Medical and Surgical Adhesive Composition and Process for its Preparation

PCT WORLD INTELLECTUAL PROPERTY ORGANIZATION Intemational Bureau INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 6 : A61L 25/00, C09J 133/20 (21) International Application Number: PCI‘/IB96/00210 (22) International Filing Date: 30 January I996 (30.0l.96) (30) Priority Data: FI95A0000l7 31 January 1995 (31.0l.95) IT (71) Applicant (for all designated States except US): SAYBROOK TRADING LIMITED [—/—]; Vantexpool Plaza, Wickhams Cay 1, P.0. Box 873, Road Town, Tortola (VG). (72) Inventor; and (75) InventorIApplicant (for US only): LEPLYANIN, Gennadiy Viktorovich [RU/RU]; Apartment 5, Dzerdginskogo 20, Kaliningrad, Moscow, 141070 (RU). (11) International Publication Number: (43) International Publication Date: WO 96/23532 8 August 1996 (08.08.96) (81) Designated States: AL, AM, AT, AU, AZ, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LS, LT, LU, LV, MD. MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TI‘, UA, UG, US, UZ, VN, ARIPO patent (KE, LS, MW, SD, SZ, UG), Eurasian patent (AZ, BY, KG, KZ, RU, TJ, TM), European patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG). Published With international search report. Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of amendments. (54) Title: MEDICAL AND SURGICAL ADHESIVE COMPOSITION AND PROCESS FOR ITS PREPARATION (57) Abstract A medical and surgical adhesive composition is described which provides an increased elasticity of the adhesive film and which is free of side effects, comprising 2-ethyl cyanoacrylate, butyl acrylate and 3-methacryloxy sulfolane. AM AT AU BB BE BF BG 3.] BR BY CA CF CG CH CI CM CN CS CZ DE DK FOR THE PURPOSES OF INFORMATION ONLY Codes used to identify States party to the PCI‘ on the front pages of pamphlets publishing intemational applications under the PCT. Annenia Austria Australia Barbados Belgium Burkina Faso Bulgaria Benin Brazil Belarus Canada Central African Republic Congo Switzerland Cote d’Ivoire Cameroon China Czechoslovakia Czech Republic Germany Denmark Estonia Spain Finland France Gabon United Kingdom Georgia Guinea Greece Hungary Ireland Italy Japan Kenya Kyrgystan Democratic People's Republic of Korea Republic of Korea Kazakhstan Liechtenstein Sri Lanka Liberia Lithuania Luxembourg Latvia Monaco Republic of Moldova Madagascar Mali Mongolia Mauritania Malawi Mex ioo Niger Netherlands Norway New Zealand Poland Portugal Romania Russian Federation Sudan Sweden Singapore Slovenia Slovakia Senegal Swaziland Chad Togo Tajikistan Trinidad and Tobago Ukraine Uganda United States of America Uzbekistan Vie! Nam 10 15 20 25 30 35 WO 96/23532 PCTIIB96/00210 -1- DESCRIPTION MED L ND I AL ADHESIVEC MP SITI N AND PRQQESS FQR ITS PREPARATIQN The present invention relates to medical and surgical adhesives and particularly to medical and surgical adhesive compositions comprising 2-ethyl cyanoacrylate. It is known that conventional medical and surgical adhesives are synthesized starting from derivatives of 2-cyanoacrylic acid. They show remarkable adhesive properties, fonning a strong film which is easily adsorbed by the human organism. The most important feature of derivatives of cyanoacrylic acid (particularly esters) is their capacity of polymerizing in a wet environment at body temperature in a few seconds. Derivatives of 2-cyanoacrylic acid are therefore used in order to glue tissues in surgical operations on kidneys, pancreas, liver, cholecyst, ureters and bile ducts, in cardiovascular and thoracic surgery, in ophthalmology, in order to glue muscles, subcutaneous tissue, epidennis and cutaneous injuries, in plastic surgery of cross ligaments in the knee articulations, in obstetrics, in gynaecology and so on. A disadvantage of derivatives of cyanoacrylic acid is a remarkable and, in some cases, acute inflammatory reaction of the glued tissues. In the first 24 hours after the glueing of said tissues, e.g. with 2-ethyl cyanoacrylate, an acute segmental reaction appears around the adhesive film with manifestations of different levels according to the different tissues. In bony tissues said reaction is weak and disappears within a week, whereas on vasal walls it dicreases at the end of the second week and on the walls of carotid and ureters it continues for a month. The most acute inflammation has been observed in the muscular tissues. In order to reduce inflammatory reactions caused by derivatives of 2-cyanoacrylic acid it was used a mixture of antibiotics and other anti-inflammatory agents. However, the choice is quite limited, and such a mixture does not completely solve the problem. Furthennore, hydroxyl, amino and amido groups contained in most anti-inflammatory drugs produce a quick polimerization of compositions, with a consequent quick decadence. A further disadvantage of cyanoacrylates is represented by the inadequate elasticity and by the fragility of the final film, which tends to crack just after its formation. Accordingly, it is an object of the present invention to provide a medical and surgical adhesive which overcomes the above mentioned disadvantages, has a simple use and is resistant in time. It was surprisingly found that if 2-ethyl cyanoacrylate is combined with two particular compounds, the resulting adhesive is characterized by the following CONFIRMATION COPY 10 15 20 25 30 35 WO 96/23532 PCT/IB96/00210 -7- ._ advantages: absence of cutaneous inflammation, absence of flesh inflammation and of enteral walls inflammation by glueing enteral loops without torsions or perforations; by applying enteral anastomoses with a stitch reinforcement; by sealing enteral anastomoses made with suture thread, with a gap between the stitches increased till 10 mm. Furthermore, it has been observed an increase in the elasticity of the adhesive film (till reaching the cutaneous elasticity) which guarantees the suture strength. The finally resulting film, furthemiore, does not crack and does not modifies its features for 10-15 days. The present invention provides a new medical and surgical adhesive composition comprising: a) 65-90% by weight of 2-ethyl cyanoacrylate b) 5-17.5% by weight of 3—methacryloxy sulfolane c) 5-17.5% by weight of butyl acrylate, wherein the percentages are based on the total weight of the composition. The 3—methacryloxy sulfolane acts as an anti-inflammatory agent vvich avoids the onset of inflammations in the tissues, therewith favouring their quick cicatrization. If its content is less than 5% by weight, the tissue irritation is not completely avoided, whereas if it is more than 17.5% said irritation lasts longer. A preferred amount of 3—methacryloxy sulfolane is comprised between 7.5 and 12.5% by weight, based on the total weight of the composition. A more preferred amount is 10% by weight. Analogously, the use of butyl acrylate allows to increase the elasticity of the adhesive film. In fact it has been found that its insertion in the composition allows the film not to crack, not to break, not to cause a tissue retraction (the film elasticity reaches a value corresponding to the skin elasticity) and to remain without changes for 10-15 days. The adhesive presents excellent features and resorbs in 30-45 days. If the amount of butyl acrilate is less than 5% a retraction of the glued tissues and a film fragmentation are observed. A preferred amount of butyl acrylate is comprised between 7.5 and 12.5% by weight, based on the total weight of the composition. A more preferred amount is 10% by weight. A preferred composition to be used as a medical and surgical adhesive comprises therefore: a) 75-85% by weight of 2-ethyl cyanoacrylate, b) 7.5-12.5% by weight of 3—methacryloxy sulfolane and c) 7.5-12.5% by weight of butyl acrylate, wherein the percentages are based on the total weight of the composition. The obtained adhesive presents a high stability. This feature allows its conservation for two years after its production, if it is kept at a temperature not higher than 4°C. 10 15 20 30 35 WO 96/23532 PCT /IB96/002l0 '5 -3- A fiirther object of the present invention is to provide a process for the preparation of the aforesaid medical and surgical adhesive, comprising the mixing of the three components under controlled conditions (temperature and humidity) and their continuous stirring till obtaining an adhesive product which can be stored for a further use. In particular, 3-methacryloxy sulfolane is mixed with butyl acrylate till complete dissolution, at a temperature of I 8-20 °C and at air relative humidity comprised between 50 and 60%. Afterwards, the resulting solution is dissolved in 2-ethyl cyanoacrylate. For preparing 3-methacryloxy sulfolane. methacrylic acid and 3-oxy sulfolane are reacted at a temperature of 60—70°C, at low pressure, with a suitable solvent, preferably toluene or benzene, distilling the formed water. It is optionally advisable to add an acid catalyst. in particular sulfuric acid or para-toluensulfonic acid (0.5-l%). In order to prevent a mixture polimerization. hydrochinone can be used. e.g. in an amount of 0.5% referring to the mixture total weight. 3-methacryloxy sulfolane precipitates in the fomi of a beige or white powder. Melting point 40 °C, total yield 80%. The present invention is further described in the following examples. Example l 10% by weight of 3-methacryloxy sulfolane (thereafter referred to as SAK) is mixed with l0% by weight of butyl acrylate (therafter referred to as BAK) till complete dissolution, at room temperature (I 8-20°C) and with a relative humidity of 50-60%. The resulting solution is dissolved in 80% by weight of 2-ethyl cyanoacrylate (thereafter referred to as ECAC). The mixture is continuously stirred till obtaining an adhesive composition which does not crack when it is applied in the form of a thin film, and whose elasticity corresponds to the one of the skin. The adhesive resorbs in 40 days. Example 2 Example 1 is repeated varying the amounts of the components as follows: ECAC 85% by weight, SAK 7.5% by weight, BAK 7.5% by weight. The use of the adhesive does not cause inflammations, but a light cutaneous flush which disappears after 2-3 hours. The film does not crack for 15 days. and the elasticity corresponds to the one of the skin. Examplg 3 Example 1 is repeated, varying the amounts of the components as follows: ECAC 75% by weight, SAK 12.5% by weight, BAK 12.5% by weight. The resulting film is elastic and does not crack for 16 days. No tissue inflammation was l0 15 20 25 WO 96123532 PCT/IB96/00210 -4- observed. The adhesive was used for glueing skin and flesh injuries, as well as for the suture of anastomoses and in gut operations. Test results 45 tests were performed, which were divided as follows: a) l5 tests conceming the glueing of enteral loops without torsions or perforations; b) 15 tests conceming the applying of enteral anastomoses with the adhesive reinforced by stitches; c) 15 tests conceming the suture of enteral anastomoses, increasing the gap between the stitches till 10 mm or more in order to reduce the injury of the enteral wall. Glueing the injured wall, the tissues to be glued are put together and smeared with a thin layer of adhesive. The flaps of the injury are pressed for 2-3 minutes in order to strengthen the sutures. In said lapse of time the adhesive acts on the joined flaps, thus favouring a perfect adhesion. The adhesive film is elastic and does not break for 10-] 5 days. No tissue inflammations have been observed, and the adhesive resorbs in 30-45 days. According to the perfonned tests it is possible to state that an adhesive composition according to the present invention shows a complete absence of cutaneous inflammations, of flesh inflammation and of enteral walls inflammation by glueing enteral loops, without torsions or perforations. No evident inflammatory reactions were observed by applying enteral anastomoses with a stitch reinforcement and by sealing enteral anastomoses made with suture thread, with a gap between the stitches increased till 10 mm. Finally, it is obtained an increased elasticity of the adhesive film (till reaching the skin elasticity) which guarantees the suture strength. The film does not crack and does not modify its features for 10-15 days. If methacrylic acid and 3-oxysulfolene-4 are reacted as described for the preparation of 3-methacryloxy sulfolane, 3-methacryloxysulfolene-4 is obtained which can be used in the composition of the adhesive as an altemative to 3-methacryloxy sulfolane. 10 15 20 25 30 35 WO 96/23532 PCT/IB96/00210 - 5 - CLAIMS 1. A medical and surgical adhesive composition comprising: a) 65-90% by weight of 2-ethyl cyanoacrylate, b) 5-17.5% by weight of 3-methacryloxy sulfolane. c) 5-17.5% by weight of butyl acrylate, the percentages being based on the total weight of the composition. 2. A composition according to claim 1 comprising: a) 75-85% by weight of 2-ethyl cyanoacrylate, b) 7.5-12.5% by weight of 3-methacryloxy sulfolane and c) 7.5-12.5% by weight of butyl acrylate, the percentages being based on the total weight of the composition. 3. A composition according to claim 1 or claim 2 whrein the 3-methacryloxy sulfolane is replaced by 3—methacryloxysulfolene-4. 4. A process for the production of an adhesive composition to be used in medical and surgical field. characterized in that: (a) 5-17.5% by weight of 3-methacryloxy sulfolane is mixed with 5-1 7.5% by weight of butyl acrylate till complete dissolution, at a temperature of 18-20°C and at air relative humidity comprised between 50 and 60%, (b) the resulting solution is dissolved in 65-90% by weight of 2-ethyl cyanoacrylate, wherein the percentages are based on the total weight of the composition. 5. A process according to claim 4, wherein: (a) 7.5-12.5% by weight of 3-methacryloxy sulfolane is mixed with 7.5-l2.5% by weight of butyl acrylate till complete dissolution, at a temperature of l 8-20°C and at air relative humidity comprised between 50 and 60%, (b) the resulting solution is dissolved in 75-85% by weight of 2-ethyl cyanoacrylate, wherein the percentages are based on the total weight of the composition. 6. A process according to claim 4 or claim 5, wherein the 3-methacryloxy sulfolane is replaced by 3-methacryloxysulfolene-4. 7. Use of 3-methacryloxy sulfolane for the production of an adhesive composition to be used in medical and surgical field. 8. Use of 3-methacryloxy sulfolane for the production of a medical and surgical adhesive composition having anti-inflammatory properties. INTERNATIONAL SEARCH REPORT lnterrwttonal Application No PCTVIB 96/00210 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 A6lL25/00 C09J133/20 Accordin-__ lntemational Patent Classification (IPC) or to both national clasnfication and IPC B. FIELDS SEARCHED Minimum documentation searched (clasification system followed by classification symbols) IPC 6 A61L Documentation searched other than rriinimum documentation to the extent that such documents are included in the fields searched Electromc data base consulted dunng the international search (name of data base and. where practical. search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document. with indication, where appropnate, of the relevant pamges Relevant to claim No. DATABASE NPI week 9218 Derwent Publications Ltd., London, GB; AN 92-148365 XP002003593 & SU,A,1 005 455 (USSR BASHKIR CHEMISTRY INSTITUTE) , 30 July 1991 see abstract DATABASE WPI week 9208 Derwent Publications Ltd., London, GB; AN 92-062719 XP002003594 & SU,A,1 455 709 (BASHKIR CHEMISTRY INSTITUTE) , 23 June 1991 see abstract E Further documents are listed in the continuation of box C. Q Patait farmly members are listed in annex. ' Speual categories of cited documents : _ _ 1‘ later document published after the intemational filing date or priority date and not in conflict with the application but cited to understand the pnnciple or theory underlying the ‘A’ document defining the general state of the art which is not considered to be of particular relevance invention E °Ffh":‘°t:“m"" bu‘ P"bh‘h‘d °“ °' ‘M’ m‘ ""‘m‘“°ml ‘X’ document of particular relevance; the claimed invention ‘"3 cannot be conndered novel or cannot be considered to ‘L’ document which may throw doubts on pnonty claim(s) or involve an inventive step when the document is taken alone “.'h‘d" " °"‘3'e‘° °‘'-‘h1‘‘h 9“ P“h"°‘“°"! 3" °{ ‘“°""' ‘Y’ document of parucular relevance; the claimed invention “uh” °' ° ’ ‘wad '°”°“ ('5 ‘Fem "Q cannot be considered to involve an inventive step when the '0‘ document refernng to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments. such combination being obvious to a person skilled ‘P’ document published prior to the international filing date but '" "h° m‘ later than the pnonty date claimed '&' document rnernber of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 18 June 1996 Authorized officer 22 May 1996 Name and mailing address of the ISA European Patent Office, P.B. Slllx Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+ 3|-70)1l40-2040, Tx. 3| 65] epo nl, Fax: (-9 3|-70) 340-30l6 (1s.os.95) Peltre, C Form PCT,/ISA/Ill) (second sheet) (July I992)