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WO2020043834A1 - Feuille de polyuréthane - Google Patents

Feuille de polyuréthane Download PDF

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Publication number
WO2020043834A1
WO2020043834A1 PCT/EP2019/073109 EP2019073109W WO2020043834A1 WO 2020043834 A1 WO2020043834 A1 WO 2020043834A1 EP 2019073109 W EP2019073109 W EP 2019073109W WO 2020043834 A1 WO2020043834 A1 WO 2020043834A1
Authority
WO
WIPO (PCT)
Prior art keywords
polyurethane foam
foam sheet
pharmacologically active
polyurethane
active agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2019/073109
Other languages
English (en)
Inventor
Fang Yang
Frank WALBOOMERS
Jinlong SHAO
John Arnoldus JANSEN
Lili Lin
Yi ZUO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Radboud Universiteit Nijmegen
Original Assignee
Stichting Katholieke Universiteit
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from NL2021630A external-priority patent/NL2021630B1/en
Application filed by Stichting Katholieke Universiteit filed Critical Stichting Katholieke Universiteit
Publication of WO2020043834A1 publication Critical patent/WO2020043834A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/425—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/146—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A61L2300/206—Biguanides, e.g. chlorohexidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • the present invention relates to a flexible polyurethane foam sheet comprising a pharmacologically active agent, a process of preparing such a sheet, and to the use of such a sheet for the treatment / prophylaxis of the human or animal body.
  • a prosthesis connected with a socket to the body, is the treatment-of-choice for the replacement of a missing body part.
  • a prosthesis connected via a socket is associated with many and serious disadvantages, including impaired mobility, pain, sensitivity problems and serious skin ulceration.
  • bone-anchored percutaneous implants or osseointegration prostheses have been developed, which provide a direct functional and strong connection between the external device and the patient’s own bone.
  • the stoma is the skin opening through which the osseointegration prosthesis extends.
  • the stoma can become contaminated with bacteria and thus may cause infections.
  • the clinical picture of a local stoma infection is redness of the skin around the stoma, stump swelling, pus secretion and sometimes severe stoma pain.
  • a problem with known polyurethane foam wound guards is that they are provided to the user in a certain diameters / shapes that corresponds to envisaged applications, for example rings and cylinders for covering cylindrical elements.
  • EP 2272545 discloses that disadvantages of such wound guards is that it requires adhesive tape to fix it to the skin and the foam disc absorbs serous fluid making the wound guard floppy. Because of these problems, it is necessary to change the wound guard frequently. The wound guard may swell as it absorbs serous fluid and can become difficult to handle.
  • H Forster et el / Journal of Orthopaedic Research 22 (2004) 671-677 discloses a polyurethane sleeve, having a gentamicin impregnated coating on the inner and outer surfaces, has been developed to inhibit bacterial colonization on external fixation pins and wires.
  • the antimicrobial sleeves are placed over the pins and wires, at the time of surgery, and manually pushed through the subcutaneous tissue up to the point of contact with the bone.
  • Polyurethane sleeves as disclosed by H Forster et al are not suitable for osseointegration prosthesis because the prosthesis cannot be adjusted to the diameter, length and shape of the sleeve.
  • WO 2012/007929 A1 discloses a wound dressing device for use with a cannula or a catheter comprising polyurethane MS50P(w) Lendell medical foam available from Filtrona Porous Technologies x, an antimicrobial agent contained within the matrix and a haemostatic agent contained within the matrix.
  • polyurethane MS50P(w) Lendell medical foam available from Filtrona Porous Technologies x
  • an antimicrobial agent contained within the matrix
  • a haemostatic agent contained within the matrix.
  • this type of polyurethane foam is mechanically weak and difficult to handle.
  • the inventors have developed a flexible, polyurethane foam sheet which can be shaped to fit the percutaneous element extending from, for example, an osseointegration site.
  • the invention provides an elastic sheet that the user of can easily place around a protruding element and secure it around said element by virtue of the self-adhesive property of the polyurethane foam sheet, dispensing with the need for any secondary attachment means.
  • the present invention provides a flexible, polyurethane foam sheet comprising a pharmacologically active agent dispersed within said foam,
  • polyurethane is a copolymer having the structure according to formula (I):
  • HS denotes a hard block segment being prepared from an aliphatic diisocyanate and/or cycloaliphatic diisocyanate and a diol chain extender
  • SS denotes a soft block segment being a polyol having a number average molecular weight in the range of 1 ,000 to 20,000 g/mol
  • polyurethane has a number average molecular weight (Mn) ranging from 4000 to 50,000 g/mol, preferably between 1 ,000 and 15,000.
  • Mn number average molecular weight
  • the high average molecular weight of the polyol in combination with the aliphatic nature of the diisocyanate provides a flexible network that enables the polyurethane foam sheet to be easily deformed and held in place due to self-adhesive property of the polyurethane.
  • the polyurethane foam is able to absorb wound exudate and withstand the pressures exerted between the prosthesis and osseointergration site.
  • the present polyurethane foam is therefore suitable for use as a sheath, wrap or covering for percutaneous elements extending from an osseointegration site.
  • the present invention also relates to a polyurethane foam sheet as defined herein for use in a method of treatment or prophylaxis of the human or animal body. Description of embodiments
  • a flexible, polyurethane foam sheet comprising a pharmacologically active agent dispersed within said foam
  • polyurethane is a copolymer having the structure according to formula (I):
  • HS denotes a hard block segment being prepared from an aliphatic diisocyanate and/or cycloaliphatic diisocyanate and a diol chain extender
  • SS denotes a soft block segment being a polyol having a number average molecular weight in the range of 1 ,000 to 20,000 g/mol
  • polyurethane has a number average molecular weight (Mn) ranging from 4000 to 50,000 g/mol, preferably between 1 ,000 and 15,000.
  • Mn number average molecular weight
  • weight percentages are based on the total weight of the concentrate.
  • segment and “block” mean a polymeric structure of any length.
  • a long polymeric structure is often referred to as a block, whereas a short polymeric structure is often referred to as a segment. Both these conventional meanings are understood to be comprised in the term “segment” as well as in the term “block” as used herein.
  • HS hard segment
  • the term“soft segments” means a segment of the polyurethane copolymer that comprises a diol.
  • biocompatible means that the sheet of the present invention as well as wear debris and the materials generated during placement do not cause a substantial immune response, sensitization, irritation, cytotoxicity or genotoxicity.
  • prosthesis and “prosthetic are used interchangeably to denote an artificial body part.
  • the polyurethane foam sheet is highly flexible, absorbent, and conformable to different percutaneous elements.
  • the sheet has a density of at least 0.25g/cm 3 , and more preferably at least 0.30 g/cm 3 .
  • Particularly preferred sheets have a density in the range 0.25 to 0.75 g/cm 3 .
  • the sheet has a Young’s modulus in the range of from 0.3 to 0.7 MPa.
  • the polyurethane foam sheet of the present invention is able to withstand the pressures exerted in, for example, femoral osseointegrated prosthetics.
  • the sheet has a porosity of at least 50%, preferably a porosity in the range of 60 to 80%.
  • the porosity of the sheet not only enables the sheet to be a reservoir for a pharmacologically active agent but the sheet is also capable of absorbing wound exudates.
  • the sheet of the present invention and the medical devices made therefrom are biocompatible and have properties that make the devices especially useful including tensile modulus of between about 0.1 MPa to about 30 MPa, preferably about 0.3 MPa to about 15 MPa, a tear strength of greater than or equal to about 3 N/mm, and flexibility (strain at break) of about 100 % or higher.
  • tensile modulus between about 0.1 MPa to about 30 MPa, preferably about 0.3 MPa to about 15 MPa, a tear strength of greater than or equal to about 3 N/mm, and flexibility (strain at break) of about 100 % or higher.
  • These advantageous properties are in part due to the high molecular weight of the polymers in the foam and in part due to the interconnectivity of the polymers in the foam. This high molecular weight and interconnectivity are achieved by the process of making the polyurethane polymer and by the process of making the foam from the polyurethane polymer.
  • the sheet preferably has a hardness of a of 60 to 85, more preferably 70 to 85 and most preferably 75 to 85 as measured using a‘Shore durometer’ using ASTM D2240-03 Standard Test Method for Rubber Property— Durometer Hardness, ASTM International, West Conshohocken, PA, 2003
  • the polyurethane has a number average molecular weight (Mn) ranging from 1 ,000 to 50,000 g/mol, preferably between 4,000 and 15,000.
  • the final average molecular weight of the polymer in the foam is preferably in the range of 2 kDa to 100 kDa.
  • the average molecular weight of the polymer is in the range of 5 kDa to to 80 kDa. More preferably, the average molecular weight of the polymer in the foam is 10 kDa to 60 kDa.
  • the sheet preferably has at least one substantially flat surface and at least one straight edge.
  • the at least one flat surface can allow the sheet to be brought into close proximity with a surface about which it is wrapped.
  • the at least one straight edge can allow the edge of the sheet to be brought into close abutment with the body surface from which the osseointegration prosthesis extends.
  • the shape of the sheet can be adapted to suit the osseointegration site of the prosthesis.
  • the sheet comprises two substantially straight, parallel opposing edges.
  • the sheet can have a square or rectangular shape, more preferably a rectangular shape, wherein the rectangular shape preferably has a width of 5-20mm, length of 10-100mm and a thickness of 0.5-3mm.
  • a rectangular shape enables the sheet to be rolled-up by the patient into a shape that is suitable to fit over elements extending from an osseointegration site.
  • An advantage of the present invention is that the sheet can be tailored to the needs of the patient, and also fitted by the patient. By virtue of the self-adhesive property, overlapping ends of the sheet can be pressed together to secure the sheet around an element.
  • polyurethane foam sheet according to the present invention does not require secondary attachment means to secure the sheet in use, i.e. to secure the sheet around a protruding element.
  • a diisocyanate is to be understood as a compound having the formula OCN-R-OCN, wherein R is a C2-C14 aliphatic or cycloaliphatic radical, preferably a C2- C14 alkylene or cycloalkylene radical. If R is an aliphatic radical, it is preferred that the OCN-groups are terminal groups.
  • the aliphatic radicals may be linear or branched and are preferably linear. More preferably, R is a C3-C12 aliphatic or cycloaliphatic radical, and even more preferably, R is a C3 examples and preferred embodiments of the diisocyanates are given below.
  • Aliphatic diisocyanates and cycloaliphatic diisocyanates can be used in the method of the invention include, for example, the known aliphatic cycloaliphatic diisocyanates selected from the group consisting of 4,4’-Methylene dicyclohexyl diisocyanate, 4,4'- dicyclohexanemethane (H12MDI, 4,4’-HMDI or reduced MDI), 1 ,4-trans cyclohexane-diisocyanate (CHDI), isophorone diisocyanate (IPDI), 1 ,6-diisocyanatohexane or hexamethylene diisocyanate trimer (HDI trimer), 1 ,4-butane diisocyanate (BDI), hydrogenated MDI (HMDI), lysine diisocyanate and combinations thereof.
  • the known aliphatic cycloaliphatic diisocyanates selected from the group consisting of 4,4’-Methylene
  • the aliphatic diisocyanate is a cyloaliphatic diisocyanate, more preferably the cycloaliphatic diisocyanate is isophorone diisocyanate or the mixture of isophorone diisocyanate and lysine diisocyanate.
  • the polyurethane has a hard segment prepared from the reaction of an aliphatic isocyanate and a diol chain extender.
  • the chain extender is selected from the group consisting of ethylene glycol, 1 ,2-propylene glycol, 1 ,3-propanediol, 1 ,4-butanediol, 1 ,6-hexanediol, diethylene glycol, 2-methyl-1 , 3-propanediol, 3-methyl-1 ,5-pentanediol, 2, 2-dimethyl-1 , 3-propanediol, 2,2,4- trimethyl-1 ,5-pentanediol, 2-methyl-2-ethyl-1 , 3-propanediol and combinations thereof.
  • the hard segment is preferably present in an amount ranging from 51 to 70 wt.% and the soft segment is present in an amount ranging from 30 to 49 wt.% of the total weight of the polyurethane.
  • the polyol is selected from the group of polyether polyols, polyglycolide, and mixtures thereof.
  • the polyol may be a polyester or copolyesters made by ring-opening polymerization of cyclic reactants, based on, for example, e-caprolactone, lactide, glycolide, delta-valerolactone, 1, 4- dioxane-2-one, l,5-dioxepan-2-one, oxepan-2,7-dione; polycarbonates and copolycarbonates based on, for example 1 ,6-hexanediol polycarbonate; polycarbonates and copolycarbonates made by ring-opening polymerization based on, for example, trimethylenecarbonate (1 ,3-dioxane- 2-one), tetramethylenecarbonate, 1 ,3-dioxepan-2-one or 1 ,3,8,10- tetraoxacyclotetradecane
  • Preferred polyols are the ones that are made by ring opening polymerization of oxygen containing compounds.
  • a particularly preferred polyol is poly(glycolide)diol, which is prepared by the ring-opening polymerization of glycolide.
  • the reaction to form the polyol can be carried out in accordance with procedures which are known in polyurethane chemistry.
  • Polyols made by ring opening polymerization are normally synthesized in the presence of a catalyst (e.g. stannous octoate, dibutyl stannous laurate).
  • the polyol polyether has the formula H(OCH 2 (CH 2 )xCH 2 ) y OH, wherein x an integer from 2 to 8, preferably 4 to 6, and y is in the range of 30-500, preferably 50- 400, more preferably 100-300.
  • Preferred polyol polyethers include poly(tetramethylene ether) glycols.
  • the polyglycolide is a polyglycolide of formula [CH 2 - (CH 2 ) 4 -COO] n , HO[OCCH(CH 3 )]nOH, H0[C0CH(CH 3 )0]m[C0CH 2 0]nH, or H[OCH 2 CH 2 ] n OH.
  • the polyether polyol and/or polyglycolide has a number average molecular weight (M n ) ranging from 1 ,000 to 20,000 g/mol, preferably between 2,000 and 18,000.
  • the polyurethane of the present invention may in fact have a certain polymeric weight distribution.
  • a mixture of polyurethanes based on different compounds is meant. This mixture may be the result of different types of polyol (soft) segment and/or of different types of the urethane segment.
  • the urethane segment may be based on a mixture of different diols and/or diisocyanates.
  • a single polyurethane polymer molecule may comprise a mixture of hard segments.
  • the polyurethane is the reaction product of an aliphatic diisocyanate, a polyol and a chain extender, said chain extender being a diol.
  • the foamed polyurethane sheet is obtainable by a process comprising reacting:
  • the polyurethane has a number average molecular weight (Mn) ranging from 1 ,000 to 50,000 g/mol and wherein a pharmacologically active agent is provided prior to or post foaming of the pre-polymer.
  • Mn number average molecular weight
  • the present invention relates a process for the preparation of a polyurethane foam sheet as defined herein, wherein the process comprises the steps of:
  • a pharmacologically active agent is added to the cross-linked prepolymer before or after step iii).
  • the process allows for incorporation of a pharmacologically active agent either pre- or postfoaming.
  • the resulting elastic sheet provides a sustained release of the active overtime.
  • the high average molecular weight of the polyol, in combination with the aliphatic nature of the diisocyanate provides a flexible network that enables the polyurethane foam sheet to be easily deformed.
  • the polyurethane foam is able to absorb wound exudate and withstand the pressures exerted between the prosthesis and osseointergration site.
  • the present polyurethane foam is therefore suitable for use as a covering for percutaneous elements extending from an osseointegration site.
  • the diisocyanate used in step i) is to be understood as a compound having the formula OCN-R-OCN, wherein R is a C2-C14 aliphatic or cycloaliphatic radical, preferably a C2-C14 alkylene or cycloalkylene radical. If R is an aliphatic radical, it is preferred that the OCN-groups are terminal groups.
  • the aliphatic radicals may be linear or branched and are preferably linear. More preferably, R is a C3-C12 aliphatic or cycloaliphatic radical, and preferred embodiments of the diisocyanates are given above.
  • the polyol used in step i) is selected from the group of polyether polyols, polyglycolide, and mixtures thereof.
  • the polyol may be a polyester or copolyesters made by ring-opening polymerization of cyclic reactants, based on, for example, e-caprolactone, lactide, glycolide, delta- valerolactone, l,4-dioxane-2-one, l,5-dioxepan-2-one, oxepan-2,7-dione; polycarbonates and copolycarbonates based on, for example 1 ,6-hexanediol polycarbonate; polycarbonates and copolycarbonates made by ring-opening polymerization based on, for example, trimethylenecarbonate (1 ,3-dioxane- 2-one), tetramethylenecarbonate, 1 ,3-dioxepan-2-one or 1 ,3,8, 10- tetrao
  • step iii) of the process according to the present invention foaming of the polymer is carried out.
  • the foaming agent is water or sodium hydrogen carbonate, more preferably water. It has been found that the using water or sodium hydrogen carbonate as foaming agent enables the production of a sleeve without the need for organic solvents in the foaming step, increasing the biocompatibility of the foam.
  • the pharmacologically active agent is added during step ii), and wherein a second pharmacologically active agent is added after step iii).
  • the pharmacologically active agent added during step ii) does not react with the pre-polymer or cross-link catalyst.
  • the pharmacologically active agent is selected from the group consisting of analgesics, anti-inflammatory agents, antimicrobial agents and combinations thereof. It has been found that a flexible polyurethane sheet according to the present invention provides a simple, user friendly way to apply analgesics, anti-inflammatory agents, antimicrobial agents and combinations thereof directly to the site of osseointeg ration implantation.
  • the pharmacologically active agent is an analgesic selected from the group consisting amido-esters or amido-amiides.
  • the amido-amides preferably being selected from the group consisting of N-(2,6-Dimethylphenyl)-N2,N2-diethylglycinamide (lidocaine), 1-Butyl-N-(2,6- dimethylphenyl)-2-piperidinecarboxamide (bupivacaine), N-(2-Methylphenyl)-2-(1- pyrrolidinyl)propanamide (aptocaine) and salts thereof.
  • amido-esters are preferably selected from the group consisting of procaine, and tetracaine
  • the analgesic is an amido-amide selected from the group consisting of N-(2,6-Dimethylphenyl)-N2,N2- diethylglycinamide or N-(2,6-Dimethylphenyl)-N2,N2-diethylglycinamide hydrochloride monohydrate.
  • the pharmacologically active agent is an antimicrobial agent and preferably the antimicrobial agent is N,N""-1 ,6-Hexanediylbis[N'-(4- chlorophenyl)(imidodicarbonimidic diamide)] (chlorhexidine) or N,N""-1 ,6-Hexanediylbis[N'-(4- chlorophenyl)(imidodicarbonimidic diamide)] digluconate (chlorhexidine digluconate) and preferably the antimicrobial agent is selected from the group consisting of triclosan, povidone iodine, polyhexamethyelene biguanide, N,N""-1 ,6-Hexanediylbis[N'-(4-chlorophenyl) (imidodicarbonimidic diamide)] (chlorhexidine).
  • the anti-inflammatory agent is a non-steroidal anti-inflammatory.
  • the non-steroidal anti-inflammatory is a propionic acid selected from the group consisting of 2-(3- Phenoxyphenyl)propanoic acid (Fenoprofen), (2R)-2-(2-Fluoro-1 , T-biphenyl-4-yl)propanoic acid (tarenflurbil), 2-(3-Benzoylphenyl)propanoic acid (ketopteur), (2S)-2-(4-lsobutylphenyl)propanoic acid (ibuprofen), (2S)-2-(6-Methoxy-2-naphthyl)propanoic acid (naproxen), 3-(4,5-Diphenyl-1 ,3- oxazol-2-yl)propanoic acid (oxaprozin).
  • the pharmacologically active agent is incorporated into the polyurethane post-synthesis.
  • the pharmacologically active agent is dissolved or suspended in a suitable solvent such as water at a concentration typically of from about 0.01 % to about 20% w/v, for example from about 0.1 % to about 10 wt.%, will be contacted with the polyurethane foam by immersion.
  • suitable temperatures for the immersion are in the range of 0 °C to 80 °C, preferably in the range of 5 °C to 50° C.
  • the foam is then removed from the solvent. It may be dried in air or other atmosphere, for example at a temperature in the range of 20 °C to 80 °C, or it may be freeze-dried.
  • the resulting material is sterilized, for example by gamma-irradiation.
  • the loading of the foam with the therapeutic agent may readily be determined based upon the weight of the solution taken up by the foam. Suitable loadings for antimicrobials such as chlorhexidine salts, are from about 0.1 wt.% to about 10 wt.%, for example from about 0.5 wt.% to about 5 wt.%, based on the dry weight of the foam.
  • the present invention relates to a polyurethane foam sheet as defined herein for use in a method of treatment or prophylaxis of the human or animal body.
  • the inventors provide for the first time a polyurethane foam that is suitable for the treatment or prophylaxis of the human or animal body.
  • the polyurethane as defined herein is suitable for the treatment or prophylaxis of patients with osseointegrative implants.
  • the patients may be human or animal, for example companion animals such as cats and dogs.
  • the treatment involves at least partially covering a percutaneous element of an implant with the polyurethane foam sheet.
  • the implant is an osseointegrated prosthesis.
  • a patient is provided with information concerning daily stoma care.
  • painkillers and antibiotics may be provided.
  • the present invention overcomes the need for painkillers and/or antibiotics to be prescribed as the polyurethane foam sheet of the present invention provides local administration of pharmacologically active agents such as painkillers and antibiotics.
  • the polyurethane foam sheet when located on a percutaneous element is not in contact with bone.
  • Osseointegrated implants extend through a stoma that is located in muscle, subcutaneous fat or skin tissue.
  • the polyurethane foam sheet can be fitted around the percutaneous element by the user, for example a patient, therefore the method of treatment does not involve an invasive surgical procedure in order to place the polyurethane foam sheet in position.
  • the treatment is selected from the treatment of infection(s), pain or inflammation associated with an osseointegration prosthetic.
  • Fig. 1 shows the release profiles for polyurethane foam sheets made according to the present invention:
  • Panel A shows the percentage release of chlorhexidine (1 wt.%, circles; 5 wt.%, squares) over time.
  • Panel B shows the percentage release of lidocaine (1 wt.%, circles; 2 wt.%, squares; 4 wt.%, up triangle; 8 wt.% down triangle) over time.
  • Panel C shows the mass (mg) release of chlorhexidine (1 wt.%, circles; 5 wt.%, squares) over time.
  • Panel D shows the mass (mg) release of lidocaine (1 wt.%, circles; 2 wt.%, squares; 4 wt.%, up triangle; 8 wt.% down triangle) over time
  • the porosity of the open pores in the materials was measured by liquid displacement method as reported by L. Li, Y. Zuo, Q. Zou, B. Yang, L. Lin, J. Li, Y. Li, Hierarchical Structure and Mechanical Improvement of an n-HA/GCO-PU Composite Scaffold for Bone Regeneration, ACS Applied Materials & Interfaces, 7 (2015) 22618-22629.
  • water density, p
  • a dry sample with weight W1 and volume V was immersed in ultrapure water and vacuum-repressurized until no air bubbles released from the sample. The total weight of the water impregnated material was recorded as W2. 5 samples from each group was measured.
  • the porosity (P) of the material was calculated by:
  • the tensile strength and modulus of the samples were determined using a mechanical testing machine (AUTOGRAPH AG-IC 20/50KN, Japan). Specimens were cut to 2mm-thick sheets and then trimmed according to the American Standard Test and Measurement (ASTM D 638-02a) norm (specimen type V). The cross-head speed was set to 1 mm/min. Prior to the measurement, all specimens were conditioned for at least 48 h at 20°C under relative humidity of 45-55% and the values were averaged from five measurements.
  • Durometer testing was done using Tacklock FO GS-744G, a durometer designed for measurement of sponge and foam materials. The measurements of hardness were made according to the standard measuring procedures for durometers, ASTM D2240-03 Standard Test Method for Rubber Property— Durometer Hardness, ASTM International, West Conshohocken, PA, 2003, www.astm.org.
  • the concentration of lidocaine and chlorhexidine was detected by reverse-phase (RP)-HPLC according to previously reported methods: [Y. Xue, M. Tang, Y. Hieda, J. Fujihara, K. Takayama, H. Takatsuka, H.
  • the HPLC system consisted of a Hitachi L-2130 pump, a Hitachi L-2400 UV detector, a Hitachi L-2200 autosampler, and a LiChrospher RP-18 endcapped HPLC column (125 mm c 4 mm, particle size 5 pm).
  • the mobile phase consisted of acetonitrile: ammonium acetate (0.0257 M), pH 4.85 (adjusted with acetic acid) in the ratio of 60/40 (v/v).
  • the injection volume was 20 pL with a flow rate of 0.5 mL/min.
  • the concentration of lidocaine was quantified at 254 nm using a standard calibration curve in the concentration range between 5 and 1000 gg/mL.
  • the mobile phase consisted of acetonitrile/ultrapure water (40:60, v/v, containing 0.1 v/v% trifluoroacetic acid and 0.1 v/v% triethylamine). 50 pL supernatants were injected with a flow rate of 1 mL/min at chamber temperature of 40°C. The concentration of CHX was quantified at 260 nm using a standard calibration curve in the concentration range between 0.1 and 200 pg/mL.
  • a polyurethane according to the invention was prepared by copolymerization and simultaneous forming process.
  • 45 g of polytetramethylene ether glycerol (PTMG, Mn ⁇ 2000) and 1 1.2 g Isophorone diisocyanate (IPDI) was stirred in a plastic beaker at 200 revolutions per minute at 70°C and the reaction was kept for 3 hours to form the prepolymer.
  • 2 ml 1 ,4-Butanediol was used as chain extender to crosslink the prepolymer for 2 hours.
  • 10 pi ditinbutyl dilaurate was used as a catalyst to accelerate the crosslinking process.
  • 1 ml 2% NaHCCh was added as a foaming agent and the reaction was kept for another 30 min or until the stir was stopped.
  • the mixture was incubated at 90 °C overnight to react thoroughly and form porous polyurethane.
  • the mixture was either kept in a beaker to form a bulk material or smeared on a Petri-dish to form membranes. All the process was conducted at a relative humidity of 45-55%.
  • D1 states the polyurethane foam used is type MS50P(w) Lendell medical foam available from
  • the mixture was incubated at 90 °C overnight to react thoroughly and form porous polyurethane.
  • the mixture was either kept in a beaker to form a bulk material or smeared on a Petri-dish to form membranes. All the processes were conducted at a relative humidity of 45- 55%.
  • the bulky porous polyurethane was first cut into desired shapes, e.g. rectangular sheets (width 5-20 mm, length 10-10 0mm) of 0.5-3 mm thickness.
  • desired shapes e.g. rectangular sheets (width 5-20 mm, length 10-10 0mm) of 0.5-3 mm thickness.
  • the polyurethane sheets were immersed in drug solutions and vacuumed. The sheets were then lyophilized.
  • Polyurethane foams prepared comprising pharmacologically active agents in Table 3

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Abstract

La présente invention concerne une feuille de mousse de polyuréthane souple comprenant un agent pharmacologiquement actif, un processus de préparation d'une telle feuille, et l'utilisation d'une telle feuille pour le traitement et/ou la prophylaxie du corps humain ou animal.
PCT/EP2019/073109 2018-08-30 2019-08-29 Feuille de polyuréthane Ceased WO2020043834A1 (fr)

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CN201811004960 2018-08-30
CN201811004960.X 2018-08-30
NL2021630A NL2021630B1 (en) 2018-09-14 2018-09-14 Polyurethane sheet
NL2021630 2018-09-14

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EP2272545A2 (fr) 2004-09-23 2011-01-12 The University of Nottingham Article médical antimicrobien et son procédé de préparation
WO2012007929A1 (fr) 2010-07-14 2012-01-19 Hemcon Medical Technologies (Ip) Limited Dispositif de traitement des plaies utilisable avec une canule ou un cathéter
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CN106046309A (zh) * 2015-11-20 2016-10-26 徐永祥 一种可完全生物降解的交联聚氨酯、其制备方法以及用其制备的多孔海绵
CN107286313A (zh) * 2017-07-10 2017-10-24 陕西瑞盛生物科技有限公司 一种可降解的聚氨酯泡沫及其应用
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WO2005025440A1 (fr) * 2003-09-16 2005-03-24 Dr. Graham Matheson Inc. Appareil dentaire servant a devier le tissu gingival
EP2272545A2 (fr) 2004-09-23 2011-01-12 The University of Nottingham Article médical antimicrobien et son procédé de préparation
EP1649834A1 (fr) * 2004-10-25 2006-04-26 ESKA Implants GmbH & Co. Logement intramusculaire sous-cutané pour implant transcutané fixe
WO2009070564A2 (fr) * 2007-11-27 2009-06-04 Macrochem Corporation Compositions et procédés utilisables dans le cadre de la prévention d'infections associées à des implants transcutanés ostéointégrés
WO2012007929A1 (fr) 2010-07-14 2012-01-19 Hemcon Medical Technologies (Ip) Limited Dispositif de traitement des plaies utilisable avec une canule ou un cathéter
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