WO2012107385A1 - Prépolymères biodégradables - Google Patents

Prépolymères biodégradables Download PDF

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Publication number
WO2012107385A1
WO2012107385A1 PCT/EP2012/051931 EP2012051931W WO2012107385A1 WO 2012107385 A1 WO2012107385 A1 WO 2012107385A1 EP 2012051931 W EP2012051931 W EP 2012051931W WO 2012107385 A1 WO2012107385 A1 WO 2012107385A1
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WO
WIPO (PCT)
Prior art keywords
prepolymer
hydrogel
radical
isocyanate
reactive component
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/EP2012/051931
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German (de)
English (en)
Inventor
Christoph Eggert
Heike Heckroth
Sebastian Dörr
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.)
Covestro Deutschland AG
Original Assignee
Bayer MaterialScience AG
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
Application filed by Bayer MaterialScience AG filed Critical Bayer MaterialScience AG
Publication of WO2012107385A1 publication Critical patent/WO2012107385A1/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
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/60—Liquid-swellable gel-forming materials, e.g. super-absorbents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/08—Processes
    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/56—Polyacetals
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2220/00—Compositions for preparing gels other than hydrogels, aerogels and xerogels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2230/00—Compositions for preparing biodegradable polymers

Definitions

  • the present invention relates to a prepolymer for the production of biodegradable hydrogels, to a process for the preparation of the prepolymers of the invention, to a prepolymer obtainable by the process according to the invention, to a biodegradable hydrogel obtainable using the prepolymer of the invention and to a dosing system for the application of the hydrogel.
  • Adhesions are one of the most common complications after abdominal and pelvic surgery. Adhesions are fibrous bands that generally develop within the first seven days after surgery during the healing process. As a result, tissues and organs, which are normally separated from each other, grow together, resulting in a variety of complications such as hypertension. chronic pain, infertility or a life-threatening intestinal obstruction may occur. To avoid such complications, products have been developed in recent years that can reduce the formation of adhesions. Among others, hydrogels have also been used as adhesion barriers. Hydrogels are hydrous polymers whose chains are covalently linked to a three-dimensional network. In water, these networks swell up to an equilibrium volume while retaining their shape.
  • the network formation occurs predominantly via chemical linkage of the individual polymer chains, but is also physically possible by electrostatic, hydrophobic or dipole / dipole interactions between individual segments of the polymer chains.
  • the choice of the monomers used for the polymer synthesis, the type of crosslinking and the crosslinking density can be used to set desired properties of the hydrogels in a targeted manner.
  • hydrogels are based on poly (meth) acrylic acids, poly (meth) acrylates, polyurethanes, polyvinylpyrrolidone or polyvinyl alcohol. They are generally well-tolerated by living tissues and are therefore often suggested for use as adhesion barriers.
  • Polyurethane hydrogels of hydrophilic NCO prepolymers are known per se. They are used for the medical treatment of wounds and are used, for example, as wound dressings. They have the advantage of keeping especially dry wounds in a controlled manner moist, which has a favorable effect on wound healing.
  • DE 10 2006 050 793 describes polyurethane hydrogels based on aliphatic NCO polyether prepolymers. To prepare the hydrogel, the prepolymers are reacted with compounds containing hydroxyl groups, and the resulting polymer is then brought into contact with water. The hydrogels are also used as adhesion barriers. However, the described systems are not, or at least very slowly, biodegradable in the body. In general, mining takes longer than six months. An adhesion barrier, on the other hand, should be degraded in a much shorter time, as it should temporarily protect the organs from growing together only during the wound healing process. In the non-prepublished European patent application with the application number
  • the object of the present invention was to provide a prepolymer for the production of biocompatible hydrogels, which are biodegraded within a period of a few days.
  • a hydrogel By reacting the prepolymer of the present invention with an isocyanate-reactive component having at least two Zerewitinoff active hydrogens to form a polyurethane and mixing the polyurethane with water, a hydrogel can be obtained which, under physiological conditions, within a few days (ie, less than 14 Days) is reduced.
  • a hydrogel is considered degradable under physiological conditions when it dissolves in an isotonic NaCl solution (containing 0.9 weight percent NaCl dissolved in water) at 37 ° C.
  • Such a prepolymer can be used to prepare a hydrogel which is particularly fast, ie. within less than 7 days.
  • the R 1 and / or R 2 may be a linear or branched C 1 to C 6 radical which is optionally substituted in the chain by heteroatoms.
  • the radicals R 1 and / or R 2 can be a C 1 to C 4 alkyl radical and very particularly preferably a CH 2, CH 2 -CH 2, CH 2 -CH 2 -CH 2, C H 2 -CH-CH 3, CH 2 -CH 2 -CH 2 -CH 2, CH 2 -CH 2 Be -CH-CH3, CH2-CH (CH3) -CH2, CH2-C (CH3) 2 or CH2-CH2-O-CH2-CH2 radical.
  • the prepolymers and thus also the polymers of a hydrogel obtainable therefrom have a particularly high hydrophilicity, which leads to an improved water absorption.
  • R 3 is an aliphatic C 2 to C 8, preferably an aliphatic C 4 to C 6 radical and very particularly preferably a (C 3) radical or an isophoryl radical
  • the invention further relates to a process for preparing a prepolymer according to the invention, in which a vinyl ether Ri (OCHCH 2) m with a polyol R 2 (OH) n + i with acid catalysis to form a polyacetal polyol and the polyacetal polyol with a polyisocyanate R3 (NCO) are 0 + i implemented.
  • a vinyl ether Ri (OCHCH2) m are 1,4-butanediol divinyl ether, triethyl- englykoldivinylether, tetraethylene glycol
  • polyols R2 (OH) n + i for example, ethylene glycol, 1,2- and 1,3-propanediol, 1,3- and 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, neopentyl glycol can be used , 1,4-bis-hydroxymethylcyclohexane, 2-methyl-1,3-propanediol, 2,2,4-trimethyl-pentanediol-1,3-dipropylene glycol, polyethylene glycols, polypropylene glycols, dibutylene glycol, polybutylene glycols, bisphenol A, polycarbonate polyols, polyester polyols, Polyester-polyether polyols and polyether polyols.
  • Suitable acid catalysts are, for example, p-toluenesulfonic acid, ethanesulfonic acid, methanesulfonic acid and / or sulfuric acid.
  • particularly suitable polyisocyanates have an average NCO functionality of 2 to 2.6 and more preferably from 2 to 2.4.
  • the polyisocyanates may be monomeric aliphatic and / or cycloaliphatic di- or triisocyanates, in particular 1,4-butylene diisocyanate (BDI), 1,6-hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), 2,2,4- and / or 2,4,4-trimethylhexamethylene diisocyanate, the isomeric bis (4,4'-isocyanatocyclohexyl) methanes and / or mixtures thereof of any isomer content, 1,4-cyclohexylene diisocyanate, 4-isocyanatomethyl-1,8-octane diisocyanate (Nonane triisocyanate), and / or alkyl-2,6-diisocyanatohexanoate (lysine diisocyanate) with C 1 -C 8 -alkyl groups and / or mixtures of the above polyisocyanates act.
  • the reaction of the vinyl ether Ri (OCHCH2) m with the polyol R2 (OH) n + is preferably carried out in THF as a solvent at room temperature under an inert atmosphere, paying particular attention to dry starting materials and solvents.
  • the addition reaction is initiated by the addition of up to 1200 ppm of catalyst (eg, p-toluenesulfonic acid). This leads to a rise in the temperature of the reaction mixture. After the exotherm has subsided, the previously added catalyst can be neutralized or deactivated with the aid of a simple to double equivalent amount of amine and the solvent stripped off.
  • catalyst eg, p-toluenesulfonic acid
  • the per se known catalysts such as amines or tin compounds and stabilizers such as benzoyl chloride, Isophthaloylchlo- rid, dibutyl phosphate or methyl tosylate can be used in the preparation of prepolymer.
  • the polyacetal polyol is reacted with an excess of polyisocyanate.
  • low-volatile amines are then added and the unreacted excess of polyisocyanate is removed by thin-layer distillation.
  • compounds having a boiling point at a pressure of 1023 mbar of greater than 250 ° C. can be used as low-volatile amines.
  • one or more of the compounds of the group triheptylamine, triisooctylamine, tribenzylamine, trihexylamine, tris (2-ethylhexyl) amine can be used with particular preference.
  • the prepolymers of the invention are obtained in particularly high yield and purity.
  • the prepolymers contain less than 0.5 wt .-%, in particular less than 0.03 wt .-% of monomeric di- and / or triisocyanate.
  • Another object of the invention is a prepolymer obtainable by the process according to the invention.
  • a hydrogel is also the subject of the invention, which is obtainable by reacting a prepolymer according to the invention with an isocyanate-reactive component which has at least two Zerewitinoff-active hydrogen atoms to form a polyurethane and mixing the polyurethane with water.
  • Zero Hydrogen bonded to N, O, or S is referred to as "Zerewitinoff-active” hydrogen (sometimes referred to as “active hydrogen”) if it yields methane by reaction with methyl magnesium iodide, according to a method discovered by Zerewoffoff Typical examples of compounds with Zerewitinoff active hydrogen are compounds which contain carboxyl, hydroxyl, amino, imino or thiol groups as functional groups.
  • the isocyanate-reactive component may be an organic polyol having at least two OH functions. It may preferably be an organic diol or triol and more preferably a compound selected from the group glycerol, trimethylolpropane (TMP).
  • TMP trimethylolpropane
  • isocyanate-reactive component an organic polyamine having at least two NH / NH 2 functions. Preference is given here to a diamine or triamine. This may in particular be selected from the group hexamethylenediamine, 2-methylpentamethylenediamine, ethylenediamine, spermidine, spermine dihexamethylenetriamine, diethylenetriamine.
  • isocyanate-reactive components are, for example, aspartates, trilysin, sugars, chitosan
  • the isocyanate-reactive component may also be a polyamine obtainable by hydrolysis of a prepolymer of the invention.
  • such an isocyanate-reactive component can be obtained by adding the prepolymer to water, where it then reacts to form the amine.
  • NCO prepolymer preferably 1 equivalent of NCO prepolymer can be mixed with 1 equivalent of isocyanate-reactive component and either by heating to 50-80 ° C or by the addition of 5 to 50 ppm catalyst (eg DBTL, stannous octoate) at Room temperature to be cured.
  • ppm catalyst eg DBTL, stannous octoate
  • the resulting specimens can then be immersed in water to the desired degree of swelling, depending on the crosslinking density swelling levels of up to 500% (w / w) can be achieved.
  • the use of heat or catalysts for curing can usually be dispensed with.
  • the hydrogel can be formed in situ, in which 1 equivalent NCO prepolymer with 1 equivalent of isocyanate-reactive component in up to 95% by weight (based on the mass of the finished hydrogel) of water and mixed.
  • the components are stirred together at room temperature.
  • the stirring can also be carried out at temperatures of 23 to 40 or from 30 to 80 ° C.
  • the temperature may also be below room temperature, for example in the range of 5 to 23 or even from -10 to +10 ° C.
  • a magnetic stirrer with Wienrhackfisch has proven to be advantageous, but it can also be a Speedmixer or a laboratory standard rempligel- or Gitterrrocker be used.
  • the choice of mixing unit depends, for example, on the quantity to be mixed and its viscosity.
  • stirring can also be carried out under a protective gas atmosphere, for example under nitrogen. Normally, however, it does not work under a protective gas atmosphere. Furthermore, it is also possible to mix under normal pressure. However, it can also be applied under slightly elevated pressure, e.g. be stirred at 1013 to 1035 mbar or under reduced pressure, for example at 800 to 1013 mbar.
  • the hydrogel can be stained.
  • z As methylene blue or the food color Brilliant Blue FCF.
  • the dye is preferably added to the water in the preparation.
  • pharmacologically active agents such as antiphlogistics, analgesics with and without anti-inflammatory effect, antimicrobial agents, vasodilators and / or growth factors are incorporated into the hydrogel.
  • hydrogel according to the invention as an adhesion barrier and its use as a coating agent for sealing, bonding or covering cell tissues, wherein cell tissue can be both human tissue tissue and animal cell tissue.
  • the hydrogel according to the invention as tissue adhesive, drug-releasing implant or scaffold material for tissue engenieering objects of the invention are also.
  • a metering system with two chambers in which the first chamber, the prepolymer according to the invention and the second chamber containing the isocyanate-reactive component, which has at least two Zerewitinoff-active hydrogen atoms, and water, the subject of the invention.
  • the necessary components are applied by means of the dosing system with a suitable applicator on the protected organ.
  • the hydrogel forms a protective polymer film on the organ. This adheres to the organ surface without penetrating the tissue. The film can be removed mechanically without damaging the tissue. It will otherwise be mined after a few days.
  • Polyethylene glycol 600 (polyethylene glycol of number average molecular weight of 600 g / mol, Aldrich)
  • HDI 1,6-hexamethylene diisocyanate
  • IPDI Isophorone diisocyanate
  • OH number Unless expressly stated otherwise, the OH number was determined volumetrically in accordance with DIN ISO 17025.
  • NCO content Unless otherwise stated, the NCO content was determined volumetrically in accordance with DIN-EN ISO 11909.
  • Viscosity The viscosity was determined according to ISO 3219 at 23 ° C.
  • Residual monomer content The residual monomer content was determined in accordance with DIN ISO 17025.
  • the molecular weights were determined by gel permeation chromatography (GPC) as follows: The calibration is carried out with polystyrene standards having a molecular weight of Mp 1,000,000 to
  • the eluent is tetrahydrofuran p.A. used.
  • the following parameters are observed during the double measurement: Degassing: Online - Degasser; Flow: 1 ml / min; Analysis time: 45 minutes; Detectors: refractometer and UV detector; Injection volume: 100 ⁇ - 200 ⁇ .
  • Degassing Online - Degasser; Flow: 1 ml / min; Analysis time: 45 minutes; Detectors: refractometer and UV detector; Injection volume: 100 ⁇ - 200 ⁇ .
  • the calculation of the molecular weight averages Mw; Mn and Mp as well as the polydispersity Mw / Mn are software-supported. Baseline points and evaluation limits are defined in accordance with DIN 55672 Part 1.
  • Example 2 168 g of hexamethylene diisocyanate (1 mol) and 0.1% by weight of benzoyl chloride were introduced at 80 ° C. and 196.5 g of polyacetal P2 (0.05 mol) were added dropwise over 1 h. The mixture was then stirred until reaching a constant NCO content at 80 ° C. The resulting mixture was removed at 140 ° C using a short path evaporator, the residual monomer. This resulted in a low-monomer NCO-terminated polyacetal P2AH, P2BH, P2DH.
  • Example 3 222.3 g of isophorone diisocyanate (1 mol) and 0.1% by weight of benzoyl chloride were introduced at 80 ° C. and 211.3 g of polyacetal PI (0.05 mol) were added dropwise over 1 h. The mixture was then stirred until reaching a constant NCO content at 80 ° C. The resulting mixture was removed at 150 ° C using a short path evaporator, the residual monomer. This resulted in a low-monomer NCO-terminated polyacetal P1AI, P1BI, P1CI, P1DI, P1EI.
  • NCO-terminated polyacetals prepared in Examples 1-4 had the following properties:

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Dispersion Chemistry (AREA)
  • Materials Engineering (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Polyurethanes Or Polyureas (AREA)

Abstract

La présente invention concerne un prépolymère s'utilisant dans la fabrication d'hydrogels biodégradables de formule générale (I) dans laquelle R1 et R2 désignent respectivement, indépendamment l'un de l'autre, un alkyle C1-C10 cyclique, linéaire ou ramifié, éventuellement aussi substitué dans la chaîne par des hétéroatomes, ou un reste comportant des motifs répétitifs (CH2)pO(CH2)p où p = 1 à 4, R3 désigne un reste alkyle C2-C10 aromatique ou aliphatique, linéaire ou ramifié, éventuellement également substitué dans la chaîne par des hétéroatomes, et k = 1 à 10, m = 1 à 4, n = 1 à 4 et o = 1 à 3. Par ailleurs, l'invention a pour objet un procédé de fabrication des prépolymères selon l'invention, un prépolymère pouvant être obtenu au moyen du procédé selon l'invention, un hydrogel biodégradable pouvant être obtenu par la utilisation du prépolymère selon l'invention, ainsi qu'un système de dosage pour l'application de l'hydrogel.
PCT/EP2012/051931 2011-02-09 2012-02-06 Prépolymères biodégradables Ceased WO2012107385A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP11153809.6 2011-02-09
EP11153809 2011-02-09

Publications (1)

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WO2012107385A1 true WO2012107385A1 (fr) 2012-08-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103539919A (zh) * 2013-10-28 2014-01-29 苏州大学 一种具有形状记忆功能的聚氨酯脲水凝胶的应用
WO2023146587A1 (fr) * 2022-01-15 2023-08-03 Vivos, Inc., d/b/a Advanced Medical Isotope Corporation Gel de radiothérapie et son procédé de préparation
US12521452B2 (en) 2019-07-01 2026-01-13 Vivos, Inc. Radiotherapy gel and method of preparing the same

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1428874A (en) * 1973-05-02 1976-03-17 American Cyanamid Co Polyurethane prepolymers prepared from polyformals
SU922114A1 (ru) * 1980-09-22 1982-04-23 Предприятие П/Я В-8415 Способ получени полиацеталей
JP2003119281A (ja) * 2001-10-15 2003-04-23 Maruzen Petrochem Co Ltd ポリアセタール、その製造方法及び分解方法
JP2005307083A (ja) * 2004-04-23 2005-11-04 Maruzen Petrochem Co Ltd リサイクル性ポリウレタンおよびその製造法
DE102006050793A1 (de) 2006-10-27 2008-04-30 Bayer Materialscience Ag Neuartige Hydrogele auf Basis aliphatischer NCO-Prepolymere
WO2009106245A2 (fr) * 2008-02-28 2009-09-03 Bayer Materialscience Ag Barrières anti-adhérences postopératoires
WO2011047789A1 (fr) * 2009-10-21 2011-04-28 Bayer Materialscience Ag Hydrogel biodégradable

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1428874A (en) * 1973-05-02 1976-03-17 American Cyanamid Co Polyurethane prepolymers prepared from polyformals
SU922114A1 (ru) * 1980-09-22 1982-04-23 Предприятие П/Я В-8415 Способ получени полиацеталей
JP2003119281A (ja) * 2001-10-15 2003-04-23 Maruzen Petrochem Co Ltd ポリアセタール、その製造方法及び分解方法
JP2005307083A (ja) * 2004-04-23 2005-11-04 Maruzen Petrochem Co Ltd リサイクル性ポリウレタンおよびその製造法
DE102006050793A1 (de) 2006-10-27 2008-04-30 Bayer Materialscience Ag Neuartige Hydrogele auf Basis aliphatischer NCO-Prepolymere
WO2009106245A2 (fr) * 2008-02-28 2009-09-03 Bayer Materialscience Ag Barrières anti-adhérences postopératoires
WO2011047789A1 (fr) * 2009-10-21 2011-04-28 Bayer Materialscience Ag Hydrogel biodégradable

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103539919A (zh) * 2013-10-28 2014-01-29 苏州大学 一种具有形状记忆功能的聚氨酯脲水凝胶的应用
US12521452B2 (en) 2019-07-01 2026-01-13 Vivos, Inc. Radiotherapy gel and method of preparing the same
WO2023146587A1 (fr) * 2022-01-15 2023-08-03 Vivos, Inc., d/b/a Advanced Medical Isotope Corporation Gel de radiothérapie et son procédé de préparation

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