degradable binder, method of coating a support surface with a binder to provide the surface with one

专利摘要:
degradable photoreticulator. A degradable linker of the formula photo ^ 1 ^ -lg-photo ^ 2 ^ is described herein, where photo ^ 1 ^ and photo ^ 2 ^ independently represent at least one photoreactive group and lg represents a linker group comprising a or more solicon atoms or one or more phosphorus atoms. the detachable linker includes a covalent bond between at least one photoreactive group and the linker group, where the covalent bond between at least one photoreactive group and the linker group is interrupted by at least one heteroatom. Also disclosed is a method of coating a support surface with degradable binder, coated support surfaces and medical devices.
公开号:BR112012024919B1
申请号:R112012024919
申请日:2011-03-29
公开日:2019-01-02
发明作者:V Kurdyumov Aleksey；G Swan Dale
申请人:Surmodics Inc；
IPC主号:

专利说明:

"DEGRADABLE BINDING AGENT, METHOD OF COVERING A SUPPORT SURFACE WITH A BINDING AGENT TO PROVIDE THE SURFACE WITH ONE OR MORE LATENT REACTIVE GROUPS, SUPPORT SURFACE AND COATED MEDICAL DEVICE" [001] This order is being filed as an International Patent Application PCT on March 29, 2011, in the name of SurModics, Inc., a US national company, applicant for the designation of all countries except the US, and Aleksey V. Kurdyumov, an American citizen, and Dale G. Swan , an American citizen, applicants for US designation only, and claims priority to US Patent Application Serial Number 61 / 319,127, filed on March 30, 2010, the contents of which are hereby incorporated by reference.
TECHNICAL FIELD [002] The present invention relates to a binding agent having one or more photoactivable groups. In particular, the invention provides a degradable binding agent.
BACKGROUND OF THE INVENTION [003] Photochemically reactive functional groups (photoreactive groups) are functional groups that, when exposed to an appropriate energy source, undergo a transformation from an inactive state (ie, basic state) to a reactive intermediate, capable of forming covalent bonds with appropriate materials. Photoreactive groups can be used, for example, to derive a target molecule (e.g., thermochemically), and then photochemically bond the derived target molecule to a surface. Photoreactive groups can also be used as photoinitiators for polymerization reactions.
SUMMARY OF THE INVENTION [004] This document discloses a degradable binding agent having the formula Photo ¹ -LG-Photo ² , where Photo ¹ and Photo ² , independently, represent
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2/44 at least one photoreactive group and LG represents a linking group. In one embodiment, one or more photoreactive groups include an aryl ketone. In a particular embodiment, one or more photoreactive groups include benzophenone.
[005] In one embodiment, the linking group includes one or more silicon atoms or one or more phosphorus atoms, where each photoreactive group is independently linked to the linking group by a covalent bond that includes at least one heteroatom. In one embodiment, at least one heteroatom is selected from oxygen, nitrogen, selenium, sulfur, or a combination of them. In one embodiment, at least one photoreactive group, the heteroatom and the linking group form an ether or an amine.
[006] In a more particular embodiment, the linking group includes a silicon atom covalently linked to at least two photoreactive groups. In another embodiment, the linking group includes at least two silicon atoms. In another embodiment, the linker group has the formula Si-Y-Si, where Y represents a linker that can be null, an amine, ether, straight or branched C1-C10 alkyl, or a combination of them. In one embodiment, Y is selected from O, CH2, OCH2CH2O and O (CH2CH ₂ O) n, where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30.
[007] In another embodiment, the linker group includes one or more phosphorester bonds and / or one or more phosphoramide bonds, where one or more phosphorester bonds and / or one or more phosphoramide bonds form a covalent bond with at least one photoreactive group, such that the linker group includes at least two photoreactive groups. In one embodiment, the linker group is covalently linked to three photoreactive groups, where each photoreactive group is covalently linked to the linker group by a phosphorester or phosphoramide bond. In another embodiment, the linker group includes at least one phosphorus atom with a phosphorus-oxygen double bond (P = O), where at least one photoreactive group is attached to pe
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3/44
I minus one phosphorus atom. In yet another embodiment, the linker group includes a phosphorus atom with a phosphorus-oxygen double bond (P = O), where at least two or three photoreactive groups are covalently linked to the phosphorus atom. In another embodiment, the linking group includes at least two phosphorus atoms, where at least one phosphorus atom includes a phosphorus-oxygen double bond (P = O), and at least one or at least two photoreactive groups are covalently linked to each phosphorus atom.
[008] According to one embodiment, the degradable binding agent is capable of, with the activation of one or more photoreactive groups, covalent bonding to a surface, target molecule, or a combination of them. A method of coating a support surface with a binding agent is also provided to provide the surface with latent reactive groups. In one embodiment, the method includes the steps of: providing a support surface; apply the degradable binding agent to the support surface; and illuminating the binding agent on the support surface, under conditions suitable for activating a first photoreactive group to join the binding group to the surface, where a second photoreactive form remains unattached to the support surface and is capable of reverting to a latent reactive state . A support surface containing a coating is also provided which includes a polymer layer joined to the surface by a degradable binding agent, in which a first photoreactive group of the binding agent, when activated in the presence of the supporting surface, is able to join the binding agent to the support surface, and a second photoreactive group of the binding agent, when activated in the presence of a coating agent, is able to bond the coating to the surface. Also described in this document is a combination that includes a medical device and a polymeric coating, where the coating is attached to the medical device by a degradable binding agent.
[009] This summary is an overview of some of the teachings of the presen
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4/44 is requested and is not intended to be an exclusive or exhaustive treatment of this matter. Additional details are found in the detailed description and in the attached claims. Other aspects will be apparent to people skilled in the art by reading and understanding the detailed description below and examining the drawings that form a part of it, each of which is not to be considered in a limiting sense. The scope of the present invention is defined by the appended claims and their legal equivalents.
BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG. 1 shows a reaction pathway for the generation of a degradable binding agent, as described in this document.
[0011] FIG. 2 shows a reaction pathway for the generation of a degradable binding agent, as described in this document.
[0012] FIG. 3 shows a reaction pathway for the generation of a degradable binding agent, as described in this document.
[0013] FIG. 4 shows a reaction pathway for the generation of a degradable binding agent, as described in this document.
[0014] FIG. 5 shows a reaction path for the generation of a degradable binding agent, as described in this document.
[0015] FIG. 6 shows a reaction pathway for the generation of a degradable binding agent, as described in this document.
[0016] FIG. 7 shows a reaction pathway for the generation of a degradable binding agent, as described in this document.
[0017] FIG. 8 shows a reaction pathway for the generation of a degradable binding agent, as described in this document.
[0018] Although the invention is susceptible to several modifications and alternative forms, its details have been shown by way of example and drawings, and will be described in detail. It must be understood, however, that the invention
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5/44 is not limited to the particular modalities described. On the contrary, the intention is to cover all modifications, the equivalents, and the alternatives that affect the spirit and scope of the invention.
DETAILED DESCRIPTION [0019] A degradable binding agent is described in this document. The degradable linker includes one or more photoreactive groups and a linker group, where each photoreactive group is independently joined to the linker group by a degradable link. In other embodiments, the degradable binding agent includes two or more photoreactive groups. In yet other embodiments, the degradable binding agent includes three or more photoreactive groups. In one embodiment, the binding agent is capable of, by activating one or more photoreactive groups, covalently bonding to a surface, target molecule, or a combination of them. In particular, each photoreactive group of the binding agent may be able to be activated to form a covalent bond with the target surface or molecule.
[0020] The binding agent described in this document is particularly useful for applications where it is desirable to have a binding agent that can degrade over time. For example, in some situations, it may be desirable to have a surface coating on an implanted device, with one property initially and a different property over time. In such a case, the degradable binding agent can be used to apply a coating to the implanted device that degrades over time to expose a surface or base covering with one or more different properties. In one embodiment, the bonding agent is used to attach a hydrophobic coating to a surface. In another embodiment, the binding agent is used to attach a hydrophilic coating to a surface. In yet another embodiment, the degradable binding agent is used to apply a hydrophilic coating to an implantable medical device that will degrade over time to expose a surface cover or hydro base.
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6/44 phobic or vice versa.
[0021] In some situations, it may be desirable to include one or more bioactive agents in a surface coating. In one embodiment, the binding agent can be used to release one or more bioactive agents. For example, the binding agent may be suitable for use in combination with a drug release coating, in particular for use in relation to bioactive agents that can tolerate (eg, remain effective) exposure to ultraviolet radiation.
[0022] In one embodiment, one or more photoreactive groups of the binding agent can be used as an initiator for photopolymerization. In one embodiment, the binding agent is used in relation to a composition that is capable of polymerization in situ. In one embodiment, the binding agent can be used in relation to a biodegradable, biocompatible polymer foam. In one embodiment, the binding agent is used in relation to a biodegradable foam used to treat wounds, such as deep or cavernous wounds. For example, the binding agent can be used in relation to a biocompatible foam formed using biocompatible monomers or macromers in combination with a polymerization initiator and gas generation components.
[0023] In another embodiment, the binding agent can be used in the generation of degradable grafts, for tissue engineering. For example, the binding agent can be used to generate a degradable three-dimensional structure, sometimes referred to as a polymeric frame or extracellular matrix, for the union and migration of cells. The polymeric frame can be used in connection with tissue engineering technology for the restoration and / or replacement of parts of tissues and / or organs or tissues and / or whole organs (eg, bone, cartilage, blood vessels, bladder, etc.). In addition to providing a frame with a desired porosity and pore size, to facilitate cell seeding and diffusion
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7/44 of both cells and nutrients, the binding agent is biodegradable. Biodegradability is often an important factor in the development of the tissue frame, so that the graft can be absorbed by the surrounding tissues and the need for surgical removal can be avoided.
Deplatable binding agent [0024] As discussed above, the degradable binding agent includes one or more photoreactive groups attached to a binding group. The degradable binding agent can be represented by the formula Photo ¹ -LG-Photo ² , where Photo ¹ and Photo ² , independently, represent at least one photoreactive group and LG represents a binding group. The term linker group, as used in this document, refers to a segment or group of molecules, configured to join two or more molecules together, where the linker group is capable of degrading under one or more conditions. In one embodiment, the linking group includes at least one silicon atom. In another embodiment, the linking group includes at least one phosphorus atom.
[0025] The term degradable linker group, as used in this document, refers to a portion configured to join one molecule to another, where the linker group is capable of dividing under one or more conditions. The term biodegradable, as used in this document, refers to degradation in a biological system, and includes, for example, enzymatic degradation or hydrolysis. It should be noted that the term degradable, as used in this document, includes both enzymatic and non-enzymatic (or chemical) degradation. It is also understood that hydrolysis can occur in the presence of, or without, an acid or base. In one embodiment, the binding agent is soluble in water. In another embodiment, the binding agent is not soluble in water.
[0026] In addition to providing a degradable bond, the linker group can function as a spacer, for example, to increase the distance between the photoreactive groups of the linker. For example, in some situations, you can
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It is desirable to provide a spacer to reduce the steric impediment that may result between the photoreactive groups, which could interfere with the ability of the photoreactive groups to form covalent bonds with a support surface, or to serve as a photoinitiator for polymerization . As described in this document, it is possible to vary the distance between the photoreactive groups, for example, by increasing or decreasing the spacing between one or more photoreactive groups.
[0027] As described here, one or more photoreactive groups can be linked to a linker group by a degradable link. In one embodiment, the degradable link between the photoreactive group and the linker group includes at least one heteroatom, including, but not limited to, oxygen, nitrogen, selenium, sulfur or a combination thereof. In one embodiment, a photoreactive group, the linking group and the heteroatom form an ether (R ¹ -OR ² ), where R ¹ is a photoreactive group and R ² is a linking group. In another modality, a photoreactive group, the linker group and the heteroatom form an amine,
R ¹ - l ^ l - R ²
R ³ where R ¹ is a photoreactive group, R ² is a linking group, and R ³ is hydrogen, aryl or alkyl, a photoreactive group, or a hydroxyl or its salt. In one embodiment, R ³ is cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination of them. The stability of the ether and / or amine bond can be influenced, depending on the size (eg, chain length, branch, volume, etc.) of the substituents. For example, larger substituents will generally result in a more stable bond (ie, a binding agent that is slower to degrade in the presence of water and / or acid).
[0028] In one embodiment, the linking group includes one or more atoms of itself
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9/44 lyric. In a particular embodiment, the linker group includes a silicon atom (which can be referred to as a monosilane) covalently attached to at least two photoreactive groups. In another embodiment, the linking group includes at least two silicon atoms (which can be referred to as a disilane). In one embodiment, the linker group can be represented by the formula Si-Y-Si, where Y represents a linker that can be null (eg, the linker group includes a direct Si-Si bond), an amine, ether, straight or branched C1-C10 alkyl, or a combination thereof. In one embodiment, Y is selected from O, CH2, OCH2CH2O and O (CH2CH2O) n, where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30. One embodiment of a silane binding agent is shown below
where R ¹ , R ² , R ⁸ and R ⁹ can be any substitution, including, but not limited to, H, alkyl, halide, hydroxyl, amine, or a combination thereof; R ³ , R ⁴ , R ⁶ and R ⁷ can be alkyl, aryl or a combination thereof; R ⁵ can be any substitution, including, but not limited to, O, alkyl or a combination thereof; and each X, independently, can be O, N, Se, S, or alkyl, or a combination of them. A specific modality is shown below:
[0029] In one embodiment, the degradable binding agent can be represented by the formula
Photo - Sji - (CH ₂ ) _n - S | i - Photo R ² R ⁴ where Photo ¹ and Photo ² , independently, represent one or more groups
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10/44 photoreactives en is an integer between 1 and 10, where the degradable binding agent comprises a covalent bond between at least one photoreactive group and the linker group, where the covalent bond between at least one photoreactive group and the linker group is broken by at least one heteroatom. In general, a longer hydrocarbon chain between the two silicon atoms will tend to increase the flexibility of the binder and may facilitate cross-linking between a greater number of polymers, than a binder with a shorter carbon chain, since photoreactive groups can react with the polymers located further away from each other. In the formula shown above, R ¹ , R ² , R ³ , R ⁴ are, independently, alkyl or aryl, including, but not limited to, cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In a more particular embodiment, R ¹ -R ⁴ are independently phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof. In another embodiment, R ¹ -R ⁴ can also be, independently, a photoreactive group. In yet another embodiment, R ¹ -R ⁴ may also be, independently, hydroxyl or its salt. In one embodiment, the hydroxyl salt includes a counterion that is lithium, sodium, potassium, or a combination of them.
[0030] In another embodiment, the binding agent can be represented by the formula
Photo - S | i - Photo
R ² where Photo ¹ and Photo ² , independently, represent one or more photoreactive groups, where the degradable binding agent comprises a covalent bond between at least one photoreactive group and the linker, where the covalent bond between at least one photoreactive group and the linker group is interrupted by at least one heteroatom; R ¹ and R ² are, independently, alkyl or aryl, including,
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11/44 but not limited to cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In a more particular embodiment, R ¹ and R ² are, independently, phenyl, methyl, ethyl, isopropyl, tbutyl, or a combination of them. R ¹ and R ² can also independently be a photoreactive group, where the degradable binding agent comprises a covalent bond between at least one photoreactive group and the linker group, where the covalent bond between at least one photoreactive group and the linker group is interrupted by at least one heteroatom; or hydroxyl or its salt. In one embodiment, the hydroxyl salt includes a counterion which is lithium, sodium, potassium, or a combination of them. One embodiment of a monosilane binding agent is shown below [0031] In another embodiment, the linking group includes one or more phosphorous atoms. In one embodiment, the linker group includes a phosphorus atom (which can also be referred to as a monophosphorus linker group). In another embodiment, the binding agent includes two phosphorus atoms (which can also be referred to as a bis-phosphorus linking group). In one embodiment, the linker group comprises at least one phosphorus atom with a phosphorus-oxygen double bond (P = O), where at least one or two photoreactive groups are attached to the phosphorus atom. In another embodiment, the linking group comprises a phosphorus atom with a phosphorus-oxygen double bond (P = O), where two or three photoreactive groups are covalently linked to the phosphorus atom. In another embodiment, the linking group comprises at least two phosphorus atoms, where at least one phosphorus atom includes a phosphorus-oxygen double bond (P = O), and at least one or two photoreactive groups are covalently linked to each atom of phosphor.
[0032] In a more particular embodiment, the binding agent can be represented by the formula:
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12/44
Ο
Photo ¹ -!> - Photo ²
R where Photo ¹ and Photo ² independently represent one or more photoreactive groups, where the degradable binding agent comprises a covalent bond between at least one photoreactive group and the linker, where the covalent bond between at least one photoreactive group and the group ligand is interrupted by at least one heteroatom and R is alkyl or aryl, a photoreactive group, hydroxyl or its salt, or a combination of them. In one embodiment, the hydroxyl salt includes a counterion which is lithium, sodium, potassium, or a combination of them. In a more particular embodiment, R is cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic or a combination of them. In a more particular embodiment, R is phenyl, methyl, ethyl, isoproyl, t-butyl, or a combination of them.
[0033] In another embodiment, the degradable binding agent can be represented by the formula:
Photo ¹ - fj'- Photo ²
R where Photo ¹ and Photo ² independently represent one or more photoreactive groups, where the degradable binding agent comprises a covalent bond between at least one photoreactive group and the linker, where the covalent bond between at least one photoreactive group and the group ligand is interrupted by at least one heteroatom and R is alkyl or aryl, a photoreactive group (where the covalent bond between the photoreactive group and the ligand group can be interrupted by at least one heteroatom), hydroxyl or its salt, or a combination of them . In one embodiment, the hydroxyl salt includes a counterion which is lithium, sodium, potassium, or a combination of them. In a more particular modality, R is cyclic, linear or
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13/44 branched, saturated or unsaturated, aromatic or heteroaromatic or a combination thereof. In one embodiment, R is phenyl, methyl, ethyl, isoproyl, t-butyl, or a combination of them.
[0034] In another embodiment, the degradable binding agent can be represented by the formula:
OO ^{11 11} 2
Photo ¹ - - Y - fj * - Photo ² R ¹ R where Photo ¹ and Photo ² independently represent one or more photoreactive groups, where the degradable binding agent comprises a covalent bond between at least one photoreactive group and the binding group, where the covalent bond between at least one photoreactive group and the linker group is interrupted by at least one heteroatom; Y represents a linker that can be null (ie, not present, such that the linker group includes a direct PP bond), N or O, straight or branched C1-C10 alkyl, or a combination thereof; and R ¹ and R ² are, independently, alkyl, aryl, a photoreactive group (where the covalent bond between the photoreactive group and the linking group can be interrupted by at least one heteroatom), hydroxyl or its salt, or a combination thereof. In one embodiment, Y is selected from O, CH2, OCH2O, OCH2CH2O and O (CH2CH2O) n, where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30. In one embodiment, the counterion of the hydroxyl salt is 0 lithium, 0 sodium, 0 potassium, or a combination of them. In a more particular embodiment, R ¹ and R ² are independently cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic hydrocarbons, or a combination of them. In one embodiment, R ¹ and R ² are, independently, phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination of them. In general, a longer hydrocarbon chain between the two phosphorus atoms will tend to increase the flexibility of the binding agent and
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14/44 can facilitate cross-linking between a greater number of polymers, than a binding agent with a shorter carbon chain, since reactive photoreactive groups can react with the polymers located further apart. In one embodiment, Y can be O, CH2, OCH2CH2O and O (CH2CH2O) n, where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30. An embodiment is shown below in which R ¹ , R ² , R ⁴ and R ⁵ can be any substitution, including, but not limited to H, alkyl, halogen, amine, hydroxyl, or a combination thereof; R ³ can be any substitution, including, but not limited to, O, alkyl, or a combination thereof; and each X can, independently, be O, N, Se, S, alkyl, or a combination of them. In one embodiment, the binding agent includes one or more phosphorester bonds and one or more phosphoramide bonds, and can be represented by the formula:
where X and X ² are, independently, O, N, Se, S or alkyl; R ¹ and R ² are, independently, one or more photoreactive groups, and X ³ is O, N, Se, S, alkyl or aryl; R ³ is alkyl or aryl, including, but not limited to, cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In a more particular embodiment, R ³ is phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination of them. R ³ can also be a photoreactive group or a hydroxyl or its salt. In one embodiment, the counterion of the hydroxyl salt is 0 lithium, 0 sodium, 0 potassium, or a combination thereof.
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15/44
In one embodiment, the binding agent comprises a triphosphorester, which can be represented by the formula o
103- P-OR ²
where R ¹ and R ² are independently one or more photoreactive groups, and R ³ is alkyl or aryl, including, but not limited to, cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In a more particular embodiment, R ³ is phenyl, methyl, ethyl, isopropyl, tbutyl, or a combination of them. R ³ can also be a photoreactive group or a hydroxyl, or a salt thereof. In one embodiment, the hydroxyl salt counterion is lithium, sodium, potassium, or a combination of them.
[0035] Some specific modalities include the following binding agents:
(a) bis (4-benzoylphenyl) hydrogen phosphate:
(b) sodium bis (4-benzoylphenyl phosphate):
(c) tris (4-benzylenphenyl) phosphate:
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(d) tetrakis (4-benzoylphenyl) methylenebis (phosphonate)
[0036] In another embodiment, the binding agent comprises a wet triphosphor, which can be represented by the formula.
R ² θ R ³ ! f II f ₄ where R ¹ -R ⁶ are, independently, a photoreactive group, a hydroxyl or its salt, alkyl or aryl, or a combination of them, where at least two of R ¹ R ⁶ are, independently, a photoreactive group. In one embodiment, the hydroxyl salt counterion is lithium, sodium, potassium, or a combination of them. In a more particular embodiment, R ¹ -R ⁶ are, independently, cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In a more particular embodiment, R ¹ -R ⁶ are, independently, phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination of them.
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Binding element [0037] The degradable binding agent can be formed using any suitable reaction pathway. In one embodiment, the degradable binding agent is formed by reacting a functionalized binding element with one or more, typically two or more, photoreactive groups. As used herein, the term linker refers to the linker component of the degradable binding agent before it is attached to one or more photoreactive groups. The term functionalized linker is used to indicate that the linker includes one or more reactive functional groups. In one embodiment, the linker includes one or more halogen functional groups. The term halogen refers to the functional groups fluorine, chlorine, bromine, or iodine. In another embodiment, the linker includes one or more functional groups of trifluoromethanesulfonate (CF3SO3).
[0038] In one embodiment, the bonding element includes one or more silicon atoms. In one embodiment, the linker includes one or more halogen substituents, such as fluorine, 0 chlorine, 0 bromine, 0 iodine, and combinations thereof. In another embodiment, the linker includes at least two halogen substituents. In another embodiment, the linker includes one or more substituents of trifluoromethanesulfonate (triflate). In another embodiment, the linker includes at least two triflate substituents. In a more particular embodiment, the linker includes a silicon atom with at least two halogen or triflate substituents. In another embodiment, the linker includes at least two silicon atoms. In a more particular embodiment, the linker includes two silicon atoms, where each silicon atom includes at least one halogen or triflate substituent. In one embodiment, the linker element can be represented by the formula Si-Y-Si, where Y represents a linker that can be null, an amine, ether, straight or branched C1-C10 alkyl, or a combination of them, where each atom of silicon includes at least one halogen or triflate substituent. In one embodiment, Y is
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18/44 selected from O, CH2, OCH2CH2O and O (CH2CH2O) n, where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30.
In one embodiment, the binding element can be represented by the formula

where X ¹ and X ² are independently halogen, such as fluorine, chlorine, bromine, iodine; trifluoromethanesulfonate; or a combination of them, and n is an integer between 1 and 10. R1-R4 are independently alkyl or aryl, including, but not limited to, cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination their. In a more particular embodiment, R ¹ -R ⁴ are, independently, phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof. In another embodiment, R ¹ -R ⁴ can also independently be halogen. In yet another embodiment, R ¹ -R ⁴ may also be, independently, hydroxyl or its salt. In one embodiment, the hydroxyl salt includes a counterion which is 0 lithium, 0 sodium, 0 potassium, or a combination thereof.
[0039] In another embodiment, the binding element can be represented by the formula
where X ¹ and X ² are, independently, halogen; such as fluorine, chlorine, bromine, and iodine; or trifluoromethanesulfonate; R ¹ and R ² are, independently, alkyl or aryl, including, but not limited to, cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In
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19/44 a more particular embodiment, R ¹ and R ² are, independently, phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof. R ¹ and R ² can also be, independently, halogen, hydroxyl or hydroxyl salt. In one embodiment, the hydroxyl salt includes lithium, sodium, potassium, or a combination of them, as a counterion.
[0040] In another embodiment, the linker includes one or more phosphorous atoms. In one embodiment, the linker element comprises at least one phosphorus atom with a phosphorus-oxygen double bond (P = O), where at least one halogen or trifluoromethanesulfonate substituent is attached to at least one phosphorus atom. In another embodiment, the linker comprises a phosphorus atom with a phosphorus-oxygen double bond (P = O), where two or three halogen or trifluoromethanesulfonate substituents are independently covalently linked to the phosphorus atom. In another embodiment, the linker comprises at least two phosphorus atoms, where at least one phosphorus atom includes a phosphorus-oxygen (P = O) double bond, and at least one or two halogen or trifluoromethanesulfonate substituents are covalently attached to every atom of phosphorus. In a particular embodiment, the linker comprises two phosphorus atoms.
[0041] In a more particular embodiment, the binding element can be represented by the formula
where X ¹ and X ² are, independently, halogen; such as fluorine, chlorine, bromine, and iodine; or trifluoromethanesulfonate; and R is alkyl or aryl, halogen, hydroxyl or a hydroxyl salt, or a combination thereof. In one embodiment, the hydroxyl salt includes a counterion which is lithium, sodium, potassium, or a combination of them.
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20/44
In a more particular embodiment, R is cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination of them. In a more particular embodiment, R is phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination of them.
[0042] In another embodiment, the degradable binding element can be represented by the formula:
where X ¹ and X ² are independently halogen, such as fluorine, chlorine, bromine, and iodine; or trifluoromethanesulfonate and R is alkyl or aryl, halogen, trifluoromethanesulfonate, hydroxyl or its salt, or a combination thereof. In one embodiment, the hydroxyl salt includes a counterion which is lithium, sodium, potassium, or a combination of them. In a more particular embodiment, R is cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination of them. In one embodiment, R ¹ and R ² are, independently, phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination of them.
[0043] In another embodiment, the degradable binding element can be represented by the formula:
X ^ pY-If-X ² where X ¹ and X ² are, independently, halogen, such as fluorine, chlorine, bromine, and iodine; or trifluoromethanesulfonate, Y represents a linker that can be zero, an amine, an ether, straight or branched C1-C10 alkyl, or a combination thereof; and R ¹ and R ² are, independently, alkyl, aryl, halogen, hydroxyl or its salt, or a combination thereof. In one mode, Y is selected from O, CH2,
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21/44
OCH2CH2O and O (CH2CH ₂ O) n, where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30. In one mode The counterion of the hydroxyl salt is lithium, 0 sodium, 0 potassium, or a combination thereof. In a more particular embodiment, R ¹ and R ² are, independently, cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic hydrocarbons, or a combination of them. In one embodiment, R ¹ and R ² are, independently, phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination of them.
Preparation Methods [0044] The degradable binding agent can be formed using any suitable reaction pathway. In one embodiment, the degradable binding agent is formed by reacting a halogenated or trifled binding element with one or more, typically two or more, photoreactive groups, for example, via a nucleophilic substitution reaction. As used herein, the term binding element refers to the binding group component of the degradable binding agent before it is attached to a photoreactive group. As used herein, the term halogenated refers to the presence of one or more halogen substituents, including 0 fluorine, 0 chlorine, 0 bromine, or 0 iodine, which may, under the appropriate conditions, serve as a leaving group in a nucleophilic substitution reaction. As used in this document, the term trifluido refers to the presence of one or more functional groups trifluoromethanesulfonate (CF3SO3-) that can, under the appropriate conditions, serve as a leaving group in a nucleophilic substitution reaction.
[0045] Examples of nucleophilic substitution reactions include, but are not limited to, the following. In one embodiment, a degradable binding agent is formed by linking two molecules of 4-hydroxybenzophenone with a halogenated disilane binding element, by a nucleophilic substitution reaction, to form a degradable binding agent, as shown in Figure 1. In
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22/44 another embodiment, a degradable binding agent is formed by linking two molecules of 4-hydroxybenzophenone with a halogenated disilyl binding element, by a nucleophilic substitution reaction, to form a degradable binding agent, as shown in Figure 2. yet another embodiment, a degradable binding agent is formed by linking two 4-hydroxybenzophenone molecules with a dichlorosilane binding element, by a nucleophilic substitution reaction, to form a degradable binding agent, as shown in Figure 3. In another embodiment, a degradable binding agent is formed by reacting phosphorous trichloride with 4-hydroxybenzophenone, in a base presence, such as pyridine or diisopropylethyl amine, as shown in Figure 4. In another embodiment, a degradable binding agent is formed by reaction of phosphoryl chloride with 4-hydroxybenzophenone, in the presence of a base, such as pyridine or ad iisopropylethyl amine, as shown in Figure 5. In another embodiment, a degradable binding agent is formed by reacting the diphosphorous halide with 4-hydroxybenzophenone, as shown in Figure 6. In another embodiment, a degradable binding agent is formed by converting 4-hydroxybenzophenone in its phosphite derivative, by reaction of hydroxybenzophenone with PCI3. The resulting phosphite is reacted with halide, such as chlorine, using the conditions of MichaelisArbusov to generate the degradable binding agent, as shown in Figure 7. In an alternative route, the degradable binding agent is formed using the phosphite as a starting material. , as shown in Figure 8.
Photoreactive groups [0046] As used in this document, the term photoreactive group refers to a molecule having one or more functional groups that are capable of responding to a specific applied external stimulus to undergo active species generation and form a covalent bond with a adjacent chemical structure, which can be provided by the same or a different molecule. The fotorreati groups
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23/44 you are those groups of atoms in a molecule that keep their covalent bonds unchanged under storage conditions, but that, with activation by an external energy source, form one or more covalent bonds with other molecules. In one embodiment, photoreactive groups can generate active species, such as free radicals, with the absorption of electromagnetic energy. Photoreactive groups can be chosen to be sensitive to different portions of the electromagnetic spectrum, including, for example, the visible and ultraviolet portions of the spectrum. Photoreactive groups are described, for example, in U.S. Pat. No. 5,002,582, the disclosure of which is incorporated herein by reference.
[0047] In one embodiment, the photoreactive group includes a substituent capable of reacting with the halogenated or trifled linker. In a more particular embodiment, the photoreactive group contains a hydroxyl substituent (ΌΗ) or amine (-NR2), where the amine substituent can be a primary amine or a secondary amine.
[0048] In one embodiment, the functionalized photoreactive group can be represented by the formula Photo-Y-OH, where Y represents a linker that can be null, an amine, an ether, straight or branched C1-C10 alkyl, or a combination their. In one embodiment, Y is selected from O, CH2, OCH2CH2O and O (CH2CH ₂ O) n, where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30. In another modality, the functionalized photoreactive group can be represented by the formula
Photo -Y - N - R.
I ^{1 R} 2 where Y represents a linker that can be null, an amine, an ether, straight or branched C1-C10 alkyl, or a combination thereof, and R1 and R2 are independently alkyl or aryl, including, but not limited to limited to cyclical, linear
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24/44 or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In a more particular embodiment, Ri and R2 are, independently, phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination of them. In one embodiment, Y is selected from O, CH2, OCH2CH2O and O (CH2CH2O) n, where n is an integer between 1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1 and 30.
[0049] In one embodiment, the halogenated binder reacts with the amine or hydroxyl substituent on the photoreactive group, to provide a degradable binding agent. An advantage of a photoreactive group with a reactive amine substituent is that the amine substituent is able to react with additional halogen substituents on other linkers, which may result in the amine substituent of a first photoreactive group attaching to more than than a binding element. For example, a first photoreactive group can be joined to a first linker group by a first amine, and a second photoreactive group can then be joined to the first linker and the first photoreactive group by the same (first) amine. If desired, the degradable binding agent can also include a third photoreactive group joined to the first binding group by a second amine and, if desired, a fourth photoreactive group can also be joined to the first binding agent and the third photoreactive group by the second amine. An example is shown below, where R independently may be alkyl or aryl, including, but not limited to, cyclic, linear or branched, saturated or unsaturated, aromatic or heteroaromatic, or a combination thereof. In a more particular embodiment, R can be independently a photo-reactive group, where the covalent bond between the photoreactive group and the linking group is interrupted by at least one heteroatom; phenyl, methyl, ethyl, isopropyl, t-butyl, or a combination of these:
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[0050] In one embodiment, the photoreactive group includes a photoreactive aryl ketone, such as acetophenone, benzophenone, anthraquinone, anthrone, and anthrone-type heterocycles (ie, heterocyclic analogs of anthrone, such as those having N, O, or S in position 10), or their substituted derivatives (eg, substituted on the ring). Examples of aryl ketones include the heterocyclic derivatives of anthrone, including acridone, xanthone, and thioxanthone, and their ring substituted derivatives. An example includes thioxanthone, and its derivatives, having excitation energies greater than about 360 nm. In one embodiment, the photoreactive group is a benzophenone functionalized with an amine or hydroxyl substituent at positions 3 or 4 (i.e., 3- or 4-aminobenzophenone or 3- or 4-hydroxybenzophenone). As discussed above, functionalized benzophenone can include a linker between the benzophenone photoreactive group and the amine or hydroxyl substituent. Examples of binders include an amine, an ether, straight or branched C1-C10 alkyl, or a combination thereof.
[0051] The functional groups of such ketones are readily capable of undergoing the activation / inactivation / reactivation cycle described in this document. Benzophenone is an example of a photoreactive portion that is capable of photochemical excitation, with the initial formation of an excited singlet state that is subjected to crossing between systems up to the triplet state. The excited triplet state can be inserted into carbon-hydrogen bonds by removing a hydrogen atom (from a support surface, for example), thus creating a pair of radicals. The subsequent breakdown of the radical pair results in the formation of a new carbon-carbon bond. If a reactive bond (eg, carbon-hydrogen) is not available for bonding, the excitation induced by ultraviolet light from the
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26/44 benzophenone group is reversible and the molecule returns to the energy level of the basic state with the removal of the energy source. Photoactable aryl ketones, such as benzophenone and acetophenone, are subject to multiple reactivation in water and can increase the efficiency of the coating.
[0052] Azides constitute a class of photoreactive groups and include derivatives based on arylazides (C6R5N3), such as phenyl azide and particularly 4-fluor-3-nitrophenyl azide, acyl azides (-CO-N3), such as benzoyl azide and p-methylbenzoyl azide, azido formats (-O-CO-N3), such as ethyl azidoformate, phenyl azidoformate, sulfonyl azides (-SO2-N3), such as benzene sulfonyl azide, and phosphoryl azides (RO) 2PON3, such as diphenyl phosphoryl azide and diethyl phosphoryl azide. Diazo compounds constitute another class of photoreactive groups and include diazoalkane derivatives (-CHN2), such as diazomethane and diphenyldiazomethane, diazoketones (-CO-CHN2), such as diazoacetophenone and 1-trifluormethyl1-diazo-2-pentanone, diazoacetates ( -O-CO-CHN2), such as tbutyl diazoacetate and phenyl diazoacetate, and beta-keto-alpha-diazoacetates (-CO-CN2 -CO-O-), such as t-butyl alpha diazoacetoacetate. The other photoreactive groups include diazirines (-CHN2), such as 3-trifluoromethyl-3-phenyldiazirine, and ketenes (CH = C = O), such as 0 ketene and 0 diphenylketene.
[0053] With the activation of the photoreactive groups, the binding agents are covalently linked to each other, to other molecules, or to a surface by covalent bonds through the residues of the photoreactive groups. The illustrative photoreactive groups, and their residues, with activation, are shown as follows. ___________________
Photoreactive
Group aryl azides acyl azides azidoformates amine (R-NH-R ') amide (R-CO-NH-R') carbamate (R-O-CO-NH-R ')
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sulfonyl azides sulfonamide (R-SO2-NH-R ') phosphoryl azides phosphoramide ((RO) ₂ PO-NH-R ') diazoalkans new C-C connection diazoketones new C-C bond and ketone diazoacetates new C-C bond and ester beta-keto-alpha-diazoacetate- new C-C and beta- tos ketoester aliphatic azo new C-C connection diazyrines new C-C connection ketenes new C-C connection photoactivated ketones new C-C link and alcohol
[0054] The photoinitiation of free radicals can occur through several mechanisms, including photochemical intramolecular photocleaving, hydrogen removal, and redox reactions. In one embodiment, photoinitiation occurs by removing hydrogen from the polymerizable groups.
[0055] Intramolecular photocleavage involves a homolytic alpha dividing reaction between a carbonyl group and an adjacent carbon atom. This type of reaction is generally referred to as a Norrish type 1 reaction. Examples of molecules that exhibit Norrish type 1 reactivity and useful in a polymeric initiation system include those derived from benzoin ether and acetophenone. For example, in a embodiment where the binding agent is provided in the form of a quinone having adjacent carbonyl groups (e.g., camphorquinone), photoinitiation occurs by dividing the intramolecular bond.
[0056] A second mechanism, the hydrogen removal, can be of intra- or intermolecular nature. A system that employs this mechanism can be used without additional energy transfer receptor molecules and by removing non-specific hydrogen. However, this system is most commonly used
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28/44 with an energy transfer receptor, typically a tertiary amine, which results in the formation of both aminoalkyl radicals and cetyl radicals. Examples of molecules that exhibit hydrogen removal reactivity and useful in a polymeric initiation system include the benzophenone and camphorquinone analogs.
[0057] A third mechanism involves the photosensitization reactions using photoresistable or photo-oxidizable dyes. In most cases, photoresistable dyes are used in conjunction with a reducing agent, typically a tertiary amine. The reducer intercepts the induced triplet, producing the dye radical anion and the reducer radical cation.
[0058] In one embodiment, photoinitiation generates active species, such as free radicals, including nitranes, carbenes, and excited states of ketones, with the absorption of electromagnetic energy. This excited photoinitiator, in turn, removes the hydrogen atoms from the available sources in proximity to the photoinitiator, eg, polymerizable species, applied to the prepared surface. This removal of hydrogen thus generates a free radical site within the polymerizable species from which polymerization can occur.
[0059] Typical free radical polymerization includes four steps: initiation, propagation, and termination. At initiation, a free radical derived from an initiator increases a monomer molecule to form an active center. The other initiation reactions include adding the molecule to the head or removing hydrogen, and the reaction mechanism depends on the structures of the radical and the monomer. The propagation or growth reaction includes the rapid addition of monomer molecules to the radical species. The most common propagation mechanism occurs in head to tail mode. However, propagation can also occur in head to head, tail to head, and tail to tail modes. Upon termination, the polymer chain stops growth by destroying the propa radicals
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29/44 gation. Usually, in the absence of species that destroy radicals, the chain termination occurs through bimolecular interaction of radicals (eg, radical combinations or disproportionate).
[0060] In one embodiment, the binding agent includes a conjugated cyclic diketone having, directly or indirectly, one or more substituents that include negatively charged groups, and where each ketone group of the diketone is adapted to serve as a photoreactive portion, capable of being activated to provide a free radical. In one embodiment, the cyclic conjugated diketone is a quinone selected from benzoquinone, camphorquinone, naphthoquinone, and substituted or unsubstituted anthraquinone.
Charged Groups [0061] In one embodiment, the binding agent includes one or more charged groups to improve properties, such as water solubility, hemocompatibility and / or antithrombogenicity. As used in this document, a charged group generally refers to a group that is present in ionic form in solution, i.e., carries an electrical charge under conditions (e.g., pH) of use. The type and number of groups loaded on a binding agent can vary. In one embodiment, the binding agent includes a sufficient number and type of charged groups to provide the agent with water solubility (at room temperature and optimum pH) of at least about 0.1 mg / ml, at least about 0, 5 mg / ml, and at least about 1 mg / ml. In one embodiment, the binding agent is configured for use in a surface coating process and has a solubility level of at least about 0.1 mg / ml.
[0062] In one embodiment, one or more charged groups are introduced into the binding agent by the inclusion of a hydroxyl salt, such as a salt of lithium, sodium, potassium, or a combination of them over the binding agent.
Surface Modification
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30/44 [0063] In one embodiment, the degradable binding agent is used to form a coating on a substrate surface. In one embodiment, the coating is hydrophobic. In another embodiment, the coating is hydrophilic. The coating can be formed in any suitable manner, e.g., by simultaneous or sequential bonding of the binding agent and chemical compounds (e.g., molecules containing polymerizable groups) to a support surface. In one embodiment, the method involves a two-step process, involving sequential steps in which the bonding agent is first bonded to the surface, after which the compounds are polymerized on it using the bonded agent photoinitiator. An advantage of a sequential approach is that such a light curing allows the generation of thin polymer layers on the support surface. The resulting polymer layer is typically highly adherent, of uniform thickness, and is highly durable. In addition, the solutions used to form the polymer layer can be applied (e.g., through solution application, dip coating, spray coating, knife coating, and cylinder coating) to any support surface any surface morphology. The resulting polymer layer, in turn, can be adapted to cover uneven surfaces, as well as relatively uniform, smooth surfaces. The polymerizable species can also be joined to the support surface simultaneously with the binding agent, providing suitable reaction conditions to allow such simultaneous binding of the binding agent and polymerization of the polymerizable species.
The photoinitiator group (i.e., the second photoreactive group, or latent reactive group) can be identical to, or different from, the first photoreactive group used to attach the binding agent to a support surface. In one embodiment, the first and second photoreactive groups are adapted to be independently activated by light of different wavelengths (eg, ultraviolet light)
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31/44 versus visible light).
[0065] With the activation of the photoreactive groups in the presence of a support surface, the second photoreactive group (s) remains (m) not connected to the support surface and reverses (m ) to its inactive state (eg, latent) to serve (in) as photoinitiator groups. While not claiming to be bound in theory, it appears that the ability of a photoreactive group to remain unattached (and therefore serve as a photoinitiator) is a factor, at least in part, in several reaction conditions (eg, time and intensity of the wavelength of illumination, concentration of the reagent, etc.) and / or restrictions imposed by the size and / or the structure of the binding agent itself. The photoinitiator thus remains available to be subsequently activated by a suitable energy source and, thus, to start light curing.
[0066] In one embodiment, the binding agent described in this document is applied to a surface having carbon-hydrogen bonds with which the photoreactive groups can react to immobilize the binding agents. In one embodiment, the support surface provides removable hydrogen atoms, suitable for covalent bonding with the activated group. In another embodiment, the surface can be modified (eg, through pretreatment with a suitable reagent) to provide removable hydrogen atoms on the surface.
[0067] The method described in this document is suitable for use with a variety of support surfaces, including hydrogel polymers, silicone, polypropylene, polystyrene, poly (vinyl chloride), polycarbonate, poly (methyl methacrylate), parylene and any of the various organosilanes used to pre-treat glass or other inorganic surfaces. Photoreactive binding agents can be applied to surfaces in any suitable way (eg, in solution or by dispersion), then photoactivated by uniform lighting to immobilize them on the surface. Examples of suitable hydrogel polymers
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32/44 are selected from silicone hydrogels, hydroxyethyl methacrylate polymers, and glyceryl methacrylate polymers.
[0068] Other suitable surface materials include polyolefins, polystyrenes, poly (methyl methacrylates), polyacrylonitriles, poly (vinyl acetates), poly (vinyl alcohols), polymers containing chlorine, such as poly (vinyl chloride), polyoxymethylenes, polycarbonates, polyamides, polyimides, polyurethanes, phenolics, amino-epoxy resins, polyesters, silicones, cellulose-based plastics, and rubber-type plastics . See, in general, Plastics, p. 462-464, in Concise Encyclopedia of Polymer Science and Engineering, Kroschwitz, ed., John Wiley and Sons, 1990, the disclosure of which is incorporated herein by reference. In addition, supports, such as those formed from pyrolytic carbon and silylated surfaces of glass, ceramic, or metal, are suitable for surface modification.
[0069] Such materials can be used to manufacture various devices capable of being provided, before, during and / or after their manufacture, with a polymer layer. Implant devices are a general class of suitable devices, and include, but are not limited to, vascular devices, such as grafts, stents, catheters, valves, artificial hearts, and devices that assist the heart; orthopedic devices, such as joint implants, fracture restoration devices, and artificial tendons; dental devices, such as dental implants and fracture restoration devices; ophthalmic devices, such as lenses and glaucoma drain leads; and other catheters, synthetic prostheses and artificial organs. Other suitable biomedical devices include dialysis tubing and membranes, blood oxygenating tubing and membranes, blood bags, sutures, membranes, cell culture devices, chromatographic support materials, biosensors, and the like.
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33/44 [0070] The modification of the surface can be achieved using photopolymerization (eg, through polymerization via free radicals). According to the present method, a selected surface is contacted with a binding agent, as described above. During and / or after the application of the binding agent, the surface is illuminated with UV light of the appropriate wavelengths, thereby activating the photoreactive groups. The binding agent is thus immobilized on the surface, by means of the first photoreactive groups (with the second photoreactive groups reverting to the inactive form), and the excess binding agent can then be optionally removed, leaving a prepared surface, with a base layer of binding agent.
[0071] The binding agent can be applied to the surface of interest in any suitable way. For example, the binding agent can be applied by dip coating or by dispersing the agent on the surface (for example, by spray coating). Suitable methods of application include solution application, dip coating, spray coating, knife coating, and cylinder coating. In one embodiment, the binding agent is applied to the surface by means of spray coating, since this method of application provides increased thickness of the binding agent on the support surface, thereby improving the durability of the graft.
[0072] In the sequential approach described in this document, a solution containing the polymerizable compounds can be applied to a prepared surface. The solution can be illuminated in situ to activate the second photoreactive group (s) that serves as a photoinitiator (s), thus initiating polymerization via free radicals by removing of hydrogen. In one embodiment, photopolymerization takes place in an inert atmosphere, since oxygen interferes with polymerization via free radicals. Deoxygenation can occur using an inert gas
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34/44 te, such as nitrogen.
[0073] Once the system has been deoxygenated, the surface can again be illuminated with UV light of the appropriate wavelength. This second illumination, thus, activates the second photoreactive group (s) that serves as (a) photoinitiator (s) of polymerization via free radicals. In one embodiment, lighting generates the excited state of the photoreactive group, allowing the excited molecule to remove hydrogen from available sources, eg, molecules containing polymerizable groups. Such removal of hydrogen generates a free radical site, from which polymerization can occur.
[0074] The method includes the steps of providing a support surface and applying a binder to the support surface. In one embodiment, the method additionally includes a step of illuminating the binding agent to photochemically bond the binding agent to the surface. In one embodiment, the method additionally includes a step of providing a plurality of molecules containing polymerizable groups of free radicals and illuminating the molecules containing the polymerizable groups and the binding agent to initiate the polymerization of the molecules containing the polymerizable groups on the support surface.
[0075] In one embodiment, the binding agent is used in relation to a plurality of molecules, each containing one or more polymerizable groups. According to this modality, the photoreactive group serves as an initiator to initiate the polymerization of the polymerizable groups. As used in this document, the polymerizable group refers to a group that is adapted to be polymerized by initiation via generation of free radicals, and by photoinitiators activated by visible or long-wavelength ultraviolet radiation.
[0076] A variety of polymerizable compounds are suitable for use as with the binding agent described in this document. In one embodiment, polymerization products (eg, a polymer layer resulting from polymerization
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35/44 via free radicals) are hydrophilic or are capable of being modified to provide hydrophilic characteristics under appropriate reaction conditions (eg, pH). In addition, the polymerizable groups of such compounds can include those adapted to participate in polymerization via free radicals. In one embodiment, the compounds include at least one polymerizable free radical component (e.g., a vinyl group), and at least one functional group with a high affinity for water. Such functional groups with a high affinity for water can be negatively charged, positively charged, or electrically neutral.
[0077] Suitable polymerizable compounds are selected from monomeric polymerizable molecules (eg, organic monomers), and macromeric polymerizable molecules (eg, organic macromers). As used herein, the macromer will refer to a macromolecular monomer having a molecular weight of about 250 to about 25,000, and from about 1,000 to about 5,000.
[0078] Suitable polymerizable compounds may contain electrically neutral hydrophilic functional units, for example, derivatives of acrylamide and methacrylamide. Examples of suitable monomers containing electrically neutral hydrophilic structural units include acrylamide, methacrylamide, Nalkylacrylamides (e.g., Ν, Ν-dimethylacrylamide or methacrylamide, N-vinylpyrrolidinone, N-vinylacetamide, N-vinyl formamide, acrylate hydroxide, acrylate). , hydroxyethyl methacrylate, hydroxypropyl acrylate or methacrylate, glycerol monomethacrylate, and glycerol monoacrylate).
Alternatively, suitable polymerizable compounds containing electrically neutral hydrophilic functional units include molecules whose polymers, once formed, can be readily modified (e.g., hydrolyzed by the addition of ethylene oxide) to provide products with increased affinity for Water. Examples of suitable monomers of this type include the
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36/44 glycidyl acrylate or methacrylate, whose polymers contain epoxy groups that can be readily hydrolyzed to provide glycol structures having a high affinity for water.
[0080] Examples of suitable monomeric polymerizable molecules, which are negatively charged at appropriate pH levels, include acrylic acid, methacrylic acid, maleic acid, fumaric acid, itaconic acid, AMPS (sulfonic acrylamidomethylpropane), vinyl phosphoric acid, vinylbenzoic acid, and the like.
[0081] Alternatively, suitable monomeric polymerizable molecules, which are negatively charged at appropriate pH levels, include molecules whose polymers, once formed, can be readily modified (eg, through hydrolysis by adding oxide ethylene) to provide products with increased affinity for water. Examples of suitable monomers of this type include maleic anhydride, whose polymers contain anhydride groups which can be readily hydrolyzed to provide carboxylic acid groups, or can be readily reacted with amines to provide amide / acid structures with high water affinity, and esters polymerized vinyls.
[0082] Examples of suitable monomeric molecules, which are positively charged at appropriate pH levels, include 3-aminopropylmethacrylamide (ΑΡΜΑ), methacrylamidopropyltrimethylammonium chloride (MAPTAC), Ν, Ν-dimethylaminoethyl methacrylate, N, acrylate -diethylaminoethyl, and the like.
[0083] Alternatively, the positively charged monomeric polymerizable molecules include those molecules that can be readily modified (eg, through hydrolysis by adding ethylene oxide) to provide products with increased water affinity, as well as a charge posi
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37/44 uses, for example, glycidyl methacrylate, the polymeric products of which can be reacted with amines (eg, ethylamine), to provide hydroxyamino compounds. In some cases, these materials will contain a structural unit with an inherent positive charge, such as, for example, with fully quaternized ammonium structures. In other cases, the positively charged structural unit will exist at certain pH values, particularly at acidic pH values.
[0084] In an alternative embodiment, the polymerizable compounds include the macromeric polymerizable molecules. Suitable macromers can be synthesized from monomers, such as those illustrated above. According to one embodiment, the polymerizable functional components (eg, vinyl groups) of the macromer can be located at either end of the polymer chain, or at one or more points along the polymer chain, in a random structural mode or not random.
[0085] The number of polymerizable groups of free radicals per molecule can be varied according to the application. For example, a macromer can be used with only one free radical polymerizable unit. In other situations, however, a macromer with more than one, for example, two or more polymerizable units per macromer can be used. In addition, the macromer may contain structural characteristics to provide improved affinity for water in a manner typically unavailable in small molecule structures (eg, hydrophilic poly (ethylene glycol) materials).
Examples of suitable macromeric polymerizable compounds include methacrylate derivatives, monoacrylate derivatives, and acrylamide derivatives. Macromeric polymerizable compounds include poly (ethylene glycol) monomethacrylate, methoxypoly monomethacrylate (ethylene glycol), poly (ethylene glycol) monoacrylate, monomethylacrylamide poly (acrylamide), poly (acrylamide-co-3-methacrylamide), polyacrylamide, polyacrylamide poly monomethacrylate (alcohol
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38/44 vinyl), poly monoacrylate (vinyl alcohol), poly dimethacrylate (vinyl alcohol), and the like.
[0087] Such macromers can be prepared, for example, by first synthesizing a hydrophilic polymer of the desired molecular weight, followed by a polymer modification step to introduce the desired level of polymerizable functional units (e.g., vinyl). For example, acrylamide can be copolymerized with specific amounts of 3-aminopropylmethacrylamide comonomer, and the resulting copolymer can then be modified by reaction with methacrylic anhydride to introduce functional methacrylamide units, thereby producing a useful macromer.
[0088] Poly (ethylene glycol) of a desired molecular weight can be synthesized or purchased from a commercial source, and modified (eg, by reaction with methacrylyl chloride or methacrylic anhydride) to introduce the units of terminal methacrylate ester, to produce a suitable macromer. Some applications may benefit from the use of macromers with polymerizable units located at, or close to, the end of polymer chains, while other uses may benefit from having the polymerizable unit (s) located ( s) along the hydrophilic polymeric main chain.
[0089] Such monomeric and macromeric polymerizable molecules can be used alone or in combination with each other, including, for example, combinations of macromers with other macromers, monomers with other monomers, or macromers combined with one or more monomers of small molecules , capable of providing polymeric products with the desired affinity for water. In addition, the aforementioned polymerizable compounds can be provided in the form of amphoteric compounds (e.g., zwitterions), thereby providing both positive and negative charges.
Biodegradable Polymer Foams
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39/44 [0090] In another embodiment, the binding agent can be used in relation to a composition that is capable of polymerization in situ. In one embodiment, the binding agent can be used in relation to a biodegradable, biocompatible polymer foam. The biodegradable foam used for the treatment of wounds is described, for example, in US Patent Publication No. 2009/0093550, the disclosure of which is hereby incorporated by reference in this document in its entirety.
[0091] In one embodiment, a biodegradable foam is formed using an application composition that includes a polymerizable component, a polymerization initiator, and a gas release component. Suitable polymerization initiators include photoinitiators, including the photoreactive groups of the binding agent described in this document. An application composition can be used to form biocompatible foam in situ, or as a preformed foam.
[0092] Biocompatible polymer foams can be formed from macromers that include polymerizable group (s), which generally refers to chemical groups that are polymerizable in the presence of free radicals. A polymerizable group generally includes a carbon-carbon double bond, which can be an ethylenically unsaturated group or a vinyl group. With the initiation of a polymerization reaction in the application composition, the polymerizable groups are activated by the propagation of free radicals in the composition, and covalently linked with other polymerizable groups. As a result of covalent bonding, a cross-linked polymeric matrix is formed. The gas bubbles are generated in the application composition by foaming agents while the polymerization of the macromers (which causes the formation of the polymeric matrix) is taking place. As a result, a foam is formed, with the air pockets (also referred to in this document as cells) partially or completely surrounded by a matrix wall.
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40/44 crosslinked polymer.
[0093] Examples of polymerizable groups include, but are not limited to, acrylate groups, methacrylate groups, ethacrylate groups, 2-phenyl acrylate groups, acrylamide groups, methacrylamide groups, itaconate groups, and styrene groups. In some respects, the macromers of the invention include one or more methacrylate groups.
[0094] The polymerizable groups can be pendent from the macromer in more than one position along the polymeric main chain. In some cases, the polymerizable groups are randomly located along the length of the polymeric main chain. Such random spacing typically occurs when the macromer is prepared from a polymer having reactive groups along the length of the polymer, and the polymer is reacted with a limited molar amount of a compound having the polymerizable group. For example, the polysaccharides described in this document have hydroxyl groups along the length of the polysaccharide, and a part of these hydroxyl groups is reacted with a compound having a reactive hydroxyl group and a polymerizable group.
[0095] In other cases, one or more polymerizable groups are pendent from the macromer at one or more defined positions along the polymeric main chain. For example, a polymer used for macromer synthesis may have a reactive group at its end, or reactive groups at its ends. Many polymers prepared from monomers with reactive oxygen-containing groups (such as oxides) have hydroxyl-containing terminal ends that can be reacted with a compound having a reactive hydroxyl group and a polymerizable group, to provide the macromer with polymerizable groups at their ends .
[0096] Macromers are based on biocompatible polymers. The term biocompatible (which can also be referred to as compatible with tissue)
Petition 870180070224, of 8/13/2018, p. 54/65
41/44 generally refers to the inability of a component, composition, or article to promote a measurable adverse biological response in the body. A biocompatible component, composition, or article may have one or more of the following properties: non-toxic, non-mutagenic, non-allergenic, non-carcinogenic, and / or non-irritating. A component, composition, or biocompatible article, however small, can be harmless and tolerated by the body. A biocompatible component, alone, can also improve one or more functions in the body.
EXAMPLES
Example 1: Preparation of a degradable disilane binding agent [0097] A degradable binding agent with the formula shown above can be prepared as follows:
[0098] 4-hydroxybenzophenone (0.992 g) is placed in a 50 ml round-bottom flask, dried in an oven, under an inert atmosphere. Anhydrous DCM (30 ml) and pyridine (0.5 ml) are added to the reaction mixture. The reaction mixture is allowed to stir at room temperature for 5 min. 1,8-bis (chlorodimethylsilyl) octane (0.786 g) is added simultaneously, using a syringe, and the reaction mixture is allowed to stir for an additional 16 h at room temperature. The product is purified by column chromatography, using silica gel.
Example 2: Preparation of a degradable monosilane binder [0099] A degradable binder with the formula shown above was prepared as follows:
[00100] 4-hydroxybenzophenone (2 g) was placed in a bottom flask
Petition 870180070224, of 8/13/2018, p. 55/65
42/44 round of 100 mL, dried in an oven, under an inert atmosphere. Anhydrous DCM (50 ml) and pyridine (1.22 ml) were added to the reaction mixture. The reaction mixture is allowed to stir at room temperature for 5 min. The diisopropyl dichlorosilane (1 g) was added simultaneously, using a syringe, and the reaction mixture was allowed to stir for an additional 16 h at room temperature. The reaction mixture was filtered and washed with DI water (2 x 25 mL), 0.5 N HCI (25 mL), DI water (25 mL), sat. NaHCO3. aq. (25 ml) and DI water (25 ml). The solution was dried over Na2SO4 and the solvent was evaporated in vacuo. The product was further purified by column chromatography using silica gel.
Example 3: Preparation of a degradable disilane binder
[00101] A degradable binding agent with the formula shown above can be prepared as follows:
[00102] 4-Aminobenzophenone (2 eq) is placed in a round-bottom flask dried in an oven, under an inert atmosphere. Anhydrous DCM and pyridine (2.5 eq) are added to the reaction mixture. The reaction mixture is allowed to stir at room temperature for 5 min. 1,2-bis (chlorodimethylsilyl) methane (1 eq) is added simultaneously, using a syringe, and the reaction mixture is allowed to stir for an additional 16 h at room temperature. Multifunctional structures are prepared by reacting more than 1 eq of 1,2-bis (chlorodimethylsilyl) methane with 4aminobenzophenone, to form a degradable binding agent having multiple photoreactive groups.
Example 3: Preparation of a degradable bisphosphorous binding agent
Petition 870180070224, of 8/13/2018, p. 56/65
43/44 [00103] A degradable binding agent is formed by reacting methylenebis (phosphonic dichloride) (1 eq) with 4-hydroxybenzophenone (2 eq), in anhydrous DCM, using pyridine (2.5 eq) as a base. The resulting product can be converted to its salt to increase water solubility.
[00104] It should be noted that, as used in this specification and in the appended claims, the singular forms one, one, o and a include plural referents, unless the content is clearly dictated by the other. It should also be noted that the term or is generally used in its sense that includes and / or, unless the content clearly dictates otherwise.
[00105] The foregoing discloses the modalities of the invention. In the Descriptive Report and in the claims, the term about is used to modify, for example, the amount of an ingredient in a composition, concentration, volume, process, and similar values and their ranges, to describe the various modes of disclosure. The term about refers to the variation in numerical quantity that can occur, for example, through typical measurement and handling procedures, used to prepare compounds, compositions, concentrates or formulations for use; through accidental error in these procedures; through differences in the manufacture, source, or purity of the starting materials or ingredients used to carry out the methods, and similar close considerations. The term about also includes quantities that differ due to the aging of a formulation with a particular initial concentration or mixture, and quantities that differ due to mixing or processing a formulation with a particular initial concentration or mixture. Where modified by the term about, the claims attached to it include equivalents to these quantities.
[00106] It should also be noted that, as used in this specification and in the appended claims, the expression configured describes a system, device, or other structure that is built or configured to carry out
Petition 870180070224, of 8/13/2018, p. 57/65
44/44 perform a particular task or adopt a particular configuration. The expression configured can be used interchangeably with other similar expressions, such as arranged, arranged and configured, constructed and arranged, constructed, manufactured and arranged, and the like.
[00107] All publications and patent applications in this specification are indicative of the level of common skill in the technique to which this invention relates. All publications and patent applications are incorporated into this document by reference in the same proportion as if each individual publication or patent application was specifically and individually indicated by reference.
[00108] This request is intended to cover the adaptations or variations of this matter. It is to be understood that the above description is intended to be illustrative, not restrictive. It should be readily apparent that any one or more of the design features described in this document can be used in any combination with any particular configuration. With the use of the metal injection molding process, such design features can be incorporated without substantial additional manufacturing costs. That the number of combinations is too numerous to describe, and the present invention is not limited by, or to, any particular illustrative combination described in this document. The scope of this matter should be determined with reference to the appended claims, together with the total scope of equivalents to which such claims are entitled.

权利要求:
Claims (12)
[1]
1. Degradable binding agent CHARACTERIZED by the fact that it comprises a formula selected from:
(a) where R ¹ and R ⁹ are H, alkyl, halide, hydroxyl or amine; R ² and R ⁸ are H, alkyl, halide or amine; R ³ , R ⁴ , R ⁶ and R ⁷ are alkyl or aryl; R ⁵ is null, an amine, ether, straight or branched C1-C10 alkyl, O or O (CH2CH2O) n, where n is an integer between 1 and 30; and each X, independently, is O, N, Se, S, NH or alkyl (CH2 is an exception);
(b) where R ¹ , R ² , R ⁴ and R ⁵ are H, alkyl, halogen, amine or hydroxyl; R ³ is null, N, O, straight or branched C1-C10 alkyl, OCH2O and O (CH2CH2O) n, where n is an integer between 1 and 30; R ⁶ and R ⁷ are independently a hydroxyl or a salt thereof, cyclic, linear, branched, saturated, unsaturated, aromatic or heteroaromatic hydrocarbon; and each X can independently be O, N, Se, S or alkyl; and (c) where R ¹ , R ² , R ⁴ and R ⁵ are H; R ³ is alkyl (ethyl group is an exception), aryl, aryl ketone, benzophenone or hydroxyl or salt thereof (ONa is an exception); and each X, indePetition 870180070224, of 08/13/2018, p. 59/65
[2]
2/3 pending, it is O, N, Se, S or alkyl.
2. Degradable binding agent according to claim 1 (a), CHARACTERIZED by the fact that R ¹ and R ⁹ are H, alkyl, halide, hydroxyl or amine; and R ⁵ is O or straight or branched C1-C10 alkyl.
[3]
Degradable binding agent according to claim 1 (b), CHARACTERIZED by the fact that R ¹ , R ² , R ⁴ and R ⁵ are H, alkyl, halogen, amine or hydroxyl; R ² and R ^{7 8} are H, alkyl, halide or amine; and R ³ is O or straight or branched C1-C10 alkyl.
[4]
Degradable binding agent according to claim 1 (b) or 1 (c), CHARACTERIZED by the fact that it comprises a phosphorester bond or a phosphoramide bond.
[5]
5. Degradable binding agent according to claim 1, CHARACTERIZED by the fact that the binding agent is capable of, with the activation of one or more benzophenone moiety groups, covalent binding to a surface, target molecule, or a combination of them.
[6]
6. Degradable binding agent, according to claim 1 (c), CHARACTERIZED by the fact that it comprises the following formula:
O
[7]
7. Method of coating a support surface with a binding agent to provide the surface with one or more latent reactive groups, CHARACTERIZED by the fact that it comprises:
a) provide the support surface;
b) applying to the support surface the degradable binding agent as defined in any one of claims 1 to 5, or bis (4-benzoylphenyl phosphate) of
Petition 870180070224, of 8/13/2018, p. 60/65
3/3 sodium; and
c) lighting the binding agent on the support surface under conditions suitable to activate a first portion of benzophenone to attach the binding agent to the surface, in which a second portion of benzophenone remains unattached to the support surface and is able to revert to a latent reactive state.
[8]
8. Support surface CHARACTERIZED by the fact that it contains a coating comprising a layer of polymer joined to the surface by the degradable binding agent as defined in claim 1, or sodium bis (4-benzoylphenyl phosphate), wherein a first benzophenone portion of the agent binder, when activated in the presence of the support surface, is able to attach the binding agent to the support surface, and a second benzophenone portion of the binder, when activated in the presence of a coating agent, is able to attach the coating to the surface .
[9]
Support surface according to claim 8, CHARACTERIZED by the fact that it comprises a hydrophobic polymeric coating.
[10]
Support surface according to claim 8, CHARACTERIZED by the fact that it comprises a hydrophilic polymeric coating.
[11]
Support surface according to claim 8, CHARACTERIZED by the fact that the binding agent releases the polymeric coating of the medical device as the binding agent degrades over time.
[12]
12. Coated medical device CHARACTERIZED by the fact that it comprises: a medical device and a polymeric coating, wherein the coating is joined to the medical device by the degradable binding agent as defined in claim 1 or sodium bis (4-benzoylphenyl phosphate).

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2018-05-15| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|

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2018-11-13| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2019-01-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 29/03/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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PCT/US2011/030319|WO2011123441A1|2010-03-30|2011-03-29|Degradable photo-crosslinker|

---