Adhesive Composition for Surgical Use

United States Patent [19] Hyon et al. US006103778A [11] Patent Number: [45] Date of Patent: 6,103,778 Aug. 15,2000 [54] ADHESIVE COMPOSITION FOR SURGICAL USE [75] Inventors: Suong-Hyu Hyon; Naoki Nakajima, both of Kyoto, Japan [73] Assignee: BMG Inc., Kyoto, Japan [21] Appl. No.: 09/162,491 [22] Filed: Sep. 28, 1998 [30] Foreign Application Priority Data Feb. 12, 1998 [JP] Japan ................................ .. 10—069203 [51] Int. Cl.7 .. C08L 67/00; A61K 31/765 [52] U.S. Cl. ......................... .. 523/111; 523/118; 524/539; 525/411; 525/412; 525/415; 525/450 [58] Field of Search ................................... .. 523/111, 118; 524/539; 525/411, 412, 415, 450 [56] References Cited U.S. PATENT DOCUMENTS 4,804,691 2/1989 English et al. ........................ .. 523/118 5,514,371 5/1996 Leung et al. .......................... .. 526/300 5,550,172 8/1996 Regula et al. ........................ .. 523/118 FOREIGN PATENT DOCUMENTS 3273679 11/1988 Japan ................................... .. 523/118 OTHER PUBLICATIONS Odian, George, Principles of Polymerization, 2d Ed., New York, Wiley & Sons, 1981, p. 21. Primary Examiner—AndreW E. C. Merriam Attorney, Agent, or Firm—Jordan and Hamburg LLP [57] ABSTRACT An adhesive composition for surgical use including an ot-cyanoacrylate adhesive composition with a polymer char- acteristic for biodegrading and bioabsorbing the adhesive into the body of a living organism. It is preferred that the polymer is a co-polymer of DL-lactic acid and e-caprolactone or a co-polymer of DL-lactic acid, ethylene glycol and e-caprolactone, or a co-polymer of ethylene glycol and e-caprolactone. 4 Claims, 2 Drawing Sheets U.S. Patent Aug. 15,2000 Sheet 1 0f2 6,103,778 1500 1000 500 Adhesion strength (gf) Additive amount of co—Do|ymer (w/w%) Fig. 1 Adhesion Properties of Novel Adhesive Molecular Weight of co-polymer ; 1x1O5(o), 6x1O4(A), 4x1O4(u), Biobond (0), Fibrin (A) U.S. Patent Aug. 15,2000 Sheet 2 of2 6,103,778 80 70 60 50 40 30 20 10 0 10 20 30 40 50 Additive amount of co-polymer (W/W°/0) Hardness of Hardened NBCA specimen Fig. 2 Hardness of Hardened Novel Adhesive after Polymerization ; 1x1O5(o), 6x1O4(A), 4x1O4(U) 6,103,778 1 ADHESIVE COMPOSITION FOR SURGICAL USE BACKGROUND OF THE INVENTION 1. Field of The Invention The present invention relates to adhesive compositions for surgical use. More particularly, it relates to novel compositions, which are adjusted to have a suitable viscosity and a reduced cytotoxicity. The novel compositions have a softness similar to the soft tissue of a living organism and are easily biodegraded and bioabsorbed into the living organism at a moderate speed after healing. These novel compositions result from improving ot-cyanoacrylate adhesive composi- tion. 2. Description of The Related Art Suturing and anastomosis of a wound is one of the most important operating techniques in any surgical operation. Therefore, the healing speed of the wound makes most of the difference between a good or a poor operation. Nowadays, the material compositions and operating methods for improving the speed of healing are continuously improving. For example, there have been improvements in methods for suturing a wound, and many good sutures have become readily available as a result. However, special techniques are still necessary in operations involving microvascular anas- tomosis and nerve sutures. Therefore, new inventions con- cerning adhesive methods for use in the living body system are needed to shorten surgical operations. There are many proposed reports and inventions all over the world for the above purpose. The ot-cyanoacrylate adhesive compositions are already widely sold in the market as adhesive compositions for surgical use. However, they remain of limited use in special clinical applications, because they often leak due to the low viscosity of the composition. The leakage sometimes dam- ages the soft tissue. Additionally, these adhesive composi- tion have a high cytotoxicity for the living cell. The inventors of this patent have already disclosed several means (JP. Pat. 116409/ 1995) to remedy the above defects. This patent concerns new compositions for surgical use, in which a homo-polymer of lactic acid (DL-, D- and L- type), a co-polymer of lactic acid and glycolic acid or a co-polymer of lactic acid and e-caprolactone are added to the ot-cyanoacrylate adhesive composition as a thickening agent and a stabilizer. The resulting composition is easily biode- gradable and bioabsorbable into the body of the living organism. However, this patent fails to disclose the cytotoxicity of the surgical adhesive composition for the living cell, and, therefore, the cytotoxicity for the living cell is still uncertain. Weight-average molecular weights of the homo-polymer of DL-lactic acid and the co-polymer of lactic acid and e-caprolactone are about 140,000 and 220,000 respectively, which is a relatively high molecular weight, so they are suitable as a thickening agent. The patent also fails to disclose the effects of molecular weight on plasticizing after hardening, and the hydrolyzing velocity of co-polymer compositions of lactic acid and e-caprolactone when employed as a thickening agent. SUMMARY OF THE INVENTION The present invention proposes a novel adhesive compo- sition for surgical use adding a polymer characteristic to an ot-cyanoacrylate adhesive composition to biodegrade and bioabsorb it into the body of a living organism. It is preferred 10 15 20 25 30 35 40 45 50 55 60 65 2 that the polymer is a co-polymer of DL-lactic acid and an e-caprolactone, or a co-polymer of DL-lactic acid, ethylene glycol and e-caprolactone, or a co-polymer of ethylene glycol and e-caprolactone. It is highly preferred that the ratio of the composition is in the range of 70:30 to 30:70, that the weight-average molecular weight of the co-polymer of DL-lactic acid and e-caprolactone are 10,000 to 120,000, and that the concentration of the co-polymer is in the range of 1 to 50 weight by weight percent. It is also preferred that the glass transition temperature of the polymer is in the range from 0 to —30° C. The novel adhesive compositions of the invention can be easily adjusted to any degree of thickening agent to control viscosity. The hardened polymer, after polymerization, exhibits a softness and has an affinity to the body of a living organism, such as blood vessels, skin and viscera. It is possible that wider applications can be added to former uses of ot-cyanoacrylate, because the composition is widely applied to hemostasis. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic view illustrating the adhesion properties between swine skin and n-butyl-cyanoacrylate (NBCA)by adding polymers of various weight-average molecular weights of DL-lactic acid and e-caprolactone (mole ratio of 50:50 by DL-lactic acid and e-caprolactone), and also illustrating comparison of adhesion strengths with adhesive sold in the market, such as, “Biobond” (fabricated by Yoshitomi Ph.) and “Fibrin Glue” (fabricated by Fujisawa Ph.). FIG. 2 is a schematic view illustrating the hardness of a hardened NBCA specimen after polymerization according to the addition of various weight-average molecular weights of DL-lactic acid and e-caprolactone (mole ratio of 50:50 by DL-lactic acid and e-caprolactone). The vertical axis shows the Shore Hardness of a D type. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel adhesive compo- sitions of ot-cyanoacrylate for surgical use, which have a suitable viscosity, reduced cytotoxicity to cells, a softness similar to the soft tissue of a living organism, and which are easily biodegraded and bioabsorbed into the body of the living organism at a moderate speed after healing. Essentially, healing a wound in a living organism involves hyperplasia of the connective tissue by a renaturation ability in the living organism. Therefore, it is preferable to apply an adhesive, rather than to suture, to fix and support the connective tissue, in order not to prevent the restoration ability of the living organism during the week or 10 days necessary to finally heal the wound. In other words, the role of the preferred adhesive is to fix and adhere the wound during the period needed to complete the healing process, and then easily biodegrade, and bioabsorb into the body of the living organism and disappear soon thereafter. In addition, it is also important and necessary that biodegraded products of the adhesive are not poisonous or dangerous. The preferable qualities for an adhesive in a living organism include the following: 1) The ability to adhere at room temperature (bodily temperature) under conditions of high humidity and when in contact with fat. 2) The ability to combine enough tensile strength with softness in the hardened product, especially when adhering a wound on the face. 6,103,778 3 3) Exhibiting no tissue toxicity and no carcinogenesis, and causing little reactionary resistance as a foreign body. 4) Not interfering with the healing of a wound in a living organism. 5) The ability to biodegrade and be expelled through the living organism after healing. 6) The ability to be sterilized. 7) The ability to be easily manipulated and quickly applied to the wound. It is believed that an adhesive satisfying the above con- ditions is the best adhesive for use in surgical applications. The present invention proposes novel compositions of an improved ot-cyanoacrylate adhesive composition for surgi- cal use, which has a suitable viscosity, reduced cytotoxicity, a softness similar to the soft tissue of a living organism, and which is easily biodegraded and bioabsorbed into the body of the living organism at a moderate speed after healing. In order to meet the above criteria, the present invention is a novel adhesive composition for surgical use, which is prepared by adding polymers to an otcyanoacrylate adhesive composition to provide an easily biodegrading and bioab- sorbing adhesive composition. The polymers include the co-polymer of DL-lactic acid and e-caprolactone or the co-polymer of DL-lactic acid, an ethylene glycol and e-caprolactone, or the co-polymer of the ethylene glycol and e-caprolactone. A most important factor for the surgical use of the adhesive concerns the cytotoxicity of the living cell. In other words, the adhesive composition must be safe for a living cell. Therefore, the adhesive composition has to be reduced to the level of cytotoxicity, of the living cell, when applied as a surgical adhesive. Moreover, it is difficult to increase the additive amount and adjust the thickening agent to a suitable degree by adding polymers, when the polymers have a weight-average molecular weight of more than 140,000, because the addi- tive amount depends on the molecular weight. Therefore, it is preferred that a co-polymer of DL-lactic acid and e-caprolactone have a weight-average molecular weight within a range from 10,000 to 120,000. A co-polymcr having a wcight-avcragc molecular weight of less than 10,000 shows poor properties as a polymer, such as an adhesive, while it is possible to increase the additive amount. Furthermore, it is difficult to get a soft hardened polymer with a high speed of biodecomposition and bioab- sorption into a living organism when employing a high weight-average molecular weight polymer. As previously mentioned, the speed of biodecomposition and bioabsorp- tion largely depends upon the molecular weight and crys- tallinity of the polymer. It is preferable to employ a polymer having low molecular weight and crystallinity in order to improve the properties of biodecomposition and bioabsorp- tion. In the case of a co-polymer of DL-lactic acid and e-caprolactone, the glass transition temperature largely depends on the composed ratio of the co-polymer. Therefore, when a DL-lactic acid ratio in the co-polymer is more than 70%, the glass transition temperature of the co-polymer is greater than 0° C. On the other hand, when the e-caprolactone ratio in the co-polymer is more than 70%, the glass transition temperature of the co-polymer is lower than 0° C., but the co-polymer changes hardness according to the degree of crystallinity. In conclusion, the preferable mole ratio of the DL-lactic acid to e-caprolactone in the co-polymer composition is in the range of from 70:30 to 30:70 based on the crystallinity and the softness of the co-polymer. 10 15 20 25 30 35 40 45 50 55 60 65 4 Furthermore, the co-polymer of DL-lactic acid, ethylene glycol and e-caprolactone, and the co-polymer of ethylene glycol and e-caprolactone can be employed to improve the ot-cyanoacrylate surgical adhesive. It is preferred that the molecular weight is within a range of from 10,000 to 200,000 and the composed ratio is within a range for preventing the crystallization of the co-polymer. In this invention, the co-polymers employed to improve the viscosity and the softness after hardening ot-cyanoacrylate are synthesized from lactic acid as a raw material, which widely disperses not only in the living body but also in nature, and e-caprolactone, which is widely used as a raw material for polyurethane, available for both household and industrial use. These raw materials are ordi- narily eliminated in the metabolism of the living body and exhibit no poisonous qualities. Furthermore, co-polymers of DL-lactic acid and e-caprolactone are already employed as sutures in medical use applications. Polyethylene glycol exhibits no poisonous qualities and can possibly be elimi- nated from the body when the polymer has a molecular weight of less than several ten thousands, in spite of having poor biodecomposability. The co-polymer of DL-lactic acid and e-caprolactone employed in the invention is soft, even at room temperature, and looks like rubber because the weight-average molecular weight is in a relatively low range of 10,000 to 120,000. Not only is the hardened co-polymer soft, but also the adhesive viscosity can be changed to any level by adding ot-cyanoacrylate. It is possible to reduce the usage of poi- sonous ot-cyanoacrylate when adjusting to an intensive softness and viscosity. The amount of ot-cyanoacrylate can be reduced by employing, as a thickening agent, a relatively low molecular co-polymer having a weight-average molecu- lar weight of less than 120,000. The cytotoxicity to the living cell is thus reduced to the same level as with the co-polymer of polyethylene glycol. EXAMPLES Example 1 FIG. 1 is a schematic view illustrating the changes in adhesion properties between swine skin (about 1>