WO2004084963A1

WO2004084963A1 - Porous medical adhesive comprising cyanonacrylate

Info

Publication number: WO2004084963A1
Application number: PCT/GB2004/001400
Authority: WO
Inventors: Christopher Ansell; Neil Joseph Atkin; David Robert Morsley
Original assignee: Smith and Nephew PLC
Current assignee: Smith and Nephew PLC
Priority date: 2003-03-25
Filing date: 2004-03-25
Publication date: 2004-10-07
Anticipated expiration: 2005-09-25

Abstract

Curable adhesive compositions are provided comprising a cyanoacrylate polymer admixed with a polymeric additive which is sufficiently soluble in the presence of moisture to form pores, in the adhesive composition. Typically the pores will range, in size, from 100nm to 500µm and are formed in the adhesive mass during or after the occurance of the curing of the adhesive. The ratio of the cyanoacrylate to additive polymer may suitably range from 0.001 to 75% and will produce acceptable adhesive strength, typically within the range of 0.03KPa to 1000Kpa.

Description

POROUS MEDICAL ADHESIVE COMPRISING CYANONACRYLATE

The invention relates to cyanoacrylate-based tissue adhesives. More particularly this invention relates to cyanoacrylate-based tissue adhesives in which at least one component of the adhesive breaks down to produce a porous structure in the cured adhesive.

Description of related art Adhesion of tissue is an integral part of all surgical procedures, including closure of skin wounds, reconstruction of nerve ruptures, re-attachment of transplanted tissue, sealing of blood vessels, treatment of pneumothorax and fistulas, support of vascular and intestinal anastomoses, treatment of chondral- and osteochondral defects, fracture healing, treatment of meniscal tears and ruptured ligaments, repair of tendon damage or muscle damage and attachment of implanted biomaterials and tissue engineered devices. The fundamental aim of all tissue adhesives is to hold tissue together for long enough to allow a natural biological repair. Biological repair typically involves the activation of cells in the tissue to a repair mode and formation of new tissue to fill the defect.

A number of synthetic adhesives have been manufactured for industrial and consumer use. Some of these, including cyanoacrylates, have been used to glue biological tissues. There is prior art describing the use of cyanoacrylate adhesives in tissue repair applications, for example, Barley et al., U.S. Pat. No 6,342,213, Methods for treating non-suturable wounds by use of cyanoacrylate adhesives and Hyon et al., U.S. Pat. N°: 6,316,523, Adhesive composition for surgical use. The advantage of using cyanoacrylates is that they form an extremely strong bond between tissues. However, they have not replaced the use of other fixation devices because the cyanoacrylate moiety acts as a barrier to biological repair.

It has therefore been desirable to produce cyanoacrylate adhesives that degrade after curing to allow replacement by normal tissue. This has been achieved by mixing other agents with the cyanoacrylate to modify the degradation profile. U.S. patent No. 6,299,631 describes bioabsorbable formulations comprising 2- alkoxyalkylcyanoacrylate with liquid or solid polymeric modifiers. U.S. patent No. 6,224,622 describes bioabsorbable cyanoacrylate- based tissue adhesives containing bioabsorbable copolymers. The copolymers are derived from epsilon-caprolactone, lactide and glycolide monomers or from butyl 2-cyanoacrylate, glycolide, lactide, epsilon-caprolactone monomers. U.S. patent no. 6,103,778 describes an α-cyanoacrylate adhesive composition with a polymer component for biodegrading and bioabsorbing the adhesive into the body of a living organism. The main disadvantage to degradable cyanaoacrylates is that they bulk degrade, so there is no opportunity for the bodies own tissue to gradually replace the cyanoacrylate as it degrades.

In order to overcome this problem, degradable cyanoacrylate compositions have been described in U.S. patent no. 5,866,106 that degrade to a porous structure by leaching out vitamin crystals, resulting in pores that allow nutrients and tissue to grow through thus allowing biological repair whilst retaining adhesive strength. However, such compositions that include solid additives in liquid adhesive monomer have the disadvantage of heterogenous particle distribution through the cured the adhesive. The inclusion of solid components in a liquid adhesive impairs the application of the adhesive by both weakening the bond between the two adhered surfaces and by increasing the difficulty of application to the desired site

It is therefore an objective of the present invention to provide a liquid cyanoacrylate adhesive composition that allows pores to be formed during or after adhesive curing, thus permitting the ingrowth of the host cellular tissue. In accordance with the present invention there is provided a curable adhesive composition comprising a cyanoacrylate polymer admixed with a polymeric additive which is sufficiently soluble in the presence of moisture to form pores in the adhesive composition.

Aptly, pores are formed in the adhesive mass during or after the occurrence of the curing of the adhesive.

The ratio of the cyanoacrylate to additive polymer may be upto 80% and will suitably range from 0.001 to 75% by weight, based on the weight of the additive. Ratios within this range will produce acceptable adhesive strength, typically within the range of 0.03KPa to 1000Kpa. Preferably, depending on the additive chosen, the ratio of cyanoacrylate to polymer additive will be such as to impart an adhesive strength of at least 5Kpa. Suitable adhesive compositions contain from 10 to 50% additive polymer and will an adhesive strength of from 5 to 500Kpa.

Aptly the adhesive compositions of the invention will contain pores of a size ranging from 50nm to 1000μrn, preferably from 100nm to 500μm. Pores of this size will allow the transfer of nutrients, active components and even cells between the adhered surfaces and thus permit enhanced tissue repair to occur.

Suitable cyanoacrylates for use in the present invention include alkyl 2-cyanoacylates, alkenyl 2-cyanoacrylates, carbalkoxyalkyl 2- cyanoacrylates and alkoxyalkyl 2-cyanoacrylate or mixtures thereof. Preferably the alkyl or alkenyl group of the cyanoacrylate has 1-16 carbon atoms.

Suitable polymeric additives include any polymer which soluble in aqueous media such as the moisture present in body tissue. Aptly the polymeric additive is miscible with, or soluble in the uncured adhesive and does not itself initiate premature cure of the adhesive. Preferably the additive allows the cyanoacrylate adhesive composition to remain as a liquid, in the uncured state until exposed to moisture, for example in a tissue site. Acceptable compositions allow the cyanoacrylate adhesive composition to remain in a liquid, uncured state for at least 6 months until exposed to moisture. The polymers are advantageously biodegradable. It is also preferred that the additive polymers be those that do not release an acidic byproducts, for example lactic acid, on degredation since such degradation products may damage surrounding tissue and impair the repair process.

Especially preferred polymer additives are polyacetals. These materials may be synthesised by methods, known perse from an alcohol an alcohol such as a diol or polyol with a vinyl ether. The vinyl ether may appropriately be a monovinyl ether, a divinyl ether or a polyvinyl ether. Both the vinyl ether and the alcohol may be aliphatic or aromatic and may be in the form of an oligomer or polymer. Preferably the polyacetal is derived from a diol and a divinyl ether. Either or both the diol or divinyl ether component may suitably be a biologically active molecule. The biologically active molecule or combination of molecules are typically naturally derived factors or synthetic compounds that enhance tissue repair. For many tissue repair applications angiogenic factors are preferred. Suitable angiogenic diols include monobutyrin and dibutyrins.

Adhesive compositions according to the present invention are useful for the repair of tissue defects, adhering prostheses into tissue, tissue fixation and any application where it is desirable to adhere two surfaces in a moist, i.e. nucleophilic, environment.

Since, the adhesive compositions of the invention are stable in the absence of moisture, the components may be mixed and stored in a container, adapted to allow direct dispensation to the surfaces which are required to be adhered. Alternatively, the adhesives of the invention may be stored under moisture free conditions and applied, for example by a spatula to one or both surfaces to be adhered.

Thus the present invention also provides the use of the adhesive compositions of the invention as medical adhesives and a method of tissue repair comprising applying a quantity of said medical adhesive to at least one of two or more tissue surfaces which are required to be adhered together.

The invention will be further illustrated by the following Examples and the accompanying drawings in which:

Figure 1 shows breaking strengths of cyanoacrylate-polyacetal adhesive compositions where high and low molecular weight polyacetals synthesised from poly(propylene glycol) and cyclohexane dimethanol divinyl ether were used as additives

Figure 2 shows breaking strengths of cyanoacrylate-polyacetal adhesive compositions where high and low molecular weight polyacetals synthesised from cyclohexane dimethanol and cyclohexane dimethanol divinyl ether were used as additives.

Figure 3 shows breaking strengths of cyanoacrylate-polyacetal adhesive compositions where the polyacetal was synthesised from polyethylene glycol) {Mn 3400} and tri(ethylene glycol) divinyl ether.

Figure 4 shows breaking strengths of cyanoacrylate-polyacetal adhesive compositions where the polyacetals synthesised from poly(dimethyl siloxane) and cyclohexane dimethanol divinyl ether, dodecane diol and cyclohexane dimethanol divinyl ether, and poly(tetrahydrofuran) and poly(tetrahydrofuran) divinyl ether.

Figure 5 shows weight loss of poly(THF) based polyacetal in aqueous media

Figure 6: Weight loss of 10% and 25% w/w cyclohexane based polyacetal in n-butyl cyanoacrylate adhesive in aqueous media at 37 °C. Figure 7: Weight loss of 10% and 25% w/w cyclohexane based polyacetal in n-butyl cyanoacrylate adhesive in aqueous media at 37 °C.

Figure 8: Scanning electron micrographs of PPG acetal 25%. a) surface of an adhesive composition before degradation b) The sample surface after 24 hrs at pH 5.5 revealing a rough surface indicating rapid surface degradation and erosion, c) The sample surface after 4 weeks in PBS (neutral pH) revealing pores forming in the adhesive film.

Figure 9: Synthesis of polyacetal containing monobutyrin and triethylene glycol.

Figure 10: Synthesis of polyacetal from monobutyrin and cyclohexane dimethanol divinyl ether.

Figure 11 : Synthesis of polyacetal with monobutyin and butyl vinyl ether.

Figure 12: The bond strength measurements of a range of modified adhesives stored at 5 °C for up to 11 weeks.

Figure 13 : The effect of increasing percentage (w/w) load of a monobutyrin acetal compound (monobutyrin - butyl acetal compound) on cyanoacrylate adhesive bond strength.

Figure 14 : The effect of different monobutyrin acetal chemistry on cyanoacrylate bond strength (10% w/w loading).

Figure 15: The breakdown of a polyacetal composed of triethylene glycol and monobutyrin

Figure 16: Monobutyrin release from films containing 25% and 50% (w/w) polyacetal in different conditions (samples at 37 °C stored for 7 days and samples at 60 °C stored for 20 hours). Figure 17: Weight loss of cyanoacrylate disks at 37°C and 60°C and cyanoacrylate disks with 15% (w/w) polyacetal additive at 37°C and 60°C.

Figure 18 a - e: Polyacetal cyanoacrylate adhesive degradation at 37 °C and 60 °C over a 6 month time period, a. n-butyl cyanoacrylate-polyacetal at 60 °C after 1 week. b. - d. n-butyl cyanoacrylate-polyacetal at 37 °C after 12 weeks, e. n-butyl cyanoacrylate-polyacetal at 60 °C after 12 weeks.

Figure 19: a. - c. n-butyl cyanoacrylate-polyacetal at 37 °C after 24 weeks.

Figure 20: a. - f. n-butyl cyanoacrylate-polyacetal at 60 °C after 24 weeks.

Example 1. Synthesis and degradation of cyanoacrylate / polyacetal adhesives

Polyacetals A to F as described in Tablel were synthesised according to the method described by Tomlinson et al. [Macromolecules 2002, 35, 473-480]. The required diol (e.g) and para toluene sulphonic acid were weighed into a three-necked round-bottomed flask equipped with a magnetic stirrer and fitted with a dean stark trap and a condenser. Toluene was added to the flask and the mixture was heated to -140 °C for 2 hours under a nitrogen atmosphere allowing an azeotropic distillation of the water from the toluene. After the reflux, the solution was allowed to cool to room temperature and the required divinyl ether (eg cyclohexane dimethanol divinyl ether) was added. The mixture was left stirring at room temperature for 18 hours. After reaction the acid catalyst was neutralised by passing the mixture down a short column of basic alumina. The polymer was isolated by evaporation of the solvent using a rotavapor.

Additional polyacetals as shown in Table 2 were synthesised as degradable additives to cyanoacrylate adhesive. The molar ratio of the diol to the ether was 1 :1 in each case.

Table 2: polyacetals synthesised as suitable additives

Polymer Diol Divinyl ether

G

Poly(THF) Poly(THF) vinyl ether H

Dodecane diol Cyclohexane dimethanol divinyl ether

Poly(dimethyl siloxane) hydroxy alkyl terminated Cyclohexane dimethanol divinyl ether

Mn = 5000

Molecular weight analysis:

Samples were dissolved in chloroform and filtered through 0.45 μm filters prior to analysis using gel permeation chromatography. The molecular weight of polacetals A to H was found to be:

Adhesive formulations were prepared by dissolving the polymer additive in butyl cyanoacrylate (from Chemence) in amounts as shown in the following table.

Wt of Wt of

Adhesive Polymer added polymer NBCA

(g) (g)

1 D 0.50 3.50

2 D 1.25 3.75

3 E 0.50 4.50

4 E 1.25 3.84

5 C 0.51 3.83

6 C 1.25 3.82

7 G 0.49 4.67

8 G 1.260 3.540

9 A 0.074 0.430

10 A 0.021 0.189

11 A 0.042 0.173

12 A 0.010 0.209

13 A 0.049 0.212

14 B 0.010 0.200

15 C 0.021 0.190

16 C 0.060 0.177

17 C 0.037 0.170

18 E 0.005 0.399

19 E 0.019 0.392

20 E 0.040 0.360

21 F 0.110 0.310

22 F 0.490 4.670

23 F 1.260 3.540

24 G 0.042 0.366

25 G 0.071 0.337

26 G 0.101 0.310

27 H 0.040 0.367

28 H 0.071 0.331

29 H 0.100 0.303

30 I 0.040 0.360

31 I 0.070 0.337

32 I 0.106 0.304

Adhesion testing of the compositions were carried out on costal cartilage using a Nene tensile tester at a displacement rate of 5 mm/ min. The breaking strengths of the different adhesive compositions are illustrated in figures 1 - 4. Adhesive testing of compositions containing the polyacetal additives showed no loss of adhesion strength up to a 10 % w/w additive loading level. Additive loading above 10 % w/w resulted in the adhesion strength being reduced with increasing concentration. The loss of strength is not related to molecular weight or chemistry of the additive.

Weight loss Analysis

The adhesive formulations were spread onto activator sprayed release paper with a 0.18 mm-spreading device and the NBCA was allowed to cure. Samples were cut out of the films using a 0.7cm punch if possible or, if the film was too brittle, an equivalent size sample (checked by weight) was cut out using scissors. Sample thickness was measured using a Vernier gauge and sample weight was also measured. After preparation, samples were placed in 15 ml of PBS and heated to 37°C in an orbital shaker. Three samples were prepared for weight loss analysis for each formulation. At each time point samples were removed from PBS and dried in vacuo for 2 hours and then weighed. After the samples had been weighed they were returned to the same buffer solution. Quoted are the average weight loss and standard deviation for each time point (figures 5 -

7).

The weight loss analysis for adhesives formed from the poly(THF) polyacetal sample (Polymer G) was determined by weighing 0.5056g of the polyacetal into a glass vial and 1.5027g of NBCA (n-butyl cyanoacrylate) was added to it. The average film thickness was 0.63 mm (+/- 0.15mm) and the average mass of the films was

0.0419g (+/- 0.0013g). Sample weights were measured at 2 week, 3 week and 4 weeks time points.

% Wt loss % Wt loss % Wt loss after 2 weeks after 3 weeks after 4 weeks

Average 3.86 6.82 7.21

STDEV 0.74 0.58 0.29 For the cyclohexane based polyacetals and PPG/cyclohexane based polyacetals the average thickness of the polymer discs was measured at 0.8mm +/- 0.3mm and the average weight was 35mg +/- 10mg.

The effect of degradation of the film morphology was examined using scanning electron microscopy revealing the formation of pores and a roughen surface in acid and neutral conditions (Figure 8).

Weight loss data for some of the adhesives is shown in the following Table

% % wt loss after % wt loss % wt loss % wt loss

Adhesive Degradable 1 week after 2 weeks after 4 weeks after 6 weeks

1

(PPG/CHDM 10 average 2.25 3.73 4.15 5.49 Mw = 2631 ) STD 0.34 0.94 1.51 0.85

2

(PPG/CHDM 25 average 4.91 8.35 9.60 15.68

Mw = 2631 ) STD 2.00 2.70 3.22 2.11

3 (PPG/CHDM 10 average 1.35 1.69 2.15 3.02

Mw = 10040) STD 0.18 0.69 0.74 0.74

(PPG/ CHDM 25 average 4.36 6.59 9.11 10.01

STD 0.84 0.46 1.55 1.48

(CHDM 10 average 1.14 2.11 2.89 4.54 Mw = 2600) STD 1.86 2.05 2.01 2.00

6

(CHDM 25 average 1.47 2.18 5.60 4.60 Mw = 2600) STD 0.70 0.56 0.63 0.61

7

(CHDM 10 average 0.63 2.04 3.11 5.46 Mw = 38000) STD 0.52 0.26 0.64 1.11

8

(CHDM 25 average 4.24 6.90 9.78 12.61 Mw = 38000) STD 0.56 0.61 0.80 0.27

Example 2. Synthesis and inclusion of bioactive polyacetals into cyanoacrylate adhesives

All the acetal synthesis are based on a published article (Tomlinson, R., et al., 2002, Macromolecules, 35, 473 - 480). J. Monobutyrin-polvacetals

0.01 M Monobutyrin was added to 30 ml of anhydrous toluene in a RB flask and stirred at 50 °C. 0.01 g of para toluene sulhonic acid (pTSA) was added as a catalyst. 0.005M Triethylene glycol divinyl ether (TDGE) was added and stirred at 50 °C for 3 hours. The solution was then washed through a column of basic aluminium oxide to remove the catalyst. The solvent was removed and the residual oil (monobutyrin-acetal - J1 ) collected as a suitable additive for cyanoacrylate adhesives. The reaction schematic is shown in Figure 9. Similar poylacetals (J-2) were made using cyclohexane dimethanol divinyl ether and monobutyrin according to the reaction shown in Figure 10.

K. Monobutyrin reacted with butyl vinyl ether

0.0016M Monobutyrin was added to 10ml of toluene with 0.003g of pTSA and mixed. 0.0032M of butyl vinyl ether was added and mixed overnight at room temperature. The solution was filtered through aluminium oxide with additional toluene to remove the catalyst. The solvent was removed and the product collected as a suitable additive for cyanoacrylate adhesives (Figure 11 ).

Adhesive Formulation

The monobutyrin compounds J-1 , J-2 and K described above were added to ethyl-cyanoacrylate or n-butyl cyanoacrylate in the amounts shown in Figure 12 to examine miscibility and stability. The samples were stored in plastic eppendorf at 5 °C. Daily viscosity checks and mechanical testing of bond strength at set time points were used to confirm stability of the additive in cyanoacrylate monomer. The absence of any phase separation indicated good miscibility of the additives into the monomer solutions. The samples remained as liquid over 11 weeks storage and strength measurements indicated no significant loss in adhesive properties The bonding strengths of each of the adhesive formulations is also shown in Figure 12.

Effect of additive on cyanoacrylate properties

The effect of the additives on the cyanoacrylate adhesive was examined using mechanical testing of the bond strength (Figures 13 and 14). The strength of the adhesive is only affected when the load is increased above 10%. This is in agreement with previous research that indicates a maximum load before adhesive failure is 50 % (w/w). The chemistry of the different monobutyrin acetals does not affect the bond strength. This is supported in previous studies that conclude that only the amount of additive blended into the cyanoacrylate has an effect on adhesive properties.

Release of monobutyrin

The breakdown of polyacetals in aqueous environments is detailed in Tomlinson, R., et al., 2002, Macromolecules, 35, 473 - 480. The products are shown to be biocompatible diols and acetaldehyde, e.g. monobutyrin and triethylene glycol (Figure 15).

NMR analysis of monobutyrin acetal compounds exposed to slightly acidic buffer (10% (w/w) bis tris pH 5.6) reveals acetaldehyde formation (9.5 ppm ¹H NMR) and acetal breakdown (4.8 ppm ¹H NMR).

Monobutyrin was observed to be released into buffer from 25% and 50% (w/w) Polyacetal-monobutyrin/cyanoacrylate films over 5 weeks at 37 °C (Figure 16). The effect of increased temperature on release was revealed to increase the rate of monobutyrin release from the films.

Monobutyrin bioactivitv:

Monobutyrin is a bioactive molecule that has been demonstrated to improve wound healing in tissue. The most likely cause of this improved healing is through an angiogenic effect. However, while strong evidence exists to support this claim, the exact mechanism of action is still open to debate. Our modified adhesive provides a mechanism for the release of monobutyrin into a wound environment. It is envisaged that from 1 ng/ml to 10 mg/ml of monobutyrin could be released from the adhesive as breakdown occurs.

Example 3. Manufacture cyanoacrylate-polvacetal samples

Polyacetal was first prepared by reacting cyclohexane dimethanol and cyclohexane dimethanol divinyl ether in a 1 :1 molar ratio according to the procedure described in Example 1. The polyacetal was then mixed with n-butyl cyanoacrylate to create an adhesive containing 15% (w/w) of the polyacetal. 18 Disks, each 10 mm in diameter and about 1 mm thick were formed. 6 disks were weighed for the weight loss study.

Half the disks were stored at 60°C in sterile PBS solution (pH 7.3) contained in polypropylene screw cap tubes and the remaining half stored at 37°C in PBS contained in sealed glass vials.

Control data (n-butyl cyanoacrylate disks) were also prepared and stored under identical conditions

Weight Loss Study

The n-butyl cyanoacrylate disks stored in PBS buffer at stored 37 °C and 60 °C revealed no significant weight loss over a 6 month period.

Three of the disks formed from the adhesive blend and stored at 37 °C showed a weight loss of about 8% ± 1% of the total weight and three of the disks formed from the blend and stored at 60 °C showed a weight loss of around 15% ± 3% of the total weight. These results are reported in Figure 17. The weight loss is attributed to the degradation and removal of the polyacetal additive within the cyanoacrylate disks. After 6 months (24 weeks) approximately half of the polyacetal has been removed from the disks at 37 °C. At 60 °C, the full 15% w/w polyacetal additive had been removed by 4 months (16 weeks). No additional weight loss was observed after this time to indicate any cyanoacrylate degradation.

Scanning Electron Microscopy Analysis

The remaining disks stored respectively at 37 °C. and 60 °C. were investigated under SEM.

SEM analysis (figures 18-20) of the samples revealed discrete particulate material of approximately 10μm in size on the surface of the polycyanoacrylate/polyacetal sample after the 1 week degradation period (fig.18a). Pores of between 100-500nm in diameter had began to appear in the surface of this specimen after 3 month degradation at 37°C (fig.18b-d). The sample degraded 60 °C for 3 months possessed a topography comparable to the 37 °C sample although the pores exhibited appeared to have increased in size to between 0.5-1 μm in diameter (fig.18e). After 6 month degradation at 37 °C the pores apparent in the sample were between 100-500nm in diameter (19a-c), of a comparable size to the pores observed in the sample after 3 month degradation at 37 °C (fig.18b- d). Interestingly, the pores were apparently in the greatest concentration around the folds observed in the surface of the sample (fig.19b). Increasing the temperature for the same degradation period again resulted in a significant increase in the size of the pores apparent (fig.20a-f). The degradation rate of material across this sample appeared to be heterogeneous. Pores of a greater diameter than 1μm were apparent in areas of this sample and these pores appeared to be interconnected (fig.20b&c). Significantly large areas of the sample were observed to possess channels of 100μm in length and 10μms in diameter penetrating deep into the material (fig.20d&e) with the islands of the material between the channels exhibiting a 'honeycomb' appearance (fig.20f).

Claims

1. A curable adhesive composition comprising a cyanoacrylate polymer admixed with a polymeric additive which is sufficiently soluble in the presence of moisture to allow pores to be formed during or after curing of the adhesive.

2. A composition as claimed in claim 1 wherein the cyanoacrylate alkyl 2-cyanoacylate, alkenyl 2-cyanoacrylate, carbalkoxyalkyl 2-cyanoacrylate or alkoxyalkyl 2- cyanoacrylate and wherein the alkyl group of the cyanoacrylate has from 1to16 carbon atoms.

3. A composition as claimed in claim 1 or claim 2 where the pores formed will be in the size range of 50nm to 1000μm

4. A composition as claimed in any one of the preceding claims wherein the polymeric additive is miscible with or soluble in the uncured adhesive and does not itself initiate premature cure of the adhesive.

5. A composition as claimed in any one of the preceding claims comprising upto 80% by weight of the polymeric additive.

6. A composition as claimed in any one of the preceding claims wherein the polymeric additive is a biodegradable polymer

7. A composition as claimed in claim 6 wherein the biodegradable polymeric additive degrades to form non acidic breakdown products.

8. A composition as claimed in any one of the preceding claims wherein the polymeric additive is a polyacetal

9. A composition as claimed in claim 8 wherein the polyacetal is synthesised from an alcohol and a vinyl ether.

10. A composition as claimed in claim 9 wherein the vinyl ether is a divinyl ether.

11. A composition as claimed in claim 9 or claim 10 wherein the alcohol is a diol or polyol.

12. A composition as claimed in any one of the preceding claims comprising alkyl 2-cyanoacylate and a polyacetal.

13. A composition as claimed in any one of claims 9 to 12 wherein the diol or divinyl ether component is a biologically active molecule

14. A cyanoacrylate adhesive composition of claim 13 where the biologically active molecule is an angiogenic factor

15. A cyanoacrylate adhesive composition of claim 14 where the angiogenic factor is monobutyrin or a dibutyrin.

16. The use of a cyanoacrylate adhesive composition of any of the preceding claims as a medical adhesive for adhering tissue.

17. A medical device comprising a moisture proof container or dispenser containing a curable adhesive composition as claimed in any one of claims 1 to 15.