WO2018150186A1 - Matériaux adhésifs aux tissus - Google Patents
Matériaux adhésifs aux tissus Download PDFInfo
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- WO2018150186A1 WO2018150186A1 PCT/GB2018/050408 GB2018050408W WO2018150186A1 WO 2018150186 A1 WO2018150186 A1 WO 2018150186A1 GB 2018050408 W GB2018050408 W GB 2018050408W WO 2018150186 A1 WO2018150186 A1 WO 2018150186A1
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- Prior art keywords
- polymer
- tissue
- freeze
- adhesive
- dried
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960002607 sulconazole Drugs 0.000 description 1
- SKIVFJLNDNKQPD-UHFFFAOYSA-N sulfacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 SKIVFJLNDNKQPD-UHFFFAOYSA-N 0.000 description 1
- 229960002673 sulfacetamide Drugs 0.000 description 1
- 239000003894 surgical glue Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 229910000811 surgical stainless steel Inorganic materials 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 1
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- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- CRDAMVZIKSXKFV-UHFFFAOYSA-N trans-Farnesol Natural products CC(C)=CCCC(C)=CCCC(C)=CCO CRDAMVZIKSXKFV-UHFFFAOYSA-N 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229960003500 triclosan Drugs 0.000 description 1
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 description 1
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- GAAKLDANOSASAM-UHFFFAOYSA-N undec-10-enoic acid;zinc Chemical compound [Zn].OC(=O)CCCCCCCCC=C GAAKLDANOSASAM-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C09J139/00—Adhesives based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Adhesives based on derivatives of such polymers
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Definitions
- This invention relates to a tissue-adhesive polymer intended for application to internal and external surfaces of the body for therapeutic purposes.
- the present invention relates to a tissue-adhesive polymer comprising vinyl
- pyrrolidone-derived units and acrylate-derived units containing at least one ester group and a tissue-reactive group are examples of pyrrolidone-derived units and acrylate-derived units containing at least one ester group and a tissue-reactive group.
- the invention also relates to a process for the preparation of the polymer, more specifically a process for the preparation of the polymer as a freeze-dried product.
- sheets comprising a solvent-cast or freeze-dried tissue- contacting layer comprising the polymer, liquid formulations comprising the polymer that form tissue-adhesive hydrogels upon reaction with crosslinkable reactants, and implantable medical devices coated with the polymer.
- the invention further relates to a novel monomer.
- the invention further relates to freeze-dried tissue-adhesive polymers and polymer compositions comprising a polymer that contains tissue-reactive functional groups. It relates to articles comprising said freeze-dried polymer or polymer composition, particularly articles comprising sheets of said freeze-dried polymer composition coated with non-adhesive polymer films, and to implantable medical devices coated with the freeze-dried polymer composition and methods for their manufacture.
- adhesive materials may be in the form of sheets, films, gels or liquids and may be either self-adhesive (by either chemical or physical means) or require energy (eg light) to promote chemical reaction.
- Tissue-adhesive polymers of N-vinyl pyrrolidone, acrylic acid and acrylic acid-N- hydroxysuccinimide (NHS) ester are known. These materials, when formulated into sheets, offer strong adhesive performance via a combination of electrostatic forces (eg hydrogen bonding and/or van der Waals forces) and covalent bonding (reaction of NHS-ester functionality with nucleophilic groups present on proteinaceous surfaces to form covalent bonds).
- WO2004/087227 discloses a polymer of vinyl pyrrolidone and acrylic acid NHS ester.
- WO2006/013337 discloses a film comprising a preformed and crosslinked matrix that is formed from one or more polymers, at least one polymer being a terpolymer of vinyl pyrrolidone, acrylic acid and acrylic acid NHS ester.
- the film adheres to tissue and is described for use as the tissue-contacting layer of a tissue-adhesive sheet or a coating on an implantable medical device.
- WO2007/088402 discloses a multilamellar tissue-adhesive sheet with a
- tissue-contacting layer that comprises a terpolymer of vinyl pyrrolidone, acrylic acid and acrylic acid NHS ester.
- the in vivo resorption period of polymers of N-vinyl pyrrolidone, acrylic acid and acrylic acid NHS ester may be 6 months or more. In certain applications it is desirable to use a tissue-adhesive polymer that takes a shorter time to be completely resorbed in vivo.
- tissue-adhesive polymer comprising: a) vinyl pyrrolidone-derived units of general formula (I):
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently represent H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy or halo; and acrylate-derived units of general formula (II):
- R 7 is -H or -CH3
- X is a tissue-reactive group.
- R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is substituted C1-6 alkyl or substituted C1-6 alkoxy
- substituents that may be present include C1-6 alkyl, -OH, -OR 9 , -COOH
- R 9 is C1-6 alkyl.
- the polymer is completely resorbed in vivo within about 1 -12 months depending on composition and molecular weight.
- complete resorption we mean that the polymer is broken down by hydrolysis, enzymatic action or otherwise, in vivo, and absorbed, metabolised or otherwise removed to the extent that the polymer is no longer detectable by eye or histological analysis.
- wound healing restores the normal morphology and therefore, over time, the cellular environment around the site of the polymer becomes clinically unremarkable.
- Resorption may be complete within about 9 months. Resorption may be complete within about 6 months. Resorption may be complete within about 4.5 months.
- Resorption may take at least one month to complete, at least 2 months to complete or at least 3 months to complete.
- the polymer may take between about 1 and 12 months to be resorbed, between about 2 and 9 months to be resorbed, between about 3 and 6 months to be resorbed, or between about 3 and 4.5 months to be resorbed in vivo.
- the polymer of the present invention comprises vinyl pyrrolidone-derived units of general formula (I) (also referred herein as unit (I)). These units may be
- N-vinyl-2-pyrrolidone ie an N- vinyl-2-pyrrolidone monomer of general formula (III):
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently represent H, optionally substituted C-1 -6 alkyl, optionally substituted C1 -6 alkoxy or halo.
- the polymer may be prepared by including the N-vinyl-2-pyrrolidone monomer of general formula (III) in the polymerisation reaction mixture in an amount of about 50 to 97.5 mol %, in an amount of about 70 to 95 mol %, in an amount of about 80 to 95 mol % or in an amount of about 85 to 90 mol %.
- the polymer may be prepared by including the N-vinyl-2-pyrrolidone monomer of general formula (III) in the
- mol % is the mole fraction for the monomeric component in question, in the above case the N-vinyl-2-pyrrolidone of general formula (III), multiplied by 100 (ie the number of moles of that monomeric component divided by the total number of moles of monomer in the reaction mixture, multiplied by 100).
- the polymer comprises a vinyl pyrrolidone-derived unit of general formula (I) wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently represent H, in which case the starting monomer is N-vinyl-2-pyrrolidone (NVP).
- NDP N-vinyl-2-pyrrolidone
- Polyvinyl pyrrolidone is water-soluble and therefore it is believed that the
- vinyl pyrrolidone-derived units (I) increases the water solubility of the polymer, its overall solubility depending on the proportion of those units in the polymer, the nature of the R 1 , R 2 , R 3 , R 4 , R 5 and R 6 substituents and the solubility of the other units in the polymer.
- the vinyl pyrrolidone-derived units also provide the polymer with its initial contact adhesion or "tack" by forming hydrogen bonds and van der Waals interactions between its amide residues and the tissue surface.
- the polymer of the present invention also comprises an acrylate-derived unit of general formula (II) (also referred herein as unit (II)).
- Unit (II) may be incorporated into the polymer by polymerisation of the appropriate acrylate monomer (IV): wherein
- R 7 is -H or -CH3
- X is a tissue-reactive group.
- the polymer of the invention will generally comprise a polyolefin-type chain, referred to herein as the polymer "backbone” with pendant groups determined by the particular monomers (III) and (IV) that are used.
- tissue-reactive functional group we refer to groups that are chemically reactive towards the tissue to which the polymer is, in use, applied, or which exhibit increased reactivity to tissue.
- tissue-reactive functional groups on unit (II) confer adhesive properties to the polymer by reacting with nucleophilic groups on proteinaceous surfaces, for example amines on a tissue surface, and forming covalent bonds.
- Tissue-reactive functional groups that may be of utility in the present invention are any functional groups capable of reaction (under the conditions prevalent when the polymer is applied to tissue, ie in an aqueous environment and without the application of significant amounts of heat or other external energy) with functional groups present at the surface of the tissue to form covalent bonds.
- the functional groups present at the surface of the tissue include thiol and amine groups, and tissue-reactive functional groups therefore include groups reactive to thiol and/or amine groups.
- Examples are: imido ester, p-nitrophenyl carbonate, N-hydroxysuccinimide (NHS) ester, epoxide, isocyanate, acrylate, vinyl sulfone, orthopyridyl-disulfide, maleimide, aldehyde, and
- R 8 may be, for example, imidyl, p-nitrophenyl or N-hydroxysuccinimidyl.
- monomer (IV) is mono(2-acryloyloxyethyl) succinate-R 8 (referred to herein as MAES-R 8 ):
- monomer (IV) is 2- carboxyethyl acrylate-R 8 (referred to herein as CEA-R 8 ):
- monomer (IV) is mono(2-methacryloyloxyethyl) succinate-R 8 (referred to herein as MMES-R 8 ):
- the carboxyl groups may be converted to
- NHS N-hydroxysuccinimide esters.
- the term NHS is intended to encompass not only N-hydroxysuccinimide itself, but also derivatives thereof in which the succinimidyl ring is substituted.
- An example of such a derivative is
- R 8 is NHS
- the acrylate- derived unit (II) is:
- NHS-functionalised MAES is a novel compound and therefore, in a further aspect of the invention, there is provided mono(2-acryloyloxyethyl)succinate N-hydroxysuccinimide ester.
- MAES-NHS may be prepared by the derivatisation of the carboxylic acid functionality of MAES with NHS utilising dicyclohexylcarbodiimide as a coupling agent in a suitable dry solvent, using techniques known to those skilled in the art. It follows that polymers are novel, which polymers comprise the acrylate-derived unit:
- N-hydroxysuccinimide acrylate ester monomers mono-(2- methacryloyloxyl)-ethyl succinate N-hydroxysuccinimide ester and 2-carboxyethyl acrylate N-hydroxysuccinimide ester, are described. These monomers are used in the manufacture of synthetic polymeric cell culture surfaces suitable for the culture of difficult-to-culture cells, including undifferentiated embryonic stem cells.
- US201 1 /275154 also describes acrylate monomers with an N-hydroxysuccinimide moiety for use in the preparation of a synthetic cell culture surface to support the growth of cells including undifferentiated embryonic stem cells.
- MAES has been incorporated in a polymer.
- MAES has been incorporated in a tissue- adhesive polymer for medical applications such as haemostasis, wound healing, joining, sealing and reinforcing tissue, or the delivery of therapeutic agents.
- a tissue- adhesive polymer for medical applications such as haemostasis, wound healing, joining, sealing and reinforcing tissue, or the delivery of therapeutic agents.
- Monomer (IV) is used to incorporate degradable, adhesive side-chains into the polymer.
- MAES or MMES two ester groups are included in each side chain.
- CEA or CMEA one ester group is included in each side chain. These ester groups facilitate degradation of the polymer and therefore the use of MAES or MMES is generally preferred as they contain two degradable ester linkages.
- monomer (IV) is MAES-R 8 .
- the polymer may be prepared by including monomer (IV) in the polymerisation reaction mixture in an amount of about 2.5 to 50 mol %, in an amount of about 5 to 30 mol %, in an amount of about 5 to 20 mol % or in an amount of about 10 to 15 mol %.
- the polymer may be prepared by including monomer (IV) in the
- the tissue-adhesive polymer may also comprise an ester-containing unit of general formula (V):
- Ester-containing units of general formula (V) may be incorporated into the polymer backbone by adding a cyclic ketene acetal that undergoes free radical ring-opening during polymerisation.
- 2-Methylene-1 ,3-dioxepane (MDO) is a cyclic ketene acetal that is particularly suitable, introducing ester-containing units of the following formula into the polymer backbone:
- MDO introduces additional degradable ester groups within the polymer backbone and can therefore be added to increase the speed at which the polymer is resorbed in vivo.
- a cyclic ketene acetal may be included in the polymerisation reaction mixture in an amount of up to about 20 mol %, up to about 15 mol %, or up to about 10 mol %.
- a cyclic ketene acetal may be included in the polymerisation reaction mixture in an amount of about 0 to about 20 mol %, in an amount of about 5 to 20 mol %, in an amount of about 5 to 15 mol % or in an amount of about 10 to 15 mol %.
- the tissue-adhesive polymer may also comprise acrylic acid- derived units of general formula
- acrylic acid which may be incorporated by including acrylic acid in the polymerisation mixture in an amount up to about 20 mol %.
- acrylic acid provides the polymer with additional initial adhesive tack due to van der Waals forces and/or hydrogen bonding between the available carboxylic acid moiety on the acrylic acid and the surface of the tissue.
- the inclusion of acrylic acid reduces the solubility of the polymer in water and may cause or at least contribute to inflammation on the tissue surface with which the polymer is in contact.
- the decision whether to include acrylic acid, and in what amount will depend on the balance of properties required for the intended application of the polymer.
- Acrylic acid may be included in the polymerisation reaction mixture in an amount of up to about 20 mol %, up to about 15 mol %, or up to about 10 mol %.
- Acrylic acid may be included in the polymerisation reaction mixture in an amount of about 0 to about 20 mol %, in an amount of about 5 to 20 mol %, in an amount of about 5 to 15 mol % or in an amount of about 10 to 15 mol %.
- the monomers are polymerised in the presence of a crosslinker to form a crosslinked polymer.
- Crosslinking improves the cohesive strength of the polymer and may therefore improve its performance, yet the polymer remains biodegradable because of its degradable ester groups.
- the crosslinker itself contains degradable ester groups.
- the crosslinker is a PEG-diacrylate of general formula (VII):
- n 1 -1000 in which case the polymer will contain crosslinking units of general formula VIII:
- n 1 -1000
- n may be 1 -100. In some preferred embodiments, n may be 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10. For instance, n may be 3.
- a crosslinker may be included in the polymerisation reaction mixture in an amount of about 0 to 5 mol %, about 1 to 4 mol %, or about 2 to 3 mol %. For instance, a crosslinker may be included in an amount of about 2.5 mol %.
- PEG-diacrylate crosslinker of general formula (VII) incorporates polyethylene glycol (PEG) moieties into the polymer.
- PEG polyethylene glycol
- the tissue-adhesive polymers of the invention are not prepared with a PEG-diacrylate crosslinker. In some embodiments, the tissue-adhesive polymers of the invention do not contain PEG moieties.
- a method for the manufacture of a polymer comprising vinyl pyrrolidone-derived units of general formula (I) and acrylate-derived units of general formula (II), which method comprises polymerisation of one or more vinyl pyrrolidone monomers of general formula (III) and one or more acrylate monomers of general formula (IV).
- Solution free-radical polymerisation is a suitable method of making the polymer of the present invention: monomers (III) and (IV) may be polymerised in a suitable solvent in the presence of a free radical initiator using techniques known to those skilled in the art. Thus, polymerisation may be carried out in a solvent.
- the optional additional monomers eg MDO, acrylic acid and/or crosslinker
- Any solvent that solubilises all the reagents and the final polymer may be suitable.
- the preferred solvent is DMSO.
- the molecular weight of the polymer and the distribution of monomer units can be adjusted by altering the ratio of monomers to initiator, feed rates, reaction
- distribution of units we refer to the pattern of monomer units along the backbone (ie main chain) of the polymer.
- the distribution is “even” if the monomer units occur in a regular, substantially alternating pattern, whilst being distributed uniformly throughout the length of the polymer.
- the distribution may be described as “blocky” if significant numbers of the same monomer unit occur together, ie as blocks.
- a polymer of the invention containing about 90 mol % vinyl pyrrolidone- derived units of general formula (I) and about 10 mol % acrylate-derived units of general formula (II) will have an "even” distribution if the local ratio of 9:1 is substantially the same throughout the polymer.
- the distribution of units (I) and (II) in the polymer may be altered by adjusting the feed time of monomers (III) and (IV) in the polymerisation reactive mixture.
- a more even distribution may be achieved by slowing down the rate of addition (increasing the feed time, ie a "starve-fed” polymerisation).
- Starve-fed polymerisation allows the monomers in the vessel to react before more are added, and is a well-known technique for controlling the distribution of monomers with different activities in a polymer.
- a feed time of at least 6 hours may be required to generate a polymer with a relatively even distribution of units (I) and (II) using the monomers NVP and MAES- NHS.
- Polymers in which units (I) and (II) are more evenly dispersed have been shown to have significantly better adhesive performance than corresponding blocky polymers prepared using shorter feed times.
- reaction solvent is DMSO
- a suitable means of recovering the polymer from the reaction mixture is, surprisingly, freeze-drying (lyophilisation).
- Standard methods of recovery known in the art eg precipitation or vacuum evaporation
- the polymer is soluble in many of the solvents that are normally used for recovery (eg water, hexane or diethyl ether), particularly when the reaction solvent is also present.
- solvents that are normally used for recovery
- polyvinyl pyrrolidone when precipitation of a polymer made from N-vinyl pyrrolidone and MAES-NHS monomers is attempted, it is typical to observe that polyvinyl pyrrolidone)-rich and/or low molecular weight fractions are solubilised, leaving poly(MAES-NHS)-rich and/or high molecular weight fractions behind.
- Lyophilisation of the reaction mixture provides a better method of recovering all fractions of the polymer as a solid.
- the utility of freeze-drying was unexpected both for isolation of the tissue-adhesive polymer and subsequent processing.
- Freeze-drying was not considered in relation to the tissue-adhesive polymers previously described by the inventors (such as the terpolymer of vinyl pyrrolidone, acrylic acid and acrylic acid NHS ester), because those polymers are not soluble in water and it is usual to freeze-dry from an aqueous solution.
- the exemplified compositions described in WO2004/087227 contain powdered albumin (porcine or human serum albumin) and a powdered tissue- adhesive polymer.
- the albumin is obtained in powder form by freeze-drying a buffered aqueous solution of the protein.
- the tissue-adhesive polymer which is insoluble in water, is manufactured using precipitation and then ground to a powder.
- the freeze-dried albumin and precipitated tissue-adhesive polymer powders are mixed and compressed into a tissue adhesive sheet. Freeze-drying was only considered for the water-soluble component.
- tissue-adhesive polymers previously described by the inventors can render them soluble in water (eg increasing the vinyl pyrrolidone content).
- the tissue-adhesive polymer according to the first aspect of the present invention is advantageously soluble in water.
- tissue-reactive functional groups are susceptible to hydrolysis and therefore tissue-adhesive polymers would degrade on contact with or when dissolved in water, certainly within the time span required for freeze-drying.
- WO2013/053753 discloses a haemostatic composition comprising a biocompatible polymer in particulate form and a crosslinker comprising tissue-reactive groups (such as NHS-ester groups).
- the crosslinker is a hydrophilic polymeric component such as PEG-NHS.
- WO2013/053753 suggests that it is important that the composition is manufactured such that the reactive groups of the hydrophilic crosslinker are retained and are able to react once the composition is applied to a wound. To achieve that,
- the crosslinker may be (a) processed in an aqueous medium at a very low pH; (b) melted and then sprayed or printed onto the surface of the matrix; (c) a dry form of the hydrophilic crosslinker may be sprinkled onto the matrix; or (d) a solution of the hydrophilic crosslinker in an inert organic solvent (eg dry ethanol, dry acetone or dry dichloromethane) may be used to apply the crosslinker to the matrix.
- an inert organic solvent eg dry ethanol, dry acetone or dry dichloromethane
- WO201 1/079336 also discloses a haemostatic composition comprising crosslinkable components that contain tissue-adhesive functional groups. It refers to a composite sponge comprising a porous matrix of a biomaterial, such as collagen, and a first and second crosslinkable component.
- the first crosslinkable component is a multi- nucleophilic alkylene oxide and the second crosslinkable component a multi- electrophilic polyalkylene oxide.
- the Examples include collagen sponges that are treated with an acidic solution (pH 3.0, hydrochloric acid) of
- Both WO2013/053753 and WO201 1 /079336 disclose the use of an acid (acetic acid or hydrochloric acid) to lower the pH and inhibit hydrolysis of the tissue-reactive functional groups, which are NHS-ester groups.
- an acid acetic acid or hydrochloric acid
- this is undesirable because a large proportion of the acid will be extracted under vacuum during the freeze-drying process, meaning that some hydrolysis is inevitable. Also, any acid remaining after processing will result in a product that has a residual low pH, which will reduce crosslinking reactivity.
- WO2002/034304 describes a freeze-dried polymeric matrix in the form of a sheet, patch or film suitable for application to moist surfaces of the body.
- the matrix comprises a naturally occurring or synthetic polymerisable and/or crosslinkable material that supports wound healing (eg albumin or carboxymethyl cellulose
- CMC CMC
- a synthetic polymer having bioadhesive properties eg
- polyvinylpyrrolidone PVP
- PVP polyvinylpyrrolidone
- Aqueous solutions of the polymerisable and/or crosslinkable material and the synthetic polymer having bioadhesive properties are cast in layers and heated to partially or fully crosslink the materials and evaporate the water. The crosslinked layer or laminate is then freeze- dried. It is notable that the synthetic polymer having bioadhesive properties does not contain tissue-reactive functional groups capable of reaction with functional groups present at the surface of the tissue to form covalent bonds.
- DMSO is not commonly used as a solvent for freeze-drying due to its low vapour pressure and high boiling point (189°C).
- a dry, non-aqueous solvent such as DMSO.
- tissue- adhesive polymers to be freeze-dried without degradation of the tissue-reactive functional groups. Care must be taken to avoid water contamination throughout all stages of the process to prevent hydrolysis of the NHS-ester chemistry. This may be achieved by drying the DMSO using 3A molecular sieves and minimising the time that frozen DMSO-sheets are open to air.
- the solid freeze-dried polymer may be milled to form a powder and the powder may be delivered in that form, producing a crosslinked hydrogel upon hydration or contact with moist tissue surfaces. It may be delivered as a single component or may be mixed with other ingredients such as reaction promotors (eg buffer salts) or secondary reactive species (eg synthetic or natural species that contain amine or thiol moieties, for instance albumin), all in powder form. Alternatively, the powder (or powder mixture) may be compressed to form a sheet (or the tissue-contacting layer of a multilayer sheet) or a three-dimensional device (eg plug or pellet). The powder may also be used to coat a sheet or medical device.
- reaction promotors eg buffer salts
- secondary reactive species eg synthetic or natural species that contain amine or thiol moieties, for instance albumin
- the powder (or powder mixture) may be compressed to form a sheet (or the tissue-contacting layer of a multilayer sheet) or a three-dimensional device (eg plug or pellet
- the powdered, freeze-dried polymer is typically processed further.
- the polymer may be delivered in liquid format by dissolving the powdered, freeze- dried polymer in aqueous solution.
- the polymer solution may be mixed with a second aqueous solution containing nucleophilic materials at the surface of the tissue or shortly before application, to form a tissue-adhesive crosslinked hydrogel.
- the powdered, freeze-dried polymer may be dissolved in a solvent and cast as a film or a layer in a sheet having one or more layers.
- the powdered, freeze-dried polymer may be dissolved in a dry, non-aqueous solvent and freeze-dried to form a freeze-dried matrix in the form or a sheet or other article.
- the freeze-dried matrix has a high porosity and high surface area for fluid
- tissue-adhesive polymer of the invention may be suitable, in any of these formats, for application to both internal and external tissue surfaces of the body, ie it may be applied topically to the exterior of the body (ie to the skin) or to internal tissue surfaces such as surfaces of internal organs during surgical procedures.
- the solid polymer may be milled to form a powder and may be delivered in that form, as a single component or in admixture with other particulate components (eg other materials having tissue-reactive functional groups and buffer materials).
- other particulate components eg other materials having tissue-reactive functional groups and buffer materials.
- delivering the polymer as a powder in particular the fact that a powder formulation adheres to the tissue surface and does not spread unduly. On contact with the tissue surface the formulation becomes hydrated, thereby causing reaction between the tissue-reactive functional groups and the underlying tissue surface. Such reactions between the tissue-reactive functional groups and the underlying tissue result in high adhesion between the formulation and the tissue surface. Reaction may also take place between the tissue-reactive functional groups and the other components of the formulation to form a strong, flexible and
- tissue-adherent gel absorbs physiological fluids (as a consequence of application onto exuding tissue surfaces), and any additional solutions used to hydrate the formulation following application (such fluids can be commonly used solutions used in surgical irrigation), becoming gelatinous and adherent to the tissue surfaces, and thereby providing an adhesive sealant, haemostatic and pneumostatic function.
- a powdered formulation is essentially inactive until hydrated by contact with the tissue surface, so the shelf-life may be considerable.
- the polymer may also be delivered in powder form by compressing the powder into sheets, using a compressed powder layer in a multilayer sheet, or by compressing the powder to form another three-dimensional article, such as a plug.
- the aqueous solubility of the polymer according to the first aspect of the invention allows the polymer to be delivered in a liquid format, for instance in a syringe or spray.
- a tissue-adhesive crosslinked hydrogel may be formed in situ by preparing an aqueous solution of the polymer (eg dissolving the powdered freeze-dried product in water) and mixing that solution containing the polymer with a second aqueous solution containing nucleophilic materials (ie materials having nucleophilic groups for instance amines or thiols).
- the solutions may be delivered separately and mixed in situ or they may be mixed shortly before delivery.
- the functional lifespan of the tissue-adhesive solution is typically up to 6 hours due to hydrolysis of the NHS-ester groups.
- the rate of hydrolysis may be slowed by decreasing the pH to 4 or below. However, this also inhibits reactivity towards the nucleophilic component in the second solution (eg amine) and proteinaceous tissue surfaces.
- the second solution containing nucleophilic materials may be a solution of synthetic or natural material. Suitable examples include poly(ethylene imine (PEI), 2-armed or 4-armed poly(ethylene glycol)-amine, natural or recombinant albumin, trypsine, or poly(ethylene glycol)-thiol.
- a chromophore may be included in one or more of the solutions to aid visualisation.
- a spray may provide a useful format for delivering either the separate solutions or a pre-mixed solution.
- Liquid formulations may be applied to the surface of a tissue at a surgical site via open or minimally invasive surgical techniques.
- the crosslinked hydrogel product may be used, for example, to adhere tissues, seal (eg achieve haemo or pneumostatsis), join or occlude tissues, or to deliver an active to a target tissue.
- a liquid composition for application to the surface of a tissue comprising a tissue-adhesive polymer, which polymer comprises vinyl pyrrolidone-derived units of general formula (I):
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently represent H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy or halo.
- R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is substituted Ci-e alkyl or substituted Ci-e alkoxy
- substituents that may be present include C1-6 alkyl, -OH, -OR 9 , -COOH
- tissue-adhesive polymer of the invention may be dissolved in an appropriate solvent in order to be cast as a film or as a layer in a sheet having one or more layers.
- the polymer is obtained as a freeze-dried product, powdered, dissolved in solvent and cast as a single-layered film or sheet.
- the resulting film or sheet may be perforated.
- a multilayer sheet can be prepared, for example by solvent-casting one or more layers of the tissue-adhesive polymer of the claimed invention with layers of one or more other synthetic or natural polymers.
- the layers may alternate or may not.
- the layers of one or more other synthetic or natural polymers may be structural layers that may comprise a non-adhesive polymer.
- tissue-adhesive sheet comprising a structural layer or laminate comprising a non-adhesive polymer, and a tissue- adhesive layer comprising a tissue-adhesive polymer, which tissue-adhesive polymer comprises: a) vinyl pyrrolidone-derived units of general formula (I)
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently represent H, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy or halo; and acrylate-derived units of general formula (II)
- R 7 is -H or -CH3
- X is a tissue-reactive group.
- R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is substituted C1-6 alkyl or substituted C1-6 alkoxy
- substituents that may be present include C1-6 alkyl, -OH, -OR 9 , -COOH
- R 9 is C1-6 alkyl.
- the individual layers may be cast sequentially from volatile solvent on top of each other.
- Non-adhesive polymers that may be used in the structural layer or laminate are preferably degradable polymers and may be synthetic or naturally-occurring materials.
- Suitable synthetic non-adhesive polymers include biodegradable aliphatic polyesters, for instance poly(glycolide), poly(L-lactide), poly(D-lactide), poly(DL- lactide), poly(caprolactone) and copolymers thereof in any ratio of monomers.
- the structural layer or laminate comprises poly(DL- lactide-co-glycolide) (50/50 molar ratio) (PLGA) or poly(L-lactide-co-caprolactone) (70/30 molar ratio) (PLC).
- Naturally-occurring materials that may be suitable for use in the structural layer or laminate are collagen and chitosan.
- the function of the structural layer or laminate may be to provide a non-adhesive backing and/or to increase the strength of the sheet.
- a tissue-adhesive sheet having a non-adhesive coating will adhere only to the target tissue and not to surrounding tissues (eg the pleural or peritoneal wall). Such a non-adhesive coating will typically have a thickness of about 4-50 ⁇ .
- the sheet may also incorporate a surface marking comprising a visible chromophore, for example FD&C Blue No 1 or
- the sheet may have the polymer of the present invention on one or both surfaces (ie be single- or double-sided).
- a single- or double-sided sheet intended to seal/join two opposing tissue surfaces may be perforated to allow tissue- ingrowth.
- the perforations may be square or circular holes.
- the dimensions of the perforations may be, but are not limited to, a width or diameter of about 1 to 10 mm.
- sheet is meant an article with a thickness that is considerably less than its other dimensions.
- the sheet may have an overall thickness of about 0.01 to 1 mm, typically 25-50 ⁇ .
- the sheet may be produced with, or subsequently cut to, dimensions from a few square millimetres to hundreds of square centimetres.
- the tissue-adhesive polymer according to the first aspect of the invention may be dissolved in a dry, non-aqueous solvent and freeze-dried to form sheets or other articles.
- the polymer is prepared in DMSO, isolated by freeze-drying and powdered. Then the powdered freeze-dried product may be re-dissolved in a dry, non-aqueous solvent, with or without other components, poured into a mould and freeze-dried again to form the final freeze- dried polymer composition.
- the non-aqueous solvent is capable of fully dissolving the tissue-adhesive polymer.
- the solution must be able to be frozen and the solvent must be capable of being removed by sublimation in the freeze-drying (lyophilisation) process.
- the non-aqueous solvent is dimethyl sulfoxide (DMSO).
- the tissue-adhesive polymer of the invention may be freeze-dried in combination with one or more additional components, included for example to alter the structure, flexibility and strength, colour or adhesive properties, or to introduce therapeutic agents, such as anti-inflammatories, anti-infective agents or clotting agents.
- additional components included for example to alter the structure, flexibility and strength, colour or adhesive properties, or to introduce therapeutic agents, such as anti-inflammatories, anti-infective agents or clotting agents.
- the tissue-adhesive polymer may be freeze-dried in combination with a structural component such as poly(lactide-co-glycolide) (PLGA) or other biodegradable aliphatic polyester.
- PLGA poly(lactide-co-glycolide)
- the additional component(s) must also be soluble in a dry non-aqueous solvent.
- composition comprising a tissue-adhesive polymer according to the first aspect of the invention.
- the polymer composition may substantially comprise the tissue-adhesive polymer of the present invention.
- the polymer composition may consist entirely or substantially of the tissue-adhesive polymer, the polymer comprising more than 80%, more than 90%, more than 95% or more than 99% by weight of the polymer composition.
- the tissue-adhesive polymer of the invention may comprise at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least about 80% by weight of the polymer composition.
- the tissue-adhesive polymer may comprise less than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or less than about 10% by weight of the polymer composition.
- the tissue-adhesive polymer may comprise between about 10% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60% by weight of the polymer composition.
- tissue-adhesive polymer may comprise about 50% by weight of the polymer composition.
- the freeze-dried polymer composition may consist solely of the tissue-adhesive polymer or may be a homogenous mixture of the tissue-adhesive polymer with one or more additional components.
- a visible light-absorbing chromophore may be added to the solution of polymer in non-aqueous solvent before freeze- drying to give the freeze-dried polymer composition a distinguishing colour.
- chromophores examples include Methylene Blue (methylthioninium chloride) and FD&C Blue No 1 .
- Additional components may be added to alter the structure, flexibility or strength of the freeze-dried composition, or to alter its structural integrity or gelation
- the tissue-adhesive polymer may be freeze-dried in combination with a structural component, for example poly(lactide) or poly(lactide-co-glycolide) (PLGA), in order to increase the structural integrity of the freeze-dried product so that it retains an open structure upon hydration, rather than forming a continuous gel, and acts more like a scaffold.
- a structural component for example poly(lactide) or poly(lactide-co-glycolide) (PLGA)
- PLGA poly(lactide-co-glycolide)
- tissue-adhesive polymer and the structural polymer may be a homogenous single freeze-dried layer or two or more freeze-dried layers of the separate polymers conjoined during manufacture.
- the structural component may comprise more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, or more than about 80 % by weight of the polymer composition.
- the structural component may comprise less than about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or less than about 10% by weight of the polymer composition.
- the structural component may comprise between about 10% and 90%, between about 20% and 80%, between about 30% and 70%, or between about 40% and 60% by weight of the polymer composition.
- the structural component may comprise about 50% by weight of the polymer composition.
- the product that is created and retained following freeze-drying has a more open structure compared, for example, to a solid homogenous film or sheet comprising the same polymer, and therefore it has a higher porosity and higher surface area for fluid absorption. This generally leads to an improvement in moisture uptake and wettability, and consequently the rate of adhesion between the polymer and the tissue and the haemostatic properties of the polymer may be improved.
- the density and porosity of the freeze-dried polymer composition are determined by the concentration of polymer solids dissolved in solution prior to freeze-drying. A concentrated solution will lead to a stiff, dense matrix with a relatively low porosity. Conversely, a dilute solution will lead to a flexible matrix with a relatively high porosity. Precise control over the physical appearance and characteristics of the freeze-dried polymer composition to suit a particular application is thus possible.
- the freeze-dried polymer composition is also advantageous because it is essentially inactive until hydrated upon and following contact with the tissue surface, so its shelf-life may be considerable, for example more than six months when stored appropriately at room temperature.
- the freeze-dried polymer composition may be described as a "matrix" in view of its more open structure.
- the tissue-adhesive polymer rapidly becomes a gelatinous and sticky hydrogel when it hydrates and reacts with a tissue surface and/or proteinaceous fluids. This is in contrast to the haemostatic collagen matrices described in the prior art which are described as “sponges” or “pads” and act as scaffolds, retaining the open structure of the dried matrix upon hydration rather than gelling.
- the freeze-dried polymer composition according to the invention may be entirely synthetic, or substantially so, being free or substantially free of materials of human or animal, particularly mammalian, origin, eg wherein such materials account for less than 1 %, more preferably less than 0.5 % or less than 0.1 % of the polymer composition.
- materials of human or animal particularly mammalian, origin, eg wherein such materials account for less than 1 %, more preferably less than 0.5 % or less than 0.1 % of the polymer composition.
- One situation in which a relatively small proportion of material of human or animal origin may be present is where that material takes the form of one or more therapeutically active agents that are included in the formulation and are of such origin.
- the freeze-dried polymer composition does not contain biological material, eg material that occurs naturally in a living being.
- biological materials include collagen, gelatin, albumin, haemoglobin, fibrinogen, fibrin, casein, fibronectin, elastin, keratin, laminin, and polysaccharides such as glycosaminoglycan, starch, cellulose, dextran, hemicellulose, xylan, agarose, alginate and chitosan.
- the freeze-dried polymer composition does not contain cellulose.
- the freeze-dried polymer composition does not contain gelatin.
- the freeze-dried polymer composition does not contain albumin.
- the freeze-dried polymer composition does not contain a modified polysaccharide such as carboxymethyl cellulose (CMC).
- CMC carboxymethyl cellulose
- the freeze-dried polymer composition of the present invention is prepared by freeze- drying the polymer from a dry non-aqueous solution. The process must be undertaken in the absence of water to ensure that the tissue-reactive functional groups are not hydrolysed.
- a freeze-dried polymer composition comprising the tissue- adhesive polymer according to the first aspect of the invention, which method comprises the steps of:
- the dry, non-aqueous solvent is DMSO.
- the freeze-dried polymer composition of the invention may be in the form of a sheet.
- sheet is meant that the freeze-dried polymer composition has a thickness that is considerably less than its other dimensions.
- the freeze-dried sheet may have an overall thickness of about 0.05 to 10 mm, typically 0.5 to 5 mm.
- the sheet may be produced with, or subsequently cut to, dimensions from a few square millimetres to hundreds of square centimetres.
- the freeze-dried polymer composition may take the form of a plug or pellet, which may be used to seal or fill cavities and holes in the body.
- plugs may be formed with any suitable shape, eg generally cylindrical, ellipsoidal or cuboidal.
- Another suitable three-dimensional structure that is envisaged is a cylindrical filament that may be used for securing other devices in place, in the manner of a suture.
- the freeze-dried polymer composition may be formed in a three-dimensional structure by using the appropriately shaped freeze-drying mould or by grinding the freeze-dried product to a powder and compressing to form the required shape. Structures having more complex shapes may also be produced, for example by using shaped moulds.
- Examples include pre-formed connectors, eg for the end-to-end or end-to-side anastomotic apposition and closure of vessels, fasteners such as staples or barbed pins for holding tissues together, or fixing plugs to be fitted, for example, into holes in bone to provide anchorages for mechanical fasteners such as screws or for dental crowns.
- fasteners such as staples or barbed pins for holding tissues together
- fixing plugs to be fitted, for example, into holes in bone to provide anchorages for mechanical fasteners such as screws or for dental crowns.
- the freeze-dried tissue-adhesive polymer composition of the present invention may be used as the tissue-contacting component in a tissue-adhesive article that contains two or more different components.
- a tissue-adhesive article comprising a freeze-dried polymer composition according to the invention.
- the tissue-adhesive article of the invention is a multilamellar sheet having two or more layers.
- the multilamellar sheet includes a layer or laminate comprising a non-adhesive polymer to provide a non-adhesive backing and/or increase the strength of the sheet.
- the non-adhesive material is a synthetic polymer.
- suitable polymers include biodegradable polyesters such as poly(glycolide), poly(L-lactide), poly(D-lactide), poly(DL-lactide), poly(caprolactone) and copolymers thereof in any ratio of monomers.
- the non-adhesive polymer is poly(DL-lactide-co-glycolide) (PLGA) or poly(L-lactide-co-caprolactone) (PLC).
- the non-adhesive polymer may be cast from a solvent to provide a thin, continuous film, or several thin layers may be cast to produce a laminate.
- a surface of a sheet of the freeze-dried polymer composition may be coated with a layer or laminate of non-adhesive polymer.
- a tissue-adhesive sheet having a non- adhesive coating will adhere only to the target tissue (to which the underside of the sheet is applied) and not to surrounding tissues (eg the pleural or peritoneal wall).
- the non-adhesive coating may include a visibly-absorbing chromophore in the form of a logo or marking to enable identification of the non-tissue-contacting surface of the sheet. Examples of suitable chromophores include Methylene Blue and FD&C Blue No 1 .
- the thickness of the non-adhesive coating may be between about 4 ⁇ to ⁇ ⁇ .
- the coating may be a single layer or may be built up of several thin layers, for example to facilitate incorporation of a logo.
- a layer or laminate comprising a non-adhesive polymer may be used to form a structural layer within a multilamellar sheet.
- the multilamellar sheet may consist of a layer or laminate comprising a non-adhesive polymer with a layer of tissue-adhesive freeze-dried polymer composition on each side (ie a double-sided product).
- a double-sided multilamellar sheet or a single-layer sheet of the freeze-dried polymer composition intended to seal/join two opposing tissue surfaces may be perforated to allow tissue-ingrowth.
- the perforations may be square or circular holes. The dimensions of the perforations may be, but are not limited to, a width or diameter of about 1 to 10 mm.
- Multilamellar sheets may also be prepared from alternating layers that comprise tissue-adhesive polymer and non-adhesive polymer.
- the layers comprising tissue- adhesive polymer may all be freeze-dried layers (ie layers of freeze-dried polymer composition comprising a tissue-adhesive polymer containing tissue-reactive functional groups), or may include layers of tissue-adhesive polymer that are cast from solvent.
- the multilamellar sheet has a tissue- contacting layer of the freeze-dried polymer composition according to the invention, and alternative solvent-cast layers comprising non-adhesive polymer and tissue- adhesive polymer.
- tissue-adhesive articles of the present invention include absorbent pads, scaffolds, layers of therapeutic material or biodegradable layers containing therapeutic agents.
- the freeze-dried polymer composition of the invention may provide the tissue-contacting surface of an article that comprises an absorbent pad.
- the freeze-dried polymer composition may be used to coat a substrate.
- the invention may find application in the provision of an adhesive coating to an implantable medical device.
- Tissue-adhesive articles are envisaged in which at least part of the external surface of an implantable medical device is coated with a freeze-dried polymer composition according to the invention.
- a solution containing the tissue-adhesive polymer may be applied to a device, frozen and subsequently lyophilised to generate a freeze-dried coated medical device.
- freeze-dried polymer compositions comprising the tissue-adhesive polymer of the invention
- this method it is possible to freeze-dry both water-insoluble and water-soluble tissue-adhesive polymers without degradation of the tissue-reactive functional groups during the freeze-drying process.
- a method for the preparation of a freeze-dried polymer composition comprising a tissue-adhesive polymer containing tissue-reactive functional groups, which method comprises the steps of: a) preparing a solution comprising a tissue-adhesive polymer containing tissue-reactive functional groups in a dry, non-aqueous solvent; and
- the non-aqueous solvent is capable of fully dissolving the tissue-adhesive polymer.
- the solution must be able to be frozen and the solvent must be capable of being removed by sublimation in the freeze-drying (lyophilisation) process.
- the non-aqueous solvent is dimethyl sulfoxide (DMSO).
- Tissue-adhesive polymers containing tissue-reactive functional groups that can be freeze-dried in accordance with the present invention may also contain vinyl pyrrolidone-derived units.
- vinyl pyrrolidone-derived units is meant repeat units in the polymer that result from the addition of vinyl pyrrolidone or a derivative thereof as a monomer in the polymerisation reaction mixture.
- vinyl pyrrolidone- derived units according to general formula (I):
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently represent H, optionally substituted C-1 -6 alkyl, optionally substituted C1-6 alkoxy or halo. If any of R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is substituted Ci-e alkyl or substituted Ci-e alkoxy, substituents that may be present include C1-6 alkyl, -OH, -OR 9 , -COOH
- R 9 is Ci-e alkyl
- the present invention is believed to be the first disclosure of the freeze-drying of a polymer that contains vinyl-pyrrolidone units using DMSO.
- DMSO dimethyl sulfoxide
- tissue-adhesive polymer of the present invention may be coated onto the external surface of a preformed implantable medical device in order to render the device adhesive.
- implanted devices can become dislodged from the site of application, leading to a failure of the device to perform its intended function and/or other complications (such as inflammation, migration, tissue trauma, pain, post-surgical adhesions, fistula formation, seroma formation, haematoma and recurrence of tissue defect). Serious complications may necessitate further surgical intervention.
- tissue-adhesive polymer of the present invention may be used to modify a wide variety of implantable devices.
- implantable devices One group of implantable devices that are
- graft products intended principally for implantation to join or seal tissues, to reinforce weakened soft tissue and/or to assist the repair of internal wounds.
- the modification of proprietary graft products by application of the polymer significantly improves the placement, positioning and adhesion characteristics with no significant change in the handling or flexibility of the product.
- non-absorbable constructs including but not limited to tantalum, graphene, stainless steel and titanium, in the form of sheets, meshes, clothes, wires and complex shapes such as pacemakers may be coated.
- the surface of the device is smooth, eg a device having a smooth surgical steel exterior, then full encapsulation of the product may be required, in order that the coating remains adequately attached during use.
- the coating may wholly or partially encapsulate parts of the device or may fill interstices in the device thereby aiding physical attachment of the coating.
- the polymer of the present invention may be particularly useful in the coating of mesh-type products, fibrous products, fabrics or the like.
- biomaterial having groups that react with the tissue-reactive functional groups on the polymer, eg the tissue-reactive groups on the acrylate-derived units of general formula (II). Delivery of actives
- the polymer according to the invention may also be used for the delivery of one or more therapeutically active agents to the tissue surface to which the polymer is applied.
- the agent(s) will be slowly released, either by diffusion or as the polymer degrades over time.
- the agent(s) may be incorporated into the polymer during its manufacture, eg by admixture with the monomer(s) and any other ingredients prior to polymerisation. Alternatively, the agent(s) may be attached to a component of the polymer after the polymer is manufactured.
- tissue- adhesive sheet comprising a structural layer of material or laminate that comprises one or more synthetic polymers, and a tissue-contacting layer of material that comprises the tissue-adhesive polymer
- one or more therapeutically active agents may be covalently bonded to the tissue-contacting surface of the tissue-adhesive polymer.
- the sheet may be substantially free of therapeutically active agents.
- therapeutic agent any pharmaceutically active substance or its prodrug, or a salt or solvate of a pharmaceutically active substance.
- substantially free is meant in this context that the polymer does not contain anything that may be considered to be a therapeutic agent, or that it contains something that may be considered to be a therapeutic agent, but in such low amounts that it would have no significant therapeutic effect.
- prodrug is meant any structural derivative of a therapeutic agent which is chemically transformed within the body to exert its pharmacological or therapeutic action. For example, an ester of a therapeutic compound containing a carboxy group may be convertible by hydrolysis in vivo to the active molecule.
- Suitable therapeutic agents include analgesics (eg endorphins), anaesthetics, anti-infective agents (eg gentamicin, bacitracin, aciclovir), antineoplastics (eg doxorubicin, bleomycin), antiinflammatory agents (eg celecoxib), angiogenic agents (eg vascular epithelial growth factor, fibroblast growth factor), anti-angiogenic agents (eg endostatin), growth promoters (eg vascular epithelial growth factor, fibroblast growth factor), haemostatic agents (eg antifibrinolytics, blood coagulation factors, fibrinogen and vitamin K), and therapeutic monoclonal antibodies (eg basiliximab, trastuzumab).
- analgesics eg endorphins
- anaesthetics eg gentamicin, bacitracin, aciclovir
- antineoplastics eg doxorubicin, ble
- anti-cancer agents include doxorubicin.
- anti-infective agents include antibacterial, antifungal, antiviral and anti-parasitic agents.
- anti-infective agent any agent that is capable of acting against infections, by killing infective micro-organisms and/or inhibiting the spread of an infective micro-organism.
- Infective micro-organisms include bacteria, parasites, yeast, moulds, fungi, viruses, prions and viroids.
- Anti-infective agents suitable for use in the present invention may be drugs, such as antibiotics or antifungals.
- antimicrobial or antibacterial compounds examples include triclosan, neomycin, clindamycin, polymyxin, bacitracin, benzoyl peroxide, tetracylines such as
- sulfa drugs such as sulfacetamide, penicillins, cephalosporins such as cephalexin, and quinolones such as lomefloxacin, olfoxacin or trovafloxacin.
- Antiviral compounds that may be incorporated include acyclovir, oseltamivir, and penciclovir.
- Antifungal compounds include farnesol, clotrimazole, ketoconazole, econazole, fluconazole, calcium or zinc undecylenate, undecylenic acid, butenafine hydrochloride, ciclopirox olaimine, miconazole nitrate, nystatin, sulconazole, and terbinafine hydrochloride.
- the anti-infective agent may comprise metal ions that have anti-infective properties, for instance silver, gold or copper ions.
- the polymer of the invention may be used to deliver or pick up cells or cellular components.
- PEG polyethylene glycol PEG-diacrylate polyethylene glycol diacrylate
- Figure 1 illustrates the synthesis of mono(2-acryloyloxyethyl) succinate
- Figure 2 illustrates the synthesis of poly(NVP-co-(MAES-NHS)).
- Figure 3 illustrates the synthesis of poly(NVP-co-(MAES-NHS)-co-MDO).
- Figure 4 illustrates the synthesis of poly(NVP-co-(MAES-NHS)-co-AAc).
- Figure 5 illustrates the synthesis of poly(NVP-co-(MAES-NHS)-co-PEG-diacrylate).
- Figure 6 illustrates the synthesis of poly(NVP-co-(MAES-NHS)-co-MDO-co-PEG- diacrylate).
- Figure 7 illustrates a representative tissue-adhesive sheet (not to scale) as described in Example 4.
- Figure 8 illustrates a representative tissue-adhesive article that is a sheet of lyophilised matrix with a barrier film (not to scale), as per Example 1 1 .
- Figure 9 illustrates a representative tissue-adhesive article that is a sheet of lyophilised matrix with a multilamellar barrier film (not to scale), as per Example 12.
- the polymer was isolated by lyophilisation to remove DMSO yielding a white crystalline solid. This was milled and purified by multiple washes/extractions in diethyl ether and dried under vacuum at 40 Q C for >48 hours. Recovered yield 22 to 24 g (84 to 91 wt %).
- Solution viscosity (Brookfield DV-III, spindle 40, 50 rpm, 25 Q C): 37.4 cP (10 % w/v DMSO), 7.8 cP (1 0 % w/v 1 .0M NH 4 OH).
- Aqueous GPC (Viscotek GPC Max, 50 img/mL in 0.1 M NH 4 OH, mobile phase 0.2M sodium nitrate, flow rate 0.8 imL/min, 2x30cm A6000M Viscotek GPC columns, Rl detection, conventional calibration using PVP standards 1 kDa to 3500kDa): Mn 74,000 PDI 4.0 (0.1 M NH 4 OH).
- FT-IR (Nicolet iS1 0 diamond crystal ATR): IR (neat) 2949, 1 813, 1 783, 1 737, 1 666 cm -1 .
- Viscosity was measured in DMSO (undegraded) and following hydrolysis by NH 4 OH (degraded) for a series of polymers prepared from NVP and MAES-NHS using different feed times: 1 , 1 .5, 3, 6, 8 and 16 hours.
- MAES-NHS will have a disproportionate effect on viscosity due to its bulky structure.
- a more even (and therefore spaced-out) distribution of the bulky MAES-NHS-derived units is thought to reduce entanglement, resulting in a lower viscosity.
- MDO ring-opened ester methylene CH2 multiplet at ⁇ 3.99 ppm is useful for semi-quantification of incorporation.
- MDO undergoes free-radical ring-opening during polymerisation to form additional ester bonds in the polymer backbone.
- the reaction is inefficient and the quantity in the final polymer is much lower than the starting monomer feed. It is suspected that the majority of the MDO either degrades or forms low molecular weight oligomers, which are then extracted from the polymer during the washing stage in preference to being incorporated.
- polymer refers to a polymer according to Table 1 .
- a multilamellar tissue-adhesive sheet is shown schematically in Figure 7.
- the sheet comprises a structural laminate and a tissue-contacting layer.
- the structural laminate has the form of:
- the tissue-contacting layer 4 is conjoined to the third layer 3 and comprises a polymer.
- the second and fourth layers may comprise the same polymer or different polymers.
- the first and third layers 1 ,3 each have a thickness of approximately 4 ⁇ , and the second layer 2 a thickness of approximately 5 ⁇ .
- the tissue-contacting layer 4 has a thickness of approximately 22 ⁇ .
- the sheet is prepared as follows:
- Solution A is 10g PLGA dissolved in 100ml DCM.
- Solution B is 22.5g polymer dissolved in 100ml DCM/MeOH 15/4.
- Solution C is a viscous printing ink comprised of polymer (2.25 g, 22.5 % w/v) and
- FD&C Blue 1 (or Methylene Blue) (0.09 g, 0.9 % w/v) dissolved in RO water (10 mL).
- Solution A is cast onto a release substrate such as silicone-backed release paper using a device referred to as a K bar.
- the film is dried for 30 minutes at
- Solution B is cast onto Layer 1 using a K bar.
- the film is dried for 30 minutes at 20° C/atmospheric pressure. The film is not removedfrom the release substrate.
- Solution C is printed by screen printing onto the surface of Layer 2 to form an alphanumeric trade/visualisation logo.
- Solution A is cast onto Layer 2 using a K bar.
- the film is dried for 30 minutes at 20° C/atmospheric pressure. The film is not removedfrom the release substrate.
- Solution B is cast onto Layer 3 using a K bar.
- the film is dried for 30 minutes at 20 Q C/atmospheric pressure.
- the film is then peeled from the release substrate and dried for 1 12 hrs at 45 Q C at 0.1 mbar. 1 .7 Cutting out
- the product is cut to size using specially designed cutters.
- the dried, cut down product is subjected to heat/pressure to flatten and then is stored in a foil pouch to maintain sterility and exclude moisture.
- the product is then gamma sterilised at 25-40 kGy.
- Example 5 The product is a clear opaque film with the logo visible throughout.
- tissue-adhesive sheets with the following layer thicknesses: Layer 1 :10 ⁇ , Layer 2:5 ⁇ , Layer 3:4 ⁇ , Layer 4:22.5 ⁇ .
- Adhesive performance was assess quantitatively and qualitatively, and the results are shown in Table 4.
- Quantitative adhesive performance A section of the sheet was applied onto a suitable section of freshly excised porcine liver with moderate pressure for 60 seconds. After 5 minutes, the sample was immersed in DPBS for a further 5 minutes. The energy of adhesion was quantified using a Zwick universal testing machine.
- Example tissue adhesive sheets were evaluated as surgical sealants in a range of preclinical models. The sheet was cut to a suitable size to the site of the injury allowing for at least a 1 cm overlap onto non-injured tissue. All samples showed strong adhesion, sealing and haemostatic properties, as shown in Table 5. The samples achieved a "pass" if the leak (blood, air or CSF) was controlled. Neurosurgery - dural closure (pig): 1 .5-2 cm sutured durotomy, CSF leak observed, 1 .5 x 2.5 cm tissue adhesive sheet applied with 60 seconds moderate pressure using a damp swab.
- Lung surgery - pneumostasis (pig): 5 mm punch biopsy to lung, air and blood leak observed, 5 ⁇ 5 cm tissue adhesive sheet applied with 90 seconds moderate pressure using a damp swab.
- Biodegradation and resorption may be determined by the concentration of
- hydrolysable ester groups in the tissue-adhesive polymer and the molecular weight of the degraded fragments are hydrolysable ester groups in the tissue-adhesive polymer and the molecular weight of the degraded fragments.
- Example tissue adhesive sheets were evaluated in a standard rat subcutaneous implant model to evaluate local tissue response and determine the rate of degradation/resorption.
- a 1 1 cm piece of the sheet was implanted into an identifiable subcutaneous pocket on back of a rat, with each rat receiving 4 test articles in separate pockets. Subjects were recovered for 14 and 28 days, and 3, 4.5 and 6 months.
- Macroscopic scores 0 (no resorption/degradation) to 5 (complete visible resorption).
- Table 9 describes examples of the application of tissue-adhesive hydrogel mixtures in a preclinical assessment.
- the formulations were applied by the use of a dual syringe and mixer spray tip to deliver a stream which crosslinked rapidly on contact with the tissue surface and formed an effective seal on both a durotomy and liver injury.
- a freeze dried layer of polymer alone was too fragile to be handled.
- Blending in a structure component, in this case PLGA enabled the preparation of sheets.
- the characteristics of the sheets were defined by the ratio of polymer to PLGA and the overall concentration of the materials in solution.
- tissue-adhesive sheet comprising a freeze-dried sheet and barrier layer
- a two-layer tissue-adhesive sheet is shown schematically in Figure 8.
- the sheet has the form of:
- a solution of PLGA (10 % w/v) in DCM was prepared.
- a small quantity of Methylene Blue was added to provide blue colouration.
- the solution was cast onto a release substrate such as silicone-backed release paper affixed to a glass sheet using a 10 ⁇ gauge K bar. When the solvent evaporated this resulted in a 10 ⁇ dry film of PLGA containing a blue tint. The film was dried for 30 minutes at
- a mould was placed over the PLGA film and a solution comprising polymer according to Table 1 (5 % w/v) in DMSO was poured into the mould, frozen and the DMSO removed by lyophilisation to liberate a sheet with dimensions equivalent to the volume of solution poured into the mould.
- the sheet was washed in diethyl ether to remove traces of DMSO and dried under vacuum at 40 °C for >48 hours.
- the resultant article had a blue PLGA barrier layer on one surface.
- a multilamellar tissue-adhesive sheet is shown schematically in Figure 9.
- the sheet comprises a structural laminate and a tissue-contacting layer as follows: a) a solvent cast first layer 21 of PLGA;
- the tissue-contacting fifth layer 25 is conjoined to the fourth layer 24 and comprises tissue-adhesive polymer.
- the second layer also comprises tissue-adhesive polymer.
- the first and third layers 21 , 23 each have a thickness of approximately 10 ⁇ , and the second layer 22 a thickness of approximately 3 ⁇ .
- a logo is applied to the second layer 22.
- the fourth layer 24 has a thickness of approximately 600 ⁇ .
- the tissue-contacting layer 25 has a thickness of approximately 200 ⁇ .
- the sheet was prepared as follows:
- Solution A was 10g (10 % w/v) PLGA dissolved in 100ml DCM.
- Solution B was 7.5g (7.5 % w/v) polymer dissolved in 100ml DCM/MeOH 15/4.
- Solution C was a viscous printing ink comprised of polymer (2.25 g, 22.5 % w/v) and
- Solution D was 1 g (1 % w/v) PLGA dissolved in 100ml DMSO.
- Solution E was 2.5g (2.5% w/v) polymer dissolved in 100ml DMSO.
- Solution A was cast onto a release substrate such as silicone-backed release paper affixed to a glass sheet using a ⁇ ⁇ gauge K bar. When the solvent evaporated this resulted in a 10 ⁇ dry film of PLGA. The film was dried for 30 minutes at 20°C/atmospheric pressure. The film was not removed from the release substrate.
- a release substrate such as silicone-backed release paper affixed to a glass sheet using a ⁇ ⁇ gauge K bar.
- Solution B was cast onto the first layer using a 40 ⁇ K bar. When the solvent evaporated it resulted in a 3 ⁇ dry film of A. The film was dried for 30 minutes at 20°C/atmospheric pressure. The laminate was not removed from the release substrate.
- Solution C was printed by screen printing onto the surface of the second layer to form an alpha-numeric trade/visualisation logo.
- Solution A was cast onto the second layer using a ⁇ ⁇ K bar. When the solvent evaporated this resulted in a 10 ⁇ dry film of PLGA. The film was dried for 30 minutes at 20°C/atmospheric pressure and 16 hours d 40°C/reduced pressure. The laminate was not removed from the release substrate. Freeze drying of fourth layer
- a polypropylene mould 50mm x 50mm x 5mm was affixed onto the third layer using double sided adhesive tape.
- the glass sheet with the laminate (first, second and third layers) and the mould affixed was then chilled to -20 Q C.
- Solution D (15ml) was poured into the mould. The glass sheet was returned to the freezer for at least 1 hour.
- Solution E (5ml) was poured into the mould onto the frozen fourth layer.
- the glass sheet was returned to the freezer for at least 1 hour.
- the DMSO from the fourth and fifth layers was removed by lyophilisation to liberate a sheet with dimensions equivalent to the mould.
- the sheet was washed in diethyl ether to remove traces of DMSO and dried under vacuum at 40°C for >48 hours.
- the sheet was cut to size using specially designed cutters. Sterilisation
- the dried, cut down product was subjected to pressure to flatten it and then stored in a foil pouch to maintain sterility and exclude moisture.
- the product was then gamma-sterilised at 25-40 kGy.
- the resultant article had a blue logo sandwiched between the PLGA barrier layer and freeze-dried adhesive layer.
- the resultant article was haemostatic to a bleeding liver punch biopsy in an in vivo preclinical assessment.
- the haemostatic properties of the polymer were demonstrated by mixing either the dry milled powder or a solution in saline with porcine plasma. Results are summarised in Table 1 1 .
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Abstract
L'invention concerne un polymère adhésif aux tissus destiné à être appliqué sur des surfaces internes et externes du corps à des fins thérapeutiques, comprenant des motifs dérivés de vinylpyrrolidone et des motifs dérivés d'acrylate contenant au moins un groupe ester et un groupe réactif avec les tissus. Des compositions comprenant des compositions lyophilisées contenant ledit polymère permettent d'obtenir une couche de contact avec les tissus dans des articles adhésifs aux tissus, par exemple des feuilles présentant une ou plusieurs couches. Des compositions liquides contenant ledit polymère permettent d'obtenir des hydrogels présentant des propriétés de scellement des tissus utiles.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB1702451.4A GB201702451D0 (en) | 2017-02-15 | 2017-02-15 | Freeze-dried tissue adhesive materials |
GB1702451.4 | 2017-02-15 | ||
GBGB1702429.0A GB201702429D0 (en) | 2017-02-15 | 2017-02-15 | Tissue-adhesive materials |
GB1702429.0 | 2017-02-15 |
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WO2018150186A1 true WO2018150186A1 (fr) | 2018-08-23 |
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PCT/GB2018/050408 WO2018150186A1 (fr) | 2017-02-15 | 2018-02-15 | Matériaux adhésifs aux tissus |
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GB (1) | GB2561947B (fr) |
WO (1) | WO2018150186A1 (fr) |
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WO2020231559A1 (fr) * | 2019-05-10 | 2020-11-19 | Massachusetts Institute Of Technology | Matériau sec à double face pour l'adhésion de tissus et de dispositifs humides |
CN113663117A (zh) * | 2021-08-17 | 2021-11-19 | 南方科技大学 | 一种抗溶胀生物粘合剂及其制备方法与应用 |
WO2021247262A1 (fr) * | 2020-06-04 | 2021-12-09 | Massachusetts Institute Of Technology | Matériau adhésif à détachement à la demande déclenchable |
CN115052638A (zh) * | 2019-12-03 | 2022-09-13 | 麻省理工学院 | 抗体液的组织粘合剂 |
CN118852994A (zh) * | 2024-09-25 | 2024-10-29 | 颢箔医疗科技(上海)有限公司 | 一种凝胶粘合贴片及制备方法和应用 |
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CN110694594A (zh) * | 2018-06-25 | 2020-01-17 | 香港城市大学深圳研究院 | 基于氧化石墨烯、壳聚糖及多巴胺的多孔材料的制备方法 |
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WO2020231559A1 (fr) * | 2019-05-10 | 2020-11-19 | Massachusetts Institute Of Technology | Matériau sec à double face pour l'adhésion de tissus et de dispositifs humides |
CN114173832A (zh) * | 2019-05-10 | 2022-03-11 | 麻省理工学院 | 用于粘合湿组织和装置的干双面材料 |
CN114173832B (zh) * | 2019-05-10 | 2023-09-26 | 麻省理工学院 | 用于粘合湿组织和装置的干双面材料 |
US11904067B2 (en) | 2019-05-10 | 2024-02-20 | Massachusetts Institute Of Technology | Dry double-sided material for adhesion of wet tissues and devices |
CN115052638A (zh) * | 2019-12-03 | 2022-09-13 | 麻省理工学院 | 抗体液的组织粘合剂 |
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US12054653B2 (en) | 2020-06-04 | 2024-08-06 | Massachusetts Institute Of Technology | Adhesive material with triggerable on-demand detachment |
CN113663117A (zh) * | 2021-08-17 | 2021-11-19 | 南方科技大学 | 一种抗溶胀生物粘合剂及其制备方法与应用 |
CN113663117B (zh) * | 2021-08-17 | 2022-06-21 | 南方科技大学 | 一种抗溶胀生物粘合剂及其制备方法与应用 |
CN118852994A (zh) * | 2024-09-25 | 2024-10-29 | 颢箔医疗科技(上海)有限公司 | 一种凝胶粘合贴片及制备方法和应用 |
CN118852994B (zh) * | 2024-09-25 | 2025-01-07 | 颢箔医疗科技(上海)有限公司 | 一种凝胶粘合贴片及制备方法和应用 |
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GB2561947B (en) | 2021-09-22 |
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