Cyanoacrylate Medical Adhesives-A New Era

Cyanoacrylate Medical Adhesives———A New Era Colgate® ORABASE® Soothe-N-Seal” 2 Liquid Protectant for Canker Sore Relief Upvan Narang, PhD Manager, Product Development ‘Closure Medical Corpora/tvion ‘Raleigh, North Ca-rolina’ Abstract: Cyanoacrylate, a synthetic adhesive, is a fast polymerizable liquid monomer. Serendipity led to the discovery of cyanoacrylate adhesives in 1951. Today, a specific cyanoacrylate monomer, 2-octyl cyanoacrylate, is being used in a topical medical adhesive formulation. The only over—the— counter cyanoacrylate—based product cleared by the Food and Drug Administration is Colgate® ORABASE® Soothe-N-Seal“ Liquid Protectant. Upon application, this liquid monomer formulation polymerizes instantly into a thin, flexible polymer film that adheres tenaciously to mucosal tissue. This polymer film creates a mechanical barrier that provides immediate and long— term pain relief of oral ulcerations and irritations, and maintains a natural healing environment for the area to healfl The History of cyanoacrylate Adhesives In 1951, Dr. H. W. Coover was conducting research on heat—resistant acrylate polymers at the research laboratories of Tennessee Eastman Company. To measure the refractive index of ethyl cyanoacrylate, it was placed between the two prisms of an Abbe refractometer. After measuring the refractive index, it was realized that the prisms were glued together, a loss of a $700 instrument but the discovery of cyanoacrylate adhesives.‘ The first commercial industrial~grade cyanoacrylate adhesive, Eastman 910 adhesive, was introduced in 1958.‘ The first medical application of cyanoacrylates was the use of industrial» grade material during the Korean and Vietnam wars, primarily as a hemostat— ic agent. Ethicon, a division of Johnson & Johnson, pursued the medical use of cyanoacrylates in the 1960s but failed to get approval from the Food and Drug Administration (FDA)? In 1989, Closure Medical Corporation started research on the development of a Z—octyl cyanoacrylate (Z—OCA) and devel~ oped an extremely pure form. Based on this pure 2—OCA, a medical cyano— acrylate product, DERMABOND®"“ Topical Skin Adhesive, was approved by the FDA in 1998. In 1999, using another unique 2—OCA formulation, Closure Medical Corporation received FDA clearance on the first over—the—counter (OTC) cyanoacrylate product, Colgate® ORABASE® Soothe-N-Seal“ Liquid Protectantb, indicated for use on canker sores, mouth sores, and traumatic ulcers. Recently (January 2001), Closure Medical Corporation received FDA clearance for their second OTC cyanoacrylate product, Liquid Adhesive Bandage. This uniquely formulated Z—OCA liquid bandage is indicated for use on minor cuts, minor abrasions, and minor burns and irritations in place of using regular tape adhesive bandages. In Europe and Canada, cyanoacrylate derivatives have been available as surgical tissue adhesives for many years.“ The Types of cyanoacrylates NEG H The general formula of a cyanoacrylate monomer \C=C/ is displayed (right). ‘R’ is most commonly an alkyl 0 C/ \H »- Ethicon, Somerville, NJ 08876; soo—255,25oo ’ \ " Colgate Oral Pharmaceuticals, Canton, MA 02021; 800~8Zl-Z880 Vol. 22, N0. 32 Learning Objectives: After reading this article, the reader should be able to: 0 describe the cyanoacrylate technology used to develop Colgate'5' ORABASE‘ Soothe -N - Seal” Liquid Protectant. differentiate between industrial— and medical— grade cyanoacrylate adhesives. appreciate the benefits offered by Colgate® ORABASE""“ Soothe-N-Seal” Liquid Protectant. discuss the mechanism of action for the various benefits provided by Colgate“ ORABASE”"" Soothe-N-Seal” Liquid Protectant. 2-alkyl cyanoacrylate monomer Compendium / June 2001 7 Figure 1C-3 months after th application of DERMABOND® adhesive. group such as methyl, ethyl, isopropyl, butyl, octyl, etc. Although many other esters are reported in the literaturef the most common— ly used industrial—grade cyanoacrylates are the short—chain methyl and ethyl cyanoacrylates. Unfortunately, the short alkyl—chain—cyano» acrylates proved to be toxic to tissue, pre» venting their use as medical adhesives.“ 2» OCA, a longer alkyl~chain—length cyanoacry- late, has been formulated to various products that have been approved by the FDA for use in the United Statesf‘ |ndustriaI- vs Medical-Grade cyanoacrylates The primary property that distinguishes a medical~grade from an industrial»grade cyanoacrylate is its biocompatibility. The main factors that have been found to impact the biocompatibility of cyanoacrylates are: (1) the purity of the cyanoacrylate monomer used; (2) the degradation rate of the poly— cyanoacrylate formed"'7'“’; and (3) the choice and concentration of stabilizers used. The short alkyl~chain—length polycyanoacrylates degrade rapidly, resulting in the accumula— tion of degradation products, which are reported to cause tissue reaction.“*7*9 However, longer alkyl—chain—length polycyanoacrylates iiiatniiipendinfm / June 2001 Figure 1B—lmmediate|y after application oi DERMABOND® adhesive to the laceration. degrade slowly, improving their biocompati~ bility.“*’ Industrial—grade cyanoacrylate monomers lack purity, they illicit tissue reaction, and the polycyanoacrylate films formed are brittle.“-7'” In contrast, the medical—grade cyanoacrylates, specifically Closure Medical Corporations 2—OCA, has a purity of 2 99% and the poly- Z«OCA films formed are flexible.” To manu~ facture a medical~grade cyanoacrylate, the manufacturing, formulation, and packaging processes must be very consistent. ' 2-Doivi cyanoacrylate Closure Medical Corporation’s Z—OCA is a medical—grade cyanoacrylate. Under ambient conditions (room temperature), it is a reactive liquid that will polymerize in the presence of moisture, wound fluid, or other anionic and basic materials. Mucosal surfaces are moist enough to instantly transform Z—OCA liquid monomer into a film of poly»2—OCA. The poly- 2—OCA film has the flexibility and continuity to function as an excellent microbial barrier. It adheres tenaciously to tissue and sloughs off as the wound heals and epithelializes. DERMABOND® Topical Skin Adhesive In 1998, DERMABOND® Topical Skin Adhesive, a professional product that is based on a Z—OCA formulation, was approved by the FDA for topical wound closure. It is indicated for closing lacerations and incisions in place of sutures and staples, and has been demonstrated to have wound»closure strength equivalent to 5—O suturesf‘ It provides numerous benefits to both patients and providers, such as: (1) no need for a local anesthetic; (2) no trauma from cannula punctures in and around the wound; (3) improved cosmetic outcome because there are no suture needle tracks; and (4) no need Vol. 22, NO. 32 ‘;Z}E.;;ir;3I.§..{i,f Mouth 50/*9 Ifam ‘ Figure 2~Consumer package for Colgate® 0RABASE® Soothe-N-Seal” Liquid Protectant tor Canker Sore Relief. Figure 4A—Drip two drops of the ormulation Into a well. for return visits for suture removal because DERMABOND® adhesive sloughs off as the wound heals and the skin around the lacera» tion re»epithelializes. In Figure 1A, a child presents with a lacer~ ation around the eyelid area; in Figure 1B, DERMABOND® adhesive, a liquid monomer formulation, has been applied and formed a film within approximately 1 minute. Figure 1C demonstrates the excellent cosmetic outcome. Since the introduction of DERMABOND® Topical Skin Adhesive in 1998, we estimate that it has been used with success in more than 5 million procedures. Colgate® 0RABASE® Soothe-N-Seal'”“ In 1999, based on a unique Z~OCA formu» lation, the first OTC cyanoacrylate product, Colgate® ORABASE® Soothe-N-Seal” Liquid Protectant, was cleared by the FDA. The con» sumer package (Figure 2) contains 10 applica— tor swabs, a plastic dropper bottle containing the Z~OCA formulation, and a plastic tray with 10 individual wells (Figure 3). It should be noted that the applicator swab has foam on either end; the round end is for drying the ulceration/irritation and the pointed end is for the application of the 2~OCA formulation. Vol.22, No.32 Igure 3—Contents of the consumer package for Co|gate® ORABASE“) Soothe-N-Seal” Liquid Protectant. Figure 4B~Dip the pointed end of the swab Into the well containing the formulation. Easy to Apply To apply the product on an oral ulcera— tion/irritation (Figures 4A and 4B and 5A through 5D), 2 drops of the Z—OCA formula» tion are dripped into one of the 10 wells in the tray. The pointed end of the swab is dipped into the well for a few seconds until the liquid is absorbed. The lip or cheek is pulled away from the mouth sore (Figure 5A). The ulceration/irritation is dried by gently dabbing with the round end of the swab (Figure 5B). The pointed end of the swab is dabbed on the area for no more than a second (Figure 5C). A second dab may be necessary before discarding the swab. The newly formed polymer will feel like a textured film over the area (Figure 5D). Microbial Barrier Film The polymer film formed by the Z~OCA formulation was tested in vitro for its micro» bial barrier properties. Glass penicylinders were placed in the middle of agar plates. The Z—OCA formulation pipetted into the glass penicylinder polymerized instantly on con- tact with the moist agar surface. The film was challenged with a solution containing at least 105 colony forming units (CFU) of various Compendium/June 200‘: 10 Figure 5APu|lte lip orcheek tor application. Figure 5C—Dab pointed end of the swab on the sore. microorganisms by placing the inoculum on top of the film and then incubating it under conditions appropriate to the organism. The organisms tested were Staphylococcus aureus, Escherichia coli, Candida albicans, Aspergillus niger, Staphylococcus mutans, Streptococcus mutans, Streptococcus salivarius, and Clostridium sartagoforme. As a positive control, the poly-2- OCA films formed were deliberately compro» mised by poking pinholes in the film. Figure 6A represents a film that was chal» lenged by 105 CFU of S aureus inoculum daily for 7 days. There was no growth observed at the bottom of the film, even after the repeated challenge. In contrast, within the first 24 hours, there was significant growth observed on the positive control (Figure 6B) demon» strating that the intact poly»2»OCA film is a microbial barrier. Similar results were obtained with all the organisms tested. Pain Relief and Natural Healing Environment In clinical studies, patients using this product on mouth sores such as aphthous ulcers experienced immediate and long»term pain relief.” Faster healing was observed in the investigational clinical study for this Compendium / June 2001 Figure 5B—Dry sore (remove moisture) with round en of the swab. Figure 5D——Within seconds, a poly-2—0CA film is formed over the sore. product.” It is believed that the action of the poly»Z»OCA film as a mechanical barrier is the mechanism of action for both of these product attributes. Figure 7A is a schematic representing an oral ulceration/irritation, which can be irri» tated by any external stimulus such as eating, drinking, etc. Upon application, liquid cyanoacrylate instantly polymerizes into a film that completely covers the area (Figures 5D and 7B). This film is a flexible physical and microbial barrier that adheres tenacious» ly and intimately to the mucosal tissue. Such a mechanical barrier completely protects the area from the external environment, thus providing a natural environment for healing. The film is formed within seconds of applica» tion and covers the exposed nerve endings of the area, providing instant pain relief. The film stays on for hours, providing long»term pain relief. The patient can safely eat and drink, with little or no pain, while using the product. The film gradually sloughs off the oral mucosa. other Properties The poly»Z»OCA film is odorless and tasteless. Shelf life of the product is 2 years Vol.22, No.32 Figure 6A— Glass cylinder on an agar plate containing an intact poly-2- OCA film, which has been repeat- edly challenged for 7 days with 105 CFU of S aureus. Figure 7A—— Painful irritants such as food § easily penetrate untreated canker sores. under ambient (room temperature) storage conditions. This product has been uniquely formulated and packaged to maintain stability during storage and also maintain its reactivity to set within seconds when applied on the mucosal tissue. Conclusion Colgate® ORABASE® Soothe-N-Sealm Liquid Protectant is the first OTC cyanoacry» late product cleared by the FDA. It is a liquid that sets into a film on the mucosal tissue with» in seconds of application. The resulting poly» cyanoacrylate film is a thin, tasteless, odorless, flexible microbial barrier that stays on for hours. It provides immediate and long»term pain relief and a natural healing environment for the area to heal. References 1. Coover HW: Cyanoacrylate adhesives——A day of serendipity, a decade of hard work. ACS Org Coat Appl Polym Sci Proc 48:24}, 1983. 2. Ellis DA, Shaikh A: The ideal tissue adhesive in facial Vol. 22, No.32 Figure 68- Glass cylinder on an agar plate containing a deliberately compromised poly-2—0CA ‘ film, which has ’ been challenged with 105 CFU of S aureus and incubated for 24 hours. Figure 7B— This unique liquid barrier seals nerve endings for immediate pain relief and protection from irritation up to 6 hours, allowing heal- ing to occur. 10. plastic and reconstructive surgery] Otolaryngol 19(1):68» 72, 1990. Quinn JV, Drzewiecki A, Li MM, et al: A randomized, controlled trial comparing a tissue adhesive with suturing in the repair of pediatric facial lacerations. Ann Emerg Med 22(7):1130»1135, 1993. Alhopuro S, Rintala A, Salo N, et al: Tissue adhesive vs sutures in closure of incision wounds. A comparative study in human skin. Ann Chir Gynaecol 65(5):308»312, 1976. . Shantha KL, Thennarasu S, Krishnamurti N: Develop» ments and applications of cyanoacrylate adhesives. J Adhesion Sci Technol 3(4):237, 1989. Leonard F, Kulkami RK, Brandes G et al: Synthesis and degradation of polyalkyl alpha-cyanoacrylates. J Appl Polymer Sci 102259, 1966. Toriuini DM, Raslan WF, Friedman M, et al: Histotoxicity of cyanoacrylate tissue adhesives. A com» parative study. Arch Otolaryngol Head Neck Surg 116(5):546»550, 1990. Quinn ], Wells G, Sutcliffe T, et al: A randomized trial comparing octylcyanoacrylate tissue adhesive and sutures in the management of lacerations. JAMA Z77(19):15Z7» 1530, 1997. Ikada Y: Tissue adhesives. Chu CC, Fraunhofen ]AV, Greisier HP (eds): Wound Closure Biomaterials. Boca Raton, CRC Press, pp 317-346, 1997. Kutcher M, Ludlow JB, Samuelson AD, et al: Evaluation of a bioadhesive device for the management of aphthous ulcers. I Am Dent Assoc 13Z(3):368»376, Z001. Compendium / June 2001 11