WO1996023532A1

WO1996023532A1 - Medical and surgical adhesive composition and process for its preparation

Info

Publication number: WO1996023532A1
Application number: PCT/IB1996/000210
Authority: WO
Inventors: Gennadiy Viktorovich Leplyanin
Original assignee: Saybrook Trading Limited
Priority date: 1995-01-31
Filing date: 1996-01-30
Publication date: 1996-08-08
Also published as: ITFI950017A1; AU4840696A; ITFI950017A0; IT1277811B1

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.

Description

DESCRIPTION

MEDICAL AND SURGICAL ADHESIVE COMPOSITION AND PROCESS FOR ITS PREPARATION

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-cyanoacrylιc acid They show remarkable adhesive properties, forming 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-cyanoacrylιc 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, epidermis 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-cyanoacrylιc 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 Furthermore, hydroxyl, ammo and amido groups contained m most anti-inflammatory drugs produce a quick polimeπzation 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 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, furthermore, 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 wich 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-methacryIoxy 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. - j -

A further 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 18-20 °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 (0.5-1%). 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 form of a beige or white powder. Melting point 40 °C, total yield 80%.

The present invention is further described in the following examples.

Example 1

10% by weight of 3-methacryloxy sulfolane (thereafter referred to as SAK) is mixed with 10% by weight of butyl acrylate (therafter referred to as BAK) till complete dissolution, at room temperature (18-20°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. Example 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 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) 15 tests concerning the glueing of enteral loops without torsions or perforations, b) 15 tests concerning the applying of enteral anastomoses with the adhesive reinforced by stitches, c) 15 tests concerning 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 favouπng a perfect adhesion The adhesive film is elastic and does not break for 10-15 days No tissue inflammations have been observed, and the adhesive resorbs in 30-45 days

According to the performed 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 alternative to

sulfolane

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 5-17.5% 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 7.5-12.

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 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.