SURGICAL ADHESIVE

Description

Technical field of the invention

[0001] The present invention relates in particular to compositions for use as surgical adhesives, surgical sealants, hemostatic dressings, and / or skin dressings. More specifically, the present invention relates to compositions intended for use in a process: as a surgical adhesive for the adhesion of a material to biological tissue, for the adhesion of biological tissues to each other, for the adhesion of an adhesive or substance to the surface of biological tissue; as a surgical sealant, for closing or sealing openings created by suture or staple work or by tissue resection (e.g., hemostasis, aerostasis, lymphostasis); for sealing an opening, incision, or tear in biological tissue; as a hemostatic agent to stop bleeding, alone or in conjunction with conventional hemostasis techniques such as suturing, compression, or electrocoagulation; or as a dressing on biological tissue to cover and protect a wound. These compositions can also be used to reinforce biological tissue, to fix and stabilize biological tissue, and for the treatment of skin lesions. Previous technique

[0002] A number of surgical techniques utilize surgical glues. These are primarily used to help achieve surgical hemostasis. However, the effectiveness of surgical glues for this purpose is controversial, and other uses, such as for aerostatic injection, do not show better results.

[0003] Furthermore, surgical glues have very weak adhesive properties and therefore cannot be used as adhesives or surgical sutures. Surgical glues are most often applied directly to the tissue without any surface preparation. Tissue penetration is weak or nonexistent, resulting in poor-quality bonding. Applicants have observed that current glues do not adhere well and do not penetrate tissues.

[0004] To address this problem, low-viscosity surgical adhesives have been developed. These adhesives penetrate tissues more easily, resulting in a better bond. However, these adhesives require high concentrations of monomers. Furthermore, their chemical composition can cause burns at the application site. These formulations are also difficult for the general public to use directly.

[0005] Consequently, the present invention aims to provide a new type of surgical adhesive. The compositions and process according to the invention make it possible to obtain a level of skin adhesion suitable for application by the general public. The chosen concentrations allow for rapid initiation and polymerization within a few tens of seconds, without causing tissue burns.

[0006] US2017209617A1 discloses an adhesive composition for bonding to bone and similar structures, comprising bis[2(methacryloyoxy)ethyl](Bis-2) phosphate, acrylic modified calcium phosphate MCP, acrylic monomers such as HEMA, DMAEMA, UDMA, HMDMA and campherquinone as a photoinitiator for adhesion to mineralized tissues.

[0007] WO2008082929A2 discloses a dental adhesive composition comprising MDP (10 methacryloxydecyl phosphate), MHP (6 methacryloxyhexyl phosphate) or MOP (8 methacryloxydecyl phosphate), acrylic monomers and a polyester acrylate oligomer cured with photoinitiators, for example camphorquinone for adhesion to non-mineralized tissues.

[0008] EP3514213A1 discloses adhesive compositions for medical tapes of ethylenically unsaturated phosphoric esters, acrylic monomers and peroxy pivalate initiator.

[0009] Furthermore, the chosen photopolymerizable resins, combined with polymerizable monomers, provide the resulting bond with properties of flexibility, good stability over time under the action of physiological fluids (blood exudates, perspiration), a limitation of the accumulation of perspiration or exudates at the tissue / bonding interface and good water resistance. Summary of the invention

[0010] The present invention relates in particular to compositions for use as a surgical adhesive for the adhesion of a material to non-mineralized biological tissue, for the adhesion of non-mineralized biological tissues to each other, for the adhesion of an adhesive or substance to the surface of non-mineralized biological tissue, as a surgical sealant, for closing or sealing openings created by suture or staple or by tissue resection, for sealing an opening, incision or tear in non-mineralized biological tissue, as a hemostatic agent to stop bleeding, as a dressing on non-mineralized biological tissue to cover and protect a wound, for reinforcing non-mineralized biological tissue, for fixing and stabilizing non-mineralized biological tissue, comprising: a polymerizable monomer comprising a phosphate or phosphonate function on the one hand and a methacrylate, acrylate, acrylamide or methacrylamide function on the other hand at a concentration of between 5 and 40% by mass relative to the total mass of the composition, a polymerization initiator at a concentration of between 0.5 and 2% by mass, and a photopolymerizable resin.

[0011] Within the framework of the present invention, the polymerizable monomer comprising a phosphate or phosphonate function on the one hand and a methacrylate, acrylate, acrylamide or methacrylamide function on the other hand may be designated as a "polymerizable monomer".

[0012] The applicants were able to demonstrate that the compositions they submitted exhibited superior adhesive properties and safety compared to prior art compositions. These compositions are therefore particularly suitable for topical use as dressings for wounds and / or for the treatment of all skin lesions.

[0013] Preferably, said polymerizable monomer is chosen from the group consisting of molecules having CAS numbers [14206-25-8], [14235-57-5], [86242-61-7], [932019-41-6], [1980781-17-6], [60161-88-8], [87243-97-8], [1980048-95-0], [918802-80-9], [63411-25-6], [1980064-07-0], [22432-83-3], [1980781-08-5], [252210-28-9], [1114567-37-1], [80730-17-2], [518991-74-7], [87243-96-7], [1980062-84-7], [518991-75-8], [252210-30-3], [22432-84-4], [727415-30-7], [727415-31-8], [784139-89-5] or [1194231-98-5] and their mixtures.

[0014] Preferably, the polymerizable monomer has the formula I for which R2 is H or CH3; R1, R1', R1'' are independently of each other a linear polyether radical, a linear or branched aliphatic radical in C1-C50, an aromatic radical in C6-C18, for which the carbon chain of said radicals may be interrupted by O, S, OCONH and / or may include one or more alcohol functions; R1' is H if c=0; R1" is H if a=0; b is 1, ; a or c is 1 or 0.

[0015] The term "the carbon chain of said functions can be interrupted" means that said functions are inserted into the carbon chain, i.e. are linked to carbon atoms on both sides.

[0016] Preferably, a=0, R2=H or CH3 and R'1 and R1 is a linear aliphatic chain in C1-C12.

[0017] Even more preferentially, a=0, c=0, R2=CH3 and R1 is a linear aliphatic chain in C1-C12.

[0018] Preferably, a=0, c=0, R"1=H, R'1=H, R1=linear aliphatic chain in C1-C12, b = 1, R2 = CH3.

[0019] Preferably, a=1, c=1, b=0, R1=H, R'1=R''1=linear aliphatic chain in C1-C12, R2=CH3.

[0020] Preferably, the polymerizable monomer of formula I is 10-MDP (C14H27O6P, CAS number [85590-00-7]) or MEP (C12H19O8P, CAS number [32435-46-4]).

[0021] According to another preferred embodiment, the polymerizable monomer of formula I is selected from glycerol dimethacrylate phosphate, ethylene glycol methacrylate phosphate, polyethylene glycol methacrylate phosphate, methacryloyloxy decyl hydrogen phosphate, methacryloyloxy ethyloxy hydrogen phosphate, glycerol monomethacrylate phosphate, triethylene glycol monomethacrylate phosphate, methacryloyloxy propyl phosphate, methacryloyloxy hexyl phosphate, methacrylated aminoethyl phosphonic acid, bis(glyceryl dimethacrylate) phosphate and mixtures thereof.

[0022] In the context of the present invention, the term "polymerizable monomer" is intended to designate a monomer whose polymerization can be initiated by a physical or chemical initiator.

[0023] According to a preferred embodiment, polymerization is initiated under the effect of radiation. Preferably, said radiation has a wavelength between 350 nm and 520 nm.

[0024] The polymer obtained after polymerization of the monomer is preferably a biocompatible polymer.

[0025] According to a preferred embodiment, said viscosity is less than 120 Pa.s at 20°C.

[0026] According to an even more preferred embodiment, said viscosity is less than 107 Pa.s at 20°C.

[0027] According to a highly preferred embodiment, said viscosity is less than 50 Pa.s at 20°C.

[0028] According to a highly preferred embodiment, said viscosity is greater than 20 Pa.s at 20°C.

[0029] The viscosity of the composition can notably be measured by a falling ball viscometer according to the DIN53015 standard.

[0030] According to a preferred embodiment, the composition according to the invention is not a hydrogel.

[0031] According to a preferred embodiment, said monomer has a molar mass between 250 and 500g.mol-1.

[0032] According to an even more preferred embodiment, said monomer has a concentration of between 20 and 40% by mass relative to the total mass of the composition.

[0033] According to an even more preferred embodiment, said monomer has a concentration of between 20 and 40% by mass relative to the total mass of the composition.

[0034] According to a most preferred embodiment, said monomer has a concentration of between 25 and 35% by mass relative to the total mass of the composition.

[0035] According to a preferred embodiment of the invention, said photopolymerizable resin is chosen from the group consisting of aliphatic urethane acrylate resins, hydrophobic urethane acrylate resins, aromatic urethane acrylate resins, polyether urethane acrylate resins, and mixtures thereof.

[0036] According to a preferred embodiment of the invention, said aliphatic urethane acrylate resin is selected from the group consisting of Allnex Ebecryl 230 ®< , Allnex IRR 907 ®< Allnex Ebecryl 4491 ®< , Allnex Ebecryl 1271 ®< and their mixtures.

[0037] According to a preferred embodiment of the invention, said aromatic acrylate urethane resin is Allnex Ebecryl 210 ®< .

[0038] According to a preferred embodiment of the invention, said hydrophobic urethane acrylate resin is Dymax Bomar BRC-843 S ®< .

[0039] According to a preferred embodiment of the invention, said polyether urethane acrylate resin is Dymax Bomar BR-3641AJ ®< .

[0040] The various resins identified above give the bond obtained with the composition according to the invention optimal flexibility properties while limiting the exothermicity of the polymerization reaction to an acceptable level.

[0041] According to another preferred embodiment, said composition comprises between 50% and 90%, more preferably between 60% and 80%, by mass relative to the total mass of the composition, of said photopolymerizable resin.

[0042] According to a preferred embodiment, the composition according to the invention comprises a polymerization initiator and, even more preferably, a photoinitiator. The use of a thermal or redox polymerization initiator is not excluded from the scope of the present invention. Among the usable redox initiators, the dibenzoyl peroxide / amine (trimethylaniline) pair may be mentioned in particular.

[0043] According to an even more preferred embodiment, said photoinitiator is capable of inducing polymerization under the effect of radiation between 350 and 520nm.

[0044] The said photoinitiator is preferably chosen from: 2,4,6-trimethylbenzoyl-phenylphosphinate oxide (TPO-L), camphorquinone or 4,4'-bis(diethylamino)benzophenone the latter associated with Ethyl-4-(dimethylamino)benzoate (EDB), and mixtures thereof.

[0045] According to another preferred embodiment, said composition is solvent-free.

[0046] According to a preferred embodiment of the invention, said composition comprises between 0.5 and 2% by mass of said photoinitiator, between 50 and 90% by mass of said photopolymerizable resin, between 20 and 40% by mass of polymerizable monomer.

[0047] According to a highly preferred embodiment of the invention, said composition comprises between 0.5 and 2% by mass of TPO-L or camphorquinone associated with EDB, between 50 and 90% by mass of said aliphatic acrylate urethane resin, between 20 and 40% by mass of MDP or MEP.

[0048] Within the framework of the present invention, when the concentrations of the different components of the composition according to the invention are indicated as a percentage, this refers to the percentage by mass of said component relative to the total mass of said composition.

[0049] In the context of the present invention, the term "includes" means that the composition according to the invention includes the elements mentioned. Preferably, the present invention relates to compositions comprising only the elements mentioned, to the exclusion of all others.

[0050] The composition according to the invention can be used in a remarkable process in that it comprises the following steps: (i) coat the fabric to be treated with a composition according to the invention, (ii) allow the composition to penetrate said fabric, (iii) induce the polymerization of said composition.

[0051] According to one embodiment of the invention, step (ii) is optional.

[0052] In the context of the present invention, the term "biological tissue" is intended to refer preferably to non-mineralized biological tissues.

[0053] For the sake of clarity, it is specified that, within the framework of the present invention, the term "biological tissue" does not refer to bones and teeth.

[0054] The procedure is preferably non-invasive. The term "non-invasive" means that the procedure according to the invention does not involve any surgical steps to access the tissue to be treated. Thus, the procedure according to the invention is performed on biological tissue that is directly accessible (e.g., skin) or previously made accessible by other methods.

[0055] The procedure is preferably a non-invasive procedure to cover and protect a skin lesion.

[0056] The procedure is preferably a non-invasive procedure to bring the lips of a skin wound closer together.

[0057] Alternatively, the process is a process for the adhesion of a material to a biological tissue, for the adhesion of biological tissues to each other, for the adhesion of an adhesive or substance to the surface of a biological tissue, surgical sealing, for plugging or sealing openings created by suture or staple or tissue resection (e.g., hemostasis, aerostasis, lymphostasis), for plugging an opening, incision, or tear in a biological tissue, for stopping bleeding, for covering and protecting a wound, for strengthening a biological tissue, or for fixing and stabilizing a biological tissue.

[0058] By "cutaneous", we mean a location situated on the skin, lips or oral mucosa.

[0059] According to a preferred embodiment, said step (iii) is carried out using UV or visible light radiation. The characteristics of the radiation used, in particular its power and wavelength, are adapted to the constituents of the composition, in particular to the nature of the polymerizable monomer and the nature of the polymerization initiator.

[0060] The composition according to the invention can also be comprised of a set of parts including a composition according to the invention and a radiation source.

[0061] Preferably the radiation source of the assembly of parts can emit radiation suitable for polymerizing and / or assisting polymerization and / or accelerating polymerization of the polymerizable monomer of the composition.

[0062] In the context of the present invention, the term "radiation source" refers to any artificial means capable of producing radiation with a wavelength between 350 and 520. Preferably, said UV radiation has an irradiance power between 10mW / cm2 and 100mW / cm2 and even more preferably between 17mW / cm2 and 92mW / cm2. Description of the implementation methods Skin reaction test in humans

[0063] Compositions according to the invention were deposited on the palm. The composition is deposited on the skin surface and then polymerized by UV radiation.

[0064] The presence or absence of skin reactions is observed during application and then in the days that follow. Optimization of photoinitiator concentration

[0065] Tests were carried out with compositions according to the invention comprising 30% MEP, 69.5% Ebecryl 230 and varying concentrations of TPO-L.

[0066] For photoinitiator concentrations below 0.5%, poor bond strength and a prolonged photopolymerization time (>20s) are observed, incompatible with the use of the composition.

[0067] At concentrations above 2%, an exothermic polymerization is also observed, incompatible with in vivo use of the compositions. Optimization of photopolymerization irradiance I0

[0068] Tests were carried out with compositions according to the invention comprising 30% MEP, 69.5% Ebecryl 230 and 1% TPOL.

[0069] These compositions were used according to the protocol described above and subjected to radiation with a UV source at 395nm with varying irradiances

[0070] The lower limit of irradiance (17 mW / cm²) is limited by the polymerization kinetics and oxygen inhibition of the reaction. The upper limit of irradiance (92 mW / cm²) is limited by the exothermic reaction. However, irradiance values ​​between 10 and 100 mW / cm² provide acceptable results. Effectiveness of the compositions according to the invention

[0071] The qualitative assessment of in vivo adhesion and bonding quality was evaluated on human skin (N = 1 to 3 tests). A qualitative adhesion scale was developed: 0: no adhesion at t = 0, no anchorage 1: adhesion at t = 0, very weak anchorage, detachment in a few minutes, no resistance to stress 2: adhesion at t = 0, weak anchorage, hold < 1h, no resistance to stress, rapid detachment at the edges 3: adhesion at t = 0, weak anchorage, hold 2h to 4h, low resistance to stress, rapid detachment at the edges 4: adhesion at t = 0, weak anchorage, hold 4h to 8h, low resistance to stress, rapid detachment at the edges 5: adhesion at t = 0, medium anchorage, hold 4h to 8h, medium resistance to stress, resistance to detachment at the edges 6: adhesion at t = 0, medium anchorage, hold 8h to 12h, medium resistance to stress, resistance to detachment at the edges 7: Adhesion at t = 0, average anchorage, hold for 12h to 24h, good to average resistance to stress, good resistance to edge detachment; 8: adhesion at t = 0, good anchorage, hold for 24h to 36h.Good resistance to stress, good resistance to edge delamination. 9: Adhesion at t = 0, good anchorage, hold for 36 to 48 hours, very good resistance to stress, good resistance to edge delamination. 10: Adhesion at t = 0, excellent anchorage, hold for > 48 hours, excellent resistance to stress, no edge delamination.

[0072] All the results obtained with the combination TPO-L + MEP + Ebecryl 230 are presented in Table 1.

[0073] Statistical analysis of these data revealed a major influence of the photoinitiator and adhesive monomer concentrations on adhesion and bond strength. Higher concentrations result in stronger adhesive properties, while lower concentrations lead to weaker adhesion and bond strength. The irradiance of the UV LED source (at 399 nm) also influences the adhesive properties of the bonds. Furthermore, the water sensitivity of each of the resulting adhesive layers was compatible with the use of the compositions in the process according to the invention. [Table 1] [TPOL] %wt [MEP] %wt [Ebecryl 230] %wt I0 (mW / cm²) Live performance 90° peel Time to @ Exothermic Flexibility 1 30 69 17 à 20 8 6,2 < 20s +++ ++ 0,5 20 79 17 à 20 3 N / A < 20s 0 +++ 0,5 20 79 92 4 1,1 < 20s 0 ++ 0,5 40 59 17 à 20 7 N / A < 20s 0 ++ 0,5 40 59 92 6 2,3 < 20s 0 + 2 20 79 17 à 20 6 N / A < 20s + +++ 2 20 79 92 7 0,8 < 20s + ++ 2 40 59 17 à 20 8 N / A < 20s +++ + [Table 1] represents the experimental results on the formulation TPOL + MEP + Ebecryl 230.

[0074] The results obtained in Table 2 show that the concentration of adhesive monomer can also be lowered to 5%. [Table 2] [TPOL] %wt [MEP] %wt [Ebecryl 230] %wt I0 (mW / cm²) Live performance Time to @ Exothermic Flexibility 1 30 69 17 à 20 8 < 20s +++ ++ 0,25 40 59,75 20 2 20s < t @ < 40s + + 0,1 40 59,9 20 2 40s < t @ < 60s + ++ 0,5 30 69,5 20 5 < 20s 0 ++ 1 25 74 20 8 < 20s +++ ++ 1 5 94 20 1 < 20s 0 +++ 1 10 89 20 2 < 20s 0 +++ 1 20 79 20 2 < 20s + ++ [Table 2] represents the additional experimental results on the TPOL + MEP + Ebecryl 230 formulation.

Claims

1. Composition for use as a surgical adhesive for the adhesion of a material to a non-mineralised biological tissue, for the adhesion of non-mineralised biological tissues to one another, for the adhesion of a glue or a substance at the surface of a non-mineralised biological tissue, as a surgical sealant, to seal or plug orifices created by wire or staple suture or by tissue resection, to seal an orifice, an incision or a tear in a non-mineralised biological tissue, as a haemostatic to stop bleeding, as a dressing on a non-mineralised biological tissue to cover and protect a wound, to reinforce a non-mineralised biological tissue, to fix and stabilise a non-mineralised biological tissue comprising: - a polymerisable monomer comprising a phosphate or phosphonate function on the one hand and a methacrylate, acrylate, acrylamide or methacrylamide function on the other hand at a concentration comprised between 5 and 40% by weight relative to the total weight of the composition, - a photoinitiator at a concentration comprised between 0.5 and 2% by weight, and - a photopolymerisable resin.

2. Composition according to the preceding claim, characterised in that said polymerisable monomer is selected from the group consisting of molecules having the CAS number [14206-25-8], [14235-57-5], [86242-61-7], [932019-41-6], [1980781-17-6], [60161-88-8], [87243-97-8], [1980048-95-0], [918802-80-9], [63411-25-6], [1980064-07-0], [22432-83-3], [1980781-08-5], [252210-28-9], [1114567-37-1], [80730-17-2], [518991-74-7], [87243-96-7], [1980062-84-7], [518991-75-8], [252210-30-3], [22432-84-4], [727415-30-7], [727415-31-8], [784139-89-5] or [1194231-98-5] and mixtures thereof.

3. Composition according to claim 1, characterised in that said polymerisable monomer is of formula I wherein R2 is H or CH3; R1, R1', R1'' are independently of each other a linear polyether radical, a linear or branched C1-C50 aliphatic radical, a C6-C18 aromatic radical, wherein the carbon chain of said radicals may be interrupted by O, S, OCONH and / or may comprise one or more alcohol function(s); R1' is H if c=0; R1" is H if a=0; b is 1; a or c is 1 or 0.

4. Composition according to the preceding claim, characterised in that a=0, R2=H or CH3 and R'1 and R1 is a linear C1-C12 aliphatic chain.

5. Composition according to the preceding claim, characterised in that a=0, c=0, R2=CH3 and R1 is a linear C1-C12 aliphatic chain.

6. Composition according to claim 1, characterised in that the polymerisable monomer of formula I is 10-MDP (C14H27O6P) of CAS number [85590-00-7] or MEP (C12H19O8P) of CAS number [32435-46-4].

7. Composition according to one of the preceding claims, characterised in that said polymerisable monomer has a concentration comprised between 25 and 35% by weight relative to the total weight of the composition.

8. Composition according to one of the preceding claims, characterised in that said photoinitiator is capable of inducing a polymerisation under the effect of radiation comprised between 350 and 520 nm.

9. Composition according to one of the preceding claims, characterised in that said photoinitiator is selected from the group consisting of 2,4,6-trimethylbenzoylphenylphosphinate oxide (TPO-L), camphorquinone or 4,4'-bis(diethylamino)benzophenone, the latter associated with Ethyl-4-(dimethylamino)benzoate (EDB), and mixtures thereof.

10. Composition according to one of the preceding claims, characterised in that it comprises between 0.25 and 2% by weight of said photoinitiator, between 50 and 90% by weight of said photopolymerisable resin and between 20 and 40% by weight of said polymerisable monomer.