Skin adhesive formulation

Abstract

The present invention relates to skin adhesive formulations. The skin adhesive formulations of the present invention may be useful in wound-closing applications and other medical applications. Ideally the skin adhesive formulations of the present invention exhibit higher viscosity than known skin adhesive formulations. Ideally the skin adhesive formulations of the present invention cause fewer allergic reactions and skin irritation issues in patients relative to known skin adhesives. Ideally the skin adhesive formulations are UV curable in the visible range of 400-500nm rather than moisture cure.

Description

Skin adhesive formulation

[0001] Technical field of invention:

[0002] The present invention relates to skin adhesive formulations. The skin adhesive formulations of the present invention may be useful in wound-closing applications and other medical applications. Ideally the skin adhesive formulations of the present invention exhibit higher viscosity than known skin adhesive formulations. Ideally the skin adhesive formulations of the present invention cause fewer allergic reactions and skin irritation issues in patients relative to known skin adhesives. Ideally the skin adhesive formulations are UV curable in the visible range of 400-500nm rather than moisture cure.

[0003] Background:

[0004] In 1998 the FDA approved cyanoacrylates for use as skin adhesives for surgical and trauma wounds. Cyanoacrylate adhesives are still the primary skin adhesive utilized today. However, localized skin reactions and irritation have been reported from the use of cyanoacrylates. It would be advantageous to identify an alternative skin adhesive that does not cause localized skin reactions and irritation.

[0005] Adhesives alternative to cyanoacrylates that have been proposed in the art include thiokene and thiokacrylate copolymer compositions. For example, D. Burget et al., Polymer, 2004, 45, 6561-6567 demonstrate high rates of visible light induced polymerisation for both thiokallyl ether (i.e. thiokene) and thiokacrylate systems. Both exhibit high conversion rates, however for the thiokacrylate polymerisation, a high amount of residual thiol remains. The authors propose various uses of these systems including as adhesives. A similar finding in N. B. Crame et ak, J. of Polymer Chem., 2001 , 39, 3311-3319 demonstrated that a lower amount of unreacted monomer is observed for thiokene polymerisation compared to thiokacrylate. This is a result of the acrylate participating in both copolymerisation with the thiol, as well as acrylate homopolymerisation. The presence of unreactive monomers after thiokacrylate polymerisation, and to a lesser extent thiokene polymerisation, alone means that these binary systems are unsuitable as skin adhesives, due to the possibility that the unreacted monomers will leach out of the adhesive.

[0006] Similarly, O’Brien et ak, J. Polymer Chem., 2006, 44, 2007-2014 investigate thiokacrylate copolymerisation reactions between acrylate hexanediol diacrylate (HDDA) and three differentthiols: 1 ,6-hexane dithiol, pentaerthritol tetrakis(3-mercaptopropionate) and glycol dimercaptopropionate. The authors showed that as the concentration of the thiol functional group increased, oxygen inhibition was reduced and the polymerisation rate and overall conversion rate increased. Additionally, higher functionality acrylate monomers resulted in a faster polymerisation rate due to increased viscosity and reduced oxygen diffusivity.

[0007] A further alternative to cyanoacrylate based systems are ternary acrylate / thiokene systems, which are photoinitiated and are known to proceed via both acrylate homopolymerisation and thiol-ene copolymerisation between thiol-ally I ether and thiol-acrylate groups. A. F. Senyurt et al. Macromolecules, 2007, 40, 4901-4909 investigated such a system comprising a trifunctional thiol, a triallyl ether and several multifunctional acrylate monomer. By increasing the concentration of the acrylate monomer, the resulting polymer has a highly crosslinked structure, and an increased glass transition temperature. The authors show that the presence of multifunctional acrylates (from 3 to 5 reactive acrylate groups) in combination with low molecular weight bridging groups between the acrylates, results in an increase in polymer network heterogeneity and an increase in the number of high density weak spots. Additionally H. Wei et al., J. Polymer Chem., 2007, 45 822-829 investigated the photopolymerization of a ternary acrylate-thiokene system comprising three components: a multifunctional thiol, a triallyl ether and a 16-functional acrylate.

[0008] The presence of these multiple polymerisation mechanisms may reduce the presence of unreacted monomers after curing. However, the authors have not considered these ternary systems for use as biocompatible medical adhesives, nor have they considered the properties of the cured adhesive to specifically function as a skin adhesive (e.g. the required flexibility of the cured adhesive).

[0009] Other fields of medicine have already identified the need to avoid or reduce localized reactions and irritation in materials that are used in contact with skin and other tissues and have identified solutions for this problem. For example, in the field of dentistry it is known that methacrylate-based formulations having thiokene as a reactive diluent has favourable reaction kinetics. Due to the increased conversion of these systems there is substantially less unreacted monomer in the system. The lower the amount of unreacted monomer in the system leads to less possibility for these unreacted monomers to leach out of the cured material and cause an adverse skin reaction. One specific example of a ternary methacrylate-thiokene system being used as dental restorative resin material is provided in US 8,962,709. The authors describe the advantage of reduced leaching from the cured resin. Clearly reduced leaching of unreacted monomers from the cured resin is not the only property that the cured material needs to exhibit. It is also essential that a dental restorative resin material has the mechanical properties to suit its purpose, namelya flexural modulus that is high enough for the material to act as a tooth. For that reason, the primary component in the system of US 8,962,709 is a methacrylate component. The inevitable consequence of using a methacrylate-based systems is that the resulting material will have inherently low elasticity and elongation properties. Each of these properties make methacrylate- based systems unsuitable for skin adhesives.

[0010] Neil Cramer et al, Dental Materials, 26, 2010, 799-806 also discloses various ternary methacrylate-thiokene systems as dental restorative resin materials. For the same reasons as for US 8,962,709, namely that the primary component is a methacrylate component, the materials disclosed in this document are unsuitable for skin adhesives.

[0011] Saeed Beigi et al, Dental Materials, 2013, 29(7), 777-87 evaluates various properties of dental composites, i.e. methacrylate-thiokene systems, and compares these composites with conventional methacrylate systems. The authors mention that thiokene polymers exhibit unique physical and mechanical properties which make possible their application as matrix resins of dental composites. However, formation of flexible thioether linkages during polymerization of these materials can reduce the overall mechanical properties of the resulting networks. Using ternary methacrylate-thiokene system is an accepted route for compensating this reduction in mechanical properties through contribution of regular chain growth polymerization of methacrylate moieties. Since the materials are once again methacrylate-based systems, they would not be suitable for skin adhesives for the reasons explained above.

[0012] Another problem with cyanoacrylate based adhesives is that their application can be somewhat difficult due to their very low viscosity. A low viscosity means that the adhesive can run off the application site. Not only is run-off inconvenient and undesirable, run-off also has more serious consequences as it can lead to improper application of the adhesive to the trauma site and therefore inadequate wound-closure, meaning the risk of infections is increased.

[0013] Another problem with cyanoacrylate based adhesives is that they instantly begin to cure in the presence of moisture. For example, moisture in the air and / or at the wound site will cause the cyanoacrylate based adhesive to cure. Instant curing due to exposure to moisture means that the user cannot control when the adhesive begins to cure. Uncontrolled curing is not only inconvenient and undesirable, but it can have more serious consequences as it can lead to inadequate wound-closure, meaning the risk of infections is increased.

[0014] It would be advantageous in the field of skin adhesives to identify adhesive formulations that have reduced localised irritation and skin reactions relative to conventional cyanoacrylate- based skin adhesives. It would be advantageous in the field of skin adhesives to identify adhesiveformulations having increased viscosity relative to conventional cyanoacrylate-based skin adhesives. It would be advantageous in the field of skin adhesives to have a UV curable adhesive rather than a moisture cure as it allows for curing on demand. The present invention addresses these needs.

[0015] Summary of invention:

[0016] According to a first aspect there is provided a skin adhesive formulation comprising:(A) a urethane diacrylate component having two terminal acrylate groups,per molecule and including the structure:-[(urethane component)-(polycaprolactone component)-(polyethylene glycol component)m-(C2- alkyl)-(polycaprolactone component)]o-(urethane component)- wherein each urethane component is bonded to the terminal acrylate group, optionally via a hydroxyethyl linker group; wherein m is 0-3; and wherein o is 1-5; in an amount of from 30-65 wt%;(B) a thiol component having two or more independently selected thiol groups per molecule, in an amount of from 10-35 wt%;(C) a vinyl component having two or more independently selected vinyl groups per molecule, in an amount of from 5-15 wt%;(D) a photoinitiator component, in an amount of from 0.05-5 wt%; wherein: the amount of (A) is greater than the amount of (B); wherein there is a stoichiometric excess of thiol component relative to the vinyl component.

[0017] Component A:

[0018] In an embodiment, the urethane diacrylate component includes a urethane component,, that forms part of the backbone, wherein the“-LINKER-” is an aliphatic (including cyclic) or aromatic divalent moiety. For example, the “- LINKER-” may be a C1-C20 alkanediyl or a C3-C20 cycloalkanediyl, or combination thereof.

[0019] In an embodiment, the “-LINKER-” may be a C5-C20 alkanediyl or a C5-C20 cycloalkanediyl. In an embodiment, the “-LINKER-” may be a C8-C2o alkanediyl or a C8-C2o cycloalkanediyl. In an embodiment, the “-LINKER-” may be a C10-C20 alkanediyl or a C10-C20 cycloalkanediyl. In an embodiment, the “-LINKER-” may be a C -Ci8alkanediyl or a C -Ci8cycloalkanediyl. In an embodiment, the “-LINKER-” may be a C -C alkanediyl or a C -C cycloalkanediyl. In an embodiment, the “-LINKER-” may be a C10-C14 alkanediyl or a C10-C14 cycloalkanediyl. In an embodiment, the “-LINKER-” may be a C10-C13 alkanediyl or a C10-C13 cycloalkanediyl.

[0020] In a preferred embodiment, the urethane diacrylate component includes a urethane component having the structure:

[0021] In an embodiment, the polycaprolactone component has the structure:wherein n is 1-10. The presence of a polycaprolactone component ensures the biocompatibility of the urethane diacrylate component.

[0022] In an embodiment, the polyethylene glycol component has the structure:wherein m is 0-3.

[0023] In an embodiment, the urethane diacrylate component has a structure according to Component A1 :wherein: m is 0-3 n is 1-10; and o is 1-5.

[0024] In an embodiment, m is 0. In an embodiment, m is 1. In an embodiment, m is 2. In an embodiment, m is 3. Preferably, m is 1 .

[0025] In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4. In an embodiment, n is 5. In an embodiment, n is 6. In an embodiment, n is 7. In an embodiment, n is 8. In an embodiment, n is 9. In an embodiment, n is 10. In an embodiment, n is 1 to 2. Preferably, n is greater than 1.

[0026] In an embodiment, o is 1. In an embodiment, o is 2. In an embodiment, o is 3. In an embodiment, o is 4. In an embodiment, o is 5. In an embodiment, o is 1 to 2. Preferably, o is greater than 1 .

[0027] In synthetic polymer chemistry, the average molecular weight is calculated to account for the formation of chains of differing lengths.

[0028] The number average molecular weight, Mn, is calculated from the equation:where N, is the number of chains (molecules) with a relative molecular mass of M,.

[0029] The weighted average molecular weight, Mw, is calculated from the equation:where W, is the weight of chains (molecules) with a relative molecular mass of M,.

[0030] The weighted average molecular weight is always greater than (or equal to) the number average molecular weight, emphasises the weight of heavier molecules.

[0031] The polydispersity index is determined from the ratio of MW / MN, and is a measure of the polydispersity of the system (i.e. how broad the spread of molecular weights is).

[0032] In an embodiment, the number average molecular weight, MN, of Component A, is between 14,500 - 950 g mol’1. In an embodiment, the number average molecular weight, MN, of Component A, is between 10,000 - 950 g mol’1. In an embodiment, the number average molecular weight, MN, of Component A, is between 8,000 - 950 g mol’1. In an embodiment, the number average molecular weight, MN, of Component A, is between 5,000 - 950 g mol’1. In an embodiment, the number average molecular weight, MN, of Component A, is between 2,000 - 950 g mol’1. In an embodiment, the number average molecular weight, MN, of Component A, is between 1500 - 1000 g mol’1.

[0033] In an embodiment, the urethane diacrylate compound has a glass transition temperature of less than -20°C, e.g. -21 °C or -22°C.

[0034] In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 31 to about 64 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 32 to about 63 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 33 to about 62 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 34 to about 61 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 35 to about 60 wt%.

[0035] In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 36 to about 55 wt%. In an embodiment, the diacrylate component is presentin the adhesive formulation in an amount of from about 37 to about 55 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 38 to about 55 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 39 to about 55 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 40 to about 55 wt%.

[0036] In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 36 to about 54 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 37 to about 53 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 38 to about 52 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 39 to about 51 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of from about 40 to about 50 wt%.

[0037] In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt or 40 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, 45 wt%, 46 wt%, 47 wt%, 48 wt%, 49 wt% or 50 wt%. In an embodiment, the diacrylate component is present in the adhesive formulation in an amount of 50 wt%, 51 wt%, 52 wt%, 53 wt%, 54 wt%, 55 wt%, 56 wt%, 57 wt%, 58 wt%, 59 wt% or 60 wt%.

[0038] Component B:

[0039] In an embodiment, the thiol component has an average of two or more independently selected primary, secondary or tertiary thiol (i.e. mercaptan or"SH) groups per molecule.

[0040] In an embodiment, the thiol component has an average of two primary, secondary or tertiary thiol groups per molecule. In an embodiment, the thiol component has an average of three primary, secondary or tertiary thiol groups per molecule. In an embodiment, the thiol component has an average of four primary, secondary or tertiary thiol groups per molecule. In an embodiment, the thiol component has an average of five primary, secondary or tertiary thiol groups per molecule. In an embodiment, the thiol component has an average of six primary, secondary or tertiary thiol groups per molecule.

[0041] In an embodiment, the thiol component is an organic compound having the general formula R(SH)n, wherein R is an organic residue and n is 2 to 6. In an embodiment, the thiol component is analogous to an alcohol, but in which sulfur replaces the oxygen of the alcohol group. In one embodiment, the thiol component is selected from aliphatic thiols, aromatic thiols, thiol glycolate esters and thiol propionate esters.

[0042] In an embodiment, the thiol component is selected from the group consisting of: 2, 3-Dimercapto-1 -propanol1 ,6-hexanedithiolbutane-1 ,4-diyl bis(3-mercaptopropanoate):1 ,4-bis (3-mercaptobutyroxy)butaneethylene glycol dimercaptopropionate3,3'-(butane-1 ,4-diylbis(oxy))bis(propane-1-thiol)1-4-bis (3-mercaptobutyloxy)butane2,5-dimercaptomethyl-1 ,4-dithiane

[0043] In an embodiment, the thiol component is selected from the group consisting of: 1 ,2,3-trimercaptopropane2-ethyl-2-(((3-mercaptopropanoyl)oxy)methyl)propane-1 ,3-diyl bis(3-mercaptopropanoate)trimethylol propane tris (3-mercaptobutylate) (i.e. 2-ethyl-2-(((3- mercaptobutanoyl)oxy)methyl)propane-1 ,3-diyl bis(3-mercaptobutanoate))(2,4,6-trioxo-1 ,3,5-triazinane-1 ,3,5-triyl)tris(ethane-2, 1-diyl) tris(3-mercaptopropanoate)1 ,3,5-Tris [2-(3-mercaptobutanoyloxy)ethyl]-1 , 3,5-triazine-2 ,4,6-(1 H,3H,5H)-trione

[0044] In an embodiment, the thiol component is selected from the group consisting of: pentaerythritol tetrakis (mercaptoacetate)pentaerythritol tetrakis (3-mercaptopropionate)pentaerythritol tetrakis (3-mercaptobutylate)

[0045] In an embodiment, the thiol component is selected from the group consisting of: dipentaerythritol hexakis(3-mercaptopropionate)dipentaerythritol hexakis(2-mercaptopropionate)dipentaerythritol hexakis(3-mercaptobutylate)

[0046] Preferably, the thiol component is pentaerythritol tetra(3-mercaptopropionate).

[0047] In an embodiment, the thiol component is present in the adhesive formulation in an amount of from about 15 to about 35 wt%. In an embodiment, the thiol component is present in the adhesive formulation in an amount of from about 16 to about 35 wt%. In an embodiment, the thiol component is present in the adhesive formulation in an amount of from about 17 to about 35 wt%. In an embodiment, the thiol component is present in the adhesive formulation in an amount of from about 18 to about 35 wt%. In an embodiment, the thiol component is present in the adhesive formulation in an amount of from about 19 to about 35 wt%. In an embodiment, the thiol component is present in the adhesive formulation in an amount of from about 20 to about 35 wt%. In an embodiment, the thiol component is present in the adhesive formulation in an amount of from about 20 to about 34 wt%. In an embodiment, the thiol component is present in the adhesive formulation in an amount of from about 20 to about 33 wt%. In an embodiment, the thiolcomponent is present in the adhesive formulation in an amount of from about 20 to about 32 wt%, for example: 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 wt%.

[0048] Component C:

[0049] In an embodiment, the vinyl groups includes are each independently selected from allyl, vinyl ether, vinyl ester, allyl ether, allyl ester, norbornene, diene and N-vinyl amide groups. Preferably, the vinyl groups includes are each allyl groups.

[0050] Examples of suitable vinyl components include Triallyl-1 , 3, 5-triazine-2, 4, 6-trione (TATATO); Triethyleneglycol divinyl ether (TEGDVE); Trimethylolpropane diallyl ether; bis-2,2-[4- (2-[norbom-2-ene-5-carboxylate]ethoxy)phenyl]propane (BPAEDN), 1 ,6-hexanediol di- (endo,exo-norborn-2-ene-5-carboxylate) (HDDN), 2-((bicyclo[2.2.1]hept-5- enecarbonyloxy)methyl)-2-ethylpropane-1 ,3-diyl bis(bicyclo[2.2.1]hept-5-ene-2-carboxylate) (trimethylolpropane tri-(norborn-2-ene-5-carboxylate); TMPTN), pentaerythritoltri-(norborn-2-ene- 5carboxylate) (PTN3), pentaerythritol tetra-(norbom-2-ene-5-carboxylate) (PTN4), tricyclodecane dimethanol di-(endo,exo-norborn-2-ene-5-carboxylate) (TCDMDN), and di(trimethylolpropane)tetra-(norbom-2-ene-5-carboxylate) (DT-MPTN).

[0051] The norborene compounds may be synthesized, for example, by the methods in Carioscia et al., 2007, J. Pol. Sci.: Part A: Pol. Chem. 45:5686-5696, which is incorporated herein by reference. Certain other norborene compounds may be prepared by the methods of Jacobine et al., 1992, J. Appl. Pol. Sci. 45(3):471-485, which is incorporated herein by reference.

[0052] In one preferred embodiment, the vinyl component is triallyl-1 , 3, 5-triazine-2, 4, 6- (1 H,3H,5H)-trione (TATATO).

[0053] In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 5 to about 14 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 5 to about 13 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 5 to about 12 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 5 to about 11 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 5 to about 10 wt%.

[0054] In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 6 to about 15 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 6 to about 14 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 6 to about 13wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 6 to about 12 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 6 to about 11 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 6 to about 10 wt%.

[0055] In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 7 to about 15 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 7 to about 14 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 7 to about 13 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 7 to about 12 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 7 to about 11 wt%. In an embodiment, the vinyl component is present in the adhesive formulation in an amount of from about 7 to about 10 wt%.

[0056] For example, the vinyl component may be present in an amount of 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0 wt%.

[0057] Component D:

[0058] In an embodiment, the photoinitiator comprises a visible light activated photo initiator or a UV light activated photo initiator.

[0059] In one embodiment, the photoinitiator operates following exposure to any light wavelength range within the ultraviolet and / or visible light spectrum. The choice of the wavelength range can be determined by the photoinitiator employed. In one embodiment, a full spectrum light source, e.g. a quartz-halogen xenon bulb, may be utilized for photopolymerization. In another embodiment, a wavelength range of about 320 to about 500 nm is employed for photopolymerization, e.g. 400 to 500 nm.

[0060] In an embodiment, the photoinitiator is a bis acyl phosphine oxide (BAPO). In a specific embodiment, the BAPO photoinitiator is selected from the group consisting of phenyl bis(2,4,6- trimethyl benzoyl) phosphine oxide (Irgacure 819, Ciba™) or ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L).

[0061] In an embodiment, the photoinitiator is an acylgermane compound. In an embodiment, the acylgermane compound is a compound having two acyl groups and two alkyl groups. In a specific embodiment, the acylgermane compound is bis-(4-methoxybenzoyl)diethylgermanium.

[0062] In an embodiment, the photoinitiator is a metallocene initiator. In a specific embodiment, the metallocene initiator is Bis(eta 5-2,4-cyclopentadien-1-yl)Bis[2,6-difluoro-3-(1 H-pyrrol-1- yl)phenyl]titanium (Irgacure 784, Ciba™).

[0063] In an embodiment, the photoinitiator is an alpha-hydroxyketone, such as 1-hydroxy- cyclohexylphenylketone (Irgacure 184, Ciba™).

[0064] In an embodiment, the photoinitiator is a benzyldimethyl-ketal, such as 2,2-dimethoxy-2- phenylacetophenone (DMPA, e.g. Irgacure 651 , Ciba™).

[0065] In an embodiment, the photoinitiator is selected from the group consisting of bis-(4- methoxybenzoyl)diethylgermanium, ethyl phenyl(2,4,6-trimethylbenzoyl)phosphinate, phenyl bis (2,4,6-trimethyl benzoyl) phosphine oxide, bis(eta 5-2,4-cyclopentadien-1-yl) bis[2,6-difluoro-3- (1 H-pyrrol-1-yl)phenyl]titanium, 1-hydroxy-cyclohexyl-phenylketone, 2.2-dimethoxy-2- phenylacetophenone, and any combinations thereof.

[0066] Preferably, the photoinitiator is an acylgermane compound. In a specific preferred embodiment, the acylgermane compound is bis-(4-methoxybenzoyl)diethylgermanium.

[0067] In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about 4.5 wt%. In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about 4 wt%. In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about 3.5 wt%. In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about 3 wt%. In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about 2.5 wt%. In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about 2 wt%. In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about1 .5 wt%. In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about 1 wt%. In an embodiment, the photoinitiator component is present in an amount of from about 0.05 to about 0.5 wt%.

[0068] In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of from about 0.05 to about4.5 wt%. In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of from about 0.05 to about 4 wt%. In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of from about 0.05 to about3.5 wt%. In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of from about 0.05 to about 3 wt%. In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of from about 0.05 to about2.5 wt%. In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of from about 0.05 to about 2wt%. In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of from about 0.5 to about 2 wt%. In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of from about 1.5 to about 2 wt%. In an embodiment, the photoinitiator component is ethyl phenyl(2,4,6- trimethylbenzoyl)phosphinate (TPO-L) and is present in an amount of about 2 wt%.

[0069] In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of from about 0.05 to about 4.5 wt%. In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of from about 0.05 to about 4 wt%. In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of from about 0.05 to about 3.5 wt%. In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of from about 0.05 to about 3 wt%. In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of from about 0.05 to about 2.5 wt%. In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of from about 0.05 to about 2 wt%. In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of from about 0.05 to about 1.5 wt%. In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of from about 0.05 to about 1 wt%. In an embodiment, the photoinitiator component is bis-(4- methoxybenzoyl)diethylgermanium and is present in an amount of 0.5 wt% or 1 wt%.

[0070] Component E:

[0071] In an embodiment, the skin adhesive composition further comprises an inhibitor component, in an amount of from 0-1 wt%.

[0072] The inhibitor acts as a stabiliser, preventing or delaying the formulation from curing prior to use, e.g., during storage. Without wishing to be bound by theory, the inhibitor prevents or delays premature curing by acting as a radical scavenger, thereby preventing or delaying initiation of the thiol / ene polymerisation reaction.

[0073] In an embodiment, the inhibitor component is any component that is able to scavenge and retain radicals from at least components A and B. In an embodiment, the inhibitor component is any component that is able to scavenge and retain radicals from components A, B, C, F, and G, when present.

[0074] In an embodiment, the inhibitor component comprises an inhibitor selected from: phenolic stabilisers, hydroperoxide decomposers, alkyl radical scavengers, and combinations thereof.

[0075] In an embodiment, the inhibitor component comprises a phenolic stabiliser. The phenolic stabiliser may be selected from the group consisting of:MEHQ: 4-methoxyphenolTBC: 4-tert butylcatecolHQ: HydroquinoneBHT: Butylated hydroxytoluenePyrogalloland combinations thereof.

[0076] In an embodiment, the inhibitor component comprises a hydroperoxide decomposers. The hydroperoxide decomposers may be selected from the group consisting of: triphenyl phosphite (TPP), phenyl phosphonic acid (PPA), tris(2,3,-di-(tert)-butylphenyl)phosphite (TTBPP), and combinations thereof.

[0077] In an embodiment, the inhibitor component comprises an alkyl radical scavenger. The alkyl radical scavenger may be a nitroso compound. The nitroso compound may be a nitroso aluminium salt. The nitroso compound may be N-nitroso-N-phenylhydroxylamine aluminium salt (ANPHA, Aluminium N-oxido-N-phenylnitrous amide):

[0078] In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.01 to about 1 wt%. In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.01 to about 0.5 wt%. In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.01 to about 0.25 wt%. In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.01 to about 0.2 wt%. In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.01 to about 0.1 wt%.

[0079] In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.05 to about 1 wt%. In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.05 to about 0.5 wt%. In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.05 to about 0.25 wt%. In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.05 to about 0.2 wt%. In an embodiment, the inhibitor component is present in the adhesive formulation in an amount of from about 0.05 to about 0.1 wt%.

[0080] Component F:

[0081] In an embodiment, the skin adhesive composition further comprises a methacrylate component comprises a molecule having a single methacrylate group per molecule, in an amount of from 0-20 wt%.

[0082] In an embodiment, the methacrylate component is an organic compound having the general formula, wherein R is an organic residue.

[0083] In an embodiment, the methacrylate component is selected from the group consisting of:PPGMA : Polypropylene glycol methacrylate hyl cyclohexyl methacrylate yclohexyl methacrylateBZMA Benzyl methacrylateTHFMA tetrahydrofurfuryl methacrylateSMA Stearyl methacrylatePH EMA Phenoxyethyl methacrylatePolyethylene glycol) methyl ether methacrylateIBOMA Isobornyl MethacrylateI ylateMMA Methyl methacrylateHEMA Hydroxyethyl methacrylate

[0084] In an embodiment, the methacrylate component is selected from the group consisting of:SMA Stearyl methacrylatePolyethylene glycol) methyl ether methacrylateI DMA Iso-Decyl Methacrylate

[0085] In an embodiment, the methacrylate component is selected from the group consisting of:SMA Stearyl methacrylateLauryl methacrylate

[0086] In an embodiment, the methacrylate component is Lauryl methacrylate

[0087] In an embodiment, the methacrylate component is present in an amount of from 1-20 wt%. In an embodiment, the methacrylate component is present in an amount of from 1-15 wt%. In an embodiment, the methacrylate component is present in an amount of from 5-15 wt%. In an embodiment, the methacrylate component is present in an amount of from 10-15 wt%. In an embodiment, the methacrylate component is present in an amount of from 1-14 wt%. In an embodiment, the methacrylate component is present in an amount of from 5-14 wt%. In an embodiment, the methacrylate component is present in an amount of from 10-14 wt%. In an embodiment, the methacrylate component is present in an amount of from 1-13 wt%. In an embodiment, the methacrylate component is present in an amount of from 5-13 wt%. In an embodiment, the methacrylate component is present in an amount of from 10-13 wt%. In an embodiment, the methacrylate component is present in an amount of from 1-12 wt%. In an embodiment, the methacrylate component is present in an amount of from 5-12 wt%. In an embodiment, the methacrylate component is present in an amount of from 10-12 wt%.

[0088] In an embodiment, the methacrylate component is present in an amount of 0 wt%, i.e. , the methacrylate is absent from the skin adhesive composition.

[0089] Component G:

[0090] In an embodiment, the skin adhesive composition further comprises a dimethacrylate component having two methacrylate groups per molecule, in an amount of from 0-20 wt%.

[0091] The dimethacrylate component comprises a molecule having two methacrylate groups per molecule. The dimethacrylate component is present in the skin adhesive formulation in an amount of from 0-20 wt%.

[0092] In an embodiment, the dimethacrylate component is an organic compound having the general formula, wherein R is an organic residue.

[0093] In an embodiment, the dimethacrylate component is selected from the group consisting of:EGDMA Ethylene glycol dimethacrylateDEGDMA Diethylene glycol dimethacrylateTEG DMA Triethylene glycol dimethacrylateT4EGDMA Tetraethylene glycol dimethacrylateBPADMA Bisphenol A dimethacrylateBisphenol-A-ethoxylat(2)dimethacrylate1 ,3-Butanediol DimethacrylatePolyethylene glycol) dimethacrylate (average mw 200, 600, or 750)HDDMA Hexanediol dimethacrylate

[0094] In an embodiment, the dimethacrylate component is selected from the group consisting of:EGDMA Ethylene glycol dimethacrylateDEGDMA Diethylene glycol dimethacrylateTEG DMA Triethylene glycol dimethacrylateT4EGDMA Tetraethylene glycol dimethacrylate1 ,3-Butanediol DimethacrylateHDDMA Hexanediol dimethacrylate

[0095] In an embodiment, the dimethacrylate component is HDDMA Hexanediol dimethacrylate

[0096] In an embodiment, the dimethacrylate component is present in an amount of from 1-20 wt%. In an embodiment, the dimethacrylate component is present in an amount of from 5-20 wt%. In an embodiment, the dimethacrylate component is present in an amount of from 10-20 wt%. In an embodiment, the dimethacrylate component is present in an amount of from 8-18 wt%. In an embodiment, the dimethacrylate component is present in an amount of from 10-18 wt%.

[0097] In an embodiment, the dimethacrylate component is present in an amount of 0 wt%, i.e. , the dimethacrylate is absent from the skin adhesive composition.

[0098] Component H:

[0099] In an embodiment, the skin adhesive composition further comprises a filler component in an amount of up to about 7 wt%. In an embodiment, the filler component is fumed silica. Aerosil R202™ is an example of a fumed silica that is commercially available.

[0100] In an embodiment, the filler component is present in an amount of up to about 6 wt%. In an embodiment, the filler component is present in an amount of up to about 5 wt%. In an embodiment, the filler component is present in an amount of up to about 4 wt%.

[0101] In an embodiment, the filler component is present in an amount of from about 0.1 to 7 wt%. In an embodiment, the filler component is present in an amount of from about 0.25 to 7 wt%. In an embodiment, the filler component is present in an amount of from about 0.5 to 7 wt%. In an embodiment, the filler component is present in an amount of from about 0.75 to 7 wt%. In an embodiment, the filler component is present in an amount of from about 1 to 7 wt%. In an embodiment, the filler component is present in an amount of from about 1.25 to 7 wt%. In an embodiment, the filler component is present in an amount of from about 1.5 to 7 wt%. In anembodiment, the filler component is present in an amount of from about 1.75 to 7 wt%. In an embodiment, the filler component is present in an amount of from about 2 to 7 wt%.

[0102] In an embodiment, the filler component is present in an amount of from about 0.1 to 6 wt%. In an embodiment, the filler component is present in an amount of from about 0.25 to 6 wt%. In an embodiment, the filler component is present in an amount of from about 0.5 to 6 wt%. In an embodiment, the filler component is present in an amount of from about 0.75 to 6 wt%. In an embodiment, the filler component is present in an amount of from about 1 to 6 wt%. In an embodiment, the filler component is present in an amount of from about 1.25 to 6 wt%. In an embodiment, the filler component is present in an amount of from about 1.5 to 6 wt%. In an embodiment, the filler component is present in an amount of from about 1.75 to 6 wt%. In an embodiment, the filler component is present in an amount of from about 2 to 6 wt%.

[0103] In an embodiment, the filler component is present in an amount of from about 0.1 to 5 wt%. In an embodiment, the filler component is present in an amount of from about 0.25 to 5 wt%. In an embodiment, the filler component is present in an amount of from about 0.5 to 5 wt%. In an embodiment, the filler component is present in an amount of from about 0.75 to 5 wt%. In an embodiment, the filler component is present in an amount of from about 1 to 5 wt%. In an embodiment, the filler component is present in an amount of from about 1.25 to 5 wt%. In an embodiment, the filler component is present in an amount of from about 1.5 to 5 wt%. In an embodiment, the filler component is present in an amount of from about 1.75 to 5 wt%. In an embodiment, the filler component is present in an amount of from about 2 to 5 wt%.

[0104] In an embodiment, the filler component is present in an amount of from about 0.1 to 4 wt%. In an embodiment, the filler component is present in an amount of from about 0.25 to 4 wt%. In an embodiment, the filler component is present in an amount of from about 0.5 to 4 wt%. In an embodiment, the filler component is present in an amount of from about 0.75 to 4 wt%. In an embodiment, the filler component is present in an amount of from about 1 to 4 wt%. In an embodiment, the filler component is present in an amount of from about 1.25 to 4 wt%. In an embodiment, the filler component is present in an amount of from about 1.5 to 4 wt%. In an embodiment, the filler component is present in an amount of from about 1.75 to 4 wt%. In an embodiment, the filler component is present in an amount of from about 2 to 4 wt%.

[0105] Description of the figures:

[0106] Figure 1 : UV box with 405nm switch and its irradiation profile (10cm below the LED light).

[0107] Figure 2: a dental light pen and its irradiation profile (close contact).

[0108] Figure 3: Set up showing the testing rig used for the wound closure strength test measurement.

[0109] Figure 4: A) Adhesive applied to leather; B) Adhesive applied to pig skin.

[0110] Figure 5: Total extractables (ppm) for exofin™, cyanoacrylate formulation (Comparative Example 1) and acrylate-thiokene samples with standard deviation error bars. Extractables were measured using HPLC after cured samples were left to age in saline for 15 days at 37°C.

[0111] Figure 6: Bar chart depicting the percentage of the total leached material amount for both a standard UV acrylate formulation and acrylate-thiokene formulations with varying ratios of thiokene and photointiator concentrations.

[0112] Figure 7: Structure of A1.

[0113] General synthetic process:

[0114] The following is a generic process used to produce the below examples.

[0115] Weigh out component A and heat to 60°C oven or hot box to lower viscosity.

[0116] Weigh out component D (photoinitiator) and component E (inhibitor) into a black cup.

[0117] Weigh out component C (vinyl component), component F (methacrylate component) and component G (dimethacrylate component) and add to same black cup.

[0118] Mix in speed mixer for 5 minutes at 1500rpm or until all of the solids are dissolved.

[0119] Add heated component A to same black cup.

[0120] Mix at 2200 rpm for 3 minutes.

[0121] Allow formulation to come to room temperature (25°C).

[0122] Weigh out component B (thiol component) and add to same black cup.

[0123] Mix at 2000 rpm for 45 seconds whilst maintaining temperature below 40°C when mixing.

[0124] The filler components, if present, are then added. First the silica was added according to the formulation and was mixed by hand for about 30 seconds. The mixture was then mixed in the speed mixer at 2400 rpm for 30 seconds. If any solvents are present, the solvent is then added into the formulation and mixed in the speed mixer at 2000 rpm for 30 seconds.

[0125] Curing

[0126] The irradiation of two light sources was measured by using Stella Bluewave spectrometer.

[0127] The 405nm UV box emitted light with irradiation of 2.0 mW / cm2in the range of 400nm to 500nm and 3.3 mW / cm2in the range of 315nm to 400nm (Figure 1).

[0128] The visible light dental pen emitted light with irradiation of 4.0 mW / cm2in the range of 400nm to 500nm and 1.5 mW / cm2in the range of 315nm to 400nm (Figure 2).

[0129] In an embodiment, the curing time of the adhesive composition of the present invention is 60 seconds or less.

[0130] Synthesis of Component A1 :

[0131] A mixture was produced by introducing 148.5 g of 4,4’-Methylenebis(cyclohexyl isocyanate) (0.566mol, H12MDI, manufactured by Evonik Corporation) as a diisocyanate-based compound, and 150.0 g of Polycaprolactone diol (PCLOH, Mn=530g / mol, 0.283mol, Sigma- Aldrich) into a 1 L five-necked reactor.

[0132] Subsequently, after the mixture was heated to 50° C and maintained at this temperature, a first urethane prepolymer represented by:was produced, wherein o is between 1 and 2, by introducing 40 ppm of dibutyltin dilaurate (DBTDL) as a catalyst thereinto and inducing an exothermic reaction. The produced first urethane prepolymer was found to have a weight average molecular weight (Mw) of about 1 ,750 g / mol, as measured by Size Exclusion Chromatography (SEC).

[0133] Subsequently, Component A1 was produced by adding dropwise 66.43 g of hydroxyl ethyl acrylate (HEA, 0.572mol) as a polar group-containing acrylate to the produced first urethane prepolymer and reacting the resulting mixture at 60° C and a rate of 10 g / min. The produced urethane acrylamide oligomer (Component A1) was found to have a weight average molecular weight (Mw) of about 2,000 g / mol.Polycaprolactone diol (PCLOH)CAS No. 36890-68-3, Avg. Mn~530 g / mol, n = 1-24,4'-Methylenebis(cyclohexyl isocyanate) (H12MDI)CAS No. 5124-30-1 , Molecular weight:262.35Hydroxyethyl acrylate (HEA)CAS No. 818-61-1 , Molecular weight: 116.12Dibutyltin dilaurate (catalyst)CAS No. 77-58-7, Molecular weight:631 .56

[0134] Example 1 : 1933-124

[0135] The following formulation was prepared using the general procedure set out above:

[0136] Example 2: 1933-129

[0137] The following formulation was prepared using the general procedure set out above:

[0138] Example 3: 1933-135:

[0139] The following formulation was prepared using the general procedure set out above:

[0140] Example 4: 1933-136

[0141] The following formulation was prepared using the general procedure set out above:

[0142] Example s: 1933-137

[0143] The following formulation was prepared using the general procedure set out above:

[0144] Example 6: RCM-HT-22-C

[0145] The following formulation was prepared using the general procedure set out below:

[0146] Weigh out component A and heat to 60°C oven or hot box to lower viscosity.

[0147] Weigh out component D (photoinitiator) into a black cup.

[0148] Weigh out component C (vinyl component) and add to same black cup.

[0149] Mix in speed mixer for 5 minutes at 1500rpm or until all of the solids are dissolved.

[0150] Add heated component A to same black cup.

[0151] Mix at 2200 rpm for 3 minutes.

[0152] Allow formulation to come to room temperature (25°C).

[0153] Weigh out component B (thiol component) and add to same black cup.

[0154] Mix at 2000 rpm for 45 seconds whilst maintaining temperature below 40°C when mixing.

[0155] Component I (solvent) is then added into the formulation and mixed in the speed mixer at 2000 rpm for 30 seconds.

[0156] Comparative example 1 : Exofin™ (cyanoacrylate) adhesive:

[0157] The following comparative formulation was used as Comparative Example 1 :

[0158] This formulation is commercially available from Chemence as Exofin™.

[0159] Comparative example 2: typical dental formulation (methacrylate based):

[0160] The following comparative formulation was prepared:

[0161] The following is process used to produce the above Comparative Example:

[0162] Weigh out Urethane dimethacrylate (Esstech product X-850-0000) and heat to 60°C oven or hot box to lower viscosity.

[0163] Weigh out Bis(4-methoxybenzoyl)diethylgermanium and Aluminum N- nitrosophenylhydroxylamine into a black cup.

[0164] Weigh out Triallyl triazine trione and Triethylene glycol dimethacrylate (TEGDMA) and add to same black cup.

[0165] Mix in speed mixer for 5 minutes at 1500rpm or until all of the solids are dissolved.

[0166] Add heated Urethane dimethacrylate (Esstech product X-850-0000) to same black cup.

[0167] Mix at 2200 rpm for 3 minutes.

[0168] Allow formulation to come to room temperature (25°C).

[0169] Weigh out Pentaerythritol tetra(3-mercaptopropionate) and add to same black cup.

[0170] Mix at 2000 rpm for 45 seconds whilst maintaining temperature below 40°C when mixing.

[0171] Comparative example 3: standard UV curable acrylate formulation

[0172] The following comparative formulation was prepared:

[0173] The following is process used to produce the above Comparative Example:

[0174] Weigh out component A and heat to 60°C oven or hot box to lower viscosity.

[0175] Weigh out component D (photoinitiator) into a black cup.

[0176] Weigh out component F (methacrylate component) and component G (dimethacrylate component) and add to same black cup.

[0177] Mix in speed mixer for 5 minutes at 1500rpm or until all of the solids are dissolved.

[0178] Add heated component A to same black cup.

[0179] Mix at 2200 rpm for 3 minutes.

[0180] Allow formulation to come to room temperature (25°C).

[0181] Add silica and mix by hand for about 30 seconds. The mixture was then mixed in the speed mixer at 2400 rpm for 30 seconds.

[0182] Example 7: Tensile strength and Elongation

[0183] Material properties were made and tested in accordance with ASTM D638-14.Adhesive was applied to an open faced teflon dog bone mold using a wooden tongue compressor and smoothed using a straight edge. The adhesive was than cured in the mold open faced using a broadband light for 60s at an intensity of 100 mW / cm2. Dog bones were removed from the moldusing a razor blade and let to sit for 24 hours. Dog bones were then tested on an Instron™ for tensile strength and elongation. Instron™ specifications can be listed below:Specimen Size:Gauge length: 33 mmThickness: 1 mmWidth: 6.35 mmTest speed: 5 in / min (127 mm / min).Equipment: Instron™ 3369 System ID 3365B20586Load Cell: 50 kN #2716-020

[0184] This example demonstrates that the skin adhesive compositions according to the present invention (i.e. Example 3) have elongation properties that are comparable to commercially available cyanoacrylate based skin adhesive compositions (i.e. Exofin™, Comparative Example 1), whereas formulations in which the acrylate component is exchanged for a methacrylate component (i.e. a typical dental formulation, such as those disclosed in US 8,962,709, Comparative Example 2) have much lower elongation properties.

[0185] Also shown in the table alongside the elongation (%) result is the tensile strength (MPa) value for each of the three compositions. Whilst the represented dental formulation (Comparative Example 2) exhibits much lower elongation properties, it exhibits much higher tensile strength than either the skin adhesive formulation of Example 3 or the cyanoacrylate based Exofin™ skin adhesive (Comparative Example 1), as would be expected for a dental formulation.

[0186] Example 8: Wound closure strength test

[0187] Wound closure strength test were performed following ASTM F2458-05 “Standard Test Method for Wound Closure Strengths in Tissue Adhesives and Sealants” on both genuine leather and pig skin by using a lab think tensile tester. The adhesive was applied on the top of twoadjacent substrates in a 1 cm by 2.5 cm area (Figures 3 and 4). 0.1 g of Exofin™ (Comparative Example 1) was used and 0.2 g of the formulations of Examples 1 to 6 above was applied. After the adhesive was fully cured, the maximum force to break was regarded as the wound closure strength.

[0188] Results for leather:■Q0189] * Would closure strength was measured by using a Labthink tensile tester

[0190] Results for pig skin:■Q0191] * Would closure strength was measured by using a Labthink tensile tester

[0192] Example 9: Extraction Testing of Adhesive

[0193] Preparation of PBS Buffer:

[0194] Phosphate buffered saline solution (100mM, pH 7.4) was prepared by dissolving 1 PBS tablet in 1 L deionized water.

[0195] Preparation of cured exofin™ and UV films:

[0196] Exofin™ high viscosity topical skin adhesive of Comparative Example 1 was spread evenly on an aluminium foil having an approximate area of each film is 4cm by 6cm. The weight of the films ranged between 267.5 mg and 535.1 mg. The films were left to sit for 2 hours before being removed from the foil.

[0197] The acrylate-thiokene UV cured film of Example 3 was drawn down with a drawn down bar with an approximate area of 4cm by 6 cm with a 5 mm thickness. The weight of the films ranged between 250.0 mg and 359.5 mg. The film was cured for 60 seconds with the broadband light at an intensity of 100 mW / cm2.

[0198] Extraction process:

[0199] Upon complete curing, the films were immersed in a centrifuge tube containing ~30mL of PBS buffer solution. It was ensured that the films were completely submerged in the PBS buffer solution.

[0200] Tubes were sealed tightly (using paraffin film) and transferred to the water bath shaker (Gyratory Water Bath Shaker Model G-76).

[0201] The water bath shaker was maintained at 37°C and shaken continuously.

[0202] Water levels and temperature were monitored regularly for the entire duration of the study (15 days).

[0203] A control sample (only PBS Buffer pH 7.4 100mM) was also included in the study.

[0204] HPLC method for analysis of impurities in cured adhesive films:

[0205] Results are shared in ppm as to account for the weight of the films and the amount of saline used (see Figure 5).

[0206] PBS extracts obtained after completion of the study were subject to solvent evaporation to obtain the solids for HPLC analysis using rotary vaporization.

[0207] 2-octyl cyanoacrylate was used as a standard for the Exofin™ film.

[0208] Methyl methacrylate was used as the standard for acrylate-thiol: ene film. HPLC methodHPLC 1260 with DAD detectorMobile phase A: 0.1 % H3PO in WaterMobile phase B: acetonitrileDAD wavelength: 215 nmColumn temperature: 30 CInjection volume: 5 ulColumn: Agilent Zorbax™ Eclipse plus C18 (4.6 x 100 mm, 3.5 m)

[0209] All the calibration standards were prepared in acetonitrile containing 0.05wt% H3PO4.

[0210] The total extractables (in ppm) for the formulations of the present invention are less than the total extractables exhibited by Comparative Example 1 , meaning that any localised skin irritation or allergic reactions would be expected to be reduced compared to the Comparative Example 1 .

[0211] Example 10: Viscosity properties.

[0212] Viscosity was measured with a TA Instruments Discovery HR-2 rheometer.Temperature at 25°CShear Rate: 1 rad / s to 50 rad / sSpindle: 25 mm parallel plate, ETC steelSoak Time: 10 secondsGap distance: 800 micronsTotal experiment time: 2 minutes

[0213] This example demonstrates that the skin adhesive compositions according to the present invention (i.e. Example 3) have a higher viscosity compared with commercially available cyanoacrylate based skin adhesive compositions (i.e. Exofin™, Comparative Example 1). The low viscosity of the Exofin™, Comparative Example 1 (i.e. 350 cPs) renders it difficult to apply as it is prone to dripping at the application site.

[0214] Formulations in which the acrylate component is exchanged for a methacrylate component (i.e. a typical dental formulation, such as those disclosed in US 8,962,709, Comparative Example 2) have a much higher viscosity than either the skin adhesive compositions according to the present invention (i.e. Example 3) or commercially available cyanoacrylate based skin adhesive compositions (i.e. Exofin™, Comparative Example 1). The high viscosity of a typical dental formulation, Comparative Example 2 (i.e. 3000 cPs), renders it difficult to apply and dispense the formulation.

[0215] An intermediate viscosity value of >350 cPs and <3000 cPs is advantageous. The formulations of the present invention achieve this target, intermediate viscosity.

[0216] Example 11 : Thiol: Ene Ratio Discussion:

[0217] This example illustrates that the thiol component in the formulation can readily react with the acrylate component, the methacrylate component and the “ene” component. Several formulations were made based on the formulation of Example 1 in which the ratio of thiol : ene component was varied. The formulations were as follows:

[0218] 2:1 thiokene

[0219] 1.5:1 thiokene

[0220] 1 :1 thiokene

[0221] Acrylate only

[0222] Extraction Testing of Adhesive Formulations:

[0223] Preparation of UV films:

[0224] The acrylate-thiokene UV cured films in line with the above table were drawn down with a drawn down bar with an approximate area of 4cm by 6 cm with a 5 mm thickness. The weight of the films ranged between 250.0 mg and 359.5 mg. The films were cured for 60 seconds with the broadband light at an intensity of 100 mW / cm2.

[0225] Extraction process:

[0226] Upon complete curing, the films were immersed in a centrifuge tube containing 30mL of methanol. It was ensured that the films were completely submerged in the methanol.

[0227] Tubes were sealed tightly (using paraffin film) and transferred to the water bath shaker (Gyratory Water Bath Shaker Model G-76).

[0228] The water bath shaker was maintained at 25°C and shaken continuously.

[0229] Water levels and temperature were monitored regularly for the entire duration of the study (24 hours days).

[0230] A control sample (only methanol) was also included in the study.

[0231] HPLC method for analysis of impurities in cured adhesive films:

[0232] Results are shared in ppm as to account for the weight of the films and the amount of methanol used.

[0233] Methyl methacrylate was used as the standard for acrylate-thiol: ene film.

[0234] Results for extraction testing:

[0235] In formulations having a greater proportion of thiol relative to ene (i.e. a higher thiokene ratio) less leached material was detected. Formulations having the thiokene component resulted in less leached materials compared with acrylate-only formulations. See Figure 6.

[0236] It was hypothesised that the thiokene component improves the curing of the acrylate component due to co-polymerisation of the acrylate with the thiokene alongside homopolymerisation.

[0237] It was hypothesised that a 1 :1 ratio of thiokene will cause the formulation to not go to completion. An excess of thiol is therefore beneficial to the formulation to proceed to near 100% conversion, which in turn reduces the extractable materials and yields a biocompatible adhesive.

Claims

Claims:1 . A skin adhesive formulation comprising:(A) a urethane diacrylate component having two terminal acrylate groups,, per molecule and including the structure:-[(urethane component)-(polycaprolactone component)-(polyethylene glycol cornponent)m-(C2-alkyl)-(polycaprolactone component)]o-(urethane component)- wherein each urethane component is bonded to the terminal acrylate group, optionally via a hydroxyethyl linker group; wherein m is 0-3; and wherein o is 1-5; in an amount of from 30-65 wt%;(B) a thiol component having two or more independently selected thiol groups per molecule, in an amount of from 10-35 wt%;(C) a vinyl component having two or more independently selected vinyl groups per molecule, in an amount of from 5-15 wt%;(D) a photoinitiator component, in an amount of from 0.05-5 wt%; wherein the amount of (A) is greater than the amount of (B); and wherein there is a stoichiometric excess of thiol component relative to the vinyl component.

2. The formulation according to claim 1 , wherein the urethane diacrylate component (component A) includes a urethane component,. wherein the “-LINKER-” is an aliphatic (including cyclic) or aromatic divalent moiety.

3. The formulation according to claim 2, wherein the “-LINKER-” is a C1-C20 alkanediyl or a C3-C20 cycloalkanediyl, or combination thereof.

4. The formulation according to any preceding claim, wherein the urethane diacrylate component (component A) includes a urethane component having the structure:

5. The formulation according to any preceding claim, wherein the urethane diacrylate component (component A) includes a polycaprolactone component having the structure:wherein n is 1-10.

6. The formulation according to any preceding claim, wherein the urethane diacrylate component (component A) includes a polyethylene glycol component having the structure:wherein m is 0-3.

7. The formulation according to any preceding claim, wherein the urethane diacrylate component has the structure:(A1); wherein: m is 0-3; n is 1-10; and o is 1-5.

8. The formulation according to any preceding claim, wherein the number average molecular weight (MN) of component A, is between 14,500 - 950 g mol-1.

9. The formulation according to any preceding claim, wherein the thiol component (component B) has an average of four primary, secondary or tertiary thiol groups per molecule.

10. The formulation according to claim 9, wherein the thiol component (component B) is pentaerythritol tetrakis(3-mercaptopropionate).

11. The formulation according to claims 9 and 10, wherein the thiol component (componentB) is present in the adhesive formulation in an amount of from 20-32 wt%.

12. The formulation according to any preceding claim, wherein the vinyl groups (componentC) are each independently selected from allyl, vinyl ether, vinyl ester, allyl ether, allyl ester, norbornene, diene and N-vinyl amide groups.

13. The formulation according to claim 12, wherein the vinyl group (component C) is triallyl- 1 ,3,5-triazine-2,4,6-(1 H,3H,5H)-trione.

14. The formulation according to claims 12 and 13, wherein the vinyl group (component C) is present in the adhesive formulation in an amount of 7-13 wt%.

15. The formulation according to any preceding claim, wherein the photoinitiator (componentD) comprises a visible light activated photoinitiator or a UV light activated photoinitiator.

16. The formulation according to claim 15, wherein the photoinitiator (component D) is ethyl phenyl(2,4,6-trimethylbenzoyl)phosphinate or bis-(4-methoxybenzoyl)diethylgermanium.

17. The formulation according to claims 15 and 16, wherein the photoinitiator is present in an amount of from 0.05-2 wt%.

18. The formulation according to any preceding claim, wherein the skin adhesive formulation further comprises an inhibitor component, wherein the inhibitor component is present in the adhesive formulation in an amount of from 0-1 wt%.

19. The formulation according to claim 18, wherein the inhibitor component comprises an inhibitor selected from: phenolic stabilisers, hydroperoxide decomposers, alkyl radical scavengers, and combinations thereof.

20. The formulation according to claims 18-19, wherein the inhibitor component is N-nitroso- N-phenylhydroxylamine aluminium salt.

21. The formulation according to claims 18-20, wherein the inhibitor component is present in an amount of from 0.01-0.1 wt%.

22. The formulation according to any preceding claim, wherein the skin adhesive formulation further comprises a methacrylate component comprising a molecule having a single methacrylate group per molecule, in an amount of from 1-20 wt%.

23. The formulation according to claim 22, wherein the methacrylate component is lauryl methacrylate.

24. The formulation according to claim 22 to 23, wherein the methacrylate component is present in an amount of from 10-12 wt%.

25. The formulation according to any preceding claim, wherein the skin adhesive formulation further comprises a dimethacrylate component having two methacrylate groups per molecule, in an amount of from 1-20 wt%.

26. The formulation according to claim 25, wherein the dimethacrylate component is hexanediol dimethacrylate.

27. The formulation according to claims 25 and 26, wherein the dimethacrylate component is present in an amount from 10-18 wt%.

28. The formulation according to any preceding claim, wherein the skin adhesive formulation further comprises a filler component in an amount of up to about 7 wt%.

29. The formulation according to claim 29, wherein the filler is fumed silica.

30. The formulation according to claims 29 and 30, wherein the filler component is present is present in an amount of from about 0.1 to 4 wt%.

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