Surgical Adhesives

Abstract

A composition comprising: a polymerizable monomer comprising, on the one hand, a phosphate or phosphonate functional group and, on the other hand, a methacrylate, acrylate, acrylamide or methacrylamide functional group, in a concentration ranging from 5% to 40% by weight relative to the total weight of the composition; a photoinitiator in a concentration ranging from 0.5% to 2% by weight; and a photopolymerizable resin.

Description

Technical Field

[0001] The present invention particularly relates to compositions useful as surgical adhesives, surgical sealants, hemostatic dressings and / or skin dressings. More specifically, the present invention relates to compositions useful in the following methods:

[0002] - used as surgical adhesives to adhere materials to biological tissue,

[0003] - used to adhere biological tissues to each other,

[0004] - Used to adhere adhesives or substances to the surface of biological tissue;

[0005] - used as surgical sealants,

[0006] - to seal or plug orifices created by sutures or staples or tissue resections (e.g., hemostasis, blood stasis, lymphostasis),

[0007] - to close orifices, cuts or tears in biological tissue,

[0008] - used as a hemostatic agent to stop bleeding, either alone or as an adjunct to conventional hemostatic techniques (such as suturing, compression, or electrocoagulation), or

[0009] -Used as a dressing on biological tissue to cover and protect wounds.

[0010] These compositions can also be used

[0011] - Strengthen biological tissues,

[0012] - Fixation and stabilization of biological tissues,

[0013] -For the treatment of skin lesions. Background Art

[0014] Many surgical techniques use surgical adhesives. These are primarily used to help achieve surgical hemostasis. Despite this, the effectiveness of surgical adhesives in this indication remains controversial, and other uses (such as for blood stasis) have not shown better results.

[0015] In addition, surgical adhesives have very weak adhesive properties and therefore cannot be used as adhesives, or for surgical sutures. Most of the time, surgical adhesives are applied directly to tissue without preparing the bonding surface. Penetration into the tissue is weak or non-existent, which results in low-quality bonding. Applicants have noted that current adhesives do not stick nor penetrate into tissue.

[0016] To address this problem, low viscosity surgical adhesives have been proposed. These surgical adhesives penetrate the tissue more easily, allowing for a higher quality bond to be obtained. However, these surgical glues require high concentrations of monomers. In addition, their chemical nature can cause burns at the site of the adhesive. These compositions are also difficult to use directly by the public.

[0017] Therefore, the present invention proposes to provide a new surgical adhesive. The composition and method according to the present invention allow to obtain skin adhesion levels suitable for public applications. The selected concentration enables rapid initiation and polymerization within tens of seconds without causing tissue burns.

[0018] Furthermore, the selected photopolymerizable resin, in combination with the polymerizable monomers, imparts to the obtained adhesive properties, namely flexibility, good stability over time under the action of physiological fluids (blood, exudates, sweat), limited accumulation of sweat or exudates at the tissue / adhesive interface and good water resistance. Summary of the invention

[0019] In particular, the present invention relates to a composition comprising:

[0020] - polymerizable monomers which comprise phosphate or phosphonate functional groups on the one hand and methacrylate, acrylate, acrylamide or methacrylamide functional groups on the other hand,

[0021] - a polymerization initiator,

[0022] - Photopolymerizable resin.

[0023] In the context of the present invention, polymerizable monomers comprising phosphate or phosphonate functional groups on the one hand and methacrylate, acrylate, acrylamide or methacrylamide functional groups on the other hand may be referred to as "polymerizable monomers".

[0024] Furthermore, the invention relates to the composition according to the invention for use as surgical adhesive, surgical sealant, hemostatic dressing and skin dressing.

[0025] The present invention also relates to a composition according to the present invention for use as a surgical adhesive for adhering materials to biological tissue, for adhering biological tissues to each other, for adhering adhesives or substances to the surface of biological tissue; for use as a surgical sealant to seal or plug orifices created by sutures or staples or tissue resections, to close orifices, cuts or tears in biological tissues; for use as a hemostatic agent to stop bleeding; for use as a dressing on biological tissue to cover and protect wounds, strengthen biological tissues, fix and stabilize biological tissues.

[0026] The invention also relates to a composition according to the invention for use as a surgical adhesive for adhering a material to non-mineralized biological tissue.

[0027] The invention also relates to a composition according to the invention for use as a surgical adhesive for adhering non-mineralized biological tissues to one another.

[0028] The invention also relates to a composition according to the invention for use as a surgical adhesive for attaching an adhesive or substance to the surface of non-mineralized biological tissue.

[0029] The present invention also relates to a composition according to the invention for use as a surgical sealant to seal or plug an orifice created by suture or staple suturing or tissue excision.

[0030] The invention also relates to a composition according to the invention for use as a surgical sealant to close an orifice, cut or tear in non-mineralized biological tissue.

[0031] The invention also relates to a composition according to the invention for use as a hemostatic agent to stop bleeding.

[0032] The invention also relates to a composition according to the invention for use as a surgical adhesive as a dressing on non-mineralized biological tissue to cover and protect wounds.

[0033] The invention also relates to a composition according to the invention for use as a surgical adhesive for reinforcing non-mineralized biological tissue.

[0034] The invention also relates to a composition according to the invention for use as a surgical adhesive for fixation and stabilization of non-mineralized biological tissue.

[0035] The applicant has been able to demonstrate that the compositions have superior adhesion and harmlessness compared to compositions of the prior art. These compositions are therefore particularly suitable for skin use as wound dressings and / or for the treatment of all skin lesions.

[0036] Preferably, the polymerizable monomer is selected from the group consisting of molecules having the following 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], [198 0781-08-5], [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.

[0037] Preferably, the polymerizable monomer has formula I

[0038]

[0039] in

[0040] R2 is H or CH3;

[0041] R1, R1', R1" are independently linear polyether radicals, linear or branched C 1- C 50 Aliphatic free radicals, C6-C 18 Aromatic free radicals, wherein the carbon chain of the free radical may be interrupted by O, S, OCONH and / or may contain one or more alcohol functional groups;

[0042] If c=0, R1' is H;

[0043] If a=0, R1" is H;

[0044] b is 1;

[0045] a or c is 1 or 0.

[0046] The term "the carbon chain of the functional group may be interrupted" means that the functional group is inserted into the carbon chain, that is, is bonded to carbon atoms on both sides.

[0047] Preferably, a=0, R2=H or CH3, R'1 and R1 are straight chain C1-C 12 Fat chain.

[0048] Even more preferably, a=0, c=0, R2=CH3, and R1 is a linear C1-C 12 Aliphatic chain.

[0049] Preferably, a=0, c=0, R"1=H, R'1=H, R1=linear C1-C 12 Aliphatic chain, b=1, R2=CH3.

[0050] Preferably, a=1, c=1, b=0, R1=H, R'1=R"1=linear C1-C 12 Aliphatic chain, R2=CH3.

[0051] Preferably, the polymerizable monomer of formula I is 10-MDP (C 14 H 27 O6P, CAS No. [85590-00-7]) or MEP (C 12 H 19 O8P, CAS number [32435-46-4]).

[0052] 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, methacryloyloxydecyl hydrogen phosphate, methacryloyloxyethoxy hydrogen phosphate, glycerol monomethacrylate phosphate, triethylene glycol monomethacrylate phosphate, methacryloyloxypropyl phosphate, methacryloyloxyhexyl phosphate, methacrylated aminoethylphosphonic acid, bis(glycerol dimethacrylate) phosphate and mixtures thereof.

[0053] In the context of the present invention, the term "polymerizable monomer" refers to a monomer that can be polymerized by a physical or chemical initiator.

[0054] According to a preferred embodiment, the polymerization is initiated under the action of radiation. Preferably, the wavelength of the radiation is between 350 nm and 520 nm.

[0055] Preferably, the polymer obtained after polymerisation of the monomers is a biocompatible polymer.

[0056] According to a preferred embodiment, the viscosity is lower than 120 Pa.s at 20°C.

[0057] According to an even more preferred embodiment, the viscosity is lower than 107 Pa.s at 20°C.

[0058] According to a very preferred embodiment, the viscosity is lower than 50 Pa.s at 20°C.

[0059] According to a very preferred embodiment, the viscosity is higher than 20 Pa.s at 20°C.

[0060] In particular, the viscosity of the composition can be measured according to standard DIN 53015 by means of a falling ball viscometer.

[0061] According to a preferred embodiment, the composition according to the invention is not a hydrogel.

[0062] According to a preferred embodiment, the molar mass of the monomer is 250 g.mol -1 Up to 500 g.mol -1 .

[0063] According to a preferred embodiment, the concentration of the monomer is between 5% and 40% by weight relative to the total weight of the composition.

[0064] According to an even more preferred embodiment, the concentration of said monomers is between 20% and 40% by weight relative to the total weight of the composition.

[0065] According to an even more preferred embodiment, the concentration of said monomers is between 20% and 40% by weight relative to the total weight of the composition.

[0066] According to a very preferred embodiment, the concentration of said monomers is between 25% and 35% by weight relative to the total weight of the composition.

[0067] According to a preferred embodiment of the present invention, the photopolymerizable resin is selected from the group consisting of aliphatic urethane acrylate resins, hydrophobic urethane acrylate resins, aromatic urethane acrylate resins, polyether urethane acrylate resins and mixtures thereof.

[0068] According to a preferred embodiment of the present invention, the aliphatic acrylate polyurethane resin is selected from Allnex Ebecryl Allnex IRR Allnex Ebecryl Allnex Ebecryl and mixtures thereof.

[0069] According to a preferred embodiment of the present invention, the aromatic polyurethane acrylate resin is Allnex Ebecryl

[0070] According to a preferred embodiment of the present invention, the hydrophobic polyurethane acrylate resin is Dymax Bomar

[0071] According to a preferred embodiment of the present invention, the polyether polyurethane acrylate resin is Dymax Bomar

[0072] The different resins described above impart optimal flexibility to the bonds obtained with the composition according to the invention, while limiting the exotherm of the polymerization reaction to an acceptable level.

[0073] According to another preferred embodiment, the composition comprises 50% to 90% by weight, even more preferably 60% to 80% by weight of the photopolymerizable resin, relative to the total weight of the composition.

[0074] According to a preferred embodiment, the composition according to the invention comprises a polymerization initiator, even more preferably a photoinitiator. The use of thermal polymerization initiators or redox polymerization initiators is not excluded from the scope of the invention. Among the redox initiators that can be used, mention may be made in particular of the dibenzoyl peroxide / amine (trimethylaniline) pair.

[0075] According to an even more preferred embodiment, the photoinitiator is capable of inducing polymerization under the action of radiation between 350 nm and 520 nm.

[0076] Preferably, the photoinitiator is selected from: 2,4,6-trimethylbenzoylphenylphosphinate oxide (TPO-L), camphorquinone or 4,4'-bis(diethylamino)benzophenone (the latter in association with ethyl 4-(dimethylamino)benzoate (EDB)), and mixtures thereof.

[0077] Advantageously, the photoinitiator is used in a concentration of 0.25% to 2% by weight, preferably 0.5% to 2% by weight.

[0078] According to another preferred embodiment, the composition contains no solvent.

[0079] According to a preferred embodiment of the present invention, the composition comprises 0.5 to 2 wt % of the photoinitiator, 50 to 90 wt % of the photopolymerizable resin, and 20 to 40 wt % of the polymerizable monomer.

[0080] According to a very preferred embodiment of the invention, the composition comprises 0.5 to 2 wt % of TPO-L or camphorquinone associated with EDB, 50 to 90 wt % of the aliphatic polyurethane acrylate resin, 20 to 40 wt % of MDP or MEP.

[0081] In the context of the present invention, when the concentration of the different components of the composition according to the invention is expressed as a percentage, it consists of the weight percentage of said component relative to the total weight of said composition.

[0082] In the context of the present invention, the term "comprising" means that the composition according to the present invention comprises said elements. Preferably, the present invention relates to a composition comprising only said elements and not any other elements.

[0083] The present invention also relates to a method, which is significant in that the method comprises the following steps:

[0084] - (i) coating the tissue to be treated with a composition according to the invention,

[0085] - (ii) allowing the composition to penetrate into said tissue,

[0086] - (iii) inducing polymerization of said composition.

[0087] According to an embodiment of the present invention, step (ii) is optional.

[0088] In the context of the present invention, the term "biological tissue" preferably refers to non-mineralized biological tissue.

[0089] For the sake of clarity, in the context of the present invention, the term "biological tissue" does not refer to bones and teeth.

[0090] Preferably, the method according to the invention is non-invasive. The term "non-invasive" means that the method according to the invention does not involve a surgical step of entering the tissue to be treated. Therefore, the method according to the invention is performed directly on an accessible biological tissue (e.g. the skin) or is previously accessible by other methods.

[0091] Preferably, the method according to the present invention is a non-invasive method for covering and protecting skin lesions.

[0092] Preferably, the method according to the invention is a non-invasive method for bringing the edges of a skin wound closer to each other.

[0093] Optionally, the method according to the present invention is a method for adhering a material to biological tissue, for adhering biological tissues together, for adhering an adhesive or substance to the surface of a biological tissue, as a surgical sealant to seal or plug an orifice created by suture or staple suturing or tissue resection (e.g., hemostasis, hemostasis, lymphostasis), to close an orifice, incision or tear in a biological tissue, to stop bleeding, to cover and protect a wound, to reinforce a biological tissue, or to fix and stabilize a biological tissue.

[0094] The term "cutaneous" is understood to mean areas located on the skin, lips or oral mucosa.

[0095] According to a preferred embodiment, said step (iii) is carried out using UV radiation or visible light. The characteristics of the radiation used, in particular its power and wavelength, are adapted to the ingredients of the composition, in particular the nature of the polymerizable monomers and the nature of the polymerization initiator.

[0096] The invention also relates to a set of parts comprising a composition according to the invention and a radiation source.

[0097] Preferably, the radiation source of the set of parts can emit radiation suitable for polymerizing and / or assisting and / or accelerating polymerization of the polymerizable monomers of the composition.

[0098] In the context of the present invention, the term "radiation source" refers to any artificial device capable of generating radiation with a wavelength of 350 to 520. Preferably, the irradiance power of the UV radiation is 10mW / cm2 to 100mW / cm2, even more preferably 17mW / cm2 to 92mW / cm 2 . DETAILED DESCRIPTION

[0099] Human skin reaction test

[0100] A composition according to the invention has been deposited on the palm of the hand. The composition is deposited on the skin surface and then polymerized by UV radiation.

[0101] During the setup period and then over the next few days, watch for skin reactions.

[0102] Optimization of photoinitiator concentration

[0103] Tests have been carried out with compositions according to the invention comprising 30% MEP, 69.5% Ebecryl 230 and variable concentrations of TPO-L.

[0104] At photoinitiator concentrations below 0.5%, poor bond retention over time and long photopolymerization times (>20 s) that are not suitable for use of the composition are observed.

[0105] At concentrations above 2%, exothermic polymerization was also observed, rendering the composition unsuitable for in vivo use.

[0106] Optimization of photopolymerization irradiance I0

[0107] Tests have been carried out with a composition according to the invention comprising 30% MEP, 69.5% Ebecryl 230 and 1% TPO-L.

[0108] These compositions have been used according to the previously described protocol and irradiated at 395 nm using a UV source with variable irradiance.

[0109] The lower limit of irradiance (17mW / cm 2 ) is limited by polymerization kinetics and oxygen inhibition of the reaction. The upper limit of irradiance (92mW / cm 2 ) is limited by the exothermic reaction. Nevertheless, at 10 mW / cm 2 and 100mW / cm 2 Irradiance values ​​in between allow acceptable results to be obtained.

[0110] Effectiveness of the composition according to the invention

[0111] Qualitative assessment of in vivo adhesion and bonding quality has been evaluated on human skin (N=1 to 3 tests). A qualitative adhesion scale has been developed:

[0112] 0: No adhesion and no anchoring at t = 0

[0113] 1: Adhesion at t = 0, very weak anchoring, detachment after a few minutes, no stress resistance

[0114] 2: Adhesion at t = 0, weak anchoring, maintained for < 1h, no stress resistance, rapid detachment at the edge

[0115] 3: Adhesion at t = 0, weak anchoring, maintained for 2h to 4h, low stress resistance, rapid detachment at the edge

[0116] 4: Adhesion at t = 0, weak anchoring, maintained for 4h to 8h, low stress resistance, rapid detachment at the edge

[0117] 5: Adhesion at t = 0, average anchorage, hold for 4h to 8h, average stress resistance, edge resistance to detachment

[0118] 6: Adhesion at t = 0, average anchorage, hold for 8h to 12h, average stress resistance, edge resistance to detachment

[0119] 7: Adhesion at t = 0, average anchorage, hold for 12h to 24h, good to average stress resistance, good edge detachment resistance

[0120] 8: Adhesion at t=0, good anchoring, maintain 24h to 36h, good stress resistance, good edge detachment resistance

[0121] 9: Adhesion at t=0, good anchoring, 36h to 48h, very good stress resistance, good edge detachment resistance

[0122] 10: Adhesion at t=0, good anchorage, retention >48h, excellent stress resistance, no detachment at the edge.

[0123] All results obtained with the TPO-L+MEP+Ebecryl 230 combination are reported in Table 1.

[0124] Statistical processing of these data reveals the main influence of the concentration of photoinitiator and adhesive monomer on adhesion and retention performance. The higher these concentrations, the stronger the adhesion performance. Conversely, low concentrations lead to reduced adhesion and retention levels. The irradiance of the LED UV source (at 399nm) also affects the adhesion performance of the bond. In addition, the sensitivity of each adhesive layer obtained to water is suitable for the use of the composition in the method of the present invention.

[0125] [Table 1]

[0126]

[0127] [Table 1] shows the experimental results of the TPOL+MEP+Ebecryl 230 formulation.

[0128] The results obtained in Table 2 show that the binder monomer concentration can also be reduced to 5%.

[0129] [Table 2]

[0130]

[0131] [Table 2] shows the supplementary test results of the TPOL+MEP+Ebecryl 230 formula.

Claims

1. Use of a composition as a surgical adhesive for bonding materials to non-mineralized biological tissues, for bonding non-mineralized biological tissues to each other, for bonding substances to the surface of non-mineralized biological tissues; as a surgical sealant for closing or blocking orifices created by sutures or staples or by tissue resection, for closing orifices, incisions or tears in non-mineralized biological tissues; as a hemostatic agent for hemostasis; as a dressing on non-mineralized biological tissues for covering and protecting wounds, for strengthening non-mineralized biological tissues, for fixing and stabilizing non-mineralized biological tissues, the composition comprising: - a polymerizable monomer comprising, on the one hand, a phosphate or phosphonate functional group and, on the other hand, a methacrylate, acrylate, acrylamide or methacrylamide functional group, in a concentration ranging from 5% to 40% by weight relative to the total weight of the composition, - a photoinitiator in a concentration ranging from 0.5% to 2% by weight relative to the total weight of the composition, and - a photopolymerizable resin; the photopolymerizable resin is selected from the group consisting of aliphatic urethane acrylate resins, hydrophobic urethane acrylate resins, aromatic urethane acrylate resins, polyether urethane acrylate resins and mixtures thereof; The polymerizable monomer has formula I [Chemical formula 1] in R2 is H or CH3; R1, R'1, and R"1 are independently a linear polyether group, a linear or branched C1-C 50 Aliphatic groups, C6-C 18 Aromatic groups, wherein The carbon chain of the group can be interrupted by O, S, OCONH and / or contain one or more alcohol functions; If c = 0, R'1 is H; If a=0, R"1 is H; b is 1; a or c is 1 or 0.

2. The use of the composition according to claim 1, characterized in that The composition is used to bond an adhesive to the surface of non-mineralized biological tissue.

3. The use of the composition according to claim 1, characterized in that a=0,R2=H or CH3,R′1 and R1 are straight chain C1-C 12 Aliphatic chain.

4. The use of the composition according to claim 3, characterized in that a=0,c=0,R2=CH3,R1 is a straight chain C1-C 12 Aliphatic chain.

5. The use of the composition according to claim 1, characterized in that The polymerizable monomer of formula I is 10-MDP (C 14 H 27 O6P) or MEP(C 12 H 19 O8P).

6. The use of the composition according to any one of claims 1 to 5, characterized in that The concentration of the polymerizable monomer is 25 wt % to 35 wt % relative to the total weight of the composition.

7. The use of the composition according to any one of claims 1 to 5, characterized in that The photoinitiator is capable of inducing polymerization under the action of radiation from 350 nm to 520 nm.

8. The use of the composition according to claim 7, characterized in that The photoinitiator is selected from the group consisting of 2,4,6-trimethylbenzoylphenylphosphinate oxide (TPO-L), camphorquinone or 4,4'-bis(diethylamino)benzophenone associated with ethyl 4-(dimethylamino)benzoate (EDB), and mixtures thereof.

9. The use of the composition according to any one of claims 1 to 5, characterized in that It contains 0.25 wt % to 2 wt % of the photoinitiator, 50 wt % to 90 wt % of the photopolymerizable resin, and 20 wt % to 40 wt % of the polymerizable monomer, wherein the total of the components is 100 wt %.

10. A non-invasive method for covering and protecting skin lesions, characterized in that It includes the following steps: - (i) coating the tissue to be treated with a composition as defined in any one of claims 1 to 9, - (iii) inducing polymerization of said composition.

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