Medical sealant

Abstract

A sealant and techniques for preparing and using the sealant are disclosed. The sealant may comprise three components, namely an electrophile, a nucleophile, and a doping component, which together form the sealant. The electrophile may comprise a first electrophile having a first functionality of a first reactive group. The nucleophile may comprise a first nucleophile having a second functionality of a second reactive group. The doping component may comprise a second electrophile having a third functionality of the first reactive group beyond the first functionality, and / or a second nucleophile having a fourth functionality of the second reactive group beyond the second functionality. The doping component may be present in an amount sufficient to provide a molar contribution of 2 to 20% of the first and / or second reactive groups in the sealant.

Description

[Technical Field]

[0001] This invention relates to a multi-component sealant for medical use. [Background technology]

[0002] Medical sealants are used, for example, as auxiliary materials for primary closure using sutures, surgical mesh, and staples. Medical sealants such as pulmonary sealants and vascular sealants are used to prevent leakage of blood, air, or other bodily fluids after surgery or injury. Sealants are particularly important for preventing postoperative complications, including infection.

[0003] Medical sealants typically consist of one or more materials that adhere to a specific location on the body by curing or gelling in place after application. However, the use of such sealants can be difficult if movement occurs after application but before the sealant has cured or gelled. Therefore, in addition to other desirable performance characteristics (e.g., high tensile strength, high elongation at break, and low modulus of elasticity), it is preferable that medical sealants also have a very short curing or gelling time.

[0004] Conventional sealants have not yet been able to provide all the desired performance characteristics for medical sealants. [Overview of the project] [Means for solving the problem]

[0005] Various shortcomings in the prior art are addressed by the compositions and techniques of the disclosed subject matter as follows:

[0006] In some embodiments, a sealant may be provided. The sealant may comprise three components, namely an electrophile, a nucleophile, and a doping component, which together form the sealant. The electrophile may comprise a first electrophile material (such as a polymer or biomaterial) having a first functionality of a first reactive group. The nucleophile may comprise a first nucleophile material (such as a polymer or biomaterial) having a second functionality of a second reactive group. The doping component may comprise a second electrophile material (such as a polymer or biomaterial) having a third functionality of the first reactive group beyond the first functionality, and / or a second nucleophile material (such as a polymer or biomaterial) having a fourth functionality of the second reactive group beyond the second functionality. The doping component may be present in an amount sufficient to provide a molar contribution of 2 to 20% of the first and / or second reactive groups in the sealant.

[0007] In some embodiments, the first nucleophilic polymer may include a first multi-armed nucleophilic PEG, which may be bioabsorbable in vivo. The first multi-armed nucleophilic PEG may be a PEG-amine such as 4-armed PEG-NH2-HCl. The second nucleophilic polymer may be a second multi-armed nucleophilic PEG, which may be bioabsorbable in vivo. The second multi-armed nucleophilic PEG may be, for example, 6 and / or 8-armed PEG-NH2-HCl.

[0008] In some embodiments, the first electrophilic polymer may include a first multi-arm electrophilic PEG, which may be bioabsorbable in vivo. The first multi-arm electrophilic PEG may be a PEG-NHS ester such as 4-arm PEG-succinimidyl glutarate (SG). The second electrophilic polymer may be a second multi-arm electrophilic PEG, which may be bioabsorbable in vivo. The second multi-arm electrophilic PEG may be, for example, 6- and / or 8-arm PEG-SG.

[0009] In some embodiments, the sealant (such as electrophilic components, nucleophilic components, and / or doping components) may include additives. In some embodiments, the additives may be antioxidants such as tocopherol or derivatives thereof. In some embodiments, the antioxidants may be α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocotrienol, or a combination thereof. In some embodiments, the additives may be colorants such as FD&C Blue #1, FD&C Blue #2, FD&C Green #3, FD&C Yellow #6, or a combination thereof. In some embodiments, the additives may be contrast agents.

[0010] In some embodiments, the electrophile component may include an acidic buffer for reconstituting the first electrophile polymer, and the nucleophile component may further include an alkaline buffer for reconstituting the first nucleophile polymer. In various embodiments, the pKa of the buffer for reconstituting the first nucleophile polymer may be about 7.9 pKa to about 9.7 pKa. In various embodiments, the pH of the nucleophile component after reconstituting the buffer for the first nucleophile polymer may be at least 0.05 pH units higher than the pKa of the buffer. In some embodiments, the pH of the nucleophile component after reconstitution is about 9.0 to about 10.5. In various embodiments, the buffer for reconstituting the first electrophile polymer may have a concentration of about 3.5 mM to about 15 mM and a pH of about 4.0 to about 7.0 before reconstitution. In various embodiments, the pH of the buffer for reconstituting the first electrophile polymer may be about 4.0 to less than 5.0 before reconstitution.

[0011] In some embodiments, the final concentrations of the first nucleophile and the first electrophile in the sealant are approximately 39 mg / mL to approximately 87 mg / mL, and the first nucleophile, the second nucleophile, the first electrophile, and the second electrophile each have a molecular weight of approximately 20 kDa.

[0012] In some embodiments, a system may be provided. The system may include a sealant disclosed herein and an applicator having an applicator body configured to hold a first component of the sealant in a first spatial volume and a second component of the sealant in a second spatial volume separate from the first spatial volume, and configured to allow the first component and the second component to be combined. The first component may include an electrophilic component and optionally at least a portion of a doping component. The second component may include a nucleophilic component and optionally at least a portion of a doping component.

[0013] In some embodiments, a kit may be provided. The kit may include a plurality of storage containers. The kit may include a first storage container containing dried first nucleophilic polymer powder. The kit may include a second storage container containing an alkaline buffer for preparing the first electrophilic polymer composition. The kit may include a third storage container containing dried first electrophilic polymer powder. The kit may include a fourth storage container containing an acidic buffer for preparing the first electrophilic polymer composition. The kit may include at least one additional container. The at least one additional container may be a storage container containing dried second nucleophilic polymer powder and / or a storage container containing dried second electrophilic polymer powder. The sealant is formed after combining the first nucleophilic polymer composition and the first electrophilic polymer composition.

[0014] In some embodiments, a method for using a sealant may be provided. The sealant may be formed by combining a first nucleophilic polymer composition with a first electrophilic polymer composition and curing the sealant. The sealant may be an embodiment of the sealant disclosed herein.

[0015] The method may include forming a first nucleophilic polymer composition by adding an alkaline buffer to a first nucleophilic polymer. The method may also include forming a first electrophilic polymer composition by adding an acidic buffer to a first electrophilic polymer. In some embodiments, forming a first nucleophilic polymer composition may also include adding a second nucleophilic polymer, and / or forming a first electrophilic polymer composition may also include adding a second electrophilic polymer.

[0016] In some embodiments, the method may include adding an antioxidant to the first nucleophilic polymer composition and / or the first electrophilic polymer composition. In some embodiments, the method may include irradiating the first nucleophilic polymer composition and / or the first electrophilic polymer composition, which may include X-ray irradiation up to about 40 kilogray (kGy). In some embodiments, the 4-arm PEG-amine, 4-arm PEG-NHS ester, and 6-arm or 8-arm PEG-amine and / or PEG-NHS ester are irradiated in a hypoxic environment, and the 4-arm PEG-amine and any 6-arm or 8-arm PEG-amine are in a protonated form. In various embodiments, forming a sealant may include mixing the first nucleophilic polymer composition and the first electrophilic polymer composition using an applicator device and applying them simultaneously to a substrate such as patient tissue.

[0017] In some embodiments, a method for preparing a sealant may be provided. This method may include forming an electrophilic polymer composition by mixing an alkaline buffer with a first electrophilic polymer having a first functionality of a first reactive group and a second electrophilic polymer having a second functionality of the first reactive group exceeding the first functionality (optionally), and separately forming a nucleophilic polymer composition by mixing an acidic buffer with a first nucleophilic polymer having a third functionality of a second reactive group and a second nucleophilic polymer having a fourth functionality of the second reactive group exceeding the third functionality (optionally). The electrophilic polymer composition should contain the second electrophilic polymer, and / or the nucleophilic polymer composition should contain the second nucleophilic polymer. This method may include simultaneously delivering the electrophilic polymer composition and the nucleophilic polymer composition onto a substrate using an applicator device that provides sufficient mixing of the electrophilic polymer composition and the nucleophilic polymer composition, and then curing the sealant on the substrate.

[0018] In some embodiments, the first electrophile polymer may be a 4-arm PEG, the second electrophile polymer may be a 6-arm and / or 8-arm PEG, and the first nucleophile polymer may be a 4-arm PEG, and the second nucleophile polymer may be a 6-arm and / or 8-arm PEG. In some embodiments, the first electrophile polymer, the second electrophile polymer, the first nucleophile polymer, and the second nucleophile polymer may be bioabsorbable in vivo.

[0019] In some embodiments, the first nucleophile and an optional second nucleophile may be irradiated before mixing with the alkaline buffer and the first electrophile, and the optional second electrophile may be irradiated before mixing with the acidic buffer.

[0020] In some embodiments, the method may include adding 730 ppm to about 3000 ppm of a colorant to the first electrophile polymer, where the first electrophile polymer is in the form of a dry powder before being mixed with the acid buffer.

[0021] In some embodiments, the first nucleophilic polymer may be in the form of a dry powder, and at least about 65% of the first nucleophilic polymer in dry powder form has a particle size of about 250 micrometers to about 1250 micrometers. In some embodiments, the first nucleophilic polymer may be in the form of a dry powder, and at least about 20% of the first nucleophilic polymer in dry powder form has a particle size greater than 710 micrometers. In some embodiments, the first electrophilic polymer may be in the form of a dry powder, and at least about 80% of the first electrophilic polymer in dry powder form has a particle size of about 250 micrometers to about 1250 micrometers. In some embodiments, the first electrophilic polymer may be in the form of a dry powder, and at least about 40% of the first electrophilic polymer in dry powder form has a particle size greater than 500 micrometers.

[0022] In some embodiments, the pKa of the acidic buffer for the nucleophilic polymer composition may be from about 7.9 pKa to about 9.7 pKa. In some embodiments, the pH of the nucleophilic polymer composition may be at least 0.05 pH units higher than the pKa of the acidic buffer. In some embodiments, the nucleophilic polymer composition may have a pH of about 9.0 to about 10.5 after reconstitution. In some embodiments, the alkaline buffer for the nucleophilic polymer composition may have a concentration of about 180 mM to about 220 mM and a pH of about 9.34 to about 9.76 before reconstitution. In some embodiments, the acidic buffer for the electrophilic polymer composition may have a concentration of about 3.5 mM to about 15 mM and a pH of about 4.0 to about 5.0 before reconstitution.

Brief Description of the Drawings

[0023] The accompanying drawings, which are incorporated herein and form a part hereof, illustrate embodiments of the invention and, together with the general description of the invention given above and the detailed description of the embodiments given below, serve to explain the principles of the invention. [Figure 1]Illustrative examples of various embodiments of the system. [Figure 2] Illustrative examples of various embodiments of the system. [Figure 3] Flowchart of a method for using a sealant. [Figure 4] Flowchart of a method for producing a sealant. [Figure 5] Graph showing rupture pressure measurements of a control sealant and embodiments of the sealants disclosed herein. [Figure 6] Graph showing displacement measurements of a control sealant and embodiments of the sealants disclosed herein. [Figure 7] Graph showing displacement measurements of a control sealant and embodiments of the sealants disclosed herein.

[0024] It is understood that the accompanying drawings are not necessarily to scale and present somewhat simplified representations of various features illustrative of the basic principles of the invention. For example, certain design features of a series of operations disclosed herein, including the specific dimensions, orientations, locations, and shapes of various illustrated components, are in part determined by a particular intended application and use environment. Certain features of the illustrated embodiments are enlarged or distorted relative to other features to facilitate visualization and clear understanding. In particular, thin features may, for example, be thickened for clarity or for illustration purposes.

Mode for Carrying Out the Invention

[0025] In various applications, sealants are used to prevent fluids (e.g., liquids, gases, etc.) from passing through or flowing through openings. To do so, sealants are required to provide certain essential mechanical properties, which may vary depending on the specific application. While it is known that curing speed can be improved by using several modifiers, such improvements typically come at a cost, in the form of a reduction in mechanical properties. The sealants disclosed improve the rate of gelation or curing while maintaining essential mechanical properties.

[0026] Specifically, the disclosed sealants surprisingly and unexpectedly maintain a polymerization time and polymerization rate that is favorable for, for example, medical sealants, while also maintaining a desirable range of mechanical properties such as shear modulus. In one embodiment, the sealants provided herein include a combination of nucleophilic and electrophilic polymers of equal molecular weight, doped with additional nucleophilic and / or electrophilic polymers with increased functionality, as well as an optimal buffering system. PEGs with molecular weights of about 15 kDa to about 50 kDa are preferred for use in the disclosed sealants. Where used herein, the term “about [a specific number]” is intended to include values ​​within ±10% of that specific number. For example, “about 1” is intended to include values ​​of 0.9 to 1.1.

[0027] The polymerization kinetics of the sealants provided herein can be determined as follows: (a) The maximum shear modulus, which is a measure of the stiffness of this sealant, (b) polymerization time (k) defined as the time required to achieve 50% of the final structure of the sealant, and (c) Polymerization rate defined as the maximum slope of the shear modulus.

[0028] Polymerization time (k) analyzes the shear modulus over time, normalized to the maximum shear modulus. Polymerization time not only provides an understanding of the curing time (the time required to achieve the final structure) but also allows for the indirect determination of the initial curing time, i.e., the time required for the sealant to stop flowing. Since sealants initially cure within a few seconds, the initial curing time cannot be directly quantified.

[0029] The polymerization rate provides a measure of the rate at which the shear modulus of the sealant increases over time. The polymerization rate is sensitive to both polymerization time and the final hydrogel structure.

[0030] The effectiveness of a sealant, or its ability to provide a strong seal, is determined by the sealant's structure. The sealant structure is measured through cohesive tensile testing and shear modulus testing.

[0031] In some embodiments, a sealant may be provided. The sealant may comprise three components that, when combined, form the sealant: an electrophile, a nucleophile, and a doping component (sometimes referred to as a “modifier” or “modifying component”).

[0032] The electrophilic component may include a first electrophilic polymer having the first functionality of the first reactive functional group. The nucleophilic component may include a first nucleophilic polymer having the second functionality of the second reactive functional group. Generally speaking, the first and second reactive groups are selected to interact to gel or cure the sealant.

[0033] For example, amine-reactive chemical groups such as N-hydroxysuccinimide (NHS) esters, imide esters, or maleimides are known to form stable conjugates, i.e., amide bonds, with amines such as primary, secondary, or tertiary amines. In some embodiments, the first reactive functional group (e.g., an electrophilic group) may be an NHS ester. Non-limiting examples of such NHS esters include succinimidyl glutarate (SG), succinimidyl valerate, succinimidyl carbonate, succinimidyl succinate, succinimidyl butanoate, succinimidyl succinamide, succinimidyl propionate, sulfosuccinimidyl glutarate, sulfosuccinimidyl valerate, sulfosuccinimidyl carbonate, succinimidyl carboxymethyl ester, sulfosuccinimidyl succinate, sulfosuccinimidyl butanoate, sulfosuccinimidyl succinamide, and sulfosuccinimidyl propionate. In some embodiments, the second reactive functional group (e.g., a nucleophilic group) may be an amine or an amine salt.

[0034] In various embodiments, the first electrophilic polymer and / or the first nucleophilic polymer may be bioabsorbable in vivo. Non-limiting examples of such bioabsorbable polymers include functionalized polyethylene glycol (PEG), polycaprolactone, and polyglycolide polymers.

[0035] As used herein, the term “functionality” refers to the average number of specific functional groups per molecule. In some embodiments, the functionality of a first nucleophilic polymer, a first electrophilic polymer, or both (F F ) is ≥ 1. In some embodiments, F is used for the first nucleophilic polymer, the first electrophilic polymer, or both. F ≥ 2. In some embodiments, F is used for the first nucleophilic polymer, the first electrophilic polymer, or both. Fis ≧3. In some embodiments, for the first nucleophilic polymer, the first electrophilic polymer, or both, F F is ≧4. In some embodiments, for the first nucleophilic polymer, the first electrophilic polymer, or both, 4≦F F ≦6 or less.

[0036] In some embodiments, the first electrophilic polymer and / or the first nucleophilic polymer may be a multi-arm PEG such as a 2-arm, 3-arm, 4-arm, ⑥-arm, or 8-arm PEG. For example, in some embodiments, the first nucleophilic polymer may be a 2-arm, 3-arm, 4-arm, or 6-arm PEG-amine (such as PEG-NH2) or PEG-amine salt (such as PEG-NH2-HCl), and the first electrophilic polymer may be a 2-arm, 3-arm, 4-arm, or 6-arm PEG-NHS ester (such as PEG-SG).

[0037] Surprisingly and unexpectedly, a small amount of a doping component having an increased functionality of a first functional group, a component having an increased functionality of a second functional group, or both, reduces the curing rate of the system compared to the curing rate when the doping component is not included.

[0038] Specifically, in some embodiments, the doping component may include a second electrophilic polymer having a third functionality of a first reactive group that exceeds the first functionality of the first electrophilic polymer. In some embodiments, the doping component may include a second nucleophilic polymer having a fourth functionality of a second reactive group that exceeds the second functionality of the first nucleophilic polymer.

[0039] In some embodiments, the functionality (F D ) of each doping component is independently F D ≧2, F D ≧3, F D ≧4, F D ≧6, or F D ≧8. In some embodiments, for each doping component, independently, 6≦FD The limit is 8.

[0040] In some embodiments, the second electrophilic polymer and / or the second nucleophilic polymer may be multi-armed PEGs such as 2-armed, 3-armed, 4-armed, 6-armed, or 8-armed PEGs. For example, in some embodiments, the second nucleophilic polymer may be a 2-armed, 3-armed, 4-armed, or 6-armed PEG-amine (such as PEG-NH2) or PEG-amine salt (such as PEG-NH2-HCl), and the second electrophilic polymer may be a 2-armed, 3-armed, 4-armed, or 6-armed PEG-NHS ester (such as PEG-SG).

[0041] As described above, each electrophilic doping component should have higher functionality than the electrophilic polymer, and each nucleophilic doping component should have higher functionality than the nucleophilic polymer. For example, if the first electrophilic polymer is 4-arm PEG-SG, the second electrophilic polymer used as a doping component may be 6-arm or 8-arm PEG-SG. Similarly, if the first nucleophilic polymer is 4-arm PEG-NH2, the second nucleophilic polymer used as a doping component may be 6-arm or 8-arm PEG-NH2.

[0042] The doping component may be present in a total amount sufficient to provide a molar contribution of 2-20% of the first and / or second reactive groups in the sealant.

[0043] In some embodiments, the sealant may utilize doping components comprising an electrophilic component of 4-arm PEG (such as 4-arm PEG-SG), a nucleophilic component of 4-arm PEG (such as PEG-amine), and amine groups from 6-arm or 8-arm PEG (such as PEG-amine) in a molar contribution of 2-10%, preferably 2-5%, which results in a faster gelation system with equivalent mechanical performance compared to sealants without doping components.

[0044] In some embodiments, the sealant may utilize doping components with a molar contribution of 2-10%, preferably 2-5%, of electrophilic components of 4-arm PEG (such as 4-arm PEG-SG), nucleophilic components of 4-arm PEG (such as PEG-amine), and electrophilic groups (such as SG groups) from 6-arm or 8-arm PEG (such as PEG-SG), which results in a faster gelation system with equivalent mechanical performance compared to sealants without doping components.

[0045] In some embodiments, the nucleophilic component may be a biologically derived material. In some embodiments, the sealant may utilize a nucleophilic component which is a biologically derived nucleophile (such as albumin), an electrophilic component which is a 4-arm PEG (such as PEG-SG), and a doping component which has a molar contribution of 2-10%, preferably 2-5%, of electrophilic groups (such as SG groups) from a 6-arm or 8-arm PEG (such as PEG-SG), which results in a faster gelation system with equivalent mechanical performance compared to a sealant without the doping component.

[0046] In some embodiments, the sealant (such as electrophilic components, nucleophilic components, and / or doping components) may include additives.

[0047] In some embodiments, the additive may be an antioxidant. The antioxidant may be added, for example, to reduce the adverse effects of any irradiation process on the polymer of the sealant. In some embodiments, the antioxidant may include BHT, tocopherol, or a combination thereof. In some embodiments, the antioxidant may include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocotrienol, or a combination thereof. In some embodiments, the antioxidant may be added at individual concentrations up to about 4000 ppm.

[0048] In some embodiments, the additives may be colorants, for example, to improve the visibility of the sealant against human tissue and to enable more consistent coverage of the target tissue. In some preferred embodiments, one or more colorants are formulated with polymer powders (e.g., in powder form, such as a first electrophilic polymer and / or a first nucleophilic polymer). Non-limiting examples of such colorants include FD&C Blue #1, FD&C Blue #2, FD&C Green #3, FD&C Yellow #6, or combinations thereof. In some embodiments, antioxidants may be added at individual concentrations up to about 3000 ppm.

[0049] In some embodiments, the additive may be a contrast agent, for example, for later localization of the sealing site or to facilitate detection by magnetic resonance imaging. In some embodiments, the contrast agent may be a nonionic contrast agent, such as iohexol, for radiopaqueness. In some embodiments, the contrast agent may be a radiopharmaceutical that enables localization of the sealing site using a radiation detection method.

[0050] In another embodiment, the sealant may contain one or more additional therapeutic agents to provide local delivery of the therapeutic agent. For example, the therapeutic agents may be one or more chemotherapeutic agents for the management of cancer.

[0051] It should be understood that the term “therapeutic agent” as used herein is intended to broadly encompass a wide range of drugs and medical substances, including but not limited to gene therapies, stem cell therapies, hemostatic agents, healing agents, adhesives, sealants, antibacterial agents, anti-infective agents, analgesics, conventional pharmaceuticals, other chemicals, liquids, powders, etc. It should also be understood that the use of the term “therapeutic agent” as used herein is not intended to limit the concepts described herein to drugs used for therapeutic purposes only. The term “therapeutic agent” as used herein is intended to encompass a wide range of medical drugs / substances, including but not limited to those used for preventive, protective, and / or therapeutic purposes, and including those used for various purposes that may not be considered “therapeutic” in the conventional sense of the word “therapeutic.” The various types of drugs / substances that may be used in accordance with the teachings herein, and the various purposes for which such drugs / substances may be used, will become apparent to those skilled in the art by considering the teachings herein. All such drugs / substances / purposes are intended to be encompassed by the use of the term “therapeutic agent” herein.

[0052] In some embodiments, the electrophile component may include an acidic buffer for reconstituting the first electrophile polymer, and the nucleophile component may further include an alkaline buffer for reconstituting the first nucleophile polymer. In various embodiments, the pKa of the buffer for reconstituting the first nucleophile polymer may be about 7.9 pKa to about 9.7 pKa. In various embodiments, the pH of the nucleophile component after reconstituting the buffer for the first nucleophile polymer may be at least 0.05 pH units higher than the pKa of the buffer. In some embodiments, the pH of the nucleophile component after reconstitution is about 9.0 to about 10. In various embodiments, the buffer for reconstituting the first electrophile polymer may have a concentration of about 3.5 mM to about 15 mM and a pH of about 4.0 to about 7.0 before reconstitution. In various embodiments, the pH of the buffer for reconstituting the first electrophile polymer may be about 4.0 to less than 5.0 before reconstitution.

[0053] Non-limiting examples of alkaline buffers include N-cyclohexyl-2-aminoethanesulfonic acid (CHES) buffer, 2-amino-2-methyl-1,3-propanediol, N-tris(hydroxymethyl)methyl-4-aminobutanesulfonic acid, N-(1,1-dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid, 3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid, and pyridoxine buffer. Non-limiting examples of acidic buffers include citrate buffer. Preferably, the acidic buffer has a pH of about 4 to about 6 or up to 7.

[0054] In some embodiments, the final concentrations of the first nucleophile and the first electrophile in the sealant may be about 39 mg / mL to about 87 mg / mL, respectively. In some embodiments, the first nucleophile, the second nucleophile, the first electrophile, and the second electrophile may each have a molecular weight of about 20 kDa, for example, including 18 kDa to 22 kDa. In some embodiments, the first nucleophile, the second nucleophile, the first electrophile, and the second electrophile may each have a molecular weight of 15 kDa to 25 kDa.

[0055] A preferred example of the first electrophilic polymer is 4-armed PEG-succinimidyl glutarate (4-armed PEG-SG-20K) (67 mg / mL) with a molecular weight of 20 kDa, available from JenKem Technology or NOF Corporation, and a preferred example of the first nucleophilic polymer is 4-armed PEG-amine (4-armed PEG-NH2-20K) (67 mg / mL) with a molecular weight of 20 kDa, available from JenKem Technology or NOF Corporation.

[0056] In some embodiments, the final concentrations of the first electrophile polymer and the first nucleophile polymer in the sealant applied to the tissue are about 39 mg / mL to about 87 mg / mL, preferably about 52 mg / mL to about 77 mg / mL, respectively. In some embodiments, the concentrations are about 67 mg / mL, respectively.

[0057] In some embodiments, a system may be provided. Referring to Figure 1, the system may include an applicator 100, which may include an applicator body 110. The applicator body may define a first internal volume 115 and a second internal volume 116, separate from the first internal volume. The applicator may be configured to hold a first component 121 of the embodiment of the sealant disclosed herein in the first internal volume and a second component 122 of the embodiment of the sealant disclosed herein in the second internal volume. The first component may include an electrophilic component of the sealant disclosed herein and optionally at least a portion of the doping component (e.g., any second electrophilic polymer). The second component may include a nucleophilic component of the sealant disclosed herein and optionally at least a portion of the doping component (e.g., any second nucleophilic polymer).

[0058] The applicator may be configured to combine a first component and a second component. For example, in some embodiments, the applicator may include a mixing chamber 130 operably coupled to a first and a second spatial volume. In some embodiments, the mixing chamber may be a static mixer in the nozzle of the applicator. The fluids forming the first and second components flow into and then out of the mixing chamber. In some embodiments, the material may flow out from the nozzle tip 140 onto the substrate 150.

[0059] As shown in Figure 1, the sealant 160 is formed on the substrate and cured. The force that pushes the fluid out of the spatial volume may vary. For example, in some embodiments, the force is gravity. In some embodiments, compressed gas may be applied to push the fluid out of the applicator. In some embodiments, a plunger 170 operably coupled to the end of the applicator opposite the nozzle can be used to mechanically push the fluid out of the first and second spatial volumes through the nozzle.

[0060] Referring to Figure 2, an alternative embodiment can be seen in which the applicator body may be bonded to the first surface 211 of the first substrate 210 (e.g., a flexible adhesive substrate). The second substrate 220 may be removably bonded to the second surface 212 of the substrate. When the second substrate is removed, the first and second components of the sealant may flow out from the first and second spatial volumes 115 and 116, respectively. The components may flow into the mixing chamber 130 through the opening 125. The mixing chamber may be defined by the first substrate or by the applicator body.

[0061] In some embodiments, a kit may be provided. The kit may include a plurality of storage containers. The kit may include a first storage container containing dried first nucleophilic polymer powder. The kit may include a second storage container containing an alkaline buffer for preparing the first electrophilic polymer composition. The kit may include a third storage container containing dried first electrophilic polymer powder. The kit may include a fourth storage container containing an acidic buffer for preparing the first electrophilic polymer composition. The kit may include at least one additional container. At least one additional container may be a storage container containing dried second nucleophilic polymer powder and / or a storage container containing dried second electrophilic polymer powder. The sealant is formed after the first nucleophilic polymer composition and the first electrophilic polymer composition are combined.

[0062] Referring to Figure 3, in some embodiments, a method 300 for using a sealant may be provided. This method may include forming the sealant by combining a first nucleophilic polymer composition with a first electrophilic polymer composition 310, and curing the sealant 320. The sealant may be an embodiment of the sealant disclosed herein. In various embodiments, forming the sealant may include mixing the first nucleophilic polymer composition and the first electrophilic polymer composition using an applicator device and applying them simultaneously onto a substrate such as patient tissue.

[0063] In some embodiments, the method may include forming a first nucleophilic polymer composition by adding an alkaline buffer to the first nucleophile 331. In some embodiments, forming the first nucleophilic polymer composition may include adding a second nucleophile (for example, to the first nucleophile or a mixture of the first nucleophile and an alkaline buffer) 332.

[0064] In some embodiments, the method may include forming a first electrophile polymer composition by adding an acidic buffer to the first electrophile 341. In some embodiments, forming the first electrophile polymer composition may include adding a second electrophile (for example, to the first electrophile or a mixture of the first electrophile and the acidic buffer) 342.

[0065] In some embodiments, the method may include adding an antioxidant to the first nucleophilic polymer composition 333 and / or adding an antioxidant to the first electrophilic polymer composition 343.

[0066] In some embodiments, the method may include irradiating a first nucleophilic polymer composition 334 and / or irradiating a first electrophilic polymer composition 344, which may include X-ray irradiation up to about 40 kilogray (kGy). In some embodiments, 4-arm PEG-amines, 4-arm PEG-NHS esters, and 6-arm or 8-arm PEG-amines and / or PEG-NHS esters are irradiated in a hypoxic environment, and the 4-arm PEG-amines and any 6-arm or 8-arm PEG-amines are in a protonated form.

[0067] Referring to Figure 4, in some embodiments, a method 400 for preparing a sealant may be provided. The method may include forming an electrophile polymer composition 410 by mixing an alkaline buffer with a first electrophile polymer having a first functionality of a first reactive group and a second electrophile polymer having a second functionality of the first reactive group exceeding the first functionality (optionally). The method may separately include forming a nucleophile polymer composition 412 by mixing an acidic buffer with a first nucleophile polymer having a third functionality of a second reactive group and a second nucleophile polymer having a fourth functionality of the second reactive group exceeding the third functionality (optionally). The electrophile polymer composition should contain a second electrophile and / or the nucleophile polymer composition should contain a second nucleophile.

[0068] In some embodiments, the first electrophile polymer may be a 4-arm PEG, the second electrophile polymer may be a 6-arm and / or 8-arm PEG, and the first nucleophile polymer may be a 4-arm PEG, and the second nucleophile polymer may be a 6-arm and / or 8-arm PEG. In some embodiments, the first electrophile polymer, the second electrophile polymer, the first nucleophile polymer, and the second nucleophile polymer may be bioabsorbable in vivo.

[0069] In some embodiments, the first nucleophilic polymer may be in the form of a dry powder, and at least about 65% of the first nucleophilic polymer in the form of a dry powder has a particle size of about 250 micrometers to about 1250 micrometers. In some embodiments, the first nucleophilic polymer may be in the form of a dry powder, and at least about 20% of the first nucleophilic polymer in the form of a dry powder has a particle size greater than 710 micrometers. In some embodiments, the first electrophilic polymer may be in the form of a dry powder, and at least about 80% of the first electrophilic polymer in the form of a dry powder has a particle size of about 250 micrometers to about 1250 micrometers. In some embodiments, the first electrophilic polymer may be in the form of a dry powder, and at least about 40% of the first electrophilic polymer in the form of a dry powder has a particle size greater than 500 micrometers.

[0070] In some embodiments, the pKa of the acidic buffer for the nucleophilic polymer composition may be about 7.9 pKa to about 9.7 pKa. In some embodiments, the pH of the nucleophilic polymer composition may be at least 0.05 pH units higher than the pKa of the acidic buffer. In some embodiments, the pH of the nucleophilic polymer composition after reconstitution may be about 9.0 to about 10.5. In some embodiments, the alkaline buffer for the nucleophilic polymer composition may have a concentration of about 180 mM to about 220 mM and a pH of about 9.34 to about 9.76 before reconstitution. In some embodiments, the acidic buffer for the electrophilic polymer composition may have a concentration of about 3.5 mM to about 15 mM and a pH of about 4.0 to about 5.0 before reconstitution.

[0071] The method may include simultaneously delivering the electrophilic polymer composition and the nucleophilic polymer composition onto a substrate using an applicator device that provides sufficient mixing of the electrophilic polymer composition and the nucleophilic polymer composition 420, and then curing the sealant on the substrate 430.

[0072] In some embodiments, the polymer may be irradiated 440. In some embodiments, the method may include irradiating the first nucleophile polymer and any second nucleophile polymer before mixing with an alkaline buffer 441. In some embodiments, the method may include irradiating the first electrophile polymer and any second electrophile polymer before mixing with an acidic buffer 442.

[0073] In some embodiments, the method may include introducing an additive into the composition 450. In some embodiments, the method may include adding a colorant, for example, 730 ppm to about 3000 ppm of a colorant 451, where the first electrophile polymer is in the form of a dry powder before being mixed with the acid buffer. In some embodiments, the method may include adding an antioxidant to the composition 452. In some embodiments, the method may include adding a contrast agent to the composition 453. These additions may be made before or after any irradiation (if used). [Examples]

[0074] The effect of doping on burst pressure To investigate the effect of high-functionality doping on structure, a burst pressure test was performed on porcine pleural tissue. The control was a combination of 62 mg / mL of 20 kDa 4-arm PEG-SG, 62 mg / mL of 20 kDa 4-arm PEG-amine, and 100 mM CHES (pH=9.35). The exemplary formulation tested was a 5% molar contribution high-functionality formulation consisting of 62 mg / mL of 20 kDa 4-arm PEG-SG, 59.85 mg / mL of 4-arm 20 kDa PEG-amine-HCl, 100 mM CHES (pH=9.35), and 1.575 mg / mL of 20 kDa 8-arm PEG-amine HCl. As shown in Figure 5, there was no significant difference between the control and the 5% doped formulation (p=0.873, 2-sample t-test). [Examples]

[0075] Effect of electrophilic doping concentration on migration distance In the case of sealants, migration distance can be considered an easily measurable surrogate for curing time. Various formulations were compared to controls to determine the effect of doping concentration on migration distance. Different nucleophilic and electrophilic polymer concentrations are shown in Table 1 below.

[0076] [Table 1]

[0077] As shown, in this study, the pure 4-arm formulations were 75 mg / mL of 4-arm PEG-SG-20k and 28.5 mg / mL of 4-arm PEG-amine-10k in 50 mM carbonate buffer (pH=10.25). Various exemplary formulations were created by varying the amount of 8-arm PEG-SG-20k until 50% of the SG groups were contributed by 8-arm PEG. The 4-arm PEG-SG-20k concentration was adjusted to maintain a constant molar concentration of the reactive group. Immediately before testing, PEG-SG was dissolved in 5 mL of 50 mM carbonate buffer at pH 9.0 and tested for migration distance on a 30-degree inclined surface using an EVISEL fibrin sealant device and a control tip.

[0078] Referring to Figure 6, in the first comparison, the 10%, 20%, and 50% doped formulations were compared to the control formulation. There was a significant effect on migration distance caused by the addition of the 8-arm PEG-SG formulation (p=0.000, one-way ANOVA). There were significant differences between replications using 0%, 10%, 20%, and 50% 8-arm PEG-SG 20k. There was no statistically significant difference in migration distance between the 20% and 50% 8-arm samples. Therefore, compared to the control formulation, the 10%, 20%, and 50% doped formulations showed a statistically significant reduction in curing time.

[0079] Referring to Figure 7, in the second comparison, the 10%, 5%, and 2% doped formulations were compared to the control formulation. As can be seen, even when the molar contribution of 8-arm PEG-SG-20k was reduced to a low 2%, there was still a statistically significant effect on the migration distance (p=0.000, one-way ANOVA). In fact, there was a significant difference between 0% and 2%, 5%, and 10%. However, there was no significant difference between 2% and 10%. Therefore, compared to the control formulation, the 2%, 5%, and 10% doped formulations showed a statistically significant reduction in curing time. [Examples]

[0080] The effect of doping concentration of nucleophiles In this study, to test the effect of nucleophilic doping on specific sealant properties, various amounts of 4-arm PEG-amine and 8-arm PEG-amine HCl 20k were added to 4-arm PEG-SG-20k while maintaining a constant molar ratio of reactive groups. The PEG-amine was dissolved in 200 mM CHES (pH=9.35). Immediately before testing, 62 mg / mL of 4-arm PEG-SG-20k was prepared in water. The sealant was filled into a two-chamber syringe and extruded into a weighing boat using a static mixing tip. After curing, all resulting gels were examined. Different nucleophilic and electrophilic polymer concentrations can be found in Table 2 below.

[0081] [Table 2]

[0082] All the resulting gels could be easily removed from the weighing boat and appeared fully reacted. As the contribution of the 8-arm PEG increased from 0% to 10%, the gels became somewhat stiffer but remained fairly flexible. In addition, the gels could be stretched without immediately breaking. Stiffness and brittleness increased with increasing doping levels. That is, the 20% and 50% doped gels became stiffer and did not deform easily under pressure. The 20% and 50% gels were more brittle compared to the lower-doped gels and could only stretch minimally without breaking. When only the edge of the gel was fixed in place and the opposite edge was pulled downward by gravity, the 20% and 50% gels did not bend under gravity as much as the lower percentage groups (e.g., the unheld edges of the 20% and 50% gels did not deflect as much as the control 2%, 5%, or 10% gels).

[0083] Certain features of the present invention are described in the context of separate embodiments for clarity, but it is understood that these may also be presented in combination in a single embodiment. Conversely, various features of the present invention are described in the context of a single embodiment for brevity, but these may also be provided separately, in any preferred partial combination, or in any other described embodiment of the present invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiment would be unable to operate without those elements.

[0084] While various forms of this disclosure have been shown and described, further adaptations of the methods and systems described herein may be achieved by appropriate modifications by those skilled in the art without departing from the scope of the invention. Some of these possible modifications have been mentioned, but others will be obvious to those skilled in the art. For example, the examples, modifications, geometric shapes, materials, dimensions, proportions, processes, etc., discussed above are illustrative and not essential. Therefore, the scope of the invention should be considered with respect to the following claims and is not limited to the details of structures and operations shown and described herein and in the drawings.

[0085] [Implementation Method] (1) A sealant, An electrophilic component comprising a first electrophilic material having the first functionality of a first reactive group, A nucleophilic component comprising a first nucleophile having a second functionality of a second reactive group, It is a doping substance, A second electrophilic material having a third functionality of the first reactive group that exceeds the first functionality, and / or A doping component comprising a second nucleophile having a fourth functionality of the second reactive group that exceeds the second functionality, The doping component is present in an amount sufficient to provide a molar contribution of 2-20% of the first reactive group and / or the second reactive group in the sealant. A sealant that, when the electrophilic component, the nucleophilic component, and the doping component are combined, produces a sealant. (2) The sealant according to Embodiment 1, wherein the first nucleophilic material is a first multi-arm nucleophilic PEG. (3) The sealant according to Embodiment 2, wherein the first multi-arm nucleophilic PEG is bioabsorbable in vivo. (4) The sealant according to Embodiment 2, wherein the first multi-arm nucleophilic PEG is a PEG-amine. (5) The sealant according to Embodiment 4, wherein the PEG-amine is 4-arm PEG-NH2-HCl.

[0086] (6) The sealant according to Embodiment 2, wherein the second nucleophilic material is a second multi-arm nucleophilic PEG. (7) The sealant according to Embodiment 6, wherein the second multi-arm nucleophilic PEG is bioabsorbable in vivo. (8) The sealant according to Embodiment 6, wherein the second multi-arm nucleophilic PEG of the doping component is a 6-arm and / or 8-arm PEG-NH2-HCl. (9) The sealant according to Embodiment 1, wherein the first electrophilic material is a first multi-arm electrophile PEG. (10) The sealant according to Embodiment 9, wherein the first multi-arm electrophilic PEG is bioabsorbable in vivo.

[0087] (11) The sealant according to Embodiment 9, wherein the first multi-arm electrophile PEG is a PEG-NHS ester. (12) The sealant according to Embodiment 11, wherein the PEG-NHS ester is 4-arm PEG-succinimidyl glutarate (SG). (13) The sealant according to Embodiment 9, wherein the second electrophilic material is a second multi-arm electrophile PEG. (14) The sealant according to Embodiment 13, wherein the second multi-arm electrophilic PEG is bioabsorbable in vivo. (15) The sealant according to Embodiment 13, wherein the second multi-arm electrophilic PEG of the doping component is a 6-arm and / or 8-arm PEG-SG.

[0088] (16) The sealant according to Embodiment 1, wherein the electrophilic component, the nucleophilic component, and / or the doping component further comprises an antioxidant. (17) The sealant according to Embodiment 1, wherein the electrophilic component, the nucleophilic component, and / or the doping component further comprises a colorant. (18) The sealant according to Embodiment 1, further comprising a contrast agent. (19) A system, The sealant described in Embodiment 1, A system comprising: an applicator having an applicator body configured to hold a first component containing a first electrophile material in a first spatial volume and a second component containing a first nucleophile material in a second spatial volume separate from the first spatial volume, wherein the applicator is configured to enable the combination of the first component and the second component. (20) A kit for preparing sealant, A first storage container containing a dried first nucleophilic polymer powder, A second storage container containing an alkaline buffer for preparing a first nucleophilic polymer composition, A third storage container containing the dried first electrophilic polymer powder, A fourth storage container containing an acidic buffer for preparing a first electrophilic polymer composition, At least one additional container, A storage container containing a dried second nucleophilic polymer powder, and / or A storage container containing a dried second electrophilic polymer powder, comprising at least one additional container, A kit in which the sealant is formed after combining the first nucleophilic polymer composition and the first electrophilic polymer composition.

Claims

1. It is a sealant, An electrophilic component comprising a first electrophilic material having the first functionality of a first reactive group, A nucleophilic component comprising a first nucleophilic material having a second functionality of a second reactive group, It is a doping substance, A second electrophilic material having a third functionality of the first reactive group that exceeds the first functionality, and / or A doping component comprising a second nucleophile having a fourth functionality of the second reactive group that exceeds the second functionality, The doping component is present in an amount sufficient to provide a molar contribution of 2 to 20% of the first reactive group and / or the second reactive group in the sealant. A sealant that, when the electrophilic component, the nucleophilic component, and the doping component are combined, produces a sealant.

2. The sealant according to claim 1, wherein the first nucleophilic material is a first multi-arm nucleophilic PEG.

3. The sealant according to claim 2, wherein the first multi-arm nucleophilic PEG is bioabsorbable in vivo.

4. The sealant according to claim 2, wherein the first multi-arm nucleophilic PEG is a PEG-amine.

5. The sealant according to claim 4, wherein the PEG-amine is 4-arm PEG-NH2-HCl.

6. The sealant according to claim 2, wherein the second nucleophilic material is a second multi-arm nucleophilic PEG.

7. The sealant according to claim 6, wherein the second multi-arm nucleophilic PEG is bioabsorbable in vivo.

8. The sealant according to claim 6, wherein the second multi-arm nucleophilic PEG of the doping component is a 6-arm and / or 8-arm PEG-NH2-HCl.

9. The sealant according to claim 1, wherein the first electrophilic material is a first multi-arm electrophile PEG.

10. The sealant according to claim 9, wherein the first multi-arm electrophilic PEG is bioabsorbable in vivo.

11. The sealant according to claim 9, wherein the first multi-arm electrophile PEG is a PEG-NHS ester.

12. The sealant according to claim 11, wherein the PEG-NHS ester is 4-arm PEG-succinimidyl glutarate (SG).

13. The sealant according to claim 9, wherein the second electrophilic material is a second multi-arm electrophilic PEG.

14. The sealant according to claim 13, wherein the second multi-arm electrophilic PEG is bioabsorbable in vivo.

15. The sealant according to claim 13, wherein the second multi-arm electrophile PEG of the doping component is a 6-arm and / or 8-arm PEG-SG.

16. The sealant according to claim 1, wherein the electrophilic component, the nucleophilic component, and / or the doping component further comprises an antioxidant.

17. The sealant according to claim 1, wherein the electrophilic component, the nucleophilic component, and / or the doping component further comprises a coloring agent.

18. The sealant according to claim 1, further comprising a contrast agent.

19. It is a system, The sealant according to claim 1, A system comprising: an applicator having an applicator body configured to hold a first component containing a first electrophile material in a first spatial volume and a second component containing a first nucleophile material in a second spatial volume separate from the first spatial volume, wherein the applicator is configured to enable the combination of the first component and the second component.

20. A kit for preparing sealant, A first storage container containing a dried first nucleophilic polymer powder, A second storage container containing an alkaline buffer for preparing a first nucleophilic polymer composition, A third storage container containing a dried first electrophilic polymer powder, A fourth storage container containing an acidic buffer for preparing a first electrophilic polymer composition, At least one additional container, A storage container containing a dried second nucleophilic polymer powder, and / or A storage container containing a dried second electrophilic polymer powder, comprising at least one additional container, A kit in which the sealant is formed after combining the first nucleophilic polymer composition and the first electrophilic polymer composition.

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