyanoacry- late adhesives in medical and veterinary practice (Shantha et al. “Developments and Applications of Cyanoacrylate Adhe- sives”, J. Adhesion Sci. Technol Vol. 3, No. 4, pp 237-260 (1989)). Cyanoacrylate adhesives have been proposed for surgical treatment such as wound adhesives, hemostatics and tissue adhesives, particularly for sutureless skin bond- ing. It is desirable that an adhesive for medical or veterinary use should be sterilizable (Al-Khawan et al. “Cyanoacrylate adhesives of potential medical use”, Adhesion 7 (Allen K. W.) Applied Science Publishers, Chap. 6, 109-133 (1983). Cyanoacrylate adhesives must be stabilized against anionic and free radical polymerization. W0 8100701 Krall describes a methyl cyanoacrylate adhesive composition for sealing fallopian tubes in female sterilization containing a polymerisation inhibitor such as an organic carboxylic acid, S02 and an antioxidant selected from hydroquinone, hyd- roquinone mono-methyl ether, butylated hydroxyanisole and their mixtures. A cyanoacrylate adhesive composition for medical use is commercially available under the Trade Mark HIS- TOACRYL BLUE from B. Braun Melsungen AG. This composition is not sterilized. Several methods which are available for positively ster- ilising liquids could be considered for application to cyanoacrylate adhesives. These include ionising radiation (electron accelerators or gamma radiation from a radioactive source such as Cobalt 60 or Caesium 137), dry-heat, steam, gas, filtration and liquid sterilisation. Aseptic filling of the adhesive immediately following manufacture is also an option. Factors to consider in choosing a sterilisation method include (a) the reactive nature of cyanoacrylates, (b) contamination due to induced chemical changes in the adhesive composition, (c) subsequent storage stability, (d) effect on bonding performance (immediate and long-term), (e) viscosity changes, (f) effect on the package or vessel used to contain the adhesive and (g) the maintenance of sterility on storage up to the time of utilisation. - Most of the above sterilisation methods are unsuitable or suffer from severe limitations in their applicability to cyanoacrylate adhesives. Electron beam accelerators have relatively low penetrating ability and would be efl"ective only in sterilising the outer surfaces of thee container or package. Dry-heat sterilisation generally involves a heating cycle at 160°—170° C. for 22 hours. This treatment would be extremely detrimental to cyanoacrylate adhesives with the strong likelihood that polymerisation would occur before the cycle was complete. Even if the adhesive survived (e.g. by incorporation of excessive levels of stabilizers) the treated product would have an adverse effect on performance and induce gross discoloration. Steam sterilisation using moist heat also involves exposure to an undesirably high tempera- 5 10 20 25 30 35 40 45 50 55 60 65 2 ture cycle (l21°—l41° C.) with the same adverse effects on the adhesive as mentioned above under the dry-heat process. In addition, the extreme sensitivity of cyanoacrylate adhe- sives to moisture would limit the adhesive container to a totally moisture impermeable package such as a sealed glass arnpoule. Gas sterilisation usually involves the use of eth- ylene oxide. While this process can be carried out at rela- tively low temperatures the reactivity of the gas combined with that of the cyanoacrylate adhesives would induce rapid polymerisation and make the treatment unworkable. Sterili- sation by filtration is not a viable method for cyanoacrylate adhesives because the pores of the filter will inevitably become blocked due to localised polymerisation. Likewise sterilisation by contact with a liquid such as formalin will only be effective on the outer surface of the container. Aseptic filling of the adhesive direct from the final receiving vessel used in the distillation stage of manufacture would in theory yield a sterile product. This follows because the cyanoacrylate prepolymer is cracked at temperatures of over 190° C. in a sealed vessel during manufacture. The composition of the final adhesive would be very limited however, as necessary additives such as stabilizers could not be conveniently added and mixed in a controlled fashion. If required, viscosity modifiers such as polymethylmethacry- late would require heating in a separate vessel to achieve dissolution and this step would destroy the sterility. Following on the unsuitable nature of the sterilisation methods discussed above it was decided to investigate the viability of using gamma irradiation from a Cobalt 60 source as an eifective method of sterilising cyanoacrylate adhe- sives. The gamma radiation emitted from a cobalt 60 source consists of high energy photons which have the ability to penetrate many materials including various plastics, liquids and metal foils. Any living microorganisms contaminating the product are deactivated and their metabolism and repro- ductive capabilities destroyed when they are exposed to a gamma radiation dose of 25 kGy. (Henon Y., “Gamma Processing, The State of the Art” in Medical Device Tech- nology, June/July 1992, pages 30-37). GB 1 281 457 (DE-OLS-2 055 658) Stehlik dating from November 1970 describes a process for irradiating mono- meric or oligomeric esters of —cyanoacrylic acid for the purpose of sterlization of tissue binding adhesives. The monomers or oligomers may be stablized with from 0.001 to 0.14 by weight of a gaseous Lewis acid inhibitor, acids such as sulphur dioxide, nitrogen oxide, boron trifluoride and hydrogen fluoride, and with from 0.1 to 0.54 by weight of a phenolic free radical polymerisation inhibitor, preferably with a mixture of sulphur dioxide and hydroquinone. The patent states that as the monomeric or oligomeric com- pounds polymerise very readily, normal sterilisation pro- cesses including ionising radiation at room temperature are completely useless. The patent also teaches that sterilization by ionising radiation of the adhesive composition in liquid form deleteriously affects the properties of the adhesive to the extent that it becomes unuseable. The patent states that only when solid adhesive material is irradiated is it possible to prevent damage to the substance both as regards its surgical usefulness and its adhesive properties as well as viscosity and stability; the patentees therefore prefer to cool the monomeric or oligomeric compounds to a temperature of not more than —30° C. The three working examples in the patent are carried out at —l96° C., —80° C. and —183° C. respectively. No stabilizers are used in any of the working examples. Example 1 states that an adhesive substance which was exposed to 0.2 Mrad (2 kGy) gamrna-ray dose at room temperature polymerised completely. 5,530,037 3 To carry out irradiation at low enough temperatures to achieve solidification of the adhesive composition is not a practical proposition for industrial production. Sterilization should be performed on the liquid adhesive temperature at or near to room temperature. A minimum dose requirement of 25 kGy (2.5 Mrad) gamma radiation is generally accepted as adequate for the purpose of sterilization (U.K. Department of Health “Qual- ity Systems for Sterile Medical Devices and Surgical Prod- ucts”, 1990 Good Manufacturing Practice, HMSO, London). A dose of 2 kGy (0.2 Mrad) would be wholly inadequate for achieving sterilization. U.S. Pat. No. 3,527,224 Rabinowitz describes a method of surgically bonding tissue using an adhesive composition based on n-pentyl alpha-cyanoacrylate which is subjected to partial polymerisation to increase its viscosity. Radiation such as gamma rays can be used to get both the desired partial polymerisation and sterilization in a one-step process. However a free-radical inhibitor must be introduced into the composition after the irradiation, with the risk of introducing bacterial contamination. The method of thickening would be diflicult to quench effectively after the desired viscosity is achieved. The present Applicants have invented a sterilized adhe- sive composition which contains monomeric cyanoacrylate in a substantially ungelled condition and which therefore is of low viscosity. The composition contains all of the nec- essary ingredients before it is sterilized by irradiation. The composition can be readily and fully sterilized by gamma irradiation with a minimum dose of 25 kGy (2.5 Mrad) at room temperature without any significant increase in vis- cosity while mantaining the necessary performance and shelf-life of the adhesive. Hydroquinone is generally used as the free-radical stabi- lizer for cyanoacrylate adhesives under normal ageing con- ditions. If a sufficient concentration (e.g. 500-1000 ppm) is present it will also be an elfective stabilizer to prevent polymerisation during gamma irradiation treatments. How- ever chemical changes to the hydroquinone molecule occur during the treatment, resulting in the conversion of approxi- mately 25% of the hydroquinone to 1,4-benzoquinone. This material is known to be toxic and its presence in an adhesive, especially if used for medical applications, would be unde- sirable. It is an object of the present invention to provide a sterilized cyanoacrylate composition which does not have the disadvantages discussed above. It is a particular object of the invention to provide a sterilized cyanoacrylate composition which is substantially free of toxic contaminants, especially 1,4-benzoquinone. SUMMARY OF THE INVENTION The present invention provides a curable cyanoacrylate adhesive composition for use in bonding, wherein the com- position has been sterilized in liquid form by gamma irra- diation and is the irradiation product of a composition comprising a) a cyanoacrylate monomer; and b) a combination of an anionic stabliser and a free-radical stabilizer in amounts effective to stabilize the compo- sition during irradiation and to stabilize the sterilized composition during storage prior to cure, wherein the free-radical stabilizer is a phenolic antioxidant selected from compounds of the formula I and II: 10 20 25 30 35 40 45 50 55 60 65 4 OH 1 R5 R1 R4 R2 R3 wherein R3 is —H, an alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms or an aryl group having 6 to 36 carbon atoms; R1, R2, R3 and R4, which may be the same or different, are each R3 or —OR5; provided that when R1, R2, R4 and R3 are each —H, R3 is not —OH; OH R5 CH 01‘ wherein R2, R3, R4 and R3 are as hereinbefore defined; R6, R7, R8, R9 and R10, which may be the same or diiferent are each R3 or —OR5; the cyanoacrylate monomer in the stabilized liquid compo- sition after irradiation being substantially ungelled. The invention further provides a method of making a curable sterile cyanoacrylate adhesive composition for use in bonding which comprises preparing a liquid composition comprising (a) a cyanoacrylate monomer (b) a combination of an anionic stabilizer and a free- radical stabilizer in amounts effective to stabilize the composition during sterilization by gamma irradiation and to stabilize the sterilized composition during stor- age prior to cure, wherein the free-radical stabilizer is a phenolic antioxidant selected from compounds of the formula I or II as defined above, and exposing the composition in liquid form to gamma irradiation in a dose suflicient to sterilize the com- position without substantial gelling of the cyanoacrylate monomer. In the compounds of Formula I or H an alkyl or alkenyl group preferably has up to 10 carbon atoms, more particu- larly up to 5 carbon atoms, most preferably up to 4 carbon atoms, and an aryl group preferably has up to 20 carbon atoms, more particularly up to 10 carbon atoms. In particularly preferred compounds of Formula I or II, at least one of R1, R2, R4 and R3 (and in the case of compounds of Formula II at least one of R7, R3 and R10) is -——C(CH3)3. Preferably also, R3 (and in the case of compounds of Formula II also R9) is selected from —CH3 and —OCH3. The most preferred compound of Formula I is butylated hydroxyanisole (BHA) which is a blend of isomers (2-tert- butyl-4-methoxy phenol and 3-tert-butyl-4-methoxy phe- ml). The preferred cyanoacrylate monomers are alkyl, alkenyl and alkoxy cyanoacrylate esters, more particularly such esters wherein the alkyl or alkenyl group has up to 10 carbon atoms, especially up to 5 carbon atoms. The cyanoacrylate monomer may be selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, iso-hexyl, 5,530,037 5 n-heptyl, iso-heptyl, n-octyl, n-nonyl, allyl, methoxyethyl, ethoxyethyl, 3-methoxybutyl and methoxyisopropyl cyanoacrylate esters. The preferred monomers are n-butyl, iso-butyl and sec- butyl cyanoacrylates because of their well known ability to bond tissue, bone tendons, etc. Other cyanoacrylate esters such as methyl, ethyl, n-propyl, n-hexyl, n-heptyl, n-octyl can also be used in such applications but suffer from certain disadvantages; e.g. methyl, ethyl and n-propyl cyanoacry- lates have less satisfactory spreadibility on wound areas and tend to induce localised inflammation. The higher homo- logues are well tolerated by the tissues but they are slower curing, give weaker bond strengths and are generally more difficult to synthesise on a commercial basis. n-Butyl cyanoacrylate is preferred for the compositions of this invention. The preferred method of the invention involves firstly the manufacture of an alkyl cyanoacrylate adhesive monomer, e.g. n-butyl cyanoacrylate, to a high and reproducible state of purity using the Knoevenagel reaction between the cor- responding alkyl cyanoacetate and paraforrnaldehyde fol- lowed by pyrolysis and distillation to remove process con- taminants. Anionic stabilizers, free-radical stabilizers, and optionally thickeners, dyes, thixotropic agents, etc. are added as required. The adhesive formulations are then packed into suitable bottles, tubes, vials etc. The filled bottles are then sealed in metal foil (e.g. aluminium foil) pouches and subjected to gamma irradiation with a dose of 25 kGy under conventional conditions i.e. at room tempera- ture. Following this treatment the adhesives and untreated controls are fully assayed and evaluated for bonding per- formance, viscosity, shelf life and especially any chemical changes which may have occurred during the irradiation stage. A range of alternative anti-oxidants were evaluated for their ability to stabilize n-butyl cyanoacrylate under normal conditions (see Example No. 3) and after gamma irradiation treatment (see Example No. 4). From examination of these findings on the basis of solubility, accelerated stability, condition after irradiation and toxicity considerations, it was found that butylated hydroxyanisole (BHA) was most suit- able. During the irradiation treatment approximately 900 ppm of BHA is degraded with the formation of a number of derivatives. These have been identified and none are deemed to be harmful (Ishizaki et al., Shokuhin Eiseigaku Zasshi, 16(4), 230-3). BHA is a well known pharmacopoieal sub- stance which is widely used as an anti-oxidant in foods and medicines and poses no significant toxicological hazard. The useful concentrations of BHA needed for the compositions of this invention are usually in the range 1000-5000 ppm. Variations may occur in the stability of the raw cyanoacry- late monomer from batch to batch, and levels of the anti- oxidant may be adjusted accordingly. Preferred concentra- tions are in the range 1500-3500 ppm, particularly above 2000 ppm. At levels less than 1000 ppm the adhesive may solidify or thicken excessively during radiation treatment due to the degradiation of 900 ppm as discussed above. At levels greater than 5000 ppm there is no additional benefit in the stabilizing efi'ect. Another preferred antioxidant is butyl hydroxy toluene (BHT, or 4-methyl-2,6-di-tert-butylphenol) which is also a well known antioxidant for food and therefore is non-toxic. However it needs to be used in larger amounts than BHA e. g. more than 2000 ppm and particularly above 2500 ppm. Other anti-oxidants which may be used include methyl hydroquinone, catechol, tert-butyl hydroquinone, 4—tert-bu- toxyphenol, 4-ethoxyphenol, 3-methoxyphenol, 2-tert-bu- 10 20 25 30 35 40 45 50 55 60 65 6 tyl-4-methoxyphenol, and 2,2-methylene-bis-(4—methyl—6- tert-butylphenol). These antioxidants may be used in different concentrations from BHA but generally in the range 500 to 10,000 ppm. The appropriate concentration can be determined by testing along the lines described below. Known anionic (acid) stabilizers for cyanoacrylate adhe- sives include Sulphur Dioxide, Sulphonic Acids, Sulphuric Acid, Sulphur Trioxide, Phosphorous Acids, Carboxylic Acids, Picric Acid, Boron Trifluoride, BF3-ether complexes, Citric Acid, Hydrofiuoric Acid, Tin (IV) Chloride, Iron (IH) Chloride, and mixtures of two or more thereof. Sulphur dioxide is particularly well known as a satisfac- tory stabilizer for cyanoacrylate adhesives under normal conditions of storage and use. Sulphur dioxide was also found to be a satisfactory anionic stabilizer during gamma irradiation treatment (EXAMPLE 6). The fate of sulphur dioxide during gamma irradiation was also investigated. It was found that all the sulphur dioxide remaining in the adhesive after irradiation was in the form of sulphuric acid. A proportion of the stabilizer was also found to be consumed during the treatment as it acted in its normal role as a polymerisation inhibitor (see Example No 6). The initial concentrations of sulphur dioxide needed to stabilize the adhesive compositions of this invention are in the range 20-150 ppm. Preferred concentrations are in the range 40—l20 ppm. At levels less than 20 ppm the adhesives may solidify or thicken excessively during irradiation or there may be insuflicient sulphur dioxide remaining to give a useful shelf-life after irradiation. The composition after irradiation should preferably contain sulphuric acid in an amount equivalent to at least 16 ppm of S02. At levels higher than 150 ppm the cure speed and general perfor- mance of the adhesive may be adversely impaired (see Example No 6). Concentration levels for other anionic stabilizers which are strong acids such as sulphonic acids, sulphuric acid, BF3 etc. are likely to be in the range of 15 to 150 ppm, and for weaker acids such as carboxylic acids are likely to be in the range of 25 to 500 ppm. As already noted, the stability of the raw cyanoacrylate monomer may vary from batch to batch, and levels of antioxidant and/or anionic stabilizer may be adjusted accordingly. The bond strength and cure speed of the adhesive com- positions described in this application were determined on nylon 66 (a polyarnide with a chemical reaction simulating skin in the context of bonding with cyanoacrylate adhesives) and pig skin. In each case adequate strengths and cure speeds were obtained. (see Example No. 6 and Example No. 7). While cyanoacrylate adhesives can be manufactured to a very high state of purity this standard may be compromised to meet the minimum requirements of industrial or consumer instant adhesives. No such compromise would be acceptable for adhesives supplied for medical and veterinary applica- tions. It is therefore desirable that the concentrations of all impurities should be identified where practical and mini- rnised by careful control of the manufacturing process. The adhesive compositions of this invention were assayed for total purity before and after sterilisation by gamma irradia- tion at a dose‘ of 25-35 kGy. (Example No 7). The effect of room temperature and refrigerated ageing on the levels of these impurities are also included in Example No. 7. Conventional additives such as thickeners, dyes and thixotropic agents may be included in the compositions as required. However for medical or veterinary use care must be taken to ensure that additives do not introduce toxic contaminants which survive or are produced by irradiation. 5,530,037 7 Polymethyl methacrylate, for example, may contain a resi- due of peroxide. Irradiation may itself cause some thicken- ing of the composition. For medical or veterinary use a maximum composition viscosity after irradiation of about 200 mPas is desirable, preferably less than 50 mPas, espe- cially less than 25 mPas. The adhesive compositions of this invention will retain their usability in bonding applications for extended periods at room temperature but are preferably stored under refrig- eration for maximum shelf-life (see Example No 7). When packaged in screw-cap bottles or tubes, an outer sealed metal foil pouch is required to preserve sterility. This barrier also prevents absorption of atmospheric moisture which can initiate premature gellation of the adhesive. The invention discloses a process and a formulation resulting in a shelf-stable, sterilisable cyanoacrylate adhe- sive which can be used for the bonding of tissue in medical and veterinary applications. The term “ppm” as used in this specification means parts per million by weight. All irradiation treatments in the following Examples were carried out in conventional manner at ambient temperature. DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1 (Comparative) A batch of n-Butylcyanoacrylate (BCA) was distilled under. reduced pressure of 1 mg Hg. The distillate was collected in a receiving vessel containing a concentrated solution of sulphur dioxide (S02) in a small volume of previously purified BCA monomer. The yield of distillate was weighed and the concentration of S02 adjusted to 0.0lO0% (100 ppm). This stabilized control BCA monomer was then divided into ainumber of parts. To these parts was added hydro- quinone (free radical stabilizer) to give the following series of samples containing the stated concentrations of hydro- quinone (HQ). Sample A 0.05% (500 ppm) HQ Sample B 0.l406% (1406 ppm) HO Sample C 0.1580% (1580 ppm) HQ Sample D 0,1714% (1714 ppm) HQ Sample E 0.2560% (2560 ppm) HQ Sample F 0.2574% (2574 ppm) HQ Portions of sample A to F were packed into small plastic bottles with screw cap closure. Each bottle was enclosed in an aluminium foil sachet which was heat sealed. The sachets and contents were then subjected to a gamma irradiation treatment, using a cobalt 60 source, with a dose of 25 Kilogray (kGy). After treatment the samples were removed from the sachets and examined visually. Sample A was found to have solidified. Samples B to F inclusive were low viscosity on inspection and the HQ content was assayed by the HPLC technique. The HQ concentrations before and after irradia- tion were as follows: 5 10 20 25 30 35 40 45 50 55 60 65 8 TABLE 1 HQ (ppm) Sample Ref. Before Irradiation After Irradiation A 500 Solidified B 1406 812 C 1580 988 D 1714 953 E 2560 1782 F 2574 1857 The results show a reduction in HQ concentration fol- lowing gamma irradiation. EXAMPLE 2 (Comparative) A sample of BCA containing 53 ppm S02 and 2983 ppm HQ was prepared as described in Example 1. A portion of the sample was subjected to a gamma irradiation dose of 25 kGy under the conditions described in Example 1. Both the untreated control and the irradiated sample were assayed to determine if any cherrrical or physical changes had occurred during the treatment. Results of the assay are in TABLE 2. TABLE 2 Untreated Control Irradiated HQ (ppm) 2983 2076 S02 (ppm) 53 ND H2SO4 (ppm) ND 60 1,4-Benzoquinone ND 552 n—Butylcyanoacetate (%) 0.20 0.20 Viscosity (rnPaS) 2.4 7.4 The detectable chemical and physical changes in the BCA composition following irradiation can be summarized as follows: (a) Approximately 25% of the hydroquinone was con- verted to 1,4-benzoquinone. (b) All the S02 was converted to sulphuric acid with 13 ppm of S02 being consumed. (c) The viscosity of the BCA monomer increased from 2.4 to 7.4 mPaS. EXAMPLE 3 (Stability Tests Without Irradiation) A batch of BCA monomer was prepared as in Example 1 and stabilized with 100 ppm S02. No free radical stabilizer was added at this stage. The batch of S02 stabilized BCA monomer was then sub-divided into a number of parts to each of which was added a known antioxidant material at a concentration of 0.54. These were mixed at room temperature and all dis- solved readily in BCA monomer except 4-tert-butoxyphe- nol. This material had poor solubility even after mixing and heating for an extended period. The efliciency of the antioxidants to act as free radical stabilizer in BCA was assessed by aging small samples of each antioxidant solution in corked glass tubes at 80° C. and 55° C. (in air circulating ovens). The time for gellation or 5,530,037 9 solidification to occur was determined by daily inspection. The Gel Time results are summarized in TABLE 3. TABLE 3 Antioxidant Gel Time (Days) (0.5% in BCA) 80° C. 55° C. Butyrated Hydroxy Anisole 18-19 83-89 Butylated Hydroxy Toluene 15-18 83-89 Methyl Hydroquinone 19-20 90-97 Catechol 20-22 104-108 tert—Buty1hydroquinone 4-7 89-90 4-t_eg-Butoxyphenol 1-3 10-12 4-Ethoxyphenol 19-20 90-92 3-Methoxyphenol 10-11 83-89 2-tert—Butyl-4—methoxyphenol 18-19 83-89 Hydroquinone 24-25 104-108 The above results, under accelerated conditions, predict with a few exceptions, that most of the antioxidants evalu- ated would be elfective free-radical stabilizers for BCA. The results also confirm that Hydroquinone is most effective in this regard. It is widely used to stabilize cyanoacrylate adhesives for industrial and household use. However it is unsuitable for use in a composition for irradiation for the reasons shown in Example 2. EXAMPLE 4 A batch of BCA monomer was prepared, free of antioxi- dants, by vacuum distillation at 1 mg Hg. Distillation of 631.1 g of relatively impure BCA gave 436 g of purified material. This was collected in a receiver containing suffi- cient SO2 concentrate to give a final concentration of 100 ppm S02. Solutions of various antioxidants were prepared in above BCA monomer at concentrations between 1000 ppm and 10,000 ppm. Details of the test solutions are in TABLE 4. Samples of each test solution were packed in small polyethylene bottles with screw-cap closures which were overwrapped individually in sealed aluminium foil pouches. The packaged samples were treated by gamma irradiation at a dose of 28.53 kGy. The viscosity of each test solution was determined before and after irradiation. The results are summarized below in TABLE 4. TABLE 4 VISCOSITY mPas TEST SOLUTION DETAILS Before After Ref. Conc. Irradi- Irradi- No. ANTIOXIDANT ppm ation ation 1 2,2‘-methylenebis(4-methyl— 2490 3.4 Gelled 6-tert—butylpheno1) 2 2,2'-methylenebis(4—methy1- 4970 3.4 Soft 6-tert-butylphenol) Gel 3 2,2'—methy1enebis(4-metl1yl— 10000 3.4 267.0 6-tert~buty1phenol) 4 Catechol 5000 3.4 9.9 5 t—Butylhydroquinone 50()0 3.4 3.4 6 4-Ethoxypbenol 5000 3.4 14.1 7 3-Methoxyphenol 50()0 3.4 Gelled 8 Butylated hydroxyanisole 10()0 3.4 Gelled 9 Butylated hydroxyanisole 2500 3.4 4.9 10 Butylated hydroxytoluene 1500 3.4 Gelled 11 Methyl hydroquinone 1500 3.4 Soft gel 20 25 30 35 40 45 50 55 60 65 10 TABLE 4-continued VISCOSITY mPas TEST SOLUTION DETAILS Before After Ref. Conc. Irradi- Irradi- No. ANTIOXIDANT ppm ation ation 12 Hydroquinone 1500 3.4 17.8 The above trials demonstrate that selection of both the type and concentration of antioxidant is necessary to obtain an efiicient free radical stabilizer for BCA to prevent gella- tion during gamma irradiation treatment. Butylated hydroxyanisole (BHA) at a concentration substantially above 1000 ppm before irradiation is the most suitable, with the preferred level being 2500 ppm. For butylated hydroxy- toluene (BHT) a higher concentration is needed than for BHA. Hydroquinone is effective as a stabilizer at relatively low levels. Derivatives of hydroquinone which do not have toxic break-down products may be selected by tests as described above. EXAMPLE 5 A batch of Ethyl Cyanoacrylate monomer was prepared using the techniques described in Example 1 and used as the basis of formulations A and B which had the following compositions: A. Ethyl cyanoacrylate stabilized with 20 ppm Boron Trifluoride and 5000 ppm Hydroquinone and thickened to a viscosity of 30 mPas by addition of 5% by weight of finely powdered polymethylmethacrylate. B. The same as formulation A above but with 20 ppm S02 added. Samples from each formulation were packaged in small polyethylene bottles with screw-cap closures and subjected to a sterilization process consisting of gamma irradiation from a Cobalt 60 source at a dose of 25 kilogray (kGy). After sterilization treatment the samples were examined visually and no significant change in viscosity was observed in either case. This example illustrates the successful sterilization of a cyanoacrylate adhesive containing thickener and anionic stabilizers alone or in combination and in conjunction with an effective concentration of a free radical stabilizer. EXAMPLE 6 A batch of BCA monomer was distilled as in Example i and stabilized with various levels of S02 and BHA as detailed below in Table 5. TABLE 5 BCA Composition Ref. BHA (ppm) S02 (ppm) 1 3034 31 2 2997 42 3 3189 50.4 4 3289 66.7 5 3267 79.8 6 3229 94 Samples of each liquid composition were packed in polyethylene bottles, overwrapped with sealed aluminium foil pouches and treated with gamma irradiation at a dosage of 25 kGy. 5,530,037 11 The irradiated samples and untreated controls were tested as follows: (a) BHA assay by HPLC. (b) S02 or 112804 by potentiometric Titration. 5 (c) Viscosity by Cannon Fenske capillary viscometer method. (d) Bond strength on Nylon 66 lapshears of dimensions 100 mm x 25 mm X 2 mm with an overlap bonded area of 312.5 ml. The bonds were clamped and cured for 12 The tests included assays for BHA, S02, viscosity and bond strength on Nylon 66 and the test methods are described in Example No. 7. Total purity as BCA was determined by gas chrornotography. 10 24 hours at RT. The bond strength was determined using a Tensile testing machine at a crosshead speed of 2 mrn/min. (e) Time to gel when aged in glass test tubes at 82° C. in an air circulating oven. 15 (1') Time to gel when aged in a polyethylene bottle at 55° C. in an air circulating oven. See Test results before irradiation (Table 6A) and after irradiation (Table 6B). TABLE 6A (Before Irradiation) Bond Gel Gel BCA Strength Time at Time at Composition BHA S02 Viscosity Nylon 66 82° C. 55° C. Ref. No. (ppm) (ppm) (mPaS) (daNcm’z) (days) (days) 1 3034 31 13.7 25 10+ 50+ 2 2997 42 14.2 27 10+ 50+ 3 3189 50.4 14.5 32 10+ 50+ 4 3289 66.7 14.5 26 10+ 50+ 5 3267 79.8 14.5 24 10+ 50+ 6 3229 94 14.5 24 10+ 50+ TABLE 6B __ (After Irradiation) Bond Gel Gel BCA Strength Time at Time at Composition BHA S02 Viscosity Nylon 66 82° C. 55° C. Ref. No. (ppm) (ppm) (mPaS) (daNcm‘2) (days) (days) 1 1995 2 9.4 21 1.5
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