Monomer-based surgical glue containing phosphate functional groups

Abstract

The present invention relates to a composition for use as a surgical adhesive for adhering materials to biological tissue, for adhering biological tissues to one another, for adhering glues or substances to the surface of biological tissue, for closing or plugging openings made by sutures or staples or by excision of tissue, as a surgical sealant for closing openings, incisions or lacerations in biological tissue, as a hemostatic agent for stopping bleeding, for covering and protecting wounds, for strengthening biological tissue, and as a dressing on biological tissue for fixing and stabilizing biological tissue, characterized in that the composition comprises a polymerizable monomer comprising a phosphate or phosphonate functional group and a methacrylate functional group.

Description

[Technical Field]

[0001] The present invention relates in particular to compositions for use as surgical adhesives, surgical sealing products, hemostatic dressings and skin dressings. More particularly, the present invention relates to a method comprising: -To adhere the material to biological tissue, -To bond biological tissues together, as a surgical adhesive for adhering glues or substances to the surface of living tissue, To occlude or embolize openings made by sutures or staples or by excision of tissue (e.g., hemostasis, aerostasis, lymphatic homeostasis), -As a surgical sealant for closing openings, incisions or lacerations in living tissue, -As a hemostatic agent to stop bleeding, either alone or in addition to conventional hemostatic techniques such as suturing, compression, or electrocoagulation - relates to a composition intended for use as a dressing for living tissue to cover and protect wounds.

[0002] These compositions also -To strengthen living tissues -Can be used to fixate and stabilize biological tissue. [Background technology]

[0003] Several surgical techniques involve the use of surgical glue. Surgical glue is primarily used to assist in achieving surgical hemostasis. However, the effectiveness of surgical glue in this indication is controversial, and other applications, such as aerostasis, have not shown better results.

[0004] Furthermore, since the surgical glue has a very low adhesiveness, it cannot be used as an adhesive or surgical suture. The application of the surgical glue is mostly directly performed on the tissue without preparing the bonding surface. Due to insufficient penetration into the tissue, the quality of the bond is low. The applicant has confirmed that the current glue does not adhere and does not penetrate the tissue.

[0005] To address this problem, low-viscosity surgical glues have been proposed. These surgical glues penetrate the tissue more easily and thus result in a better bond. However, these surgical glues require a high concentration of monomers. Furthermore, due to their chemical properties, burns can occur at the application site.

Summary of the Invention

Problems to be Solved by the Invention

[0006] As a result, the present invention proposes to provide a new type of surgical glue. The compositions and methods according to the present invention are capable of obtaining an effective and strong bond with a smaller amount of monomer than the glues of the prior art. Furthermore, in contrast to the glues of the prior art, burns do not occur on the skin with the surgical glue according to the present invention.

Means for Solving the Problems

[0007] The present invention relates in particular to a composition for use as a surgical adhesive, a surgical sealing product, a hemostatic bandage and a skin bandage. More specifically, the present invention relates to a surgical adhesive for adhering a material to a biological tissue, for mutually adhering biological tissues, for adhering a glue or a substance to the surface of a biological tissue, by means of suture or staples, or for closing or plugging an opening created by tissue resection, a surgical sealant for closing an opening, incision or laceration in a biological tissue, a hemostatic agent for stopping bleeding, a bandage for covering and protecting a wound, for strengthening a biological tissue, for fixing and stabilizing a biological tissue, and is notable in that the composition contains a polymerizable monomer containing a phosphate functional group or a phosphonate functional group and a methacrylate functional group.

[0008] According to a preferred embodiment of the present invention, the polymerizable monomer contains a phosphate functional group and a methacrylate functional group.

[0009] The applicants have been able to demonstrate that the presence of a phosphate functional group or a phosphonate in the monomer makes it possible to obtain a composition that is safer than a composition containing a chemically equivalent monomer that has an adhesive ability and contains a methacrylate functional group but does not contain a phosphate functional group.

[0010] Preferably, the polymerizable monomer is of formula I (Chemical Formula 1),

[0011]

Chemical Formula

[0012] The term "the carbon chain of the functional group may be interrupted" means that the functional group is inserted into the carbon chain, i.e., is attached to carbon atoms on both sides.

[0013] Preferably, a=0, R2=H or CH3, and R'1 and R1 are linear aliphatic chains of C1 to C12.

[0014] Even more preferably, a=0, c=0, R2=CH3, and R1 is a C1-C12 linear aliphatic chain.

[0015] Preferably, a=0, c=0, R''1=H, R'1=H, R1=C1 to C12 linear aliphatic chain, b=1, and R2=CH3.

[0016] Preferably, a=1, c=1, b=0, R1=H, R'1=R''1=C1 to C12 linear aliphatic chain, and R2=CH3.

[0017] Preferably, the polymerizable monomer of formula I is 10-MDP (C 14 H 27 O6P) or MEP(C 12 H 19 O8P).

[0018] 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, methacryloyloxyethyl oxyhydrogen phosphate, glycerol monomethacrylate phosphate, triethylene glycol monomethacrylate phosphate, methacryloyloxypropyl phosphate, methacryloyloxyhexyl phosphate, methacrylate aminoethyl phosphate, bis(glyceryl dimethacrylate) phosphate, and mixtures thereof.

[0019] In the context of the present invention, the term "polymerizable monomer" is meant to designate a monomer whose polymerization can be initiated by a physical or chemical activator.

[0020] According to a preferred embodiment, the polymerization is initiated by the effect of UV radiation. In a preferred method, the UV radiation has a wavelength of 200 nm to 400 nm, even more preferably 300 nm to 400 nm, most preferably 350 nm to 400 nm.

[0021] According to another preferred embodiment, the polymerization is initiated by the effect of radiation of wavelengths between 400 nm and 500 nm.

[0022] According to a preferred embodiment, the polymerization is initiated by a chemical activator.

[0023] The polymer obtained after polymerization of the monomers is preferably a biocompatible polymer.

[0024] Preferably, the viscosity of the composition according to the invention is less than 200 mPa.s at 20°C.

[0025] The viscosity of the composition can in particular be measured by a falling ball viscometer according to standard DIN 53015.

[0026] According to a preferred embodiment, the viscosity is less than 120 mPa.s at 20°C.

[0027] According to an even more preferred embodiment, the viscosity is less than 50 mPa.s at 20°C.

[0028] According to a more preferred embodiment, the viscosity is less than 20 mPa.s at 20°C.

[0029] According to a preferred embodiment, the composition according to the invention is not a hydrogel.

[0030] According to a preferred embodiment, the monomer has a molar mass of 250 to 500 g·mol-1.

[0031] According to a preferred embodiment, the monomer has a concentration of 10 to 60% by mass based on the total mass of the composition.

[0032] According to an even more preferred embodiment, the monomer has a concentration of 40 to 90% by mass based on the total mass of the composition.

[0033] According to a preferred embodiment, the composition further comprises a first crosslinking agent at a concentration of 4 to 30% by mass based on the total mass of the composition.

[0034] One skilled in the art can select the most suitable crosslinking agent corresponding to the polymerizable monomer used.

[0035] According to a preferred embodiment, the first crosslinking agent contains an acrylate functional group or a methacrylate functional group.

[0036] According to a preferred embodiment, the first crosslinking agent is selected from the group consisting of polyfunctional acrylates and tactrylates, particularly 1,6 - hexanediol diacrylate, trimethylolpropane triacrylate, 1,2 - ethylene glycol dimethacrylate, pentaerythritol tetraacrylate, I 3-(acryloyloxy)-2 - hydroxypropyl methacrylate (AHM), urethane dimethacrylate (UDMA), hexanediol dimethacrylate (HDDMA), triethylene glycol dimethacrylate (TEGDMA), and mixtures thereof.

[0037] According to another preferred embodiment, the first crosslinking agent is selected from the group consisting of polyfunctional acrylates including particularly hexanediol dimethyl acrylate (HDDMA), ethylene glycol dimethacrylate (EGDMA), butanediol diacrylate (BDDA), poly(ethylene glycol) diacrylate (PEGDA), and mixtures thereof.

[0038] According to a preferred embodiment, the first cross-linking agent is UDMA, having a concentration of 4.5 to 5% by weight relative to the total weight of the composition.

[0039] According to a preferred embodiment, the first crosslinking agent is TEGDMA, having a concentration of 25-30% by weight relative to the total weight of the composition.

[0040] According to another preferred embodiment, the composition further comprises 30 to 90% by weight of a second crosslinker, relative to the total weight of the composition.

[0041] According to another preferred embodiment, the second crosslinker is selected from the group comprising multifunctional poly(ethylene glycol) acrylates (functionality 2-4), including in particular SR415, SR610 and Ebecryl 11, and mixtures thereof.

[0042] According to another preferred embodiment, the second crosslinker is selected from the group comprising difunctional, acrylic, urethane aliphatic resins, including in particular Ebecryl 4991, Ebecryl 230, Ebecryl 271, Ebecryl 2221 and CN9002.

[0043] According to another preferred embodiment, the second crosslinker is selected from the group comprising difunctional acrylic, urethane, aromatic resins, including in particular Ebecryl 210, and mixtures thereof.

[0044] According to another preferred embodiment, the second crosslinker is selected from the group comprising difunctional epoxy acrylate resins, including in particular EB3639.

[0045] According to another preferred embodiment, the second crosslinker is selected from the group comprising acrylic resins, including in particular Ebecryl 8296, Ebecryl 8232, Ebecryl ODA, Ucecoat 6569, and mixtures thereof.

[0046] For the sake of clarity, some of the polymerizable monomers according to the present invention can act as crosslinking agents, and in the case of crosslinking agents, it is stated that the above preferred concentrations are not relevant.

[0047] According to a preferred embodiment, the composition further comprises a comonomer.

[0048] According to an even more preferred embodiment, the comonomer is tert-butyl acrylate, n-butyl acrylate, lauryl acrylate, lauryl methacrylate, methyl acrylate, stearyl methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, acrylic acid, methacrylic acid, 2-ethoxyethyl methacrylate, 2-ethylhexyl acrylate monomer, 2-ethylhexyl methacrylate, 2-phenyloxyethyl methacrylate, 1-(acryloyloxy)-3-(methacryloyloxy)-2-propanol, di(ethylene glycol) ethyl ether acrylate, ethyl acrylate, ethylene glycol methyl ether acrylate, ethylene glycol phenyl ether acrylate, methyl acrylate, 3-(trimethoxysilyl)propyl methacrylate, methyl methacrylate, poly(ethylene glycol) methyl ether acrylate (Mn 200-10000 g / mol), triethylene glycol dimethacrylate, tert-butyl methacrylate, triethylene glycol monoethyl ether methacrylate, 3-(tris(trimethylsilyloxy)silyl)propyl methacrylate, etc., including polybutadiene diacrylate and monofunctional or difunctional monomers selected from the group.

[0049] According to a preferred embodiment, the comonomer present in the composition according to the present invention has a concentration of 1 to 50% by mass based on the total mass of the composition.

[0050] According to a preferred embodiment, the composition according to the present invention comprises a photoinitiator. Those skilled in the art will select the most suitable photoinitiator corresponding to the emission spectrum of the light used.

[0051] The photoinitiator can be selected particularly from bisacylphosphine oxide (BAPO), bis(η5-2,4-cyclopentadien-1-yl)-bis(2,6-difluoro-3-(1H-pyrrol-1-yl)phenyl)titanium (Irgacure784), 1-[4-(2-hydroxyethoxy)phenyl]-2-hydroxy-2-methyl-1-propan-1-one (Irgacure 2959), 2,4,6-trimethylbenzoyl-phenylphosphinate oxide (TPO-L), 2,4,6-trimethylbenzoyldiphenylphosphine oxide (TPO), 2,2-dimethoxyphenyl-2-acetophenone (DMPA), camphorquinone or 4,4'-bis(diethylamino)benzophenone, (related to N-phenylglycine (NPG)), ethyl 4-(dimethylamino)benzoate (EDB), N-diisopropylethylamine (DIPEAN) or 4-(dimethylamino)benzonitrile (DMABN).

[0052] Advantageously, the photoinitiator is used at a concentration of 0.2 to 10% by mass.

[0053] According to a preferred embodiment, the photoinitiator is TPO-L.

[0054] According to another preferred embodiment, the polymerization is initiated by a chemical activator, more specifically, benzoyl peroxide related to N-phenylglycine (NPG), ethyl 4-(dimethylamino)benzoate (EDB), N-diisopropylethylamine (DIPEAN) or 4-(dimethylamino)benzonitrile (DMABN).

[0055] Advantageously, the chemical activator is used at a concentration of 0.5 to 3% by mass.

[0056] According to a preferred embodiment, the composition contains only the monomer and the photoinitiator, or only the monomer, the first or second crosslinking agent and the photoinitiator.

[0057] According to one embodiment of the present invention, the composition contains a solvent, and more preferably, the solvent is water. According to another preferred embodiment, the solvent is an alcohol, more preferably ethanol or isopropanol.

[0058] According to another preferred embodiment, the composition does not contain a solvent.

[0059] According to a preferred embodiment of the present invention, the composition contains a plug. According to an even more preferred embodiment, the plug is a basic plug, and in a highly preferred manner, the basic plug is selected from the group consisting of KOH, guanidine carbonate, Ca(OH)2, K2CO3, 2-amino-2-methyl-1-propanol (AMP), Na2CO3, resorcinol, and NaOH.

[0060] Those skilled in the art also need to select the plug concentration that is most suitable for this use. According to a highly preferred embodiment of the present invention, the composition contains a KOH concentration of 0 to 8% by mass.

[0061] According to a preferred embodiment of the present invention, the composition contains 0.1 to 5% by mass of a photoinitiator, 30 to 90% by mass of a second crosslinking agent, 1 to 50% by mass of a polymerizable monomer containing a phosphate functional group and a methacrylate functional group according to the present invention, and 1 to 50% by mass of a comonomer.

[0062] The compositions described in the following table are more particularly preferred (the amounts are percentages of the total mass of the composition).

[0063]

Table 1

[0064]

Table 2

[0065] In the context of the present invention, the term "comprise" means that the composition according to the invention comprises the recited elements. In a preferred manner, the present invention relates to a composition that contains only the recited elements and to the exclusion of other elements.

[0066] The present invention also relates to a non-invasive method for adhering materials to biological tissue, for adhering biological tissues to one another, for adhering adhesives or substances to the surface of biological tissue, for occluding or plugging openings made by sutures or staples or by excision of tissue (e.g., hemostasis, aerostasis, lymphatic homeostasis), for occluding openings, incisions or lacerations in biological tissue, for stopping bleeding, for covering and protecting wounds, for reinforcing biological tissue, or for fixing and stabilizing biological tissue, which comprises the following steps: -(i) coating the tissue to be treated with a composition according to the invention; -(ii) allowing the composition to penetrate the tissue; -(iii) notable in that it includes the step of inducing polymerization of the composition.

[0067] In the context of the present invention, the term "biological tissue" preferably means non-calcified biological tissue.

[0068] For clarity, it is stated that in the context of the present invention the term "biological tissue" does not refer to bones and teeth.

[0069] The method according to the invention is advantageously non-invasive. The term "non-invasive" means that the method according to the invention does not involve any surgical step consisting of accessing the tissue to be treated. The method according to the invention is therefore carried out on biological tissue that is directly accessible (for example, the skin) or has previously been made accessible by other methods.

[0070] According to a preferred embodiment, step (iii) is carried out using UV radiation, the properties of the UV radiation used, in particular its intensity and wavelength, being adapted to the nature of the constituents of the composition, in particular the polymerizable monomer, and its concentration in the composition.

[0071] According to another preferred embodiment, step (iii) is carried out by visible light radiation.

[0072] According to a preferred embodiment, the UV radiation has a wavelength of 350 to 400 nm.

[0073] According to a preferred embodiment, the UV radiation has an irradiance of 20 mW / cm 2 to 500 mW / cm 2 .

[0074] The present invention also relates to an assembly of parts comprising a composition according to the invention and a UV radiation source, preferably the UV radiation source of the assembly of parts being capable of emitting UV radiation suitable for polymerizing and / or supporting and / or accelerating the polymerization of polymerizable monomers of the composition.

[0075] According to another embodiment, the present invention also relates to an assembly of parts comprising the composition according to the invention and an initiator for chemical polymerization.

[0076] In the context of the present invention, the term "UV radiation source" refers to any artificial means capable of generating UV radiation, more particularly radiation with a wavelength of 200-400 nm, even more preferably 300 nm-400 nm, and very preferably 350 nm-400 nm. In a preferred method, the UV radiation has an irradiance of 20 mW / cm to 500 mW / cm, even more preferably 50 mW / cm to 150 mW / cm.

[0077] In a more preferred method, the UV radiation has a wavelength of 350 to 400 nm and an irradiance of 50 to 200 mW / cm2. DETAILED DESCRIPTION OF THE INVENTION

[0078] Materials and Methods Skin reaction test animal The compositions according to the invention and the control compositions were deposited on the back and abdomen of rabbits and rats that had previously been shaved and disinfected.

[0079] The composition is deposited on the surface of the skin and then polymerized using a light irradiation source.

[0080] The presence or absence of skin reactions will be observed during application and the next day.

[0081] Human The compositions according to the invention and the control compositions were deposited on the anterior surface of the forearm.

[0082] The composition is deposited on the surface of the skin and then polymerized by a polymerization source.

[0083] The presence or absence of skin reactions will be observed during application and the next day.

[0084] The following compositions have been tested in humans and animals:

[0085] [Table 3]

[0086] Peel test The compositions according to the invention and the control compositions were deposited on bovine pericardium samples. This step was carried out at 20°C. The pericardium samples were exposed to 395 nm UV radiation for 45 seconds to induce polymerization of the monomers. The radiation source was placed 10 cm from the pericardium.

[0087] The pericardium sample was then covered with a 17-thread woven pad, which was then treated with the same monomer solution used in the previous step.

[0088] The pericardium samples were exposed to UV radiation under the same conditions as in the previous step.

[0089] The rest time of the pad attached between Joe of the tractor is 1 minute, and the temperature inside the sample at the start of the test is 30°C ± 4°C.

[0090] Results Skin reaction test All tests conducted on humans and animals using acrylic acid or methacrylic acid-based compositions cause skin irritation and / or skin burns.

[0091] Rather, the tests conducted with the compositions according to the invention containing MDP and MEP (monomers having acrylate and phosphate functional groups) showed no obvious skin reaction.

[0092] These results clearly show that, at equivalent monomer concentrations, the compositions according to the invention are less aggressive towards the treated tissue.

[0093] Peel test Among all the tests conducted, it was observed that compositions containing monomers without phosphate functional groups did not achieve good-quality adhesion, i.e., peeling occurred at the interface between the skin and the coated fiber web.

[0094] Rather, with the compositions according to the invention containing phosphate and acrylic functional groups, good-quality adhesion can be obtained, as proven by complete peeling in the treated tissue, regardless of the monomer concentration.

[0095] Therefore, the presence of phosphate functional groups in the polymerizable monomers used in the compositions according to the invention, at equivalent concentrations and with a similar chemical structure, makes it possible to increase the resistance to rupture and is observed to ensure aggregation (i.e., bond strength) by penetration into the surface layer of the tissue to be treated.

Claims

1. A composition for use as a surgical adhesive for adhering materials to non-mineralized biological tissue, for mutually adhering non-mineralized biological tissue, for adhering glue or substances to the surface of non-mineralized biological tissue, as a surgical sealant for closing or plugging an opening created by suture or staples or by tissue resection, for closing an opening, incision or laceration in non-mineralized biological tissue, as a hemostatic agent for stopping bleeding, for covering and protecting a wound, for strengthening non-mineralized biological tissue, and for use as a dressing on non-mineralized biological tissue for fixing and stabilizing non-mineralized biological tissue, the composition comprising 10 to 60% by mass of a polymerizable monomer based on the total mass of the composition, characterized in that the polymerizable monomer contains a phosphate functional group or a phosphonate functional group and a methacrylate functional group.

2. A composition comprising a polymerizable monomer of the following formula I (Chemical Formula 1), 【Chemical 1】 - R2 is H or CH3; R1, R1', R1'' are, independently of one another, a linear polyether radical, a linear or branched aliphatic radical having 1 to 50 carbon atoms, an aromatic radical having 6 to 18 carbon atoms, the carbon chains of these radicals may be interrupted by O, S, OCONH, and / or may contain one or more alcohol functional groups; R1' is H if c = 0; R1'' is H if a = 0; b is always 1; a or c satisfies any one of (a, c) = (0, 0), (1, 0), (0, 1), (1, 1), the composition according to claim 1.

3. a = 0, R2 = H or CH ３ The composition according to claim 2, characterized in that R'1 and R1 are C1-C12 linear aliphatic chains.

4. a = 0, c = 0, R2 = CH ３ The composition according to claim 3, characterized in that R1 is a linear aliphatic chain of C1 - C12.

5. The polymerizable monomer of formula I is 10-MDP (C １４ H ２７ O ６ P) or MEP (C １２ H １９ O ８ P), and the composition according to claim 1 is characterized thereby.

6. The composition according to any one of claims 1 to 5, further comprising 4% to 30% by mass of a first crosslinking agent based on the total mass of the composition.

7. The composition according to claim 5, further comprising 30 to 90% by mass of a second crosslinking agent based on the total mass of the composition.

8. The composition according to any one of claims 1 to 7, further comprising a comonomer.

9. The comonomer is selected from the group consisting of tert-butyl acrylate, n-butyl acrylate, lauryl acrylate, lauryl methacrylate, methyl acrylate, stearyl methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, acrylic acid, methacrylic acid, 2-ethoxyethyl methacrylate, 2-ethylhexyl acrylate monomer, 2-ethylhexyl methacrylate, 2-phenyloxyethyl methacrylate, 1-(acryloyloxy)-3-(methacryloyloxy)-2-propanol, di(ethylene glycol) ethyl ether acrylate, ethyl acrylate, ethylene glycol methyl ether acrylate, ethylene glycol phenyl ether acrylate, methyl acrylate, 3-(trimethoxysilyl)propyl methacrylate, methyl methacrylate, poly(ethylene glycol) methyl ether acrylate (Mn 200 to 10,000 g / mol), triethylene glycol dimethacrylate, tert-butyl methacrylate, triethylene glycol monoethyl ether methacrylate, 3-(tris(trimethylsilyloxy)silyl)propyl methacrylate, etc., polybutadiene diacrylate and monofunctional or bifunctional monomers, the composition according to claim 8.

10. The composition according to claim 9, characterized in that the comonomer has a concentration of 1 to 50% by mass based on the total mass of the composition.

11. The composition according to any one of claims 1 to 9, further comprising a photoinitiator.

12. The composition according to claim 11, wherein the photoinitiator is selected from the group consisting of benzoylphosphine oxide (BAPO), bis(η5-2,4-cyclopentadien-1-yl)-bis(2,6-difluoro-3-(1H-pyrrol-1-yl)-phenyl)titanium (Irgacure 784), l’1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one (Irgacure 2959), 2,4,6-trimethylbenzoyl-phenylphosphinate oxide (TPO-L), 2,4,6-trimethylbenzoyldiphenylphosphine oxide (TPO), 2,2-dimethoxyphenyl-2-acetophenone (DMPA), camphorquinone or 4,4’-bis(diethylamino)benzophenone, (related to N-phenylglycine (NPG)), ethyl-4-(dimethylamino)benzoate (EDB), N-diisopropylethylamine (DIPEA) or 4-(dimethylamino)benzonitrile (DMABN).

13. The composition according to claim 11 or 12, wherein the photoinitiator is at a concentration of 0.2 to 10% by mass.

14. The composition according to claim 5, comprising 0.1 to 5% by mass of a photoinitiator, 30 to 90% by mass of a second crosslinking agent, 10 to 50% by mass of a polymerizable monomer containing phosphate functional groups and methacrylate functional groups, and 1 to 50% by mass of a comonomer.

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